PMID:  Antioxidants (Basel). 2023 Mar 3 ;12(3). Epub 2023 Mar 3. PMID: 36978880 Abstract Title:  Antioxidant and Anti-Tumor Effects of Dietary Vitamins A, C, and E. Abstract:  Oxidative stress, a condition characterized by an imbalance between pro-oxidant molecules and antioxidant defense systems, is increasingly recognized as a key contributor to cancer development. This is because the reactive oxygen species (ROS) generated during oxidative stress can damage DNA, proteins, and lipids to facilitate mutations and other cellular changes that promote cancer growth. Antioxidant supplementation is a potential strategy for decreasing cancer incidence; by reducing oxidative stress, DNA damage and other deleterious cellular changes may be attenuated. Several clinical trials have been conducted to investigate the role of antioxidant supplements in cancer prevention. Some studies have found that antioxidant supplements, such as vitamin A, vitamin C, and vitamin E, can reduce the risk of certain types of cancer. On the other hand, some studies posit an increased risk of cancer with antioxidant supplement use. In this review, we will provide an overview of the current understanding of the role of oxidative stress in cancer formation, as well as the potential benefits of antioxidant supplementation in cancer prevention. Additionally, we will discuss both preclinical and clinical studies highlighting the potentials and limitations of preventive antioxidant strategies.

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PMID:  Antioxidants (Basel). 2023 Feb 25 ;12(3). Epub 2023 Feb 25. PMID: 36978824 Abstract Title:  Low Levels of Vitamin C during Pregnancy; a Risk Marker of Progression of Diabetic Retinopathy in Type 1 Diabetic Women? Abstract:  Pregnancy is a risk factor for the development or aggravation of diabetic retinopathy. Here, we suggest a relationship between plasma vitamin C (vitC) status during pregnancy and into postpartum in type 1 diabetes and the possible progression of diabetic retinopathy based on data of 29 women. VitC was measured in first, second, and third trimesters and three months postpartum. The women had visual acuity testing and fundus photography performed at least twice during pregnancy and onto four months after birth. An overall retinopathy grade was assigned on a scale from 0 (no retinopathy) to four according to the International Clinical Diabetic Retinopathy scale. At baseline in 1st trimester, 12 women had no retinopathy; seventeen women had retinopathy in grade 1-3. The retinopathy grade increased in nine women; remained unchanged in 17 women, and improved in three women. No women had or developed proliferative retinopathy (grade 4). The level of vitC in 1st trimester predicted the possible progression of retinopathy-the lower the vitC, the more probable the progression (= 0.03; OR 1.6 (95% CI:1.06-3.2);= 29 (multiple logistic regression))-while the combined levels of 1st and 2nd trimesters and the mean vitC level of the whole pregnancy did not. The diabetes duration, retinopathy grade per se in 1st trimester, 24-h blood pressure measurements, kidney function, urinary protein, HbA1c, or lipid profile were not independent predictors of progression of retinopathy during pregnancy. Retrospectively, the women who experienced progression of their retinopathy during and into postpartum had significantly lower vitC levels in 1st trimester (= 0.02;= 9/20), combined level of vitC in 1st and 2nd trimester (= 0.032;= 7/18), and mean vitC level of the whole pregnancy (= 0.036;= 7/9), respectively. In conclusion, our results suggest that low vitC status in pregnancy could be associated with progression of diabetic retinopathy.

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PMID:  Sci Rep. 2017 Mar 21 ;7:44815. Epub 2017 Mar 21. PMID: 28322293 Abstract Title:  Tea polyphenols inhibit the growth and virulence properties of Fusobacterium nucleatum. Abstract:  Fusobacterium nucleatum plays a key role in creating the pathogenic subgingival biofilm that initiates destructive periodontitis. It is also a common resident of the human gastrointestinal tract and has been associated with inflammatory bowel disease. The aim of the present study was to investigate the effects of green and black tea extracts as well as two of their bioactive components, EGCG and theaflavins, on the growth and virulence properties of F. nucleatum. The tea extracts and components displayed various degrees of antibacterial activity that may involve damage to the bacterial cell membrane and the chelation of iron. They also prevented biofilm formation by F. nucleatum at concentrations that did not interfere with bacterial growth. In addition, the treatment of a pre-formed F. nucleatum biofilm with the green tea extract and EGCG caused a time-dependent decrease in biofilm viability. The green and black tea extracts, EGCG, and theaflavins decreased the adherence of F. nucleatum to oral epithelial cells and matrix proteins. Moreover, these tea components also attenuated F. nucleatum-mediated hemolysis and hydrogen sulfide production, two other virulence factors expressed by this bacterium. In summary, this study showed that tea polyphenols may be of interest for treating F. nucleatum-associated disorders.

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PMID:  Front Nutr. 2023 ;10:1110405. Epub 2023 Mar 6. PMID: 36969825 Abstract Title:  Can plasma vitamin C predict survival in stage IV colorectal cancer patients? Results of a prospective cohort study. Abstract:  BACKGROUND AND AIMS: In light of the inconclusive evidence on the association between vitamin C status and colorectal cancer (CRC) outcome, this study assessed the prognostic value of vitamin C in participants with metastatic CRC (mCRC).METHODS: Adults with mCRC and cancer-free controls were recruited in this prospective cohort study to allow for comparison of vitamin C levels with healthy individuals from the same population. Sociodemographic, lifestyle, medical variables, BRAF and KRAS mutations, as well as Vitamin C plasma level and food intake were evaluated. Predictors of diminished vitamin C level were assessedmultivariate logistic regression. Mortality and progression free survival (PFS) among mCRC participants were analyzed based on plasma vitamin C level.RESULTS: The cancer group (=46) was older (mean age: 6014 vs. 429.6,=0.047) and included more males (29% vs. 19%,

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PMID:  Nutr Neurosci. 2023 Mar 24:1-13. Epub 2023 Mar 24. PMID: 36961747 Abstract Title:  Vitamin C, vitamin E,-carotene and risk of Parkinson's disease: a systematic review and dose-response meta-analysis of observational studies. Abstract:  OBJECTIVE: This study aimed to explore the relationship between the intake of vitamin C, vitamin E and-carotene, and the risk of Parkinson's disease (PD).METHODS: Web of Science, Embase, PubMed, Cochrane library, CNKI, and WanFang databases were searched from inception to 29 August 2022 for observational studies reporting the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) and 95% confidence intervals (CIs) of PD by Vitamin C/Vitamin E/-carotene intake. Random-effects models, publication bias assessment, subgroup, sensitivity and dose-response analyses were were included. There was no significant association between high-dose vitamin C intake and the risk of PD compared with low-dose vitamin C intake (RR=0.98, 95%CI:0.89,1.08). Compared with low-dose intake, high-dose intake of vitamin E can prevent the risk of PD (RR=0.87, 95%CI:0.77,0.99). Compared with lower-carotene intake, there was a borderline non-significant correlation between higher intake and PD risk (RR=0.91, 95%CI:0.82,1.01), and high dose-carotene intake was found to be associated with a lower risk of PD in women (RR=0.78, 95%CI:0.64,0.96).CONCLUSION: This study shows that vitamin E intake can reduce the risk of PD and play a preventive role.

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PMID:  Pharmaceuticals (Basel). 2023 Mar 2 ;16(3). Epub 2023 Mar 2. PMID: 36986484 Abstract Title:  The Role of Tocotrienol in Arthritis Management-A Scoping Review of Literature. Abstract:  Arthritis is a cluster of diseases impacting joint health and causing immobility and morbidity in the elderly. Among the various forms of arthritis, osteoarthritis (OA) and rheumatoid arthritis (RA) are the most common. Currently, satisfying disease-modifying agents for arthritis are not available. Given the pro-inflammatory and oxidative stress components in the pathogenesis of arthritis, tocotrienol, a family of vitamin E with both anti-inflammatory and antioxidant properties, could be joint-protective agents. This scoping review aims to provide an overview of the effects of tocotrienol on arthritis derived from the existing scientific literature. A literature search using PubMed, Scopus and Web of Science databases was conducted to identify relevant studies. Only cell culture, animal and clinical studies with primary data that align with the objective of this review were considered. The literature search uncovered eight studies investigating the effects of tocotrienol on OA= 4) and RA (= 4). Most of the studies were preclinical and revealed the positive effects of tocotrienol in preserving joint structure (cartilage and bone) in models of arthritis. In particular, tocotrienol activates the self-repair mechanism of chondrocytes exposed to assaults and attenuates osteoclastogenesis associated with RA. Tocotrienol also demonstrated strong anti-inflammatory effects in RA models. The single clinical trial available in the literature showcases that palm tocotrienol could improve joint function among patients with OA. In conclusion, tocotrienol could be a potential anti-arthritic agent pending more results from clinical studies.

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PMID:  Diabetes Obes Metab. 2023 Jul ;25(7):1985-1994. Epub 2023 Apr 20. PMID: 36999233 Abstract Title:  Astaxanthin, a natural antioxidant, lowers cholesterol and markers of cardiovascular risk in individuals with prediabetes and dyslipidaemia. Abstract:  AIM: To determine the effects of astaxanthin treatment on lipids, cardiovascular disease (CVD) markers, glucose tolerance, insulin action and inflammation in individuals with prediabetes and dyslipidaemia.MATERIALS AND METHODS: Adult participants with dyslipidaemia and prediabetes (n=34) underwent baseline blood draw, an oral glucose tolerance test and a one-step hyperinsulinaemic-euglycaemic clamp. They were then randomized (n=22 treated, 12 placebo) to receive astaxanthin 12mg daily or placebo for 24weeks. Baseline studies were repeated after 12 and 24weeks of therapy.RESULTS: After 24weeks, astaxanthin treatment significantly decreased low-density lipoprotein (-0.330.11mM) and total cholesterol (-0.300.14mM) (both P

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PMID:  Toxins (Basel). 2023 Mar 21 ;15(3). Epub 2023 Mar 21. PMID: 36977123 Abstract Title:  Astaxanthin Alleviates Aflatoxin B1-Induced Oxidative Stress and Apoptosis in IPEC-J2 Cells via the Nrf2 Signaling Pathway. Abstract:  Aflatoxin B1 (AFB1), a typical fungal toxin found in feed, is highly carcinogenic. Oxidative stress is one of the main ways it exerts its toxicity; therefore, finding a suitable antioxidant is the key to reducing its toxicity. Astaxanthin (AST) is a carotenoid with strong antioxidant properties. The aim of the present research was to determine whether AST eases the AFB1-induced impairment in IPEC-J2 cells, and its specific mechanism of action. AFB1 and AST were applied to IPEC-J2 cells in different concentrations for 24 h. The AST (80M) significantly prevented the reduction in the IPEC-J2 cell viability that was induced by AFB1 (10M). The results showed that treatment with AST attenuated the AFB1-induced ROS, and cytochrome C, the Bax/Bcl2 ratio, Caspase-9, and Caspase-3, which were all activated by AFB1, were among the pro-apoptotic proteins which were diminished by AST. AST activates the Nrf2 signaling pathway and ameliorates antioxidant ability. This was further evidenced by the expression of the HO-1, NQO1, SOD2, and HSP70 genes were all upregulated. Taken together, the findings show that the impairment of oxidative stress and apoptosis, caused by the AFB1 in the IPEC-J2 cells, can be attenuated by AST triggering the Nrf2 signaling pathway.

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PMID:  Biomedicines. 2023 Mar 22 ;11(3). Epub 2023 Mar 22. PMID: 36979970 Abstract Title:  Vitamin A Deficiency and Its Association with Visceral Adiposity in Women. Abstract:  Body adiposity is associated with increased metabolic risk, and evidence indicates that vitamin A is important in regulating body fat. The aim of this study was to evaluate serum concentrations of vitamin A and its association with body adiposity in women with the recommended intake of vitamin A. A cross-sectional study was designed with 200 women divided into four groups according to Body Mass Index (BMI): normal weight (NW), overweight (OW), class I obesity (OI), and class 2 obesity (OII). The cut-off points to assess inadequate participants were retinol

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PMID:  bioRxiv. 2023 Mar 10. Epub 2023 Mar 10. PMID: 36945561 Abstract Title:  -carotene accelerates resolution of atherosclerosis by promoting regulatory T cell expansion in the atherosclerotic lesion. Abstract:  -carotene oxygenase 1 (BCO1) catalyzes the cleavage of-carotene to form vitamin A. Besides its role in vision, vitamin A regulates the expression of genes involved in lipid metabolism and immune cell differentiation. BCO1 activity is associated with the reduction of plasma cholesterol in humans and mice, while dietary-carotene reduces hepatic lipid secretion and delays atherosclerosis progression in various experimental models. Here we show that-carotene also accelerates atherosclerosis resolution in two independent murine models, independently of changes in body weight gain or plasma lipid profile. Experiments inmice implicate vitamin A production in the effects of-carotene on atherosclerosis resolution. To explore the direct implication of dietary-carotene on regulatory T cells (Tregs) differentiation, we utilized anti-CD25 monoclonal antibody infusions. Our data show that-carotene favors Treg expansion in the plaque, and that the partial inhibition of Tregs mitigates the effect of-carotene on atherosclerosis resolution. Our data highlight the potential of-carotene and BCO1 activity in the resolution of atherosclerotic cardiovascular disease.

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PMID:  Sleep Med. 2023 Jul ;107:149-156. Epub 2023 Apr 20. PMID: 37178546 Abstract Title:  Effect of yoga-based lifestyle and dietary modification in overweight individuals with sleep apnea: A randomized controlled trial (ELISA). Abstract:  BACKGROUND: Obesity is recognised as an important risk factor for obstructive sleep apnea (OSA), with obese individuals at a four times higher risk of being diagnosed with the syndrome. Treating obesity with lifestyle modification is associated with a reduction in the severity of obstructive sleep apnea. Yoga comprises lifestyle modification that includes asana (postures), pranayama (breathing techniques), dhyana (meditation) and guideline principles for healthy living (Yama and Niyama). There is a scarcity of data to evaluate the effect of yoga on OSA. This study was conducted to evaluate the efficacy of Yoga based lifestyle modification on OSA.METHODS: Consenting obese patients (BMI>23) diagnosed with obstructive sleep apnea (OSA) (AHI>5) on Polysomnography (PSG) were enrolled. Eligible patients were randomized into two groups. The control group received counselling for dietary modification (staple Indian) with regular exercise and the active intervention group received Yoga intervention as treatment (OSA module) in addition to similar dietary modification and regular exercise counselling. Polysomnography (PSG) was conducted at baseline and one year follow-up. All patients were evaluated at baseline, six months, and one year for compliance and anthropometric parameters. Additional assessment with Hamilton scales for depression and anxiety, SF-36, and the Pittsburgh sleep quality index was also conducted.RESULTS: A total of 37 eligible patients (19 in the control group and 18 in the yoga group) were recruited for the study. The age [45.73  10.71 vs. 46.22  9.39 years, p = 0.88] and gender [15(78.95%) vs. 12(66.67%), p = 0.48 (males)] distribution was similar in both groups. After adjusting for age and gender, the percentage reduction in weight between the two groups did not reach statistical significance at one year. There was no significant difference in mean AHI between the two groups at one year. However, the number of patients with more than 40% AHI reduction [2/19 (10.52%) vs 8/18 (44.44%), p = 0.02] was significantly higher in the yoga group. Additionally, within the groups, the mean AHI at one year was significantly reduced in the yoga group [51.2  28.0 to 36.8  21.0/hour, p = 0.003], while no significant change was found in the control group [47.2  23 to 38.8  19.9/hour, p = 0.08].CONCLUSIONS: Lifestyle alteration using Yoga intervention and modification of staple Indian diet may be effective in reducing OSA severity among obese patients.CTRI NUMBER: CTRI/2017/05/008462.

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PMID:  J Ayurveda Integr Med. 2023 May 20 ;14(3):100715. Epub 2023 May 20. PMID: 37216873 Abstract Title:  Adjuvant yoga therapy for symptom management of functional dyspepsia: A case series. Abstract:  Functional Dyspepsia (FD), commonly called chronic indigestion, comes under the umbrella of 'Disorders of Gut-Brain Axis'. It manifests as a cluster of upper gastrointestinal symptoms including epigastric pain or burning, postprandial fullness and early satiety. Since the pathophysiology is complex, it is often difficult to effectively manage and significantly impacts the patient's quality of life. This case series aims to elucidate the role of Yoga as an adjuvant therapy to modern medicine in providing relief of dyspeptic symptoms in such patients. Yoga is an ancient Indian mind-body practise that has the potential to be used for various brain-gut disorders. Apart from treating the gut disorders from top down (mind-gut) pathway, it may have more direct physiological effects as well. Researches on IBS and one research on abdominal pain related FGID have shown Yoga therapy to be effective in ameliorating the symptoms. In this study, we present three such cases (1 male and 2 female) having a clinical diagnosis of FD in detail. These patients were initially non-responsive to medications but later showed remarkable improvement in symptoms within one month of added Yoga therapy intervention. This study was conducted as a part of a larger study conducted at a tertiary hospital in Pondicherry in collaboration between its Yoga department and Medical Gastroenterology Department. Yoga therapy protocol was given along with their regular medical management for a month. Gastrointestinal Symptom Rating Scale (GSRS) and Dyspepsia Symptom Score questionnaires were used to assess symptoms before and after the intervention period. All three patients showed marked reductions in symptom scores both in the GSRS and Dyspepsia Questionnaire. The present case series suggests effect of adjuvant Yoga therapy in reducing symptoms of functional dyspepsia. Future studies may clarify the psycho-physiological basis of the same.

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PMID:  J Integr Complement Med. 2023 May 31. Epub 2023 May 31. PMID: 37257184 Abstract Title:  The Effects of Tele-Yoga in Ankylosing Spondylitis Patients: A Randomized Controlled Trial. Abstract:  This randomized controlled trial aimed at investigating the effects of tele-yoga on physical function, disease activity, spinal mobility, flexibility, muscular endurance, exercise capacity, balance, sleep quality, stress, depression, anxiety, quality of life (QoL), and mindfulness in patients with ankylosing spondylitis (AS).Sixty patients with AS were randomly assigned to the tele-yoga group (TYG) or wait-list control group (CG). In addition to their medical treatments, TYG participants attended online yoga classes three times per week for 8 weeks. The CG continued their standard medical treatment. Data were collected at baseline and after 8 weeks. The primary outcome measure was physical function as assessed by the Bath AS Functional Index (BASFI). Secondary outcome measures included the Bath AS Disease Activity Index (BASDAI), Bath AS Patient Global Score (BAS-G), Assessment of SpondyloArthritis International Society Health Index (ASAS HI), Bath AS Metrology Index (BASMI), sit-and-reach test, sit-up test, push-up test, incremental shuttle walk test, Balance Master test, Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), Perceived Stress Scale (PSS), 36-Item Short Form Health Survey (SF-36), and Mindful Attention Awareness Scale (MAAS).Compared with the CG (=27), participants in the TYG (=28) demonstrated significant improvements in BASFI (=0.001). The TYG also showed significant improvements in disease activity, spinal mobility, flexibility, muscular endurance, balance, sleep quality, stress, depression, and QoL compared with the CG (

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PMID:  Asian J Psychiatr. 2023 May 24 ;86:103636. Epub 2023 May 24. PMID: 37290243 Abstract Title:  Effects of a six-month yoga intervention on the immune-inflammatory pathway in antipsychotic-stabilized schizophrenia patients: A randomized controlled trial. Abstract:  BACKGROUND: Schizophrenia is a complex neuropsychiatric disorder for which several etiopathological theories have been proposed, one of the prominent ones being immune dysfunction. Recent studies on yoga as an add-on therapy have shown improvement in negative symptoms, cognition, and quality of life in schizophrenia patients. However, the biological mechanism/s of action of yoga in schizophrenia are not clear. The current study was aimed at exploring the effects of long-term (6 months) add-on yoga therapy on the immune inflammatory pathway in schizophrenia patients.METHODS: Sixty schizophrenia patients were randomized to add-on yoga therapy (YT=30) and treatment-as-usual (TAU=30) groups of which 21 patients in YT and 20 in TAU group completed the study. Blood samples and clinical assessments were obtained at baseline and at the end of 6 months. The plasma levels of nine cytokines (IL-2, IL-4, IL-5, IL-10, IL-12(p70), IL-13, GM-CSF, IFN-, and TNF-) were quantified using multiplex suspension array. The clinical assessments included SAPS, SANS, BPRS, PSS, CGI, SOFS and WHOQUOL-BREF.RESULTS: Patients in the yoga group showed significant reductions in plasma TNF-(Z = 2.99, p = 0.003) and IL-5 levels (Z = 2.20, p = 0.03) and greater clinical improvements in SAPS, SANS, PSS, and SOFS scores as compared to TAU group. Further, plasma TNF-levels exhibited a positive correlation with negative symptoms (r=0.45, p = 0.02) and socio-occupational functioning (r=0.61, p = 0.002) in the YT group.CONCLUSIONS: The findings of the study suggest that improvements in schizophrenia psychopathology with yoga interventions are associated with immuno-modulatory effects.

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PMID:  J Behav Med. 2023 Jun 9. Epub 2023 Jun 9. PMID: 37294473 Abstract Title:  Yoga practice can reduce metabolic syndrome and cardiovascular risk in climacteric women. Abstract:  To evaluate the effect of yoga on the frequency of MetS and its impact on cardiovascular risk markers in climacteric women. We recruited 84 sedentary women between 40 and 65 years diagnosed with MetS. Participants were randomly assigned to a 24-week yoga intervention or control group. We evaluated the frequency of MetS and changes in the individual components of MetS at baseline and after 24 weeks. We also assessed the impact of yoga practices on cardiovascular risk through the following markers: High-sensitivity C-reactive Protein (hs-CRP), Lipid Accumulation Product (LAP), Visceral Adiposity Index (VAI), and Atherogenic Index of Plasma (AIP). The frequency of MetS reduced significantly after 24 weeks of yoga practice (-34.1%; p

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PMID:  Heliyon. 2023 May ;9(5):e16340. Epub 2023 May 17. PMID: 37251906 Abstract Title:  Potential effects of bisphenol A on diabetes mellitus and its chronic complications: A narrative review. Abstract:  Diabetes mellitus (DM) is a metabolic disease caused by multiple factors such as genetics, environment, and lifestyle. Bisphenol A (BPA), as one of the most common endocrine-disrupting chemicals (EDCs), has been strongly implicated in the development of type 2 diabetes mellitus (T2DM). BPA exposure is associated with target organ damage in DM and may exacerbate the progression of some chronic complications of DM. This paper reviews relevant epidemiological, in vivo, and in vitro studies to better understand BPA's potential risk associations and pathological mechanisms in several chronic diabetic complications.

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PMID:  Sci Total Environ. 2023 Jun 10:164748. Epub 2023 Jun 10. PMID: 37308018 Abstract Title:  Bisphenol P and bisphenol M promote triple-negative breast cancer metastasis through activation of AKT pathways. Abstract:  Bisphenol P (BPP) and bisphenol M (BPM) are increasing in our living environment as analogues of bisphenol A (BPA), but little is known about their biological effect. In this study, we investigated the effects of low to medium dose exposure of BPP and BPM on triple negative breast cancer (TNBC). We found that BPP and BPM exposure didn't affect proliferation of TNBC cell lines MDA-MB-231 and 4T1, but significantly promoted cells migration and invasion. The effect of BPP and BPM on promoting TNBC metastasis was further confirmed in mouse models. Low concentrations of BPP and BPM significantly increased the expression of epithelial-mesenchymal transition (EMT) marker and related proteins such as N-cadherin, MMP-9, MMP-2 and Snail, and also enhanced phosphorylation of AKT both in vitro and in vivo. When PI3K inhibitor wortmannin was applied to specifically inhibit phosphorylation of AKT, the expression of target genes markedly decreased, and the TNBC metastasis induced by low-concentration BPP and BPM were reversed. In conclusion, these results showed that PI3K/AKT signaling regulate BPP/BPM-induced metastasis of TNBC by triggering EMT. This study provides insights into the effects and the potential mechanisms of BPP and BPM on TNBC, raising concerns about the risk of using these two bisphenols as the alternative of BPA.

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PMID:  Int J Mol Sci. 2023 May 31 ;24(11). Epub 2023 May 31. PMID: 37298548 Abstract Title:  Bisphenol S Reduces Pig Spermatozoa Motility through Different Intracellular Pathways and Mechanisms than Its Analog Bisphenol A. Abstract:  Bisphenol A (BPA: 2,3-bis (4-hydroxyphenyl) propane) is an environmental chemical widely used in the manufacturing of epoxy polymers and many thermoplastic consumer products. Serious concerns about its safety led to the development of analogs, such as BPS (4-hydroxyphenyl sulfone). Very limited studies about BPS's impact on reproduction, specifically in spermatozoa, exist in comparison with BPA. Therefore, this work aims to study the in vitro impact of BPS in pig spermatozoa in comparison with BPA, focusing on sperm motility, intracellular signaling pathways and functional sperm parameters. We have used porcine spermatozoa as an optimal and validated in vitro cell model to investigate sperm toxicity. Pig spermatozoa were exposed to 1 and 100M BPS or BPA for 3 and 20 h. Both bisphenol S and A (100M) significantly reduce pig sperm motility in a time-dependent manner, although BPS exerts a lower and slower effect than BPA. Moreover, BPS (100M, 20 h) causes a significant increase in the mitochondrial reactive species, whereas it does not affect sperm viability, mitochondrial membrane potential, cell reactive oxygen species, GSK3/phosphorylation or phosphorylation of PKA substrates. However, BPA (100M, 20 h) leads to a decrease in sperm viability, mitochondrial membrane potential, GSK3phosphorylation and PKA phosphorylation, also causing an increase in cell reactive oxygen species and mitochondrial reactive species. These intracellular effects and signaling pathways inhibited might contribute to explaining the BPA-triggered reduction in pig sperm motility. However, the intracellular pathways and mechanisms triggered by BPS are different, and the BPS-caused reduction in motility can be only partially attributed to an increase in mitochondrial oxidant species.

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PMID:  Nutrients. 2023 May 26 ;15(11). Epub 2023 May 26. PMID: 37299440 Abstract Title:  The Role of Vitamin D Supplementation on Airway Remodeling in Asthma: A Systematic Review. Abstract:  Asthma is a common chronic respiratory disease that affects millions of people worldwide, and its prevalence continues to increase. Vitamin D has been proposed as a potential environmental factor in asthma pathogenesis, due to its immunomodulatory effects. This systematic review aimed to evaluate the effect of vitamin D supplementation in order to prevent airway remodeling in asthmatic patients. Four electronic databases, namely PubMed, Embase, Clinical trails.gov, and CINAHL, were thoroughly searched to conduct a comprehensive literature review. The International Prospective Register of Systematic Reviews (CRD42023413798) contains a record of the registered protocol. We identified 9447 studies during the initial search; 9 studies (0.1%) met the inclusion criteria and were included in the systematic review. All included studies were experimental studies that investigated the impact of vitamin D supplementation on airway remodeling in asthma. The studies included in this review suggest that vitamin D inhibits airway smooth muscle cell contraction and remodeling, reduces inflammation, regulates collagen synthesis in the airways, and modulates the action of bronchial fibroblasts. However, one study suggests that TGF-1 can impair vitamin D-induced and constitutive airway epithelial host defense mechanisms. Overall, vitamin D appears to have a potential role in the prevention and management of asthma.

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PMID:  BMC Oral Health. 2023 Jun 13 ;23(1):387. Epub 2023 Jun 13. PMID: 37312090 Abstract Title:  Association of vitamin D in individuals with periodontitis: an updated systematic review and meta-analysis. Abstract:  BACKGROUND: There are differences in vitamin D levels between periodontitis and healthy individuals, but the effect of vitamin D on periodontitis is controversial. The purpose of this Meta-analysis is twofold: (1) compare vitamin D levels in individuals with or without periodontitis; (2) assess the effects of vitamin D supplementation during scaling and root planing (SRP) on periodontal clinical parameters in individuals with periodontitis.METHODS: A systematic search was conducted in five databases (PubMed, Web of Science, MEDLINE, EMBASE, and Cochrane library), published from the database inception to 12 September 2022. The Cochrane Collaboration Risk of bias (ROB) assessment tool, the risk of bias in non-randomized studies of intervention (ROBINS-I) tool, the Newcastle-Ottawa Quality Assessment Scale (NOS), and Agency for Healthcare Quality and Research (AHRQ) were used to evaluate randomized controlled trial (RCT), non-RCT, case-control study, and cross-sectional study, respectively. Statistical analysis was performed using RevMan 5.3 and Stata 14.0 software, with weighted mean difference (WMD), standardized mean difference (SMD) and 95% confidence intervals (CI) as the effect measures, and heterogeneity was tested by subgroup analysis, sensitivity analysis, Meta-regression.RESULTS: A total of 16 articles were included. The results of Meta-analysis showed that periodontitis was associated with lower serum vitamin D levels compared to normal population (SMD=-0.88, 95%CI -1.75~-0.01, P=0.048), while there was no significant difference in serum or saliva 25(OH)D levels between periodontitis and normal population. Additionally, the Meta-analysis showed that SRP+vitamin D and SRP alone had a statistically significant effect on serum vitamin D levels in individuals with periodontitis (SMD=23.67, 95%CI 8.05~32.29, P=0.003; SMD=1.57, 95%CI 1.08~2.06, P

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PMID:  Transl Psychiatry. 2023 Jun 14 ;13(1):204. Epub 2023 Jun 14. PMID: 37316481 Abstract Title:  Developmental vitamin D-deficiency produces autism-relevant behaviours and gut-health associated alterations in a rat model. Abstract:  Developmental vitamin D (DVD)-deficiency is an epidemiologically established risk factor for autism. Emerging studies also highlight the involvement of gut microbiome/gut physiology in autism. The current study aims to examine the effect of DVD-deficiency on a broad range of autism-relevant behavioural phenotypes and gut health. Vitamin D deficient rat dams exhibited altered maternal care, DVD-deficient pups showed increased ultrasonic vocalizations and as adolescents, social behaviour impairments and increased repetitive self-grooming behaviour. There were significant impacts of DVD-deficiency on gut health demonstrated by alterations to the microbiome, decreased villi length and increased ileal propionate levels. Overall, our animal model of this epidemiologically validated risk exposure for autism shows an expanded range of autism-related behavioural phenotypes and now alterations in gut microbiome that correlate with social behavioural deficits raising the possibility that DVD-deficiency induced ASD-like behaviours are due to alterations in gut health.

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PMID:  Eur Rev Med Pharmacol Sci. 2023 Jun ;27(11):5318-5326. PMID: 37318506 Abstract Title:  Association between vitamin D hypovitaminosis and severe forms of COVID-19. Abstract:  OBJECTIVE: Hypovitaminosis D may be associated with an increased susceptibility to infection, more severe COVID-19 forms, and a higher risk of death. The objective of this study was to investigate any possible connections between vitamin D status [as measured by serum 25-hydroxyvitamin D (25(OH)D) levels] and COVID-19 severity.PATIENTS AND METHODS: In 2021, a cross-sectional study of consecutive adult COVID-19 patients was conducted. Anthropometric data, comorbidities, hospital setting, length of stay, respiratory support, outcome data, and vitamin D status were all evaluated.RESULTS: The length of hospitalization among participants (n = 74; mean age 57.6417.83 years, 55.4% male) was 18.5810 days, the majority of the hospital setting was a medical ward (67.6%), and the respiratory support in the form of mechanical ventilation was represented by 12.2%. Hypertension (54.1%), obesity (64.9%), and overweight (64.9%) were the most common cardiometabolic risk factors. In the study group, 44.6% of participants had severe vitamin D deficiency (

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PMID:  Clin Nutr. 2023 May 22. Epub 2023 May 22. PMID: 37321901 Abstract Title:  Dietary vitamin D intake and the bladder cancer risk: A pooled analysis of prospective cohort studies. Abstract:  BACKGROUND & AIMS: Diet may play an essential role in the aetiology of bladder cancer (BC). Vitamin D is involved in various biological functions which have the potential to prevent BC development. Besides, vitamin D also influences the uptake of calcium and phosphorus, thereby possibly indirectly influencing the risk of BC. The aim of the present study was to investigate the relation between vitamin D intake and BC risk.METHODS: Individual dietary data were pooled from ten cohort studies. Food item intake was converted to daily intakes of vitamin D, calcium and phosphorus. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) were obtained using Cox-regression models. Analyses were adjusted for gender, age and smoking status (Model 1), and additionally for the food groups fruit, vegetables and meat (Model 2). Dose-response relationships (Model 1) were examined using a nonparametric test for trend.RESULTS: In total, 1994 cases and 518,002 non-cases were included in the analyses. The present study showed no significant associations between individual nutrient intake and BC risk. A significant decreased BC risk was observed for high vitamin D intake with moderate calcium and low phosphorus intake (Model 2: HR: 0.77, 95% CI: 0.59-1.00). No significant dose-response analyses were observed.CONCLUSION: The present study showed a decreased BC risk for high dietary vitamin D intake in combination with low calcium intake and moderate phosphorus intake. The study highlights the importance of examining the effect of a nutrient in combination with complementary nutrients for risk assessment. Future research should focus on nutrients in a wider context and in nutritional patterns.

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PMID:  Front Endocrinol (Lausanne). 2023 ;14:1089298. Epub 2023 May 31. PMID: 37324274 Abstract Title:  Vitamin D supplementation alleviates insulin resistance in prediabetic rats by modifying IRS-1 and PPAR/NF-B expressions. Abstract:  BACKGROUND: Prediabetes is a condition of intermediate hyperglycemia that may progress to type 2 diabetes. Vitamin D deficiency has been frequently linked to insulin resistance and diabetes. The study aimed to investigate the role of D supplementation and its possible mechanism of action on insulin resistance in prediabetic rats.METHOD: The study was conducted on 24 male Wistar rats that were randomly divided into 6 rats as healthy controls and 18 prediabetic rats. Prediabetic rats were induced with a high-fat and high-glucose diet (HFD-G) combined with a low dose of streptozotocin. Rats with the prediabetic condition were then randomized into three groups of 12-week treatment: one group that received no treatment, one that received vitamin D3 at 100 IU/kg BW, and one group that received vitamin D3 at 1000 IU/kg BW. The high-fat and high-glucose diets were continuously given throughout the twelve weeks of treatment. At the end of the supplementation period, glucose control parameters, inflammatory markers, and the expressions of IRS1, PPAR, NF-B, and IRS1 were measured.RESULTS: Vitamin D3 dose-dependently improves glucose control parameters, as shown by the reduction of fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated albumin, insulin levels, and markers of insulin resistance (HOMA-IR). Upon histological analysis, vitamin D supplementation resulted in a reduction of the islet of Langerhans degeneration. Vitamin D also enhanced the ratio of IL-6/IL-10, reduced IRS1 phosphorylation at Ser307, increased expression of PPAR gamma, and reduced phosphorylation of NF-KB p65 at Ser536.CONCLUSION: Vitamin D supplementation reduces insulin resistance in prediabetic rats. The reduction might be due to the effects of vitamin D on IRS, PPAR, and NF-B expression.

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PMID:  J Oncol Pharm Pract. 2023 Jun 15:10781552231182362. Epub 2023 Jun 15. PMID: 37321210 Abstract Title:  Safety and efficacy of Vitamin C, Vitamin E, and selenium supplementation in the oncology setting: A systematic review. Abstract:  OBJECTIVE: With rising rates of complementary and alternative medicine (CAM) use, the exploration of CAM integration into oncology treatments is becoming increasingly prevalent. Antioxidants have been proposed as potentially beneficial to prevent or treat cancer. However, evidence summaries are limited, and the United States Preventive Services Task Force has recently recommended the use of Vitamin C and E supplementation for cancer prevention. Thus, the objective of this systematic review is to evaluate the existing literature on the safety and efficacy of antioxidant supplementation in oncology patients.METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using prespecified search terms in PubMed and CINAHL. Two reviewers independently reviewed titles, abstracts, and full-text articles, with a third reviewer resolving conflicts, before the included articles underwent data extraction and quality appraisal.RESULTS: Twenty-four articles met the inclusion criteria. Of the included studies, nine evaluated selenium, eight evaluated Vitamin C, four evaluated Vitamin E, and three of these studies included a combination of two or more of these agents. The most frequently evaluated cancer types included colorectal cancer (=4), leukemias (=4), breast cancer (=3), and genitourinary cancers (=3). Most of the studies focused on the antioxidants' therapeutic efficacy (=15) or their use in protecting against chemotherapy- or radiation-induced side effects (=8), and one study evaluated the role of an antioxidant in protection against cancer. Findings were generally favorable among the studies, and adverse effects of supplementation were limited. Furthermore, the average score for all the included articles on the Mixed Methods Appraisal Tool was 4.2, indicating the high quality of the studies.CONCLUSIONS: Antioxidant supplements may provide benefits in reducing incidence or severity of treatment-induced side effects with limited risk for adverse effects. Large, randomized controlled trials are needed to confirm these findings among various cancer diagnoses and stages. Healthcare providers should understand the safety and efficacy of these therapies to address questions that arise in caring for those with cancer.

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PMID:  Drug Dev Res. 2023 Apr 13. Epub 2023 Apr 13. PMID: 37052239 Abstract Title:  Tilianin alleviates lipid deposition and fibrosis in mice with nonalcoholic steatohepatitis by activating the PPAR/Nnat axis. Abstract:  The understanding and treatment of nonalcoholic steatohepatitis (NASH) are still very limited. This study reports the therapeutic effect of tilianin on mice with NASH and further explores its possible molecular mechanisms. A mice model of NASH was established using low-dose streptozotocin combined with a high-fat diet and tilianin treatment. Liver function was assessed by determining serum aspartate aminotransferase and alanine aminotransferase in serum. Interleukin (IL)-1, IL-6, transforming growth factor1 (TGF-1), and tumor necrosis factor(TNF-) levels in serum were determined. Hepatocyte apoptosis was assessed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining. Oil Red O staining and boron dipyrrin staining were used to determine lipid deposition in liver tissues. Masson staining was used to evaluate liver fibrosis, and immunohistochemistry and western blot analysis were used to determine the expression of target proteins. Tilianin treatment significantly ameliorated liver function, inhibited hepatocyte apoptosis, and reduced lipid deposition and liver fibrosis in mice with NASH. The expression of neuronatin (Nnat) and peroxisome proliferator-activated receptor (PPAR)was upregulated, whereas that of sterol regulatory element-binding protein 1 (SREBP-1), TGF-1, nuclear factor (NF)-B p65, and phosphorylated p65 was downregulated in the liver tissues of mice with NASH after tilianin treatment. The above effects of tilianin were significantly reversed after Nnat knock-down, but its effect on PPARexpression was unaffected. Thus, the natural drug tilianin shows potential in treatig NASH. Its mechanism of action may be related to the targeted activation of PPAR/Nnat, thereby inhibiting the activation of the NF-B signaling pathway.

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PMID:  Front Immunol. 2023 ;14:1118808. Epub 2023 Apr 19. PMID: 37153565 Abstract Title:  Tilianin improves cognition in a vascular dementia rodent model by targeting miR-193b-3p/CaM- and miR-152-3p/CaMKII-mediated inflammatory and apoptotic pathways. Abstract:  INTRODUCTION: Although vascular dementia (VaD) is the second most prevalent form of dementia, there is currently a lack of effective treatments. Tilianin, isolated from the traditional drugL., may protect against ischemic injury by inhibiting oxidative stress and inflammation via the CaMKII-related pathways but with weak affinity with the CaMKII molecule. microRNAs (miRNAs), functioning in post-transcriptional regulation of gene expression, may play a role in the pathological process of VaD via cognitive impairment, neuroinflammatory response, and neuronal dysfunction. This study aimed to investigate the role of tilianin in VaD therapy and the underlying mechanism through which tilianin regulates CaMKII signaling pathways based on miRNA-associated transcriptional action.METHODS: Rats with 2-vessel occlusion (2VO), a standard model of VaD, were treated with tilianin, vehicle control, and target overexpression or downregulation. High-throughput sequencing, qRT-PCR, and western blot analyses were utilized to identify the downstream target genes and signaling pathways of tilianin involved in VaD.RESULTS: Our results showed that tilianin ameliorated cognitive deficits, neurodegeneration, and microglial and astrocytic activation in rats with 2VO. Subsequent high-throughput sequencing and qRT-PCR analyses revealed that tilianin increased the downregulated miR-193b-3p and miR-152-3p levels in the cortex and hippocampus of 2VO rats. Mechanistically, miR-193b-3p targeting CaM and miR-152-3p targeting CaMKIIwere identified to play a role in VaD-associated pathology, inhibiting the p38 MAPK/NF--B p65 pathway and decreasing TNF-and IL-6 levels. Further gain- and loss-of-function experiments for these key genes showed that tilianin-exerted cognitive improvement by activating the p38 MAPK/NF--B p65 and Bcl-2/Bax/caspase-3/PARP pathways in the brain of 2VO rats was abolished by miR-193b-3p and miR-152-3p inhibition. Moreover, CaM and CaMKIIoverexpression eliminated the elevated effects of miR-193b-3p and miR-152-3p on tilianin's protection against ischemic injury through increased inflammatory reactions and apoptotic signaling.DISCUSSION: Together, these findings indicate that tilianin improves cognition by regulating the miR-193b-3p/CaM- and miR-152-3p/CaMKII-mediated inflammatory and apoptotic pathways, suggesting a potential small-molecule regulator of miRNA associated with inflammatory signaling for VaD treatment.

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PMID:  Biol Pharm Bull. 2023 ;46(3):419-426. PMID: 36858570 Abstract Title:  Tilianin Protects against Nonalcoholic Fatty Liver Disease in Early Obesity Mice. Abstract:  Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the most frequent types of liver disease in pediatric populations with obesity. Tilianin has multiple biological activities including anti-inflammatory and antioxidant. Here, we aim to explore the functions and possible mechanisms of tilianin on NAFLD in obese children. A high-fat high-carbohydrate (HFHC) diet was used to feed 21-d-old mice. Tilianin was administered at a dose of 10 or 20mg/kg daily. HFHC-fed mice gained weight, increased liver index. The liver showed hepatocyte ballooning, inflammatory infiltration, and steatosis. Elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) and reduced the high-density lipoprotein cholesterol (HDL-C) level were found in HFHC-fed mice. Administration of tilianin significantly reduced these impairments. We further evaluated proteins related to lipid metabolism and observed that LXR, SREBP-1c, FAS and ACC1 expression were blunted following tilianin administration. In addition, tilianin suppressed reactive oxygen species (ROS) overproduction and lipid peroxide 4-Hydroxynonenal expression, ascribed to its oxidative stress-modulating capacity. Tilianin also reversed the increase in F4/80 expression and proinflammatory cytokine levels. Of note, tilianin administration resulted in decreased protein levels of active caspase-1 and NOD-like receptor protein 3 (NLRP3) in HFHC-fed mice. Our study suggests that tilianin may ameliorate NAFLD in early obese mice by modulating lipids metabolism, oxidative stress, and inflammation, which may in part involve inhibiting NLRP3 inflammasome activation.

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PMID:  J Tradit Chin Med. 2023 Feb ;43(1):42-50. PMID: 36639994 Abstract Title:  Tilianin extracted from Xiangqinglan () inhibits apoptosis induced by mitochondrial pathway and endoplasmic reticulum stress in H9c2 cells after oxygen-glucose deprivation/reoxygenation. Abstract:  OBJECTIVE: To investigate the efficacy of tilianin extracted from Xiangqinglan () on apoptosis of H9c2 cell after oxygen-glucose deprivation/reoxygenation (OGD/R) and the mechanism.METHODS: Tilianin was obtained from Beijing Inluck Science and Technology Development Co. Ltd., with purity98%. The OGD/R model was established in H9c2 cells. Flow cytometry detected the mitochondrial membrane potential, apoptosis rates, mitochondrial reactive oxygen species (ROS) and calcium ion concentration. Succinate dehydrogenase (SDH) activity, succinate content and levels of tumor necrosis factor-(TNF-), interleukin-6 (IL-6) and interleukin-1(IL-1) were detected with enzyme-linked immunosorbent assay. Western blot measured protein levels.RESULTS: Tilianin significantly reduced the apoptotic rates, ROS levels, calcium ion concentration, succinate content, and, levels of TNF-, IL-6 and IL-1of OGD/R cells, while significantly increased the membrane potential and SDH activity in mitochondria. Western blot analysis showed that tilianin significantly up-regulated p-Calmodulin-dependent protein kinaseand voltage-dependent anion selective channel levels in OGD/R cells, while significantly down-regulated p-protein kinase B, Bcl-2-associated X, and dynamin-related protein 1 levels related to apoptosis in the mitochondrial pathway. Moreover, tilianin significantly up-regulated B-cell lymphoma-2 and mitochondrial protein 2 related to the inhibition of apoptosis. Furthermore, tilianin down-regulated phosphorylated-apoptosis signal-regulated kinase 1, phosphorylated-p38 and C/EBP homologous protein related to endoplasmic reticulum stress.CONCLUSIONS: Tilianin may inhibit OGD/R-induced H9c2 cell apoptosis mediated by mitochondrial pathway and endoplasmic reticulum stress, thus protecting cardiomyocytes.

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PMID:  Phytomedicine. 2023 Jan ;109:154577. Epub 2022 Nov 25. PMID: 36610166 Abstract Title:  Tilianin improves lipid profile and alleviates atherosclerosis in ApoEmice through up-regulation of SREBP2-mediated LDLR expression. Abstract:  BACKGROUND: The huge global burden of atherosclerotic cardiovascular diseases (CVDs) represents an urgent unmet need for the development of novel therapeutics. Dracocephalum moldavica L. has been used as a traditional Uygur medicine to treat various CVDs for centuries. Tilianin is a major flavonoid component of D. moldavica L. and has potential for preventing atherosclerosis. However, the molecular mechanisms that tilianin attenuate atherosclerosis are far from fully understood.PURPOSES: The purpose of this study is to investigate the efficiency and underlying mechanisms of tilianin in controlling lipid profile and preventing atherogenesis.METHODS: The lipid-lowering effect of tilianin was evaluated in C57BL/6 and ApoEmice by systematically determining serum biochemical parameters. The effects of tilianin on the atherosclerotic lesion were observed in aortic roots and whole aortas of ApoEmice with oil red O staining. Caecal content from ApoEmice were collected for 16S rRNA gene sequence analysis to assess the structure of the gut microbiota. The inhibition of hepatosteatosis was verified by histological examination, and a liver transcriptome analysis was performed to elucidate the tilianin-induced hepatic transcriptional alterations. Effects of tilianin on the expression and function of LDLR were examined in HepG2 cells and ApoEmice. Further mechanisms underlying the efficacy of tilianin were investigated in HepG2 cells.RESULTS: Tilianin treatment improved lipid profiles in C57BL/6 and dyslipidemic ApoEmice, especially reducing the serum LDL-cholesterol (LDL-C) level. Significant reductions of atherosclerotic lesion area and hepatosteatosis were observed in tilianin-treated ApoEmice. The altered gut microbial composition in tilianin groups was associated with lipid metabolism and atherosclerosis. The liver transcriptome revealed that tilianin regulated the transcription of lipid metabolism-related genes. Then both in vitro and in vivo analyses revealed the potent effect of tilianin to enhance hepatic LDLR expression and its mediated LDL-C uptake. Further studies confirmed a critical role of SREBP2 in hepatic LDLR up-regulation by tilianin via increasing precursor and thus mature nuclear SREBP2 level.CONCLUSION: This study demonstrated the lipid-lowering effect of tilianin through SREBP2-mediated transcriptional activation of LDLR. Our findings reveal a novel anti-atherosclerotic mechanism of tilianin and underlie its potential clinical use in modulating CVDs with good availability and affordability.

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PMID:  Front Pharmacol. 2022 ;13:862584. Epub 2022 Jun 3. PMID: 35721209 Abstract Title:  Tilianin Reduces Apoptosisthe ERK/EGR1/BCL2L1 Pathway in Ischemia/Reperfusion-Induced Acute Kidney Injury Mice. Abstract:  Acute kidney injury (AKI) is a common syndrome impacting about 13.3 million patients per year. Tilianin has been reported to alleviate myocardial ischemia/reperfusion (I/R) injury, while its effect on AKI is unknown; thus, this study aimed to explore if tilianin protects I/R-induced AKI and the underlying mechanisms.The microarray dataset GSE52004 was downloaded from GEO DataSets (Gene Expression Omnibus). Differential expression analysis and gene-set enrichment analysis (GSEA) were performed by R software to identify apoptosis pathway-related genes. Then,was applied to identify the transcription factor (TF) related to apoptosis. The STRING database was used to construct a protein-protein interaction (PPI) network. Cytoscape software visualized PPI networks, and hub TFs were selected viaAutoDock was used for molecular docking of tilianin and hub gene-encoded proteins. The expression levels of hub genes were assayed and visualized by quantitative real-time PCR, Western blotting, and immunohistochemistry by establishing I/R-induced AKI mouse models.Bioinformatics analysis showed that 34 genes, including FOS, ATF4, and Gadd45g, were involved in the apoptosis pathway. In total, seven hub TFs might play important roles in tilianin-regulating apoptosis pathways. In, tilianin improved kidney function and reduced the number of TUNEL-positive renal tubular epithelial cells (RTECs) after I/R-induced AKI. Tilianin reduced the activation of the ERK pathway and then downregulated the expression of EGR1. This further ameliorated the expression of anti-apoptotic genes such as BCL2L1 and BCL2, reduced pro-apoptotic genes such as BAD, BAX, and caspase-3, and reduced the release of cytochrome c.Tilianin reduced apoptosis after I/R-induced AKI by the ERK/EGR1/BCL2L1 pathway. Our findings provided novel insights for the first time into the protective effect and underlying molecular mechanisms of tilianin on I/R-induced AKI.

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PMID:  Exp Ther Med. 2022 Apr ;23(4):293. Epub 2022 Feb 17. PMID: 35340873 Abstract Title:  Tilianin attenuates MPP-induced oxidative stress and apoptosis of dopaminergic neurons in a cellular model of Parkinson's disease. Abstract:  The flavonoid tilianin is derived from the leaves ofL. amiales and has been proven to serve a neuroprotective role in cerebral ischemia. Therefore, the aim of the present study was to determine whether tilianin could prevent oxidative stress and the apoptosis of dopaminergic neurons in Parkinson's disease (PD). The dopaminergic neuron MES23.5 cell line was treated with 1-methyl-4-phenylpyridinium (MPP) to construct a PD cell model. Following pretreatment with tilianin, the Cell Counting Kit-8 assay was used to assess cell viability. The protein and mRNA expression levels of tyrosine hydroxylase were determined using immunofluorescence, reverse transcription-quantitative PCR (RT-qPCR) and western blotting. mRNA and protein expression levels of inflammatory cytokines IL-6, IL-1and TNF-and oxidative stress-related enzymes manganese superoxide dismutase and catalase were also quantified using RT-qPCR and western blotting, respectively. Cell apoptotic rate was analyzed using the TUNEL assay and the expressions of apoptosis-related proteins Bcl-2, Bax and cleaved caspase-3 were detected by western blotting. MAPK signaling pathway-related protein expression levels were assessed via western blotting in MPP-stimulated MES23.5 cells with or without tilianin pretreatment. Tilianin was demonstrated to exert no cytotoxic effects on MES23.5 cells and was able to prevent MPP-induced reductions in cell viability. Pretreatment with tilianin also inhibited MPP-induced inflammatory cytokine secretion, oxidative stress and apoptosis of MES23.5 cells. In addition, the protein expression levels of MAPK signaling pathway-related proteins were upregulated by MPP, whereas pretreatment with tilianin downregulated these in a dose-dependent manner. The results of the present study indicated that tilianin may exert anti-inflammatory and antioxidant effects and inhibit the MAPK signaling pathway, which may ameliorate injury to dopaminergic neurons induced by PD.

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PMID:  Molecules. 2022 Jan 20 ;27(3). Epub 2022 Jan 20. PMID: 35163934 Abstract Title:  Tilianin: A Potential Natural Lead Molecule for New Drug Design and Development for the Treatment of Cardiovascular Disorders. Abstract:  Cardiovascular disorders (CVDs) are the leading risk factor for death worldwide, and research into the processes and treatment regimens has received a lot of attention. Tilianin is a flavonoid glycoside that can be found in a wide range of medicinal plants and is most commonly obtained from. Due to its extensive range of biological actions, it has become a well-known molecule in recent years. In particular, numerous studies have shown that tilianin has cardioprotective properties against CVDs. Hence, this review summarises tilianin's preclinical research in CVDs, as well as its mechanism of action and opportunities in future drug development. The physicochemical and drug-likeness properties, as well as the toxicity profile, were also highlighted. Tilianin can be a natural lead molecule in the therapy of CVDs such as coronary heart disease, angina pectoris, hypertension, and myocardial ischemia, according to scientific evidence. Free radical scavenging, inflammation control, mitochondrial function regulation, and related signalling pathways are all thought to play a role in tilianin's cardioprotective actions. Finally, we discuss tilianin-derived compounds, as well as the limitations and opportunities of using tilianin as a lead molecule in drug development for CVDs. Overall, the scientific evidence presented in this review supports that tilianin and its derivatives could be used as a lead molecule in CVD drug development initiatives.

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PMID:  Oxid Med Cell Longev. 2021 ;2021:6673967. Epub 2021 Sep 4. PMID: 34527176 Abstract Title:  Tilianin Ameliorates Cognitive Dysfunction and Neuronal Damage in Rats with Vascular Dementia via p-CaMKII/ERK/CREB and ox-CaMKII-Dependent MAPK/NF-B Pathways. Abstract:  Vascular dementia (VaD) is a common cause of cognitive decline and dementia of vascular origin, but the precise pathological mechanisms are unknown, and so effective clinical treatments have not been established. Tilianin, the principal active compound of total flavonoid extract fromL., is a candidate therapy for cardio-cerebrovascular diseases in China. However, its potential in the treatment of VaD is unclear. The present study is aimed at investigating the protective effects of tilianin on VaD and exploring the underlying mechanism of the action. A model of VaD was established by permanent 2-vessel occlusion (2VO) in rats. Human neurons (hNCs) differentiated from human-induced pluripotent stem cells were used to establish an oxygen-glucose deprivation (OGD) model. The therapeutic effects and potential mechanisms of tilianin were identified using behavioral tests, histochemistry, and multiple molecular biology techniques such as Western blot analysis and gene silencing. The results demonstrated that tilianin modified spatial cognitive impairment, neurodegeneration, oxidation, and apoptosis in rats with VaD and protected hNCs against OGD by increasing cell viability and decreasing apoptosis rates. A study of the mechanism indicated that tilianin restored p-CaMKII/ERK1/2/CREB signaling in the hippocampus, maintaining hippocampus-independent memory. In addition, tilianin inhibited an ox-CaMKII/p38 MAPK/JNK/NF-B associated inflammatory response caused by cerebral oxidative stress imbalance in rats with VaD. Furthermore, specific CaMKIIsiRNA action revealed that tilianin-exerted neuroprotection involved increase of neuronal viability, inhibition of apoptosis, and suppression of inflammation, which was dependent on CaMKII. In conclusion, the results suggested the neuroprotective effect of tilianin in VaD and the potential mechanism associated with dysfunction in the regulation of p-CaMKII-mediated long-term memory and oxidation and inflammation involved with ox-CaMKII, which may lay the foundation for clinical trials of tilianin for the treatment of VaD in the future.

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PMID:  Saudi J Biol Sci. 2021 Sep ;28(9):4900-4907. Epub 2021 Jun 24. PMID: 34466064 Abstract Title:  Tilianin inhibits the human ovarian cancer (PA-1) cell proliferation via blocking cell cycle, inducing apoptosis and inhibiting JAK2/STAT3 signaling pathway. Abstract:  Ovarian cancer is one of the deadliest gynecologic malignancies and is the seventh leading cause of mortalities and morbidities globally. Although there are various therapeutic strategies, a major challenge for scientific community is to come up with effective strategy to treat ovarian cancer. Tilianin, a polyphenol flavonoid is well known for its extensive biological actions like cardioprotective, neuroprotective, anti-oxidant, anti-inflammatory, anti-diabetic and anti-tumor properties. The current study is designed to investigate the anti-cancer action of Tilianin in ovarian cancer (PA-1) cells. The findings of this study revealed that Tilianin treatment results in significant and concentration dependent decrease in cell viability. The growth inhibiting action of Tilianin is associated with apoptosis which was confirmed by DAPI and AO/EtBr staining. The Tilianin-triggered apoptosis in PA-1 cells was correlated with elevated generation of ROS, loss of mitochondrial membrane potential, alterations in pro-apoptotic (upregulated mRNA expression of Bax) and anti-apoptotic (downregulated mRNA expression of Bcl2) factors and activation of caspase-8, -9 and -3. Cell cycle analysis revealed that Tilianin treatment prevented G1/S transition through reduced mRNA expression of cyclin D1. Additionally, the findings of this study also showed Tilianin inhibited JAK2/STAT3 signaling (downregulated expression of pJAK2, JAK2, pSTAT3, and STAT3) with no change in mRNA expression level of ERK indicating its non-involvement in the apoptotic and/or growth inhibition of ovarian cancer cells. In conclusion, the findings of this exploration provided clear evidence of anti-cancer effects of Tilianin in PA-1 cells through its anti-proliferative action, ability to induce apoptosis both through extrinsic and intrinsic pathways, cell cycle (G1/S) arrest and JAK2/STAT3 signaling inhibition.

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PMID:  Int Immunopharmacol. 2021 Jul ;96:107728. Epub 2021 May 7. PMID: 33971494 Abstract Title:  Synergistic cardioptotection by tilianin and syringin in diabetic cardiomyopathy involves interaction of TLR4/NF-B/NLRP3 and PGC1a/SIRT3 pathways. Abstract:  Diabetic cardiomyopathy (DCM) is a chronic multifactorial complication of type-2 diabetes mellitus, leading to heart failure. A combination of multifaceted therapeutics for the management of DCM is needed. Here, we investigated the combined effect of syringin and tilianin on DCM by evaluating cardiac function, inflammation, oxidative stress, apoptosis and mitochondrial function, and explored the contribution of TLR4/NF-B/NLRP3 and PGC1/SIRT3 pathways in diabetic rats and hyperglycemic-H9c2 cells. Syringin and tilianin (50 and 60 mg/kg, i.p, respectively) were administered for eight weeks, individually or in combination, to healthy and type-2 diabetic Sprague-Dawley rats. Myocardial function was recorded using a carotid catheter, mitochondrial and histopathological changes were evaluated by fluorometric and staining methods, cardiac markers and signaling pathways' proteins expression were measured through ELISA and immunoblotting. In comparison to individual treatments, combination of syringin and tilianin effectively exerted antidiabetic effects and improved cardiac function and DCM markers, reduced NLRP3/IL-6/IL-1/TNF-expression, and suppressed diabetes/hyperglycemiainduced oxidative stress in rats' heart and H9c2 cells, as demonstrated by decreased 8-isoprostane, and increased superoxide dismutase-2 levels. Mitochondrial membrane depolarization and ROS production were inhibited, and caspase-3 and Bax/Bcl2 expression downregulated by combination therapy. Combined treatment markedly inhibited up-regulation of TLR4, MyD88 and NF-B in diabetic rats. Finally, inhibition of PGC1/SIRT3 pathway by 3-TYP in hyperglycemic H9c2-cells reversed the beneficial effects of combination therapy on cardiomyocytes injury and NF-B/NLRP3/IL-1expression, without affecting TLR4/MyD88 expression. Syringin plus tilianin synergistically inhibited the diabetes-induced cardiac functional, biochemical and histopathological changes in DCM. Crosstalk between TLR4/NF-B/NLRP3 and PGC1/SIRT3/mitochondrial pathways contributed to this protection.

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PMID:  J Environ Pathol Toxicol Oncol. 2020 ;39(4):335-344. PMID: 33389905 Abstract Title:  Role of Tilianin against Acute Lung Injury in In Vitro LPS-Induced Alveolar Macrophage Cells and an In Vivo C57BL/6 Mice Model. Abstract:  Acute lung injury (ALI) is a disorder of pulmonary tissue caused by prolonged inflammation and uncontrolled oxidative stress. Tilianin is a natural polyphenol, acknowledged for its anti-inflammatory and antioxidant activities. The goal of this work was to explore the effect of tilianin in an LPS-challenged ALI model. The mechanistic investigation was carried out using both in vitro and in vivo experiments. The RAW264.7 macrophage cell and C57BL/6 mice were treated with Tilianin (10 and 20M) and then induced with LPS (1g/mL) overnight. The C57BL/6 mouse was administered LPS intratracheally (2 mg/kg) to induce ALI prior to tilianin intraperitoneal treatment (10 mg/kg). In vitro, the results showed that Tilianin reduced secretion of LPS-induced proinflammatory cytokine. In vivo, prophylactic treatment with tilianin attenuated infiltration of macrophages and histopathological changes and improved inflammation as shown by a marked reduction in inflammatory mediators found in bronchoalveolar lavage fluid (BALF). Furthermore, tilianin effectively suppressed MDA levels and GSH and SOD in ALI were increased. Collectively, these findings suggest that tilianin is a potential agent for ameliorating LPS-induced ALI.

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PMID:  Phytomedicine. 2021 Jan ;80:153392. Epub 2020 Oct 20. PMID: 33113503 Abstract Title:  Tilianin attenuates HDM-induced allergic asthma by suppressing Th2-immune responses via downregulation of IRF4 in dendritic cells. Abstract:  BACKGROUND: Acacetin 7-O--D-glucoside (tilianin) is a major constituent of Agastache rugosa, a traditional medicine that has long been used for the treatment of gastrointestinal disorders. Tilianin has a wide variety of pharmacological properties such as cardioprotective, neuroprotective, and anti-atherogenic activities. We recently discovered that tilianin has the ability to suppress MUC5AC expression in vitro. In addition, we have established an in vivo model of allergic asthma using house dust mite (HDM) that can be applied to tilianin.PURPOSE: We investigated the effects of tilianin on airway inflammation in a HDM-induced asthma mouse model and associated mechanisms.METHODS: Tilianin was treated in splenocytes cultured in Th0 condition and HDM-stimulated bone marrow-derived dendritic cells (BMDCs), and their mRNA expression and cytokines production were determined by quantitative real-time PCR and ELISA. To evaluate the effects of tilianin in an allergic asthma model, mice were sensitized and challenged with HDM. Tilianin was administered prior to challenge by oral gavage and airway hyper-reactivity (AHR) to methacholine, inflammatory cell infiltration, cytokine levels, and airway remodeling were assessed.RESULTS: Tilianin inhibited the production of Th2-related cytokines in splenocytes, which play pivotal roles in allergic airway inflammation. When treated in HDM-stimulated BMDCs, tilianin decreased Th2-skewing cytokine IL-33 and transcription factor IRF4. On the contrary, tilianin increased Th1-skewing regulators, IL-12 and IRF1. In an HDM-induced asthmatic mouse model, tilianin attenuated AHR and airway inflammation. Tilianin suppressed the expression of Th2-related cytokines, IL-13 and IL-33 in lung tissues. As seen in HDM-stimulated BMDCs, tilianin also downregulated the expression of the transcription factor IRF4 but not IRF1.CONCLUSION: Taken together, these results suggest that tilianin attenuates HDM-induced allergic airway inflammation by inhibiting Th2-mediated inflammation through the selective inhibition of the IRF4-IL-33 axis in dendritic cells.

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PMID:  Biomed Res Int. 2020 ;2020:5939715. Epub 2020 Oct 9. PMID: 33102583 Abstract Title:  Tilianin Protects against Ischemia/Reperfusion-Induced Myocardial Injury through the Inhibition of the Ca/Calmodulin-Dependent Protein Kinase II-Dependent Apoptotic and Inflammatory Signaling Pathways. Abstract:  Tilianin is a naturally occurring phenolic compound with a cardioprotective effect against myocardial ischemia/reperfusion injury (MIRI). The aim of our study was to determine the potential targets and mechanism of action of tilianin against cardiac injury induced by MIRI. Andocking model was used in this study for binding mode analysis between tilianin and Ca/calmodulin-dependent protein kinase II (CaMKII). Oxygen-glucose deprivation/reperfusion- (OGD/R-) injured H9c2 cardiomyocytes and ischemia/reperfusion- (I/R-) injured isolated rat hearts were developed asandmodels, respectively, which were both treated with tilianin in the absence or presence of a specific CaMKII inhibitor KN93 for target verification and mechanistic exploration. Results demonstrated the ability of tilianin to facilitater the recovery of OGD/R-induced cardiomyocyte injury and the maintenance of cardiac function in I/R-injured hearts. Tilianin interacted with CaMKIIwith an efficient binding performance, a favorable binding score, and restraining p-CaMKII and ox-CaMKII expression in cardiomyocytes injured by MIRI. Importantly, inhibition of CaMKII abolished tilianin-mediated recovery of OGD/R-induced cardiomyocyte injury and maintenance of cardiac function in I/R-injured hearts, accompanied by the disability to protect mitochondrial function. Furthermore, the protective effects of tilianin towards mitochondrion-associated proapoptotic and antiapoptotic protein counterbalance and c-Jun N-terminal kinase (JNK)/nuclear factor- (NF-)B-related inflammation suppression were both abolished after pharmacological inhibition of CaMKII. Our investigation indicated that the inhibition of CaMKII-mediated mitochondrial apoptosis and JNK/NF-B inflammation might be considered as a pivotal mechanism used by tilianin to exert its protective effects on MIRI cardiac damage.

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PMID:  Int Immunopharmacol. 2020 Nov ;88:106967. Epub 2020 Sep 22. PMID: 33182074 Abstract Title:  Renoprotective effects of Tilianin in diabetic rats through modulation of oxidative stress via Nrf2-Keap1 pathway and inflammation via TLR4/MAPK/NF-B pathways. Abstract:  The present study was undertaken to assess the protective effects of Tilianin (TN) on type-2 diabetes-induced renal dysfunction in experimental rats. Diabetes was induced by injecting Nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg) by i.p. and then the rats were treated with TN (10 and 20 mg/kg) daily by oral gavage for 28 days. TN treatment significantly decreases the BUN, creatinine, 24-hour urinary protein, urea, uric acid, and albumin protein levels. The protein of expression of Nrf2, NQO1, and HO-1 was augmented while the expression of Keap-1 decreased significantly. TN also reduces the oxidative/nitrosative status by lowering MDA content, NO, and MPO levels. TN exerted anti-inflammatory effects by suppressing TLR4/NF-B/MAPK signaling cascades and inhibiting MyD88, TRAF6, IB, p38MAPK, JNK, and ERK2 in the diabetic rats. Histopathological findings supported the biochemical and molecular results. The results showed that TN modulated Nrf2-Keap1 and TLR4/MAPK/NF-B signaling pathways and provided significant protection against diabetes-induced renal dysfunction.

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