PMID:  Neuropsychologia. 2023 Jun 6 ;184:108544. Epub 2023 Mar 21. PMID: 36948452 Abstract Title:  Acetaminophen changes Mu rhythm power related to pain empathy. Abstract:  Empathy is an intricate ability that entails the subjective feeling and understanding of emotions someone else may be experiencing. Acetaminophen, the active ingredient found in Tylenol, is among the most common pain medications consumed. There is new evidence, however, that suggests this common analgesic may also dampen empathic processes. However, no previous study has investigated the effect acetaminophen may have on pain empathy or mu power during a pain empathy task. Therefore, participants were randomly assigned to either an experimental (acetaminophen) or control (sugar) group in a double-blinded experimental research design aimed to measure mu power, using EEG, and behavioral responses to painful and non-painful images. Participants in the experimental group were administered 1000 mg of acetaminophen, and it was verified that participants were unaware of their group assignment. We found that mu suppression was greater in the acetaminophen group, which was strongest at electrode C3. Additionally, mu power differences between painful and non-painful images were related to trait empathy, and mu power during the painful images were positively correlated with empathy scores. Results from this study suggest that in addition to reducing physical pain, acetaminophen may also change the neural response when perceiving others in pain. The implications of these findings could possibly lead to changes in how we prescribe and administer this common drug.

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PMID:  Anal Cell Pathol (Amst). 2023 ;2023:1714884. Epub 2023 Apr 4. PMID: 37056637 Abstract Title:  Comparative Effect of the Active Substance of Thyme with N-Acetyl Cysteine on Hematological Parameters and Histopathological Changes of Bone Marrow and Liver in Rat Models of Acetaminophen Toxicity. Abstract:  Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac+100Ex, Ac+200Ex, and Ac+400Ex groups (acetaminophen+thyme extract at doses of 100, 200, 400mg/kg); and Ac+NA group (acetaminophen+NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac+NA and Ac+200Ex groups (= 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac+400Ex groups showed significant differences from those of the other test groups (

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PMID:  Front Pharmacol. 2023 ;14:1122632. Epub 2023 Mar 27. PMID: 37050900 Abstract Title:  Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products. Abstract:  Acetaminophen (APAP) is a widely used analgesic and antipyretic over-the-counter medicine worldwide. Hepatotoxicity caused by APAP overdose is one of the leading causes of acute liver failure (ALF) in the US and in some parts of Europe, limiting its clinical application. Excessive APAP metabolism depletes glutathione and increases N-acetyl-p-benzoquinoneimide (NAPQI) levels, leading to oxidative stress, DNA damage, and cell necrosis in the liver, which in turn leads to liver damage. Studies have shown that natural products such as polyphenols, terpenes, anthraquinones, and sulforaphane can activate the hepatocyte antioxidant defense system with Nrf2 as the core player, reduce oxidative stress damage, and protect the liver. As the key enzyme metabolizing APAP into NAPQI, cytochrome P450 enzymes are also considered to be intriguing target for the treatment of APAP-induced liver injury. Here, we systematically review the hepatoprotective activity and molecular mechanisms of the natural products that are found to counteract the hepatotoxicity caused by APAP, providing reference information for future preclinical and clinical trials of such natural products.

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PMID:  J Agric Food Chem. 2023 Apr 26 ;71(16):6314-6325. Epub 2023 Apr 14. PMID: 37057839 Abstract Title:  Using Inflammatory Biological Age To Evaluate the Preventing Aging Effect of a Polyphenol-Probiotic-Enhanced Dietary Pattern in Adults Aged 50 Years and Older. Abstract:  A high-compliance dietary intervention was conducted for 2 weeks in adults aged 50 years and older to investigate the preventing aging effects of a polyphenol-probiotic-enhanced diet (P-diet) by using inflammatory biological age (IBA). Following the P-diet, levels of interleukin-6 (IL-6), IL-10, and C-reactive protein were reduced. These effects were accompanied by a significant increase in the richness ofandand decrease in, as well as an increase in butyrate and acetate and decrease in lysine, uracil, and valine. We optimized a model by a back propagation artificial neural network to evaluate the degree of aging, with anof 0.68. After the P-diet intervention, IBA was younger than chronological age and the inflammatory aging potential (age) was observably reduced by 90.12%, with change inage having a direct negative association with. Overall, P-diet may alleviate chronic low-grade inflammation and thus prevent the procession of inflammatory aging.

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PMID:  Food Nutr Res. 2023 ;67. Epub 2023 Mar 24. PMID: 37056702 Abstract Title:  LP45 inhibits the RANKL/OPG signaling pathway and prevents glucocorticoid-induced osteoporosis. Abstract:  OBJECTIVE: To examine the potential effect of the probiotic strainLP45 on osteoporosis and to explore the involved molecular mechanisms.METHODS: A rat model of glucocorticoid-induced osteoporosis (GIO) was established, which was also orally administered with increasing doses of LP45 for 8 weeks. After the termination of the 8-week treatment, the tibia and femur bones of rats were analyzed for bone histomorphometry, bone mineral content (BMC), and bone mineral density (BMD). Femoral biomechanics were assessed. In addition, levels of osteocalcin, tartrate-resistant acid phosphatase 5 (TRAP5), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) in the serum and bone marrow were also measured using ELISA, Western blot, and real time-polymerase chain reaction.RESULTS: GIO caused obvious defects in tibia and femur bone structures, in terms of tissue/bone volume, trabecular separation, trabecular thickness, and trabecular number, which could be rescued by LP45 dose dependently. The GIO-induced reductions in BMC, BMD, osteoblast surfaces per bone surface (BS), as well as elevated osteoclast surface per BS were largely restored by LP45 administration dose-dependently. LP45 also increased femoral biomechanics of GIO rats. Importantly, LP45 dose-dependently restored the changes of osteocalcin, TRAP5, OPG, and RANKL in the serum as well as bone marrow of GIO rats.CONCLUSION: Oral LP45 administration could significantly prevent bone defects in GIO rats, suggesting its potential as a dietary supplement with beneficial effects against osteoporosis, which might involve the RANKL/OPG signaling pathway.

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PMID:  J Cell Physiol. 2023 Jun ;238(6):1336-1353. Epub 2023 Apr 13. PMID: 37052047 Abstract Title:  Lactobacillus plantarum postbiotics trigger AMPK-dependent autophagy to suppress Salmonella intracellular infection and NLRP3 inflammasome activation. Abstract:  We previously found that Lactobacillus plantarum (LP)-derived postbiotics protected animals against Salmonella infection, but the molecular mechanism remains obscure. This study clarified the mechanisms from the perspective of autophagy. Intestinal porcine epithelial cells (IPEC-J2) were pretreated with LP-derived postbiotics (the culture supernatant, LPC; or heat-killed bacteria, LPB), and then challenged with Salmonella enterica Typhimurium (ST). Results showed that LP postbiotics markedly triggered autophagy under ST infection, as indicated by the increased LC3 and Beclin1 and the decreased p62 levels. Meanwhile, LP postbiotics (particularly LPC) exhibited a strong capacity of inhibiting ST adhesion, invasion and replication. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) led to a significant decrease of autophagy and the aggravated infection, indicating the importance of autophagy in LP postbiotics-mediated Salmonella elimination. LP postbiotics (especially LPB) significantly suppressed ST-induced inflammation by modulating inflammatory cytokines (the increased interleukin (IL)-4 and IL-10, and decreased tumor necrosis factor-(TNF), IL-1, IL-6 and IL-18). Furthermore, LP postbiotics inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation, as evidenced by the decreased levels of NLRP3, Caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Deficits in autophagy resulted in an increase of inflammatory response and inflammasome activation. Finally, we found that both LPC and LPB triggered AMP-activated protein kinase (AMPK) signaling pathway to induce autophagy, and this was further confirmed by AMPK RNA interference. The intracellular infection and NLRP3 inflammasome were aggravated after AMPK knockdown. In summary, LP postbiotics trigger AMPK-mediated autophagy to suppress Salmonella intracellular infection and NLRP3 inflammasome in IPEC-J2 cells. Our findings highlight the effectiveness of postbiotics, and provide a new strategy for preventing Salmonella infection.

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PMID:  Nutrients. 2023 Apr 1 ;15(7). Epub 2023 Apr 1. PMID: 37049578 Abstract Title:  CCFM405 against Rotenone-Induced Parkinson's Disease Mice via Regulating Gut Microbiota and Branched-Chain Amino Acids Biosynthesis. Abstract:  Recent studies have demonstrated that disturbances in the gut microbiota and microbiota -derived metabolites contribute to the pathogenesis of Parkinson's disease (PD), suggesting that probiotic treatments that restore them may delay disease progression. This study aimed to examine the attenuating efficacy ofCCFM405 and the potential mechanisms in mice with rotenone-induced PD. Our results indicate thatCCFM405 ameliorated rotenone-induced motor deficits and constipation, decreased dopaminergic neuronal death, reduced intestinal inflammation and neuroinflammation, and raised dopamine levels, 5-HT, and associated metabolites in the striatal region of the brain in mice with PD. Sequencing of 16S rRNA from fecal microbiota revealed thatCCFM405 normalized the gut bacterial composition in mice with PD, as evidenced by the increased relative abundance of the following genus,,, and, and decreased relative abundance of,,, and. The PICRUSt-predicted gut microbiota function revealed thatCCFM405 enhanced the biosynthesis of amino acid pathways, particularly valine, leucine, and isoleucine (branched-chain amino acids, BCAAs). A non-metabolomic analysis of the serum and feces showed thatCCFM405 markedly increased the levels of BCAAs. Pathway enrichment analysis based on the KEGG database further suggested thatCCFM405 supplementation can promote BCAAs biosynthesis. Collectively,CCFM405 can help to prevent rotenone-induced PD by modulating the gut microbiota-metabolite axis. BCAAs may play a dominant role inCCFM405-associated neuroprotection in PD mice. This probiotic could be utilized as a potential food supplement in the management of PD.

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PMID:  Int J Mol Sci. 2023 Apr 5 ;24(7). Epub 2023 Apr 5. PMID: 37047769 Abstract Title:  Neuroprotective Effects ofPS128 in a Mouse Model of Parkinson's Disease: The Role of Gut Microbiota and MicroRNAs. Abstract:  Parkinson's disease (PD) is a neurodegenerative disease characterized by motor deficits and marked neuroinflammation in various brain regions. The pathophysiology of PD is complex and mounting evidence has suggested an association with the dysregulation of microRNAs (miRNAs) and gut dysbiosis. Using a rotenone-induced PD mouse model, we observed that administration ofPS128 (PS128) significantly improved motor deficits in PD-like mice, accompanied by an increased level of dopamine, reduced dopaminergic neuron loss, reduced microglial activation, reduced levels of inflammatory factors, and enhanced expression of neurotrophic factor in the brain. Notably, the inflammation-related expression of miR-155-5p was significantly upregulated in the proximal colon, midbrain, and striatum of PD-like mice. PS128 reduced the level of miR-155-5p, whereas it increased the expression of suppressor of cytokine signaling 1 (SOCS1), a direct target of miR-155-5p and a critical inhibitor of the inflammatory response in the brain. Alteration of the fecal microbiota in PD-like mice was partially restored by PS128 administration. Among them,,_6,, andwere statistically correlated with the improvement of rotenone-induced motor deficits and the expression of miR-155-5p and SOCS1. Our findings suggested that PS128 ameliorates motor deficits and exerts neuroprotective effects by regulating the gut microbiota and miR-155-5p/SOCS1 pathway in rotenone-induced PD-like mice.

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PMID:  Front Immunol. 2023 ;14:1158137. Epub 2023 Mar 23. PMID: 37033942 Abstract Title:  PsychobioticJYLP-326 relieves anxiety, depression, and insomnia symptoms in test anxious collegemodulating the gut microbiota and its metabolism. Abstract:  INTRODUCTION: Test anxiety is a common issue among college students, which can affect their physical and psychological health. However, effective interventions or therapeutic strategies are still lacking. This study aims to evaluate the potential effects ofJYLP-326 on test anxious college students.METHODS: Sixty anxious students were enrolled and randomly allocated to the placebo group and the probiotic group. Both groups were instructed to take placebo and JYLP-326 products twice per day for three weeks, respectively. Thirty unanxious students with no treatments were assigned to a regular control group. The anxiety, depression, and insomnia questionnaires were used to measure students' mental states at the baseline and the end of this study. 16S rRNA sequencing and untargeted metabolomics were performed to analyze the changes in the gut microbiota and fecal metabolism.RESULTS: The questionnaire results suggested that JYLP-326 administration could relieve the symptoms of anxiety, depression, and insomnia in test anxious students. The gut microbiomes of the placebo group showed a significantly greater diversity index than the control group (p

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PMID:  Life Sci. 2023 Jun 1 ;322:121664. Epub 2023 Apr 5. PMID: 37023957 Abstract Title:  Sulforaphane exhibits potent renoprotective effects in preclinical models of kidney diseases: A systematic review and meta-analysis. Abstract:  AIMS: Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, has received extensive attention as a natural activator of the Nrf2/Keap1 cytoprotective pathway. In this review, a meta-analysis and systematic review of the renoprotective effects of SFN were performed in various preclinical models of kidney diseases.MAIN METHODS: The primary outcome was the impact of SFN on renal function biomarkers (uremia, creatininemia, proteinuria or creatinine clearance) and secondary outcomes were kidney lesion histological indices/kidney injury molecular biomarkers. The effects of SFN were evaluated according to the standardized mean differences (SMDs). A random-effects model was applied to estimate the overall summary effect.KEY FINDINGS: Twenty-five articles (out of 209 studies) were selected from the literature. SFN administration significantly increased creatinine clearance (SMD +1.88 95 % CI: [1.09; 2.68], P 

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PMID:  Biomed Pharmacother. 2023 May ;161:114490. Epub 2023 Mar 15. PMID: 36931031 Abstract Title:  Anticancer effect and safety of doxorubicin and nutraceutical sulforaphane liposomal formulation in triple-negative breast cancer (TNBC) animal model. Abstract:  Female breast cancer is the most deadly cancer in women worldwide. The triple-negative breast cancer subtype therapies, due to the lack of specific drug targets, are still based on systemic chemotherapy with doxorubicin, which is burdened with severe adverse effects. To enhance therapeutic success and protect against systemic toxicity, drug carriers or combination therapy are being developed. Thus, an innovative liposomal formulation containing doxorubicin and the main nutraceutical, sulforaphane, has been developed. The anticancer efficacy and safety of the proposed liposomal formulation was evaluated in vivo, in a 4T1 mouse model of triple-negative breast cancer, and the mechanism of action was determined in vitro, using triple-negative breast cancer MDA-MB-231 and non-tumorigenic breast MCF-10A cell line. The elaborated drug carriers were shown to efficiently deliver both compounds into the cancer cell and direct doxorubicin to the cell nucleus. Incorporation of sulforaphane resulted in a twofold inhibition of tumor growth and the potential of up to a fourfold reduction in doxorubicin concentration due to the synergistic interaction between the two compounds. Sulforaphane was shown to increase the accumulation of doxorubicin in the nuclei of cancer cells, accompanied by inhibition of mitosis, without affecting the reactive oxygen species status of the cell. In normal cells, an antagonistic effect resulting in less cytotoxicity was observed. In vivo results showed that sulforaphane incorporation yielded not only cardioprotective, but also nephro- and hepatoprotective effects. The results of the research revealed the prospects of applying sulforaphane as a component of liposomal doxorubicin in triple-negative breast cancer chemotherapy.

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PMID:  Ecotoxicol Environ Saf. 2023 Apr 1 ;254:114747. Epub 2023 Mar 10. PMID: 36907095 Abstract Title:  Sulforaphane suppresses paraquat-induced oxidative damage in bovine in vitro-matured oocytes through Nrf2 transduction pathway. Abstract:  Sulforaphane (SFN), a bioactive phytocompound extracted from cruciferous plants, has received increasing attention due to its vital cytoprotective role in eliminating oxidative free radical through activation of nuclear factor erythroid 2-related factor (Nrf2)-mediated signal transduction pathway. This study aims at a better insight into the protective benefit of SFN in attenuating paraquat (PQ)-caused impairment in bovine in vitro-matured oocytes and the possible mechanisms involved therein. Results showed that addition of 1 M SFN during oocyte maturation obtained higher proportions of matured oocytes and in vitro-fertilized embryos. SFN application attenuated the toxicological effects of PQ on bovine oocytes, as manifested by enhanced extending capability of cumulus cell and increased extrusion proportion of first polar body. Following incubation with SFN, oocytes exposed to PQ exhibited reduced intracellular ROS and lipid accumulation levels, and elevated T-SOD and GSH contents. SFN also effectively inhibited PQ-mediated increase in BAX and CASPASE-3 protein expressions. Besides, SFN promoted the transcription of NRF2 and its downstream antioxidative-related genes GCLC, GCLM, HO-1, NQO-1, and TXN1 in a PQ-exposed environment, indicating that SFN prevents PQ-caused cytotoxicity through activation of Nrf2 signal transduction pathway. The mechanisms underlying the role of SFN against PQ-induced injury included the inhibition of TXNIP protein and restoration of the global O-GlcNAc level. Collectively, these findings provide novel evidence for the protective role of SFN in alleviating PQ-caused injury, and suggest that SFN application may be an efficacious intervention strategy against PQ cytotoxicity.

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PMID:  Adv Mind Body Med. 2023 Spring;37(2):5-8. PMID: 37315227 Abstract Title:  Effect of a Single Yoga Asana on Blood Glucose Levels in Type 2 Diabetes Mellitus: A Self-Controlled Study. Abstract:  CONTEXT: Diabetes is a metabolic disorder characterized by high blood sugar levels. Yoga has been shown to have positive effects on blood sugar levels in diabetes patients. However, there is limited research on the effects of specific yoga poses on blood sugar levels in patients with type 2 diabetes (T2DM).OBJECTIVE: This study aimed to evaluate the effect of a single yoga asana, Ardha Matsyendrasana, on random blood glucose (RBG) levels in patients with T2DM. Specifically, we aimed to investigate whether a 15-minute practice of Ardha Matsyendrasana could reduce RBG levels in patients with T2DM.DESIGN: This study employed a self-controlled design to evaluate the effect of Ardha Matsyendrasana on blood glucose levels in patients with type 2 diabetes mellitus.PARTICIPANTS: 100 patients with type 2 diabetes mellitus (T2DM) were recruited for this study.INTERVENTIONS: All participants underwent two sessions: a control session (CS) and an asana session (AS), each lasting 15 minutes. During the CS, participants rested in a sitting pose, while during the AS, they practiced Ardha Matsyendrasana. The order of the sessions was randomized, with half the participants undergoing the CS on day 1, the AS on day 2, and the other half undergoing the sessions in reverse order.OUTCOME MEASURES: We measured participants' random blood glucose (RBG) levels immediately before and after each intervention.STATISTICAL ANALYSIS: The statistical package for the compare RBG levels before and after each intervention.RESULTS: The study demonstrated a significant reduction in random blood glucose (RBG) levels in the Ardha Matsyendrasana session compared to the control session. This trend was observed in both males and females with T2DM.CONCLUSIONS: A single session of Ardha Matsyendrasana for 15 minutes can effectively reduce blood glucose levels in patients with T2DM. However, further studies are required to determine the long-term effects of this asana on glycemic control.

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PMID:  Adv Mind Body Med. 2023 Spring;37(2):24-31. PMID: 37315229 Abstract Title:  Yoga Practice Facilitates Prefrontal Oxygenation and Working Memory in Type 2 Diabetes Mellitus Patients: A Pilot Study. Abstract:  BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with cognitive decline. Lifestyle behaviors such as yoga practices play a significant role in preventing cognitive decline.PURPOSE: The goal of this study was to assess the effect of yoga intervention on working memory and prefrontal cortex (PFC) oxygenation in T2DM patients.METHODS: Twenty T2DM participants, aged between 40 and 60 years, volunteered for a 6-week study. Participants were randomized into a yoga practice (n = 10) and a waitlist control group (n = 10). The n-back task was administered to evaluate working memory before and after the intervention. While performing the working memory task, PFC oxygenation was monitored using functional near-infrared spectroscopy.RESULTS: The yoga group showed a significant improvement in working memory performance. The accuracy improved in 1-back (mean difference of 4.73%, 95% CI[0.69,8.77], P = .026) and 2-back (8.0%, 95% CI[1.89,14.1], P = .016) task conditions. The reaction time improved in 0-back (mean difference of -79.07 milliseconds, 95% CI[-128.3,-29.8]), 1-back (mean difference of -119.17 milliseconds, 95% CI[-217.5,-20.8] ) and 2-back (-76.06 milliseconds, 95% CI[-148.8,-3.3]) task conditions. In the yoga group, at post-intervention, higher oxygenation was observed during 0-back and 1-back task conditions (Beta coefficient mean difference of 211.3, 95% CI[2.8, 420.0], P = .048 and 80.5, 95% CI [3.7,157.2], P = .042 respectively) in the left PFC region compared to the pre-intervention values. The control group showed no significant change in working memory performance and PFC oxygenation.CONCLUSIONS: The study suggests that yoga practice may improve working memory performance and facilitate higher PFC oxygenation in T2DM patients. Further studies with a larger sample and a longer intervention period are required to strengthen the findings.

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PMID:  Trop Doct. 2023 Jun 15:494755231180633. Epub 2023 Jun 15. PMID: 37321800 Abstract Title:  Physical and psychological impact of yoga therapy in improving heart failure. Abstract:  Effective therapy for patients with chronic cardiac failure (CCF) entails significant lifestyle modifications as well as often complex pharmaceutical regimes to alleviate symptoms, which, however, do not actually cure many patients. The gradual loss of cardiac function is impeded but not halted by such complicated pharmacological therapy, which primarily includes angiotensin-converting enzyme inhibitors, beta-blockers and diuretics, and sometimes digoxin, aspirin, warfarin, and anti-arrhythmic agents. Patients may be advised to track their weight and modify their diuretic prescription accordingly to avoid fluid overload or dehydration as part of the treatment plan. Non-pharmacologic treatment options are routinely integrated to improve the management of somatic complaints. Yoga and specialized breathing exercises seem to help CCF patients improve their cardiorespiratory and autonomic system function, and also their quality of life. We present the evidence.

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PMID:  Int J Yoga Therap. 2023 Jan 1 ;33(2023). PMID: 37327384 Abstract Title:  Efficacy of Yoga Nidra on Depression, Anxiety, and Insomnia in Frontline COVID-19 Healthcare Workers: A Pilot Randomized Controlled Trial. Abstract:  The COVID-19 pandemic has led to a surge of mental health disturbances and the subsequent use of various mind-body therapies. Although evidence supports the benefits of yoga for mental health in a variety of disease states, information on its effects among healthcare workers during the COVID-19 epidemic is scarce. Therefore, this study evaluated and compared the efficacy of relaxation to music and yoga nidra on the mental health of frontline healthcare workers during the pandemic. This open-label randomized trial was conducted at a Level III COVID-19 care center. In the Relaxation-to-Music Group, participants received deep relaxation music, whereas those in the Yoga Nidra Group performed yoga nidra practices; both interventions were delivered through a YouTube platform and were to be done daily for 30 minutes during the healthcare workers' 2-week duty periods. The primary outcomes were measured using scores of the Patient Health Questionnaire (PHQ)-9, Generalized Anxiety Disorder (GAD)-7 scale, and Insomnia Severity Index (ISI) at the end of the duty period. A total of 79 healthcare workers were randomly divided into two groups: (1) Relaxation-to-Music (n = 40) and (2) Yoga Nidra (n = 39). Demographics; clinical characteristics; and PHQ-9, GAD-7, and ISI scores of the two groups were comparable at baseline. In the Yoga Nidra Group, PHQ-9 scores decreased significantly (5.174.25 to 3.032.40, p = 0.002) compared to the Relaxation-to-Music Group (5.684.73 to 4.342.90, p = 0.064). Similarly, GAD-7 scores decreased significantly in the Yoga Nidra Group (4.933.27 to 2.332.56, p

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PMID:  Holist Nurs Pract. 2023 Jul-Aug 01;37(4):E59-E68. PMID: 37335153 Abstract Title:  The Effects of Yoga and Stabilization Exercises in Patients With Chronic Low Back Pain: A Randomized Crossover Study. Abstract:  This study aimed to assess the effectiveness of yoga and stabilization exercises in patients with chronic low back pain. Thirty-five female patients were randomly assigned to the stabilization exercise group or the yoga group. Outcome measures were the visual analog scale (VAS), Oswestry Disability Index (ODI) and Back Performance Scale (BPS), 6-minute walk test (6MWT), Fear-Avoidance Beliefs Questionnaire (FABQ), and Pittsburgh Sleep Quality Index (PSQI). The scores of the VAS, ODI, BPS, 6MWT, and PSQI improved significantly after both interventions (P

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PMID:  Brain Behav. 2023 Jun 21:e3108. Epub 2023 Jun 21. PMID: 37340873 Abstract Title:  The impact of humor therapy on people suffering from depression or anxiety: An integrative literature review. Abstract:  OBJECTIVES: To identify and synthesize existing research on the effectiveness and feasibility of multiform humor therapy on people suffering from depression or anxiety, with the hope of benefiting future research.METHODS: An integrative literature review of quantitative, qualitative, and mixed studies was performed. The PubMed, Cochrane Library, Web of Science, Embase, and CINAHL databases were searched up to March 2022. Two independent reviewers conducted each stage of the review process, by assessing eligibility using preferred reporting items for systematic review and meta-analyses (PRISMA) and quality appraisal using the Mixed Methods Appraisal Tool, and data extraction.RESULTS: In this integrative review, 29 papers were included, containing 2964 participants across a diverse range of studies, including quantitative, qualitative, and mixed methods. The articles were from the United States, Australia, Italy, Turkey, South Korea, Iran, Israel, China, and Germany. The findings indicated that most of the subjects thought humor therapy was effective in improving depression and anxiety while a few participants considered the effect insignificant. However, more high-quality studies will be needed to confirm these conclusions.DISCUSSION: This review collated and summarized findings from studies examining the impact of humor therapy (medical clowns, laughter therapy/yoga) on people with depression or anxiety, including children undergoing surgery or anesthesia, older people in nursing homes, patients with Parkinson's disease, cancer, mental illness, and undergoing dialysis, retired women, and college students. The results from this review may help inform future research, policy, and practice in humor therapy to improve people's symptoms of depression and anxiety.IMPACT: This systematic review objectively evaluated the effect of humor therapy on depression and anxiety. As a simple and feasible complementary alternative therapy, humor therapy may provide a favorable alternative for clinicians, nurses, and patients in the future.

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PMID:  Int Immunopharmacol. 2023 Jun ;119:110236. Epub 2023 May 5. PMID: 37148772 Abstract Title:  Vinpocetine mitigates DMH-induce pre-neoplastic colon damage in rats through inhibition of pro-inflammatory cytokines. Abstract:  Colorectal cancer (CRC) is currently recognized as the third most prevalent cancer worldwide. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine. It has been found effective in ameliorating the growth and progression of cancerous cells. However, its pharmacological effect on colon damage remains elusive. Hence, in this study, we have shown the role of vinpocetine in DMH-induced colon carcinogenesis. At first, male albino Wistar rats were administered with DMH consistently for four weeks to induce pre-neoplastic colon damage. Afterward, animals were treated with vinpocetine (4.2 and 8.4 mg/kg/day p.o.) for 15 days. Serum samples were collected to assess the physiological parameters, including ELISA and NMR metabolomics. Colon from all the groups was collected and processed separately for histopathology and western blot analysis. Vinpocetine attenuated the altered plasma parameters; lipid profile and showed anti-proliferative action as evidenced by suppressed COX-2 stimulation and decreased levels of IL-1, IL-2, IL-6, and IL-10. Vinpocetine is significantly effective in preventing CRC which may be associated with its anti-inflammatory and antioxidant potential. Accordingly, vinpocetine could serve as a potential anticancer agent for CRC treatment and thus be considered for future clinical and therapeutic research.

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PMID:  J Pharm Pharmacol. 2023 May 25. Epub 2023 May 25. PMID: 37229596 Abstract Title:  Effect of vinpocetine alone and in combination with enalapril in experimental model of diabetic cardiomyopathy in rats: possible involvement of PDE-1/TGF-/ Smad 2/3 signalling pathways. Abstract:  OBJECTIVE: Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats.METHODS: Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-(TGF-) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR.KEY FINDING: Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril.CONCLUSIONS: Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-/Smad 2/3.

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PMID:  Neuroscience. 2023 Jun 7. Epub 2023 Jun 7. PMID: 37290685 Abstract Title:  Neuroprotective Effects of Vinpocetine Against Ischemia-Reperfusion Injury Via Inhibiting NLRP3 Inflammasome Signaling Pathway. Abstract:  Ischemic stroke is one of the main causes of serious disability and death worldwide. NLRP3 inflammasome is an intracellular pattern recognition receptor composed of polyprotein complex, which participates in mediating a series of inflammatory responses and is considered as a potential target for the treatment of ischemic stroke. Vinpocetine, a derivative of vincamine, has been widely used in the prevention and treatment of ischemic stroke. However, the therapeutic mechanism of vinpocetine is not clear, and its effect on NLRP3 inflammasome remains to be determined. In this study, we used the mouse model of transient middle cerebral artery occlusion (tMCAO) to simulate the occurrence of ischemic stroke. Different doses of vinpocetine (5, 10, 15mg/kg/d) were injected intraperitoneally for 3days after ischemia-reperfusion in mice. The effects of different doses of vinpocetine on the degree of ischemia-reperfusion injury in mice were observed by TTC staining and modified neurological severity score scale, and the optimal dose was determined. Then, based on this optimal dose, we observed the effects of vinpocetine on apoptosis, microglial proliferation and NLRP3 inflammasome. In addition, we compared the effects of vinpocetine and MCC950 (a specific inhibitor of NLRP3 inflammasome) on NLRP3 inflammasome. Our results show that vinpocetine can effectively reduce the infarct volume and promote the recovery of behavioral function in stroke mice, and the maximal beneficial effects were observed at the dose of 10mg/kg/d. Vinpocetine can effectively inhibit the apoptosis of peri-infarct neurons, promote the expression of Bcl-2, inhibit the expression of Bax and Cleaved Caspase-3, and reduce the proliferation of peri-infarct microglia. In addition, vinpocetine, like MCC950, can reduce the expression of NLRP3 inflammasome. Therefore, vinpocetine can effectively alleviate the ischemia-reperfusion injury in mice, and the inhibition of NLRP3 inflammasome may be an important therapeutic mechanism of vinpocetine.

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PMID:  Metab Brain Dis. 2023 Jun 19. Epub 2023 Jun 19. PMID: 37335452 Abstract Title:  New insights on the potential effect of vinpocetine in Parkinson's disease: one of the neglected warden and baffling topics. Abstract:  Vinpocetine (VPN) is an ethyl apovincaminate that has anti-inflammatory and antioxidant effects by inhibiting the expression of nuclear factor kappa B (NF-B) and phosphodiesterase enzyme 1 (PDE-1). VPN is used in the management of stroke, dementia, and other neurodegenerative brain diseases. VPN may be effective in treating Parkinson's disease (PD). Therefore, this review aimed to clarify the mechanistic role of VPN in the management of PD. VPN has protective and restorative effects against neuronal injury by reducing neuroinflammation, and improvement of synaptic plasticity and cerebral blood flow. VPN protects dopaminergic neurons by reducing oxidative stress, lipid peroxidation, glutamate neurotoxicity, and regulation of Caoverloads. VPN can alleviate PD neuropathology through its anti-inflammatory, antioxidant, antiapoptotic and neurogenic effects. VPN through inhibition of PDE1 improves cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) signaling in the dopaminergic neurons of the substantia nigra (SN). VPN improves PD neuropathology through PDE1 inhibition with a subsequent increase of the cAMP/cGMP signaling pathway. Therefore, increasing cAMP leads to antioxidant effects, while augmentation of cGMP by VPN leads to anti-inflammatory effects which reduced neurotoxicity and development of motor severity in PD. In conclusion, this review indicated that VPN could be effective in the management of PD.

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PMID:  Crit Rev Food Sci Nutr. 2023 Jun 19:1-27. Epub 2023 Jun 19. PMID: 37335106 Abstract Title:  Crosstalk between dietary pomegranate and gut microbiota: evidence of health benefits. Abstract:  Gut microbiota (GM) is an invisible organ that plays an important role in human health. Increasing evidence suggests that polyphenols in pomegranate (punicalagin, PU) could serve as prebiotics to modulate the composition and function of GM. In turn, GM transform PU into bioactive metabolites such as ellagic acid (EA) and urolithin (Uro). In this review, the interplay between pomegranate and GM is thoroughly described by unveiling a dialog in which both actors seem to affect each other's roles. In a first dialog, the influence of bioactive compounds from pomegranate on GM is described. The second act shows how the GM biotransform pomegranate phenolics into Uro. Finally, the health benefits of Uro and that related molecular mechanism are summarized and discussed. Intake of pomegranate promotes beneficial bacteria in GM (e.g.spp.,spp.) while reducing the growth of harmful bacteria (e.g.group,)., andspp., among others, biotransform PU and EA into Uro. Uro contributes to strengthening intestinal barrier and reducing inflammatory processes. Yet, Uro production varies greatly among individuals and depend on GM composition. Uro-producing bacteria and precise metabolic pathways need to be further elucidated therefore contributing to personalized and precision nutrition.

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PMID:  J Biomol Struct Dyn. 2023 May 30:1-14. Epub 2023 May 30. PMID: 37254310 Abstract Title:  In silico molecular study of hepatitis B virus X protein as a therapeutic target. Abstract:  The Hepatitis B virus is a leading cause of liver cirrhosis and hepatocellular carcinoma. HBx viral protein is considered a contributor to pathogenesis and hepatocarcinogenesis. This study aimed to screen the effect of some antiviral compounds to target HBx protein for inhibition of its function. Here, molecular docking, molcular dynsmic simulation, MM/GBSA and T-SNE methods were applied to study the complex stability and to cluster the conformations that generated in the simulation. Among the 179 compounds screened in this study, three antiviral agents (SC75741, Punicalagin, and Ledipasvir) exhibited the lowest docking energy and best interaction. Among these compounds, SC75741 was identified as a potent inhibitor of HBx that showed the best and most stable interaction during molecular dynamic simulation, and blocking a region near to HBx helix resides (aa 88-100) that is associated with cell invasion. The analysis of relative binding free energy through MM/GBSA for molecular dynamic simulation results revealed binding energy -9.9kcal/mol for SC75741, -11kcal/mol for Punicalagin, and -10.1kcal/mol for Ledipasvir. These results elucidate the possible use of these compounds in the research for targeting HBx.Communicated by Ramaswamy H. Sarma.

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PMID:  Int J Mol Sci. 2023 May 9 ;24(10). Epub 2023 May 9. PMID: 37239823 Abstract Title:  The Role of Punicalagin and Its Metabolites in Atherosclerosis and Risk Factors Associated with the Disease. Abstract:  Atherosclerotic cardiovascular disease (ACVD) is the leading cause of death worldwide. Although current therapies, such as statins, have led to a marked reduction in morbidity and mortality from ACVD, they are associated with considerable residual risk for the disease together with various adverse side effects. Natural compounds are generally well-tolerated; a major recent goal has been to harness their full potential in the prevention and treatment of ACVD, either alone or together with existing pharmacotherapies. Punicalagin (PC) is the main polyphenol present in pomegranates and pomegranate juice and demonstrates many beneficial actions, including anti-inflammatory, antioxidant, and anti-atherogenic properties. The objective of this review is to inform on our current understanding of the pathogenesis of ACVD and the potential mechanisms underlying the beneficial actions of PC and its metabolites in the disease, including the attenuation of dyslipidemia, oxidative stress, endothelial cell dysfunction, foam cell formation, and inflammation mediated by cytokines and immune cells together with the regulation of proliferation and migration of vascular smooth muscle cells. Some of the anti-inflammatory and antioxidant properties of PC and its metabolites are due to their strong radical-scavenging activities. PC and its metabolites also inhibit the risk factors of atherosclerosis, including hyperlipidemia, diabetes mellitus, inflammation, hypertension, obesity, and non-alcoholic fatty liver disease. Despite the promising findings that have emerged from numerous in vitro, in vivo, and clinical studies, deeper mechanistic insights and large clinical trials are required to harness the full potential of PC and its metabolites in the prevention and treatment of ACVD.

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PMID:  Zhongguo Zhong Yao Za Zhi. 2023 Apr ;48(7):1751-1759. PMID: 37282949 Abstract Title:  [Punicalagin inhibits hepatic lipid deposition in obese mice via AMPK/ACC pathway]. Abstract:  Hepatic lipid deposition is one of the basic manifestations of obesity, and nowadays pharmacological treatment is the most important tool. Punicalagin(PU), a polyphenol derived from pomegranate peel, is a potential anti-obesity substance. In this study, 60 C57BL/6J mice were randomly divided into a normal group and a model group. After establishing a model of simple obesity with a high-fat diet for 12 weeks, the successfully established rat models of obesity were then regrouped into a model group, an orlistat group, a PU low-dose group, a PU medium-dose group, and a PU high-dose group. The normal group was kept on routine diet and other groups continued to feed the high-fat diet. The body weight and food intake were measured and recorded weekly. After 8 weeks, the levels of the four lipids in the serum of each group of mice were determined by an automatic biochemical instrument. Oral glucose tole-rance and intraperitoneal insulin sensitivity were tested. Hemoxylin-eosin(HE) staining was applied to observe the hepatic and adipose tissues. The mRNA expression levels of peroxisome proliferators-activated receptor(PPAR) and C/EBPwere determined by real-time quantitative polymerase chain reaction(Q-PCR), and the mRNA and protein expression levels of adenosine 5'-monophosphate-activated protein kinase(AMPK), anterior cingulate cortex(ACC), and carnitine palmitoyltransferase 1A(CPT1A) were determined by Western blot. Finally, the body mass, Lee's index, serum total glyceride(TG), serum total cholesterol(TC), and low-density lipoprotein cholesterol(LDL-C) levels were significantly higher and high-density lipoprotein cholesterol(HDL-C) levels were significantly lower in the model group as compared with the normal group. The fat deposition in the liver was significantly increased. The mRNA expression levels of hepatic PPARand C/EBPand the protein expression level of ACC were increased, while the mRNA and protein expression levels of CPT-1(CPT1A) and AMPK were decreased. After PU treatment, the above indexes of obese mice were reversed. In conclusion, PU can decrease the body weight of obese mice and control their food intake. It also plays a role in the regulation of lipid metabolism and glycometabolism metabolism, which can significantly improve hepatic fat deposition. Mechanistically, PU may regulate liver lipid deposition in obese mice by down-regulating lipid synthesis and up-regulating lipolysis through activation of the AMPK/ACC pathway.

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PMID:  J Nat Med. 2023 Jun 12. Epub 2023 Jun 12. PMID: 37306932 Abstract Title:  Punicalagin alleviates the hyperproliferation of keratinocytes in psoriasis through inhibiting SKP2 expression. Abstract:  Psoriasis is a chronic inflammatory skin disorder characterized by abnormal keratinocytes proliferation and multiple immune cells infiltration in the dermis and epidermis. Although most psoriasis-related researches have been concentrated on the interleukin-23 (IL-23)/interleukin-17 (IL-17) axis, new data suggest that keratinocytes also play a pivotal role in psoriasis. Previously, we found that punicalagin (PUN), a bioactive ellagitannin extracted from Pericarpium Granati (the pericarpium of Punica granatum L.), exerts a therapeutic effect on psoriasis. However, the underlying mechanism, especially its potential modulatory effect on keratinocytes, remains obscure. Our study aims to reveal the potential regulatory effect and its underlying cellular mechanism of PUN on the hyperproliferation of keratinocytes. We used tumor necrosis factor(TNF-), IL-17A and interleukin-6 (IL-6) to induce abnormal proliferation of HaCaT cells (Human Keratinocytes Cells) in vitro. Then, we evaluated the effects of PUN through MTT assay, EdU staining and cell cycle detection. Finally, we explored the underlying cellular mechanisms of PUN via RNA-sequencing, WB in vitro and in vivo. Here, we found that PUN can directly and dose-dependently decrease TNF-, IL-17A and IL-6-induced abnormal proliferation of HaCaT cells in vitro. Mechanically, PUN suppresses the hyperproliferation of keratinocytes through repressing S-phase kinase-associated protein 2 (SKP2) expression in vitro and in vivo. Moreover, overexpression of SKP2 can partly abolish PUN-mediated inhibition of aberrantly proliferative keratinocytes. These results illustrate that PUN can reduce the severity of psoriasis through directly repressing SKP2-mediated abnormal proliferation of keratinocytes, which gives new insight into the therapeutic mechanism of PUN on psoriasis. Moreover, these findings imply that PUN might be a promising drug candidate for the treatment of psoriasis.

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PMID:  BMC Neurosci. 2023 Mar 16 ;24(1):20. Epub 2023 Mar 16. PMID: 36927298 Abstract Title:  Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer's disease. Abstract:  BACKGROUND: Vinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat's model of Alzheimer's disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (A).METHODS: Sixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. A, 4. pretreatment (Vin+A): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of A(1-42), 5. treatment (A+Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment+treatment (Vin+A+Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus.RESULTS: Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Agroup meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP).CONCLUSIONS: Vin could significantly prevent the Aeffects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aon hippocampal synaptic plasticity.

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PMID:  Iran J Basic Med Sci. 2023 Jan ;26(1):13-22. PMID: 36594060 Abstract Title:  Vinpocetine's immunomodulating, anti-oxidant, anti-inflammatory, ant-ifibrotic, and PDE inhibiting potencies ameliorate bleomycin-induced pulmonary fibrosis. Abstract:  OBJECTIVES: Pulmonary fibrosis (PF) is a global health problem with a high economic burden. Intratracheal administration of bleomycin is the best model that resembles the pathogenesis of PF in humans. Recently, vinpocetine proved to have neuroprotective, cardioprotective, hepatoprotective, anti-aging, and antifibrotic effects through its anti-oxidant, immunomodulating, and anti-inammatory activities. The present study investigated the antifibrotic potentiality of vinpocetine in a rat model of PF induced by intratracheal bleomycin administration.MATERIALS AND METHODS: PF induced by a single intratracheal instillation of 5 mg/kg bleomycin in nine-week-old Wister rats. Oral vinpocetine was used at doses of 5, 10, or 20 mg/kg to treat PF for 21 days immediately after the bleomycin instillation.RESULTS: Vinpocetine dose-dependently ameliorates PF induced by bleomycin administration since vinpocetine effectively restored the normal body weight gain rates, pulmonary architecture, and collagen fiber distribution and suppressed the elevated BALF cell count, lymphocytes and neutrophils percentage, BALF, IL-6, TNF-, and TGF-1 levels and LDH activity, lung tissue MDA level, PDE activity, hydroxyproline content, immunohistochemical expression of-SMA and CD68 positive macrophage, and fibrosis score. Meanwhile, it efficiently augmented the reduced BALF macrophage percentage, IL-10 level, lung tissue GSH level, CAT, and SOD activities.CONCLUSION: Vinpocetine may propose a new promising agent to manage PF.

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PMID:  Food Funct. 2023 Apr 3 ;14(7):3126-3138. Epub 2023 Apr 3. PMID: 36929898 Abstract Title:  Punicalagin protects against impaired skeletal muscle function in high-fat-diet-induced obese mice by regulating TET2. Abstract:  The function of skeletal muscles can be markedly hampered by obesity. Ten-eleven translocation 2 (TET2) is an important therapeutic target for ameliorating skeletal muscle dysfunction. Our previous study revealed that punicalagin (PUN) regulated TET2 in obese mice; however, whether PUN can prevent obesity-induced skeletal muscle dysfunction by regulating TET2 remains unclear. In the present study, 40 male C57BL/6J mice were divided into four groups (= 10 per group): the control (CON) group, the high-fat-diet (HFD, negative control) group, the resveratrol (positive control) group, and the PUN group. The ratio of gastrocnemius weight to body weight (0.00970.00160.00800.0011), the grip strength (120.04 g11.1098.89 g2.79), and the muscle fiber count (314.56 per visual field92.73236.44 per visual field50.58) in the PUN group were higher than those in the HFD group. Moreover, the levels of the TET2 protein, 5-hydroxymethylcytosine (5hmC), and 5-formylcytosine (5fC) in skeletal muscles were significantly lower in the HFD group than those in the CON group; these levels increased after PUN treatment. Compared with the HFD group, the phosphorylation level of AMP-activated protein kinase (AMPK)in the PUN group was higher, which effectively enhanced the stability of the TET2 protein. Besides, the ratio of (succinic acid + fumaric acid)/-ketoglutarate in the PUN group was lower than that in the HFD group (43.2112.4299.1937.07), and a lower ratio led to a higher demethylase activity of TET2 in the PUN group than in the HFD group. This study highlights that PUN supplementation protects against obesity-induced impairment of the skeletal muscle functionregulating the protein stability of TET2 and the enzymatic activity of TET2 demethylation.

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PMID:  Nutrients. 2023 Feb 19 ;15(4). Epub 2023 Feb 19. PMID: 36839395 Abstract Title:  Grape-Seed Proanthocyanidins Modulate Adipose Tissue Adaptations to Obesity in a Photoperiod-Dependent Manner in Fischer 344 Rats. Abstract:  Seasonal rhythms drive metabolic adaptations that influence body weight and adiposity. Adipose tissue is a key regulator of energy homeostasis in the organism, and its healthiness is needed to prevent the major consequences of overweight and obesity. In this context, supplementation with proanthocyanidins has been postulated as a potential strategy to prevent the alterations caused by obesity. Moreover, the effects of these (poly)phenols on metabolism are photoperiod dependent. In order to describe the impact of grape-seed proanthocyanidins extract (GSPE) on important markers of adipose tissue functionality under an obesogenic environment, we exposed Fischer 344 rats to three different photoperiods and fed them a cafeteria diet for five weeks. Afterwards, we supplemented them with 25 mg GSPE/kg/day for four weeks. Our results revealed that GSPE supplementation prevented excessive body weight gain under a long photoperiod, which could be explained by increased lipolysis in the adipose tissue. Moreover, cholesterol and non-esterified fatty acids (NEFAs) serum concentrations were restored by GSPE under standard photoperiod. GSPE consumption slightly helped combat the obesity-induced hypertrophy in adipocytes, and adiponectin mRNA levels were upregulated under all photoperiods. Overall, the administration of GSPE helped reduce the impact of obesity in the adipose tissue, depending on the photoperiod at which GSPE was consumed and on the type of adipose depots.

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PMID:  J Inflamm Res. 2023 ;16:467-492. Epub 2023 Feb 7. PMID: 36785716 Abstract Title:  Manjari Medika Grape Seed Extract Protects Methotrexate-Induced Hepatic Inflammation: Involvement of NF-B/NLRP3 and Nrf2/HO-1 Signaling System. Abstract:  OBJECTIVE: Grape Seed Extract is a natural source of various polyphenols, which have been shown to possess potent antioxidant and free radical-scavenging activities. The earlier studies have reported that grape seed extract exhibits broad-spectrum pharmacological activities. Therefore, studying the hepatoprotective effects and elucidation of mechanisms of action of the Indian Variety, Manjari Medika grape seed extract (GSE), may give an insight into therapeutic benefits. Methotrexate (MTX) is the first-line pharmacological therapy for different rheumatic diseases. The major adverse events such as hepatotoxicity are evident even in the low doses used for the treatment. The present study investigated the role of MTX on hepatic damage in murine liver and the plausible protective effects of the Indian grape variety, Manjari Medika grape seed extract, in ameliorating it.METHODS AND RESULTS: To assess the hepatological modulation, mice were divided into eight groups to investigate the ameliorative potential of this GSE (75 and 125 mg/kg) and correlate the experimental findings. The active components of the extract were assessed through UPLC-(ESI)-QToF-MS analysis. On the other hand, various biochemical and immunological indices were carried out to correlate the experimental data. The result demonstrated that the prophylactic administration of GSE reduced MTX-induced hepatic toxicity indices, which subsequently restored the hepatic morphological architecture. Moreover, the application of GSE in a dual dosage (75 and 125 mg/kg) suppressed MTX-induced reactive oxygen species generation, followed by lipid peroxidation and cellular nitrite formation. MTX-induced inflammasome activation through the redox-assisted cascade of TLR4/NF-B signaling was further reduced by applying the GSE. The results showed that the activation of cytoprotective transcription factor Nrf2 enhanced the level of endogenous antioxidants. Furthermore, through the regulation of TLR4/NF-B and Nrf2/HO-1 axis, this extract could reduce the MTX-mediated hepatic damage.CONCLUSION: Our findings suggest that Manjari Medika seed extract could be used as a therapeutic agent to relieve the side effects of MTX and other hepatic disorders.

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PMID:  Sci Rep. 2023 Feb 17 ;13(1):2849. Epub 2023 Feb 17. PMID: 36807330 Abstract Title:  Effect of a combination of pea protein, grape seed extract and lactic acid in an in vivo model of bacterial vaginosis. Abstract:  Bacterial vaginosis (BV) is a common vaginal dysbiosis characterized by a malodorous discharge and irritation. The imbalance of the vaginal microbiota plays a key role in the development of BV. It has been demonstrated that Gardnerella vaginalis (GV), a facultative anaerobic bacillus, is involved in BV. Due to the rising number of antimicrobial-resistant species, recurrence of BV is becoming more frequent in women; thus, alternative treatments to antibiotics are needed. Natural substances have recently shown a great efficacy for the treatment of vaginal dysbiosis. Thus, this study aimed to investigate the beneficial effect of a product containing pea protein (PP), grape seed extract (GS) and lactic acid (LA) in an in vivo model of Gardnerella vaginalis-induced vaginosis by intravaginal administration of GV suspension (110 CFU/20L saline). Our results demonstrated that the product containing PP, GS and LA significantly reduced GV proliferation. More specifically, it significantly preserved tissue architecture and reduced neutrophil infiltration, inflammatory markers and sialidase activity when used both as a pre- or a post-treatment. Moreover, the product displayed strong bioadhesive properties. Therefore, our data suggested that the product containing PP, GS and LA could be used as alternative preventive or curative treatment for the management of BV.

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PMID:  Life Sci. 2023 Apr 1 ;318:121492. Epub 2023 Feb 11. PMID: 36775115 Abstract Title:  Combinations of grape seed procyanidin extract and milk thistle silymarin extract against lung cancer - The role of MiR-663a and FHIT. Abstract:  AIMS: Grape seed procyanidin extract (GSE), and milk thistle silymarin extract (MTE) contain structurally distinct polyphenols, and each agent has been shown to exert antineoplastic effects against lung cancer. We hypothesize that combinations of GSE and MTE will additively enhance their anticancer effects against lung cancer.MATERIALS AND METHODS: The anti-proliferative effects of GSE, MTE and combinations were evaluated in lung neoplastic cell lines. A dose range finding (DRF) study to determine safety, bioavailability and bioactivity, followed by human lung cancer xenograft efficacy studies were conducted in female nude mice with once daily gavage of leucoselect phytosome (LP), a standardized GSE, and/or siliphos, a standardized MTE. The roles of tumor suppressors miR-663a and its predicted target FHIT in mediating the additive, anti-proliferative effecs of GSE/MTE were also assessed.KEY FINDINGS: GSE with MTE additively inhibited lung preneoplastic and cancer cell proliferations. Mice tolerated all dosing regimens in the DRF study without signs of clinical toxicity nor histologic abnormalities in the lungs, livers and kidneys. Eight weeks of LP and siliphos additively inhibited lung tumor xenograft growth. Plasma GSE/metabolites and MTE/metabolites showed that the combinations did not decrease systemic bioavailabilities of each agent. GSE and MTE additively upregulated miR-663a and FHIT in lung cancer cell lines; transfection of antisense-miR-663a significantly abrogated the anti-proliferative effects of GSE/MTE, upregulation of FHIT mRNA and protein. LP and siliphos also additively increased miR-663a and FHIT protein in lung tumor xenografts.SIGNIFICANCE: Our findings support clinical translations of combinations of GSE and MTE against lung cancer.

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PMID:  Curr Nutr Rep. 2023 Mar ;12(1):141-150. Epub 2023 Jan 24. PMID: 36692807 Abstract Title:  Grape Seed Components as Protectors of Inflammation, DNA Damage, and Cancer. Abstract:  PURPOSE OF REVIEW: Oxidative stress is related to the pathogenesis of several chronic diseases, including inflammatory processes. Free radicals excess increase not only oxidative stress but also genomic instability. Polyphenols are non-enzymatic antioxidants that act as a defense barrier against free radicals and non-radical oxidants. The purpose of this article was to review published articles relating dietary polyphenols contained in grape seed proanthocyanidin extracts with its potential for reversing DNA damage.RECENT FINDINGS: Proanthocyanidin components exert pleiotropic actions having several biological, biochemical, and significant pharmacological effects and showed the ability to reduce cytotoxicity and genotoxicity. Grape seed proanthocyanidin extracts showed the ability to reduce cytotoxicity and genotoxicity through the comet assay and the micronucleus technique.

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PMID:  Front Pharmacol. 2022 ;13:1035755. Epub 2023 Jan 6. PMID: 36686673 Abstract Title:  Grape seed proanthocyanidin extract targets p66Shc to regulate mitochondrial biogenesis and dynamics in diabetic kidney disease. Abstract:  UNLABELLED: Mitochondrial biogenesis and dynamics are associated with renal mitochondrial dysfunction and the pathophysiological development of diabetic kidney disease (DKD). Decreased p66Shc expression prevents DKD progression by significantly regulating mitochondrial function. Grape seed proanthocyanidin extract (GSPE) is a potential therapeutic medicine for multiple kinds of diseases. The effect of GSPE on the mitochondrial function and p66Shc in DKD has not been elucidated. Hence, we decided to identify p66Shc as a therapeutic target candidate to probe whether GSPE has a renal protective effect in DKD and explored the underlying mechanisms.METHODS: , rats were intraperitoneally injected with streptozotocin (STZ) and treated with GSPE. Biochemical changes, mitochondrial morphology, the ultrastructure of nephrons, and protein expression of mitochondrial biogenesis (SIRT1, PGC-1, NRF1, TFAM) and dynamics (DRP1, MFN1) were determined., HK-2 cells were transfected with p66Shc and treated with GSPE to evaluate changes in cell apoptosis, reactive oxygen species (ROS), mitochondrial quality, the protein expression.RESULTS: , GSPE significantly improved the renal function of rats, with less proteinuria and a lower apoptosis rate in the injured renal tissue. Besides, GSPE treatment increased SIRT1, PGC-1, NRF1, TFAM, and MFN1 expression, decreased p66Shc and DRP1 expression., overexpression of p66Shc decreased the resistance of HK-2 cells to high glucose toxicity, as shown by increased apoptosis and ROS production, decreased mitochondrial quality and mitochondrial biogenesis, and disturbed mitochondrial dynamic homeostasis, ultimately leading to mitochondrial dysfunction. While GSPE treatment reduced p66Shc expression and reversed these changes.CONCLUSION: GSPE can maintain the balance between mitochondrial biogenesis and dynamics by negatively regulating p66Shc expression.

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PMID:  Cells. 2023 Jan 4 ;12(2). Epub 2023 Jan 4. PMID: 36672146 Abstract Title:  Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways. Abstract:  Grapevine (L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming alsothat MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.

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PMID:  Chin J Integr Med. 2023 May ;29(5):394-404. Epub 2023 Jan 6. PMID: 36607588 Abstract Title:  Grape Seed Extract Attenuates Demyelination in Experimental Autoimmune Encephalomyelitis Mice by Inhibiting Inflammatory Response of Immune Cells. Abstract:  OBJECTIVE: To examine the anti-inflammatory effect of grape seed extract (GSE) in animal and cellular models and explore its mechanism of action.METHODS: This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17 and the inflammatory factors such as tumor necrosis factor-(TNF-), interleukin-1(IL-1), IL-6, IL-12, IL-17 and interferon-(IFN-) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay (ELISA), immunofluorescence staining and Western blot, respectively.RESULTS: GSE reduced the secretion of TNF-, IL-1and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide (P

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PMID:  Arch Rheumatol. 2022 Sep ;37(3):393-403. Epub 2022 Jul 22. PMID: 36589610 Abstract Title:  Grape seed proanthocyanidin extract induces apoptotic and autophagic cell death in rheumatoid arthritis fibroblast-like synoviocytes. Abstract:  OBJECTIVES: In this study, we aimed to evaluate the association between grape seed proanthocyanidin extract (GSPE) and rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLSs) and to investigate whether GSPE induces cell death in RA-FLSs.MATERIALS AND METHODS: The FLSs were isolated from RA synovial tissues. Cell viability and cell cycle staging were analyzed using a hemocytometer and flow cytometry. Caspase 3 and poly (ADP-ribose) polymerase (PARP) proteins were analyzed using Western blotting with z-VAD-fmk. Protein LC3 and polyubiquitin-binding protein p62 that were degraded by autophagy were evaluated using Western blotting with 3-methyladenine and chloroquine. Reactive oxygen species (ROS) were also evaluated.RESULTS: When RA-FLSs were treated with GSPE, cell viability decreased, the number of cells in sub-G1 and G2/M phases increased, and the expression of pro-PARP and pro-caspase 3 proteins decreased in a concentration-dependent manner. This result was offset, when the cells were co-treated with the pan-caspase inhibitor z-VAD-fmk. The reduced cell viability, increased expression of LC3-II protein, and reduced expression of p62 protein with GSPE treatment were offset, when RA-FLSs were co-treated with GSPE and autophagy inhibitors 3-methyladenine and chloroquine. The level of ROS in RA-FLSs treated with GSPE was significantly lower than treatment with N-acetyl-cysteine, a ROS inhibitor.CONCLUSION: Our study results show that GSPE induces apoptotic and autophagic cell death and inhibites reactive oxygen species in RA-FLSs.

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PMID:  Dose Response. 2022 ;20(4):15593258221141585. Epub 2022 Nov 22. PMID: 36458281 Abstract Title:  Hepatoprotective Effect of Grape Seed and Skin Extract Against Lithium Exposure Examined by the Window of Proteomics. Abstract:  CONTEXT: The liver is the organ by which the majority of substances are metabolized, including psychotropic drugs. Lithium (Li) used as drug for many neurological disorders such as bipolar disorders.OBJECTIVE: This study aims to assess lithium toxicity and to evaluate the hepatic-protective properties of a grape skin seed and extract (GSSE).MATERIALS AND METHODS: Twenty-four male Wistar rats were exposed for 30 days to either various lithium concentrations, GSSE alone, or lithium supplemented with GSSE. The proteomic analysis revealed alterations of liver protein profiles after lithium treatments that were successfully identified by mass spectrometry.RESULTS: Lithium treatment induced an oxidative damage by the alteration of antioxidant enzymes activities such as superoxide dismutase, CAT, and Gpx. The regulated proteins are mainly involved in the respiratory electron transport chain, detoxification processes, ribosomal stress pathway, glycolysis, and cytoskeleton. Proteins were differentially expressed in a dose-dependent manner. Interestingly, GSSE reversed the situation and restored the level of liver proteins whose abundance was modified after lithium treatment, arguing for its protective activity.CONCLUSION: Our data demonstrated the ability of proteomic analysis to underline the toxicity mechanisms of lithium in animal models. Based on these results, GSSE may be envisaged as a nutritional supplement to weaken the liver toxicity of lithium.

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PMID:  J Exp Zool A Ecol Integr Physiol. 2023 Mar ;339(2):210-219. Epub 2022 Nov 27. PMID: 36437535 Abstract Title:  Ameliorative effect of Vitis vinifera (Linn.) seed extract on lead acetate induced oxidative damage on testis and sperm quality in Wistar rats. Abstract:  Lead is considered one of the most prevalent environmental and biologically hazardous toxicants among metallic elements. It severely affects human health and especially the male reproductive system by causing reproductive organ dysfunction leading to infertility. Natural dietary antioxidants are studied for their ability to ameliorate the cells' miscellaneous damage. The current study was designed to explore the effect of Vitis vinifera (Linn.) (grape) seed extract (GSE) on lead acetate (LA)-induced oxidative damage on testis and sperm quality in rats. Twenty-four male Wistar rats were allocated into four equal groups. Group I received distilled water; Group II received LA 50mg/kg body weight (Bw); Group III received LA 50mg/kg+GSE 200mg/kg Bw; and Group IV received LA 50mg/kg+GSE 400mg/kg Bw (orally once a day for 28 days). After 28 days, levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) were estimated in the testicular tissue. The cauda of the epididymis was used to study the characteristics of the sperm, such as sperm count, motility, viability, tail-coiled sperm, and morphology. The hematoxylin and eosin staining method was used to study histomorphology. Results revealed that LA induction significantly increased MDA concentration and decreased the levels of SOD, CAT, GPx, and GSH. It also reduced the weight of the testis and testosterone hormone levels, declined the quality of sperm, and increased morphologically abnormal sperm. Moreover, LA severely altered the histomorphology of the testis, such as atrophy of the seminiferous tubule, degeneration of germinal epithelium, and increased interstitial space, compared with the control group. In Groups III and IV, coadministration of LA with GSE reduced the MDA concentration, preserved the antioxidant enzyme system and testosterone hormonal levels, restored the sperm characteristics, reduced the abnormal sperm, and improved histomorphological alterations in the testis compared with the LA-induced group. In conclusion, GSE has a potent natural antioxidant that provides promising protection against LA-induced testicular oxidative damage on testis and sperm quality in rats.

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PMID:  Molecules. 2022 Nov 10 ;27(22). Epub 2022 Nov 10. PMID: 36431850 Abstract Title:  Phenol Derivatives Obtained from Grape Seed Extract Show Virucidal Activity against Murine Norovirus. Abstract:  Human noroviruses are the most common pathogens known to cause acute gastroenteritis, a condition that can lead to severe illness among immunocompromised individuals such as organ transplant recipients and the elderly. To date, no safe and effective vaccines or therapeutic agents have been approved for treating norovirus infections. Therefore, we aimed to demonstrate the virucidal activity of grape seed extract (GSE), which contains>83% proanthocyanidins, against murine norovirus (MNV), a surrogate for human norovirus. GSE showed virucidal activity against MNV in a dose- and time-dependent manner. Atomic force microscopic analysis showed viral particle aggregates after treatment of MNV with GSE. MNV treated with 50g/mL of GSE for 10 min resulted in the absence of pathogenicity in an animal model of infection, indicating that GSE has irreversible virucidal activity against MNV particles. Thus, GSE may aid in the development of treatments for norovirus infections.

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PMID:  Chemosphere. 2023 Feb ;313:137201. Epub 2022 Nov 12. PMID: 36379430 Abstract Title:  Glyphosate mimics 17-estradiol effects promoting estrogen receptor alpha activity in breast cancer cells. Abstract:  Glyphosate, the active ingredient in several broad-spectrum herbicide formulations, has been validated and widely used throughout the world. Recent reports have questioned its safety, showing that glyphosate may act as an endocrine disruptor by promoting estrogenic activity. However, the molecular mechanism involved in this phenomenon remains unclear. Therefore, here we aimed to elucidate the mechanism by which glyphosate induces estrogenic activity using estrogen-sensitive breast cancer cell line models. Our results show that glyphosate mimics the cell effects of 17-estradiol (E2), promoting estrogen receptor(ER) phosphorylation, its degradation, and transcriptional activity at high concentrations. The molecular mechanism seems involved in the ERligand-binding domain (LBD). Molecular simulations suggest a plausible interaction between glyphosate and the LBD through a coordinated complex involving divalent cations such as Zn (II). In addition, glyphosate exposure alters the level of Cyclin-dependent kinase 7 that contribute to ERphosphorylation. Finally, glyphosate increases cell proliferation rate and levels of cell cycle regulators, accompanied by an increase in anchorage-independent growth capacity. These findings suggest that glyphosate at high concentrations, induces estrogen-like effects through an ERligand binding site-dependent mechanism, leading to cellular responses resulting from a complex interplay of genomic and non-genomic events.

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PMID:  Eur J Clin Pharmacol. 2023 Jan ;79(1):15-38. Epub 2022 Dec 1. PMID: 36450892 Abstract Title:  Silymarin as a preventive or therapeutic measure for chemotherapy and radiotherapy-induced adverse reactions: a comprehensive review of preclinical and clinical data. Abstract:  PURPOSE: Thus far, silymarin has been examined in several studies for prevention or treatment of various chemotherapy or radiotherapy-induced adverse reactions. In this review, we try to collect all available human, animal, and pre-clinical data in this field.METHODS: The search was done in Scopus, PubMed, Medline, and systematic reviews in the Cochrane database, using the following keywords: "Cancer," "Chemotherapy," "Radiotherapy," "Mucositis," "Nephrotoxicity," "Dermatitis," "Ototoxicity," "Cardiotoxicity," "Nephrotoxicity," "Hepatotoxicity," "Reproductive system," "Silybum marianum," "Milk thistle," and "Silymarin" and "Silybin." We included all relevant in vitro, in vivo, and human studies up to the date of publication.RESULTS: Based on 64 included studies in this review, silymarin is considered a safe and well-tolerated compound, with no known clinical drug interaction. Notably, multiple adverse reactions of chemotherapeutic agents are effectively managed by its antioxidant, anti-apoptotic, anti-inflammatory, and anti-immunomodulatory properties. Clinical trials suggest that oral silymarin may be a promising adjuvant with cancer treatments, particularly against hepatotoxicity (n=10), nephrotoxicity (n=3), diarrhea (n=1), and mucositis (n=3), whereas its topical formulation can be particularly effective against radiodermatitis (n=2) and hand-foot syndrome (HFS) (n=1).CONCLUSION: Further studies are required to determine the optimal dose, duration, and the best formulation of silymarin to prevent and/or manage chemotherapy and radiotherapy-induced complications.

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PMID:  Chem Biodivers. 2023 Apr ;20(4):e202200248. Epub 2023 Mar 28. PMID: 36908157 Abstract Title:  Role of NF-B/IL-1Pathway and Caspase 3 in Mediating the Hepatoprotective Effect of Rutin against Paraquat-Induced Liver Toxicity in Male Rats. Abstract:  One of the most common bipyridinium herbicides that can lead to liver toxicity is paraquat. Rutin is a bioflavonoid with antioxidant, anti-inflammatory, anti-hepatotoxic, and antimicrobial properties. The effect of rutin on paraquat-induced liver toxicity was examined in this study. 48 male rats were divided into six groups: the control group was given a normal diet; the non-treated group was given paraquat; the positive control group was given paraquat, and silymarin and the treatment groups were given paraquat and rutin at doses of 25, 50, and 100mg/kg. After fourteen days, the rats were anesthetized by xylazine-ketamine, and fasting blood samples were obtained from their hearts to measure alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), malondialdehyde (MDA), creatinine, lipid profile, antioxidant capacity, and carbonyl protein. The liver tissue was removed to measure the levels of catalase (CAT), superoxide dismutase (SOD), total protein, vitamin C, plus NF-B, IL1, and caspase-3 gene expressions. Paraquat gavage in the untreated group (group 2) for 14days in comparison with the control group induced a significant augmentation (p

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PMID:  Acta Histochem Cytochem. 2023 Feb 28 ;56(1):9-19. Epub 2023 Feb 25. PMID: 36890848 Abstract Title:  Protective Effect of Silymarin on Liver in Experimental in the Sepsis Model of Rats. Abstract:  This study, it was investigated whether silymarin has a protective effect by performing histological, immunohistochemical, and biochemical evaluations on the liver damage induced by cecal ligation perforation (CLP). CLP model was established and silymarin was treated at a dose of 50 mg/kg, 100 mg/kg, and 200 mg/kg, by oral one hour before the CLP. As an effect of the histological evaluations of the liver tissues, venous congestion, inflammation, and necrosis in the hepatocytes were observed in the CLP group. A situation close to the control group was observed in the Silymarin (SM)100 and SM200 groups. As a result of the immunohistochemical evaluations, inducible nitric oxide synthase (iNOS), cytokeratine (CK)18, Tumor necrosis factor-alpha (TNF-), and interleukine (IL)-6 immunoreactivities were intense in the CLP group. In the biochemical analysis, Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) levels were significantly increased in the CLP group, while a significant decrease was observed in the treatment groups. TNF, IL-1, and IL-6 concentrations were in parallel with histopathological evaluations. In the biochemical analysis, Malondialdehyte (MDA) level increased significantly in the CLP group, but there was a significant decrease in the SM100 and SM200 groups. Glutathione (GSH), Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase (GSH-Px) activities were relatively low in the CLP group. According to these data, it was concluded that using silymarin reduces the existing liver damage in sepsis.

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PMID:  Molecules. 2022 Dec 13 ;27(24). Epub 2022 Dec 13. PMID: 36557984 Abstract Title:  Silymarin Protects against Acute Liver Injury Induced by Acetaminophen by Downregulating the Expression and Activity of the CYP2E1 Enzyme. Abstract:  Previous studies have shown that silymarin protects against various types of drug-induced liver injury, but whether the protective mechanism of silymarin against acetaminophen-induced liver injury is related to the CYP2E1 enzyme remains unclear. In this study, we investigated the effect of silymarin on the activity and expression of CYP2E1 in vitro and in vivo. The results of in vitro studies showed that silymarin not only inhibited the activity of CYP2E1 in human and rat liver microsomes but also reduced the expression of CYP2E1 in HepG2 cells. In vivo studies showed that silymarin to its metabolite 6-OH-CLX and significantly increased the t, area under the curve (AUC) and mean residence time (MRT) of chlorzoxazone. In addition, silymarin pretreatment significantly inhibited the upregulation of Cyp2e1 expression, reduced the production of 3-cysteinylacetaminophen trifluoroacetic acid salt (APAP-CYS), and restored the liver glutathione level. The results of our study show that silymarin plays an important protective role in the early stage of acetaminophen-induced acute liver injury by reducing the activity and expression of CYP2E1, reducing the generation of toxic metabolites, and alleviating liver injury.

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PMID:  Mol Pain. 2023 ;19:17448069221148351. PMID: 36526437 Abstract Title:  Phenotypic screen identifies the natural product silymarin as a novel anti-inflammatory analgesic. Abstract:  Sensory neuron hyperexcitability is a critical driver of pathological pain and can result from axon damage, inflammation, or neuronal stress. G-protein coupled receptor signaling can induce pain amplification by modulating the activation of Trp-family ionotropic receptors and voltage-gated ion channels. Here, we sought to use calcium imaging to identify novel inhibitors of the intracellular pathways that mediate sensory neuron sensitization and lead to hyperexcitability. We identified a novel stimulus cocktail, consisting of the SSTR2 agonist L-054,264 and the S1PR3 agonist CYM5541, that elicits calcium responses in mouse primary sensory neuronsas well as pain and thermal hypersensitivity in mice. We screened a library of 906 bioactive compounds and identified 24 hits that reduced calcium flux elicited by L-054,264/CYM5541. Among these hits, silymarin, a natural product derived from milk thistle, strongly reduced activation by the stimulation cocktail, as well as by a distinct inflammatory cocktail containing bradykinin and prostaglandin E2. Silymarin had no effect on sensory neuron excitability at baseline, but reduced calcium flux via Orai channels and downstream mediators of phospholipase C signaling., silymarin pretreatment blocked development of adjuvant-mediated thermal hypersensitivity, indicating potential use as an anti-inflammatory analgesic.

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PMID:  BMC Complement Med Ther. 2022 Dec 13 ;22(1):331. Epub 2022 Dec 13. PMID: 36514062 Abstract Title:  Protective effect of silymarin on tacrolimus-induced kidney and liver toxicity. Abstract:  BACKGROUND: Tacrolimus (FK506) is an immunosuppressive agent and has toxic side effects such as nephrotoxicity, hepatotoxicity, and neurotoxicity. In our study, we aimed to investigate the protective effect of silymarin on renal and hepatic toxicity considered to be tacrolimus related.METHODS: In this 6-week experimental study, 46 eight-week-old healthy male rats were used. The groups comprised the Control (healthy rats, n=6), Tac (tacrolimus 1 mg/kg, n=8), silymarin 100 mg/kg (SLI 100 mg/kg n=8), Tac+SLI 100 (tacrolimus 1 mg/kg+SLI 100 n=8), SLI 200 (SLI 200 mg/kg n=8), and Tac+SLI 200 (tacrolimus 1 mg/kg+SLI 200 mg/kg n=8). After 6 weeks, all rats were sacrificed, and the tissue follow-up procedure was performed for kidney and liver tissues, histopathology, and in situ TUNEL analysis. Blood samples were analyzed for the total antioxidant capacity (TAC), total oxidant capacity (TOC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), albumin, total bilirubin, creatine.RESULTS: Histopathological findings of kidney and liver tissue of rats were determined to increase statistically in Tac group compared to SLI 1 00 and SLI 200 groups (P0.05). The in situ TUNEL method showed that the tacrolimus increased apoptosis while the silymarin decreased it. TOC levels increased statistically in Tac groups compared to silymarin-treated groups (P0.05), the lowest was measured in the Tac group. The ALT, AST, GGT, total bilirubin, and creatine values were higher in the Tac group than in the silymarin groups (P0.05).CONCLUSION: In our study, we determined that tacrolimus caused damage to kidney and liver tissue. Histopathological, biochemical and apoptotic findings show that silymarin has a protective effect against nephrotoxicity and hepatotoxicity caused by tacrolimus.

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PMID:  Cell Mol Biol (Noisy-le-grand). 2022 Jul 31 ;68(7):208-212. Epub 2022 Jul 31. PMID: 36495494 Abstract Title:  Silymarin protects the liver from-naphthylisothiocyanate-induced cholestasis by modulating the expression of genes involved in bile acid homeostasis. Abstract:  Cholestasis is characterized by impaired bile flow which results in inflammation, cirrhosis, and ultimately liver failure. The current study is aimed to evaluate the anti-cholestatic effect of silymarin against-naphthylisothiocyanate (ANIT) induced cholestasis. Mice were gavaged with various doses of silymarin or ursodeoxycholic acid (UDCA) for 19 days. Then they were challenged with-naphthylisothiocyanate (ANIT) and after 48 hours the animals were sacrificed to obtain blood and liver sections. Serum levels of bilirubin, aspartate transaminase (AST), alanine transaminase (ALP), and liver histology were analyzed. mRNA expression of selected transporters (Bile salt export pump (BSEP) and sodium taurocholate cotransporting polypeptide (NTCP)) and proteins (farnesoid x receptor (FXR) and Cytochrome P450 Family 7 Subfamily A Member 1 (Cyp7a1)) involved in bile acids biosynthesis, excretion and uptake were also evaluated by quantitative PCR. The results indicated that the serum levels of bilirubin, AST, and ALP were significantly higher in a cholestatic model group as compared to an untreated control group. However, in silymarin groups, the serum level of these parameters is significantly lower than in a cholestatic model group. Liver histology also showed that silymarin prevents ANIT-induced hepatic injury. mRNA expression of FXR, BSEP, and NTCP was downregulated and expression of Cyp7a1 was upregulated in a cholestatic model group as compared to an untreated control group. However, in silymarin treatment groups, the expression of FXR, BSEP and NTCP was upregulated and the expression of Cyp7a1 was downregulated as compared to the cholestatic model group. In conclusion, silymarin could alleviate hepatic injury by modulating the expression of genes involved in bile acid homeostasis.

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PMID:  Curr Med Chem. 2023 ;30(33):3775-3797. PMID: 36424777 Abstract Title:  The Radioprotective Potentials of Silymarin/Silibinin Against Radiotherapy- Induced Toxicities: A Systematic Review of Clinical and Experimental Studies. Abstract:  BACKGROUND: Although radiotherapy is one of the main cancer treatment modalities, exposing healthy organs/tissues to ionizing radiation during treatment can lead to different adverse effects. In this regard, it has been shown that the use of radioprotective agents may alleviate the ionizing radiation-induced toxicities.OBJECTIVE: The present study aims to review the radioprotective potentials of silymarin/silibinin in the prevention/reduction of ionizing radiation-induced adverse effects on healthy cells/tissues.METHODS: Based on PRISMA guidelines, a comprehensive and systematic search was performed for identifying relevant literature on the "potential protective role of silymarin/silibinin in the treatment of radiotherapy-induced toxicities" in the different electronic databases of Web of Science, PubMed, and Scopus up to April 2022. Four hundred and fifty-five articles were obtained and screened in accordance with the inclusion and exclusion criteria of the current study. Finally, 19 papers were included in this systematic review.RESULTS: The findings revealed that the ionizing radiation-treated groups had reduced survival rates and body weight in comparison with the control groups. It was also found that radiation can induce mild to severe adverse effects on the skin, digestive, hematologic, lymphatic, respiratory, reproductive, and urinary systems. Nevertheless, the administration of silymarin/silibinin could mitigate the ionizing radiation-induced adverse effects in most cases. This herbal agent exerts its radioprotective effects through anti-oxidant, anti-apoptosis, anti-inflammatory activities, and other mechanisms.CONCLUSION: The results of the current systematic review showed that co-treatment of silymarin/silibinin with radiotherapy alleviates the radiotherapy-induced adverse effects in healthy cells/tissues.

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PMID:  Arch Physiol Biochem. 2022 Nov 3:1-15. Epub 2022 Nov 3. PMID: 36328030 Abstract Title:  Silymarin inhibits the lipogenic pathway and reduces worsening of non-alcoholic fatty liver disease (NAFLD) in mice. Abstract:  CONTEXT: The role of silymarin in hepatic lipid dysfunction and its possible mechanisms of action were investigated.OBJECTIVE: To evaluate the effects of silymarin on hepatic and metabolic profiles in mice fed with 30% fructose for 8 weeks.METHODS: We evaluated the antioxidant profile of silymarin; mice consumed 30% fructose and were treated with silymarin (120mg/kg/day or 240mg/kg/day). We performed biochemical, redox status, and histopathological assays. RT-qPCR was performed to detect ACC-1, ACC-2, FAS, and CS expression, and western blotting to detect PGC-1levels.RESULTS: Silymarin contains high levels of phenolic compounds and flavonoids and exhibited significant antioxidant capacity, the fructose-fed groups showed increased levels of AST, ALT, SOD/CAT, TBARS, hepatic TG, and cholesterol, as well as hypertriglyceridaemia, hypercholesterolaemia, and increased ACC-1 and FAS. Silymarin treatment reduced these parameters and increased mRNA levels and activity of hepatic citrate synthase.CONCLUSIONS: These results suggest that silymarin reduces worsening of NAFLD.

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PMID:  Sci Rep. 2022 Sep 23 ;12(1):15872. Epub 2022 Sep 23. PMID: 36151457 Abstract Title:  Silymarin reduces retinal microvascular damage in streptozotocin-induced diabetic rats. Abstract:  Diabetic retinopathy is a severe microvascular problem in diabetes mellitus. Silymarin is a flavonoid compound, and according to previous studies, it is a bioactive compound with potent antioxidant and anti-inflammatory properties. This investigation aims to peruse the impact of silymarin against diabetic retinopathy in streptozotocin (STZ)-provoked rats. Thirty-two adult male Wistar rats were randomly allocated into the control group, STZ group, STZ+silymarin (50 mg/kg), and STZ+silymarin (100 mg/kg). STZ rats received silymarin every day until 2 months after diabetes induction. The serum and retinal tissues were collected 2 months after silymarin treatment to determine biochemical and molecular analyses. Silymarin markedly lowered the serum glucose concentration in diabetic rats. Silymarin reduced the increased levels of advanced glycosylated end products (AGEs), the receptors for AGEs (RAGE), and reactive oxygen species (ROS) in diabetic rats. Silymarin also attenuated the phosphorylation of p38 MAP kinase and nuclear factor (NF)-B p65 and diminished diabetes-induced overexpression of inflammatory cytokines, vascular endothelial growth factor (VEGF), adhesion molecules, and extracellular matrix proteins in STZ rats. Our data suggested that silymarin has protective effects against diabetic retinopathy, which might be related to the inhibition of the AGEs/RAGE axis and its antioxidant and anti-inflammatory activities.

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PMID:  Iran J Med Sci. 2022 Jul ;47(4):367-378. PMID: 35919076 Abstract Title:  Silymarin Administration Attenuates Cirrhotic-induced Cardiac Abnormality in the Rats: A Possible Role of-adrenergic Receptors and L-type Voltage-Dependent Calcium Channels. Abstract:  BACKGROUND: Cirrhotic cardiomyopathy is a well-recognized cardiac dysfunction in cirrhotic patients. Studies have confirmed the protective effects of silymarin in different types of cardiac injury. This study aimed to examine the effectiveness and molecular mechanism of silymarin against myocardial dysfunction and hypertrophy in a rat model of cirrhosis.METHODS: The experiment was performed at Alborz University of Medical Sciences (Karaj, Iran) during 2020-2021. Thirty-two male Wistar rats were randomly divided into four groups of Sham-operated (control group for surgical procedures), Bile Duct Ligated (BDL), and two Silymarin extract (SE)-treated groups of 300 and 600 mg/Kg/day. After 28 days, serum levels of AST, ALT, GGT, and ALP, liver histopathological status, as well as cardiac mechanical function, were assessed. Cardiac-adrenergic receptors (-AR), L-type voltage-dependent calcium channels (L-VDCC), and GATA4 mRNA expression were also determined using real-time RT-PCR. Data analysis was performed using the one-way ANOVA followed by Duncan's multiple range test. Histological data has been analyzed with Kruskal-Wallis nonparametric test. The analysis was performed at P0.05.RESULTS: BDL was associated with a significant elevation in serum AST, ALT, GGT, and ALP, development of necrosis and fibrosis of the liver texture, increased Heart Weight and Heart Weight to Body Weight ratio, enhanced cardiac mechanical function as well as a significant up-regulation of ventricular-AR and L-VDCC. Administration of SE600, but not SE300, significantly reduced the serum levels of the enzymes and alleviated signs of liver necrosis and fibrosis. Cirrhotic-induced cardiac dysfunction was also restored by SE600, but not by the lower dose. In addition, cardiac expression of the-AR and L-VDCC was down-regulated toward normal values by either higher or lower doses of the SE.CONCLUSION: Silymarin treatment in higher dose attenuated cirrhosis-associated cardiac remodeling and reduced cardiac mechanical dysfunctions.

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PMID:  Clin Nutr ESPEN. 2023 Apr ;54:436-442. Epub 2023 Feb 24. PMID: 36963891 Abstract Title:  Effects of adherence to the Mediterranean diet on fatigue and activities of daily living in geriatric individuals with COPD. Abstract:  BACKGROUND & AIMS: Fatigue is a commonly diagnosed symptom in cancers and many other chronic debilitating diseases. The second most important complaint after dyspnea in patients with Chronic Obstructive Pulmonary Disease (COPD) is the feeling of fatigue. Fatigue can have significant consequences on health status as it can limit patients' activities of daily living, lead to worsening prognosis, and is an indicator of mortality. It remains unclear how fatigue affects the daily life of COPD patients and what physical, social, and emotional challenges it brings. Some studies are showing that adhering to the Mediterranean diet significantly improves fatigue. In this study, the relationship between fatigue and adherence to a Mediterranean diet in COPD patients was investigated.METHODS: The present study is a descriptive, cross-sectional, and correlational study. The study population included65-year-old patients with a diagnosis of COPD who were hospitalized in Chest Diseases Clinics ofzmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital and Chest Diseases Clinic of Sivas Cumhuriyet University Hospital. The Personal Information Form, Mediterranean Diet Adherence Screener (MEDAS), COPD and Asthma Fatigue Scale (CAFS), and KATZ Activities of Daily Living Scale (Katz ADL) were used as data collection tools.RESULTS: Of the total 526 participants, 58.7% were men, 52.1% were overweight, 54.3% were ex-smokers, and 65.8% were non-drinkers. In the variables related to the disease, the mean duration of having COPD was 16.41 (SD 5.26) years. According to the GOLD classification of the participants, the severity of the disease was determined as Stage III in 57.4% of them, and the severity of dyspnea was determined as "3" (moderate severity) in 54.5% of them according to the mMRC scale. According to the results of the analysis, the mean MEDAS score was 7.84 (SD: 2.76). According to the participants' levels of adherence to the MD, of them, 43.8% had high adherence to MD and 29% had low adherence to MD. The mean CAFS score indicating the level of disease-related fatigue was 69.17 (SD: 15.73), and the lowest and highest scores were 25 and 100 respectively. According to the independence in activities of daily living of the participants, 77.3% were semi-dependent and 6.4% were independent. The comparison of the level of the participant's adherence to the MD according to their mean CAFS scores demonstrated that those who had high adherence to the MD obtained significantly lower scores than the participants in the other groups (p 

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PMID:  Curr Mol Med. 2023 Mar 20. Epub 2023 Mar 20. PMID: 36959141 Abstract Title:  Neuroprotective Potential of Hesperidin as Therapeutic Agent in the Treatment of Brain Disorders: Preclinical Evidence-based Review. Abstract:  Neurodegenerative disorders (NDs) are progressive morbidities that represent a serious health issue in the aging world population. There is a contemporary upsurge in worldwide interest in the area of traditional remedies and phytomedicines are widely accepted by researchers due to their health-promoted effects and fewer side effects. Hesperidin, a flavanone glycoside present in the peels of citrus fruits, possesses various biological activities including anti-inflammatory and antioxidant actions. In various preclinical studies, hesperidin has provided significant protective actions in a variety of brain disorders such as Alzheimer's disease, epilepsy, Parkinson's disease, multiple sclerosis, depression, neuropathic pain, etc. as well as their underlying mechanisms. The findings indicate that the neuroprotective effects of hesperidin are mediated by modulating antioxidant defence activities and neural growth factors, diminishing apoptotic and neuro-inflammatory pathways. This review focuses on the potential role of hesperidin in managing and treating diverse brain disorders.

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PMID:  Biochem Pharmacol. 2023 Apr ;210:115467. Epub 2023 Feb 26. PMID: 36849063 Abstract Title:  Geraniol ameliorates acute liver failure induced by lipopolysaccharide/D-galactosamine via regulating macrophage polarization and NLRP3 inflammasome activation by PPAR-methylation Geraniol alleviates acute liver failure. Abstract:  Geraniol (Ger), a natural acyclic monoterpene alcohol, has been reported to exert protective effects through anti-inflammation in Acute liver failure (ALF). However, its specific roles and precise mechanisms underlying anti-inflammatory effects in ALF have not yet fully explored. We aimed to investigated the hepatoprotective effects and mechanisms of Ger against ALF induced by lipopolysaccharide (LPS)/D-galactosamine (GaIN). In this study, the liver tissue and serum of LPS/D-GaIN-induced mice were collected. The degree of liver tissue injury was evaluated by HE and TUNEL staining. Serum levels of liver injury markers (ALT and AST) and inflammatory factors were measured by ELISA assays. PCR and western blotting were conducted to determine the expression of inflammatory cytokines, NLRP3 inflammasome-related proteins, PPAR-pathway-related proteins, DNA Methyltransferases and M1/M2 polarization cytokines. Immunofluorescence staining was used to assess the localization and expression of macrophage markers (F4/80 and CD86), NLRP3 and PPAR-. In vitro experiments were performed in macrophages stimulated with LPS with or without IFN-. Purification of macrophages and cell apoptosis was analyzed using flow cytometry. We found that Ger effectively alleviated ALF in mice, specified by the attenuation of liver tissue pathological damage, inhibition of ALT, AST and inflammatory factor levels, and inactivation of NLRP3 inflammasome. Meanwhile, downregulation M1 macrophage polarization may involve in the protective effects of Ger. In vitro, Ger reduced the activation of NLRP3 inflammasome and apoptosis through regulating PPAR-methylation by inhibiting M1 macrophage polarization. In conclusion, Ger protects against ALF through suppressing NLRP3 inflammasome-mediated inflammation and LPS-induced macrophage M1 polarization via modulating PPAR-methylation.

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PMID:  Front Immunol. 2023 ;14:1138215. Epub 2023 Mar 7. PMID: 36960064 Abstract Title:  Pharmacological potential of(L.) Dunal and(Willd.) Miers on the experimental models of COVID-19, T cell differentiation, and neutrophil functions. Abstract:  Cytokine release syndrome (CRS) due to severe acute respiratory coronavirus-2 (SARS-CoV-2) infection leads to life-threatening pneumonia which has been associated with coronavirus disease (COVID-19) pathologies. Centuries-old Asian traditional medicines such as(L.) Dunal (WS) andWilld.) Miers (TC) possess potent immunomodulatory effects and were used by the AYUSH ministry, in India during the COVID-19 pandemic. In the present study, we investigated WS and TC's anti-viral and immunomodulatory efficacy at the human equivalent doses using suitableandmodels. While both WS and TC showed immuno-modulatory potential, WS showed robust protection against loss in body weight, viral load, and pulmonary pathology in the hamster model of SARS-CoV2.pretreatment of mice and human neutrophils with WS and TC had no adverse effect on PMA, calcium ionophore, and TRLM-induced ROS generation, phagocytosis, bactericidal activity, and NETs formation. Interestingly, WS significantly suppressed the pro-inflammatory cytokines-induced Th1, Th2, and Th17 differentiation. We also used hACE2 transgenic mice to further investigate the efficacy of WS against acute SARS-CoV2 infection. Prophylactic treatment of WS in the hACE2 mice model showed significant protection against body weight loss, inflammation, and the lung viral load. The results obtained indicate that WS promoted the immunosuppressive environment in the hamster and hACE2 transgenic mice models and limited the worsening of the disease by reducing inflammation, suggesting that WS might be useful against other acute viral infections. The present study thus provides pre-clinical efficacy data to demonstrate a robust protective effect of WS against COVID-19 through its broader immunomodulatory activity.

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PMID:  Cureus. 2023 Mar ;15(3):e36168. Epub 2023 Mar 15. PMID: 36937128 Abstract Title:  A Study of Efficacy and Safety of Ashwagandha (Withania somnifera) Lotion on Facial Skin in Photoaged Healthy Adults. Abstract:  Background Facial skin has an essential cosmetic function in both men and women, and photoaged skin can affect the quality of life in healthy people. Ashwagandha () which is also called Indian ginseng has adaptogenic properties and is used in traditional Indian medicine to maintain balance, energize, and rejuvenate. Objective This randomized, double-blind, and placebo-controlled study assessed the efficacy and safety of topical application of lotion containing 8% standardized Ashwagandha root extract on improvement of skin parameters in the photoaged facial skin of healthy subjects. Methods Fifty-six healthy men and women aged between 18 and 60 years with Fitzpatrick phototype III-VI skin grade were randomized to receive the topical application (lotion on facial skin) of either Ashwagandha 8% (AG, n=28), or an identical placebo (PL, n=28) for 60 days. The primary outcome was the change from baseline on day 60 in the scores for global physician assessment scoring for the five dermatological signs (skin wrinkles, pores, hydration/moisture, skin brightness/tone, and pigmentation) on facial skin. Secondary outcomes were changes from baseline in the transepidermal water loss (TEWL), melanin index, hydration, and skin elasticity (R2 ratio). Another efficacy outcome was quality of life using the health-specific Short Form Health Survey-12 (SF-12). Safety was assessed using local reactions and adverse events. Three (1 AG, 2 PL) patients were lost to follow-up and per-protocol (PP) data included 53 patients (27 AG, 26 PL). For measurement data, repeated measures analysis of variance (ANOVA) was used to assess treatment effect at different time periods in the PP dataset (n=53). Two groups were compared for differences using a t-test for continuous data or a Mann-Whitney 'U' test for ordinal data. Adverse events were compared between two groups using the chi-square test. Results Greater reduction (p

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PMID:  Pharmacology. 2023 ;108(3):301-307. Epub 2023 Feb 8. PMID: 36754044 Abstract Title:  Alkaloids in Withania somnifera (L.) Dunal Root Extract Contribute to Its Anti-Inflammatory Activity. Abstract:  The anti-inflammatory properties of the medicinal plant Withania somnifera (L.) Dunal (WS) are generally related to withanolides; consistently, several strategies are under investigation to increase the concentration of these compounds in WS extracts. However, a potential toxicity of withanolides has been highlighted, thus questioning the safety of such preparations. At variance, the relative contribution of alkaloids is underrated, in spite of preliminary evidence underlining a possible pharmacological relevance. Starting from these considerations, the efficacy/safety profile of WS root extract (WSE) was compared with those of WS extracts which are enriched in alkaloids (WSA) and withanolides (WSW), respectively. MTT assay was used to evaluate cell viability. The anti-inflammatory activities of the different extracts were estimated throughout the assessment of the inhibition of lipopolysaccharide (LPS)-activated release of nitric oxide (NO) and the upregulation of iNOS and COX-2 protein in RAW 264.7 cells. Both WSA and WSW were able to reduce LPS-mediated effects in RAW 264.7 cells, suggesting that alkaloids and withanolides may contribute to the anti-inflammatory activity of WSE. A significant higher anti-inflammatory activity and a lower toxicity were observed when WSA was compared to WSW. The present results highlighted that the contribution of alkaloids to WS pharmacological effects should not be neglected. Particularly, these compounds may concur to reach a more advantageous efficacy/safety profile when WS is used for anti-inflammatory purposes.

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PMID:  Invest New Drugs. 2023 Feb ;41(1):134-141. Epub 2023 Jan 24. PMID: 36692618 Abstract Title:  Viscosalactone B, a natural LSD1 inhibitor, inhibits proliferation in vitro and in vivo against prostate cancer cells. Abstract:  Lysine-specific demethylase 1 (LSD1) has been a promising target to treat prostate cancer, and discovery of novel LSD1 inhibitors would have great clinical significance. In this work, viscosalactone B was first identified as a novel LSD1 inhibitor. Viscosalactone B isolated from Withania Somnifera displayed antiproliferative activity against PC3, DU145, C42B, PC3/MDVR, DU145/MDVR, and C42B/MDVR cells with ICvalues of 1.17, 0.72, 3.86, 2.06, 0.96 and 1.15 M, respectively. In comparison, it was a selective LSD1 inhibitor with an ICvalue of 970.27 nM and could induce a significant accumulation of LSD1 substrates H3K9me1, H3K9me2, and H3K4me1 in a concentration-dependent manner in DU145 cells. According to docking studies, it formed hydrogen bonds with the Thr11, Lys14, and Arg8 residues of LSD1. Importantly, while it displayed potent antitumor efficacy in vivo, it did not show obvious cytotoxicity on the major organs of nude mice. Therefore, viscosalactone B, as a novel LSD1 inhibitor, is a potential candidate that can be used for the treatment of prostate cancer in clinics.

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PMID:  J Cell Mol Med. 2023 May ;27(9):1250-1260. Epub 2023 Mar 27. PMID: 36967712 Abstract Title:  Hispolon induces apoptosis in oral squamous cell carcinoma cells through JNK/HO-1 pathway activation. Abstract:  Oral squamous cell carcinoma (OSCC) has a high recurrence rate and poor prognosis. Hispolon, a polyphenolic compound with antiviral, antioxidant, and anticancer activities, is a potential chemotherapy agent. However, few studies have investigated the anti-cancer mechanism of hispolon in oral cancer. This present study used the cell viability assay, clonogenic assay, fluorescent nuclear staining, and flow cytometry assay to analyse the apoptosis-inducing effects of hispolon in OSCC cells. After hispolon treatment, the apoptotic initiators, cleaved caspase-3, -8, and-9, were upregulated, whereas the cellular inhibitor of apoptosis protein-1 (cIAP1) was downregulated. Furthermore, a proteome profile analysis using a human apoptosis array revealed the overexpression of heme oxygenase-1 (HO-1) by hispolon, which was determined to be involved in caspase-dependent apoptosis. Moreover, cotreatment with hispolon and mitogen-activated protein kinase (MAPK) inhibitors revealed that hispolon induces apoptosis in OSCC cells through activation of the c-Jun N-terminal kinase (JNK) pathway and not the extracellular signal-regulated kinase (ERK) or p38 pathway. These findings indicate that hispolon may exert an anticancer effect on oral cancer cells by upregulating HO-1 and inducing caspase-dependent apoptosis by activating the JNK pathway.

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PMID:  Int J Mol Sci. 2022 Nov 21 ;23(22). Epub 2022 Nov 21. PMID: 36430965 Abstract Title:  Hispolon Cyclodextrin Complexes and Their Inclusion in Liposomes for Enhanced Delivery in Melanoma Cell Lines. Abstract:  Hispolon, a phenolic pigment isolated from the mushroom species Phellinus linteus, has been investigated for anti-inflammatory, antioxidant, and anticancer properties; however, low solubility and poor bioavailability have limited its potential clinical translation. In this study, the inclusion complex of hispolon with Sulfobutylether--cyclodextrin (SBECD) was characterized, and the Hispolon-SBECD Complex (HSC) was included within the sterically stabilized liposomes (SL) to further investigate its anticancer activity against melanoma cell lines. The HSC-trapped-Liposome (HSC-SL) formulation was investigated for its sustained drug delivery and enhanced cytotoxicity. The inclusion complex in the solid=state was confirmed by a Jobs plot analysis, molecular modeling, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), Proton nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscopy (SEM). The HSC-SL showed no appreciable deviation in size (

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PMID:  Arch Biochem Biophys. 2022 Sep 30 ;727:109303. Epub 2022 May 31. PMID: 35660410 Abstract Title:  Hispolon alleviates oxidative damage by stimulating the Nrf2 signaling pathway in PC12 cells. Abstract:  Natural products derived from the daily diet are garnering increasing attention for neurodegenerative disease (ND) treatment. Hispolon (His), a small molecule from Phellinus linteus, has been reported to have various pharmacological activities. Here, we evaluated its protective effect on a neuron-like rat pheochromocytoma cell line (PC12). Results showed that His could restore cell death induced by oxidative damage. Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) plays a significant role in maintaining cellular redox homeostasis. After treatment with His, some Nrf2-governed antioxidant genes were upregulated in a dose-dependent manner. However, the protective effect of His on PC12 cells was easily terminated by Nrf2 knockdown, demonstrating that Nrf2 is a critical component in this cytoprotective process. Taken together, our study showed that His was not only an effective activator of Nrf2 but also a promising candidate for ND treatment.

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PMID:  Molecules. 2021 Jul 26 ;26(15). Epub 2021 Jul 26. PMID: 34361649 Abstract Title:  Hispolon Induces Apoptosis, Suppresses Migration and Invasion of Glioblastoma Cells and Inhibits GBM Xenograft Tumor Growth In Vivo. Abstract:  Hispolon, a polyphenol compound isolated from, has been reported to exhibit antioxidant, antiproliferative, and antitumor activities. This study aimed to explore the antitumor effects of hispolon on glioblastoma multiforme (GBM) cells in vitro and in vivo. The results revealed that hispolon significantly inhibited GBM cell proliferation and induced apoptosis through caspase-9 and caspase-3 activation and PARP cleavage. Hispolon also induced cell cycle G2/M phase arrest in GBM cells, as supported by flow cytometry analysis and confirmed by a decrease in cyclin B1, cdc2, and cdc25c protein expressions in a dose- and time-dependent manner. Furthermore, hispolon suppressed the migration and invasion of GBM cells by modulating epithelial-mesenchymal transition (EMT) markers via wound healing, transwell assays, and real-time PCR. Moreover, hispolon significantly reduced tumor growth in DBTRG xenograft mice and activated caspase-3 in hispolon-treated tumors. Thus, our findings revealed that hispolon is a potential candidate for the treatment of GBM.

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n/a PMID:  Immunol Lett. 2021 Mar ;231:35-42. Epub 2021 Jan 8. PMID: 33428992 Abstract Title:  Hispolon inhibits RANKL induced osteoclast differentiation in vitro. Abstract:  Hispolon (HISP) is a bioactive compound isolated from Phellinu linteus. It has various pharmacological activities, including antioxidant, anti-inflammatory, and anti-cancer. However, its anti-osteoclastogenic activity has not yet been reported. Hence, in the current study, we have explored the anti-osteoclastogenic activity of HISP and elucidated the molecular mechanisms. HISP inhibited the RANKL induced differentiation of RAW 264.7 cells into osteoclasts in a dose-dependent manner. Mechanistic studies showed that HISP inhibited RANKL-mediated activation of NF-B and MAPK signaling pathways in osteoclast precursors RAW 264.7 cells. In addition, Hispolon also downregulated the expression of master transcriptional factors essential for osteoclast differentiation, such as NFATc1 and c-FOS. In conclusion, these findings establish molecular mechanisms behind the anti-osteoclastogenic activity of HISP.

PMID:  Int J Med Mushrooms. 2019 ;21(4):381-392. PMID: 31002633 Abstract Title:  Methyl-Hispolon from Phellinus lonicerinus (Agaricomycetes) Affects Estrogen Signals in MCF-7 Breast Cancer Cells and Premature Aging in Rats. Abstract:  We studied Phellinus lonicerinus to determine the cytotoxic effect and the dual estrogenic activities of methyl-hispolon and their relation to estrogen signals in vivo and in vitro. The Glide scores of methyl-hispolon-estrogen receptor(ER) and methyl-hispolon-ERdocked complexes were -7.29 kcal/mol and -6.68 kcal/mol in docking simulations. Methyl-hispolon had a significant antiproliferative effect for estrogen-sensitive ER(+) MCF-7 cells in the absence of estrogen, and it exhibited dual estrogen activities. Methyl-hispolon increased the serum E2 in rats with premature ovarian failure and fulfilled the estrogenic function in the uterus and ovary. Methyl-hispolon significantly inhibited the expression of Ras, API, ER, C-myc, and cyclinDl, as well as their gene transcription in RL95-2 cells. The phosphorylation of ERK1/2 was inhibited by methyl-hispolon. Thus, methyl-hispolon has potential use in treating estrogen deficiency-related diseases, with good antitumor effects and estrogenic activity.

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PMID:  Nutrients. 2023 Feb 2 ;15(3). Epub 2023 Feb 2. PMID: 36771459 Abstract Title:  Malvidin-3--Glucoside Ameliorates Cadmium-Mediated Cell Dysfunction in the Estradiol Generation of Human Granulosa Cells. Abstract:  Cadmium (Cd) is a frequent environmental pollutant associated with biological toxicity that can harm female reproduction. Anthocyanins have been reported to reduce the toxicity of Cd. In the present study, the protective effects and underlying mechanisms of malvidin-3--glucoside (M3G) against the toxicity of Cd on female reproduction in KGN cells (human ovarian granulosa-like tumor cells) were investigated. After treating cells with 10mol/L cadmium chloride, the results showed that M3G lessened Cd-induced KGN cell cytotoxicity better than malvidin and malvidin-3,5--diglucoside. Additionally, M3G significantly decreased the Cd-induced generation of reactive oxygen species, inhibited the Cd-induced arrest of the G2/M phase of the cell cycle, and increased estradiol (E2) production. According to transcriptomic results, M3G reduced the abnormal expression of genes that responded to estrogen. Additionally, M3G promoted the endogenous synthesis and secretion of E2 by controlling the expression of CYP17A1 and HSD17B7. The current findings indicated that M3G is of great potential to prevent Cd-induced female reproductive impairment as a dietary supplement.

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PMID:  Front Pharmacol. 2022 ;13:1038802. Epub 2023 Jan 9. PMID: 36699054 Abstract Title:  Malvidin alleviates mitochondrial dysfunction and ROS accumulation through activating AMPK-/UCP2 axis, thereby resisting inflammation and apoptosis in SAE mice. Abstract:  This study aimed to explore the protective roles of malvidin in life-threatened sepsis-associated encephalopathy (SAE) and illustrate the underlying mechanism. SAE mice models were developed and treated with malvidin for subsequently protective effects evaluation. Malvidin restored neurobehavioral retardation, declined serum S100and NSE levels, sustained cerebrum morphological structure, improved blood-brain barrier integrity with elevated tight junction proteins, and decreased evans blue leakage, and finally protect SAE mice from brain injury. Mechanistically, malvidin prevented cerebrum from mitochondrial dysfunction with enhanced JC-1 aggregates and ATP levels, and ROS accumulation with decreased lipid peroxidation and increased antioxidant enzymes. UCP2 protein levels were found to be decreased after LPS stimulation in the cerebrum and BV-2 cells, and malvidin recovered its levels in a ROS dependent manner.inhibition of UCP2 with genipin orinterference with siRNA UCP2 both disrupted the mitochondrial membrane potential, decreased ATP levels and intensified DCF signals, being a key target for malvidin. Moreover, dorsomorphin block assays verified that malvidin upregulated UCP2 expression through phosphorylating AMPK in SAE models. Also, malvidin alleviated SAE progression through inhibition of ROS-dependent NLRP3 inflammasome activation mediated serum pro-inflammatory cytokines secretion and mitochondrial pathway mediated apoptosis with weakened apoptosis body formation and tunel positive signals, and decreased Bax, cytochrome C, caspase-3 and increased Bcl-2 protein levels. Overall, this study illustrated that malvidin targeted AMPK-/UCP2 axis to restore LPS-induced mitochondrial dysfunction and alleviate ROS accumulation, which further inhibits NLRP3 inflammasome activation and mitochondrial apoptosis in a ROS dependent way, and ultimately protected SAE mice, providing a reference for the targeted development of SAE prophylactic approach.

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PMID:  Metabolites. 2022 Nov 3 ;12(11). Epub 2022 Nov 3. PMID: 36355145 Abstract Title:  Antiadhesive and Antibiofilm Effect of Malvidin-3-Glucoside and Malvidin-3-Glucoside/Neochlorogenic Acid Mixtures upon. Abstract:  Several reports on the biological activity of anthocyanin-rich extracts have been made. However, despite the association of said activity with their anthocyanin content, to the best of our knowledge, there are no previous works regarding the antimicrobial, antibiofilm and/or antiadhesive properties of anthocyanins alone. Therefore, the present work aimed to determine the effects of malvidin-3-glucoside, a major component of a previously reported extract, and the impact of its association with neochlorogenic acid (the only non-anthocyanin phenolic present in said extract), upon severalstrains with varying resistance profiles. Results show that, while malvidin-3-glucoside and malvidin-3-glucoside/neochlorogenic acid mixtures were unable to considerably inhibit bacterial growth after 24 h, they still possessed an interesting antibiofilm activity (with reductions of biofilm entrapped cells up to 2.5 log cycles, metabolic inhibition rates up to 81% and up to 51% of biomass inhibition). When considering the bacteria's capacity to adhere to plain polystyrene surfaces, the inhibition ranges were considerably lower (21% maximum value). However, when considering polystyrene surfaces coated with plasmatic proteins this value was considerably higher (45% for adhesion in the presence of extract and 39% for adhesion after the surface was exposed to extract). Overall, the studied anthocyanins showed potential as future alternatives to traditional antimicrobials in adhesion and biofilm formation prevention.

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PMID:  Eur J Pharmacol. 2022 Oct 15 ;933:175252. Epub 2022 Sep 2. PMID: 36063870 Abstract Title:  Malvidin protects against lipopolysaccharide-induced acute liver injury in mice via regulating Nrf2 and NLRP3 pathways and suppressing apoptosis and autophagy. Abstract:  Sepsis-related acute liver injury (ALI) is a fatal disease associated with many complications. Recent studies indicate that malvidin, an active flavonoid, has multiple bioactivities including anti-oxidant and anti-inflammation. However, the protective roles of malvidin against LPS-induced ALI are unknown. The purpose of this research is to explore whether malvidin has biological activities on LPS-induced ALI in mice and the underlying mechanisms. Male C57 mice were injected intraperitoneally with malvidin for five days and the mice were euthanized 6 h after LPS (10 mg/kg body weight) intraperitoneal injection. Multiple methods of H&E staining, biochemical kits, qRT-PCR assay, western blotting analysis, TUNEL and transmission electron microscope (TEM) were used. Results showed that decreased ALT, AST levels and alleviated histopathological damage of liver tissue were observed in malvidin pretreatment group in mice. Then, malvidin prevented LPS-induced reduction of antioxidant enzyme activities such as superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) via up-regulating nuclear factor E2-related factor2 (Nrf2) pathway. In addition, in malvidin pretreatment groups, mRNA levels of pro-inflammatory cytokines (TNF-IL-1, IL-6) and protein levels of NOD-like receptor protein 3 (NLRP3) inflammasome in the liver were significantly down-regulated. We also found that the malvidin could reduce the expression of apoptosis key protein and TUNEL-labeled apoptotic hepatocytes. Furthermore, malvidin inhibited the protein expression of ATG5, p62 and the ratio of LC3-II/LC3-I. In conclusion, our study firstly suggests that malvidin is a potentially protective agent against LPS-induced ALI through up-regulating Nrf2 signaling pathway, suppressing NLRP3 inflammasome and inhibiting apoptosis and autophagy.

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PMID:  J Sci Food Agric. 2023 Jul ;103(9):4638-4648. Epub 2023 Mar 31. PMID: 36935348 Abstract Title:  Blueberry extract alleviated lipopolysaccharide-induced inflammation responses in mice through activating the FXR/TGR5 signaling pathway and regulating gut microbiota. Abstract:  BACKGROUND: Blueberry extract (BE) is rich in phenols, especially anthocyanins. Anthocyanins regulate the inflammatory response in mice and may be related to gut microbiota and bile acid receptors. The aim of the present study was to explore the effects of BE on the inflammatory response by regulating gut microbiota and bile acid receptors in mice administered Escherichia coli lipopolysaccharide (LPS).METHOD: Thirty male KM mice were randomly divided into three groups: CON (control diet) group; LPS (LPS stimulation) group; and LPS+BE (LPS stimulation, 5% BE intervention) group.RESULTS: our results showed that, compared with the LPS group, the addition of BE decreased the level of inflammatory factors in serum and tissues, inhibited the TLR4/MyD88 signaling pathway, protected the intestinal barrier and activated FXR/TGR5, which was related to gut microbiota (especially Akkermansia). The active component (e.g., cyanidin 3-O-glucoside, C3G) in BE may be an important factor in regulating gut microbiota.CONCLUSION: BE alleviated the inflammatory response mainly by activating bile acid receptor expression and regulating the gut microbiota; this effect may be related to the composition of bioactive substances in BE.2023 Society of Chemical Industry.

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PMID:  Eur J Med Res. 2022 Nov 28 ;27(1):267. Epub 2022 Nov 28. PMID: 36437468 Abstract Title:  The combination of olive oil and Lepidium sativum improves the deleterious effects resulting from dexamethasone-induced osteoporosis in rats. Abstract:  INTRODUCTION: Osteoporosis is characterized by deterioration of bone microarchitecture and reduced bone mass and can increase the risk of fracture. To reduce this risk, the aim of this study was to compare the combination effects of olive oil and Lepidium sativum compared to the conventional drug therapy alendronate.METHODS: Osteoporosed-induced rat model was established by administration of dexamethasone in female adult albino rats. The serum level of Ca, P, and osteocalcin was assessed. In addition, histopathological changes and immunohistochemical expression of osteopontin within bone specimens were performed.RESULTS: Our results showed that a combination of olive oil and Lepidium sativum had a beneficial therapeutic effect in the treatment of osteoporosis as compared to alendronate therapy. This was demonstrated by increase of serum Ca, P, and osteocalcin levels in treated compared to control groups. Intriguingly, the highest effect was noticed in rats that received a combination of olive oil and Lepidium sativum compared to the individual treatment. This was reflected by an increase in the cortical bone thickness and a decrease in immunohistochemical expression of osteopontin compared to individual treated groups.CONCLUSION: We concluded that the administration of a combination of olive oil and Lepidium sativum improves bone mineral health and intensity and reduces the risk of osteoporosis in a rat model.

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PMID:  Nutrients. 2023 Mar 9 ;15(6). Epub 2023 Mar 9. PMID: 36986069 Abstract Title:  Effects of Wild Blueberries on Fat Oxidation Rates in Aerobically Trained Males. Abstract:  Wild blueberries (WBs) have been documented to decrease oxidative stress in active and sedentary populations as well as influence lipolytic enzymes and increase the rate of fat oxidation (FAT-ox) during rest. To examine the effect of WBs on the rate of FAT-ox and lipid peroxidation during submaximal exercise, 11 healthy, aerobically trained males (267.5 years, 74.97.54 kg, 10.53.2% BF) completed a 2-week washout avoiding foods high in anthocyanins, then completed a control exercise protocol cycling at 65% of VOfor 40 min. Participants then consumed 375 g/d of anthocyanins for two weeks before repeating the exercise protocol. WBs increased FAT-ox when cycling at 65% of VOby 19.7% at 20, 43.2% at 30, and 31.1% at 40 min, and carbohydrate oxidation (CHO-ox) decreased by 10.1% at 20, 19.2% at 30, and 14.8% at 40 min of cycling at 65% of VO. Lactate was lower with WBs at 20 (WB: 2.61.0, C: 3.01.1), 30 (WB: 2.20.9, C: 2.91.0), and 40 min (WB: 1.90.8, C: 2.50.9). Results indicate that WBs may increase the rate of FAT-ox during moderate-intensity activity in healthy, active males.

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PMID:  Molecules. 2023 Mar 22 ;28(6). Epub 2023 Mar 22. PMID: 36985822 Abstract Title:  The Extraction and High Antiproliferative Effect of Anthocyanin from Gardenblue Blueberry. Abstract:  Blueberries are rich in flavonoids, anthocyanins, phenolic acids, and other bioactive substances. Anthocyanins are important functional components in blueberries. We collected 65 varieties of blueberries to investigate their nutritional and functional values. Among them, Gardenblue had the highest anthocyanin content, with 2.59 mg/g in fresh fruit. After ultrasound-assisted solvent extraction and macroporous resin absorption, the content was increased to 459.81 mg/g in the dried powder. Biological experiments showed that Gardenblue anthocyanins (L) had antiproliferative effect on cervical cancer cells (Hela, 51.98g/mL), liver cancer cells (HepG2, 23.57g/mL), breast cancer cells (MCF-7, 113.39g/mL), and lung cancer cells (A549, 76.10g/mL), and no apparent toxic effects were indicated by methyl thiazolyl tetrazolium (MTT) assay, especially against HepG2 cells both in vitro and in vivo. After combining it with DDP (cisplatin) and DOX (doxorubicin), the antiproliferative effects were enhanced, especially when combined with DOX against HepG2 cells; the ICvalue was 0.02g/mL. This was further evidence that Lcould inhibit cell proliferation by inducing apoptosis. The detailed mechanism might be Linteracting with DNA in an intercalation mode that changes or destroys DNA, causing apoptosis and inhibiting cell proliferation. The findings of this study suggest that Lextract can be used as a functional agent against hepatoma carcinoma cells.

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PMID:  Am J Clin Nutr. 2023 Jun ;117(6):1306-1319. Epub 2023 Mar 25. PMID: 36972800 Abstract Title:  Wild blueberry (poly)phenols can improve vascular function and cognitive performance in healthy older individuals: a double-blind randomized controlled trial. Abstract:  BACKGROUND: Evidence suggests that the intake of blueberry (poly)phenols is associated with improvements in vascular function and cognitive performance. Whether these cognitive effects are linked to increases in cerebral and vascular blood flow or changes in the gut microbiota is currently unknown.METHODS: A double-blind, parallel randomized controlled trial was conducted in 61 healthy older individuals aged 65-80 y. Participants received either 26 g of freeze-dried wild blueberry (WBB) powder (302 mg anthocyanins) or a matched placebo (0 mg anthocyanins). Endothelial function measured by flow-mediated dilation (FMD), cognitive function, arterial stiffness, blood pressure (BP), cerebral blood flow (CBF), gut microbiome, and blood parameters were measured at baseline and 12 wk following daily consumption. Plasma and urinary (poly)phenol metabolites were analyzed using microelution solid-phase extraction coupled with liquid chromatography-mass spectrometry.RESULTS: A significant increase in FMD and reduction in 24 h ambulatory systolic BP were found in the WBB group compared with the placebo group (0.86%; 95% CI: 0.56, 1.17, P

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PMID:  J Chem Neuroanat. 2023 Jul ;130:102260. Epub 2023 Mar 24. PMID: 36965643 Abstract Title:  The effects of curcumin and blueberry on axonal regeneration after peripheral nerve injury. Abstract:  The purpose of this study was to analyze the axonal regeneration and therapeutic effects of curcumin and blueberry administration following peripheral nerve injury using stereological, electron microscopic and electrophysiological methods. Animals in were assigned into one of four groups - control (Cont), injury (Inj), injury+curcumin (Cur) and injury+blueberry (Blue). Following the induction of sciatic nerve crush injury (75 Newtons for 5 s) in the Inj, Cur, and Blue groups, the rats in the Cur group received intraperitoneal injection of 30 mg/kg curcumin (Sigma C1386) and the rats in the Blue group received 4 g/kg blueberry by gavage over a four-week period. The rats in the Cont and Inj groups were not exposed to any substance. All animals were given standard chow. Sciatic functional index analyses were performed on the 14th and 28th days after injury, and electromyography (EMG) results were recorded. Stereological analysis of the nerve was performed under light microscopy. Light and electron microscopies were used for the histopathological evaluation of the sciatic nerve. Analysis of myelinated axon numbers revealed no significant differences between the Inj group and the Cur and Blue groups. However, a significant difference was observed between the Blue and Inj groups in terms of axonal areas. EMG test results differed between the Blue and the Inj groups (p 

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PMID:  Inflammopharmacology. 2023 Jan 20. Epub 2023 Jan 20. PMID: 36662400 Abstract Title:  Pterostilbene attenuates hemin-induced dysregulation of macrophage M2 polarization via Nrf2 activation in experimental hyperglycemia. Abstract:  Macrophages exhibit a high degree of plasticity that is physiologically relevant in wound healing, and disruption in normal macrophage response leads to delayed wound closure resulting in chronic wounds. Here, we attempt to discern macrophage responses to hemin via regulation of the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) that could help us better understand the pathophysiology of diabetic foot ulcers (DFU). We demonstrate the alleviation of hemin-mediated Nrf2 suppression and M2 macrophage polarization by pterostilbene (PTS), a proven Nrf2 activator. IC-21 macrophages were treated with hemin under the normoglycemic or hyperglycemic environment with or without PTS and the expression levels of various markers, such as Nrf2 and its downstream target Heme Oxygenase-1 (HO-1), CD206, Ferroportin-1 among others were analyzed using qPCR and Western blot. Our results revealed that hemin under hyperglycemia reduced Nrf2 activation and its downstream targets, M2 polarization, and the induction of a proinflammatory cellular environment, and interestingly all of these were remedied by PTS treatment. Gelatin zymography of matrix metalloproteinase2 (MMP2) expression revealed that hemin under hyperglycemic condition significantly elevated MMP2 expression, which was reversed by PTS treatment. Further proteomic analysis using liquid chromatography with tandem mass spectrometry (LC-MS/MS) revealed a heightened cellular stress profile accompanying inflammation that was suppressed by PTS. This study has furthered our understanding on the role of Nrf2 in attenuating hemin-induced perturbations in macrophage responses and suggests a potential therapeutic target in the management of DFU.

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PMID:  Mol Pharm. 2023 Feb 6 ;20(2):1189-1201. Epub 2023 Jan 16. PMID: 36647568 Abstract Title:  Pterostilbene-Loaded Soluplus/Poloxamer 188 Mixed Micelles for Protection against Acetaminophen-Induced Acute Liver Injury. Abstract:  Excessive acetaminophen (APAP) induces excess reactive oxygen species (ROS), leading to liver damage. Pterostilbene (PTE) has excellent antioxidant and anti-inflammatory activities, but poor solubility limits its biological activity. In this study, we prepared PTE-loaded Soluplus/poloxamer 188 mixed micelles (PTE-MMs), and the protective mechanism against APAP-induced liver injury was investigated. In vitro results showed that PTE-MMs protected HO-induced HepG2 cell proliferation inhibition, ROS accumulation, and mitochondrial membrane potential destruction. Immunofluorescence results indicated that PTE-MMs significantly inhibited HO-induced DNA damage and cGAS-STING pathway activation. For in vivo protection studies, PTE-MMs (25 and 50 mg/kg) were administered orally for 5 days, followed by APAP (300 mg/kg). The results showed that APAP significantly induced injury in liver histopathology as well as an increase in serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, the above characteristics of APAP-induced acute liver injury were inhibited by PTE-MMs. In addition, APAP-induced changes in the activities of antioxidant enzymes such as SOD and GSH in liver tissue were also inhibited by PTE-MMs. Immunohistochemical results showed that PTE-MMs inhibited APAP-induced DNA damage and cGAS-STING pathway activation in liver tissues. For in vivo therapeutic effect study, mice were first given APAP (300 mg/kg), followed by oral administration of PTE-MMs (50 mg/kg) for 3 days. The results showed that PTE-MMs exhibited promising therapeutic effects on APAP-induced acute liver injury. In conclusion, our study shows that the Soluplus/poloxamer 188 MM system has the potential to enhance the biological activity of PTE in the protection and therapeutic of liver injury.

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PMID:  Nutr Neurosci. 2023 Feb ;26(2):127-137. Epub 2022 Jan 4. PMID: 36692990 Abstract Title:  Blueberry treatment administered before and/or after lipopolysaccharide stimulation attenuates inflammation and oxidative stress in rat microglial cells. Abstract:  Microglia are key regulators of inflammation and oxidative stress (OS) in the CNS. Microglia activation can lead to chronic inflammation, OS, and neurodegeneration. Blueberries (BB) reduce inflammation and OS when administered to microglia before stressors such as lipopolysaccharide (LPS), but the therapeutic value of BBs administered after activation by stressors has not been examined. Therefore, this study investigated the differential effects of pre-, post-, and pre-/post-BB on inflammation and OS in LPS-activated microglia. Rat microglia were pretreated with BB (0.5 mg/mL) or control media (C) for 24 hours, incubated overnight with LPS (0 or 200 ng/mL), and post-treated with BB or C for 24 hours. Biomarkers of inflammation (e.g. nitrite [NO], tumor necrosis factor-[TNF], inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX-2], phosphorylated IB-[pIB-]) and OS (e.g. NADPH oxidase [NOX2]) were assessed. LPS increased NO, TNF, COX-2, iNOS, pIB-, and NOX2 compared to non-stressed conditions (

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