PMID:  Vet World. 2023 Feb ;16(2):380-385. Epub 2023 Feb 26. PMID: 37042003 Abstract Title:  Potential protective effects of red grape seed extract in a rat model of malathion-induced neurotoxicity. Abstract:  BACKGROUND AND AIM: Exposure to pesticide mixtures used in agricultural practice poses a grave risk to non-target animals. This study aimed to determine whether red grape seed extract (RGSE, which is 95% bioflavonoids and equal to 12,000 mg of fresh red grape seed, and 150 mg of vitamin C) alleviated the changes in brain-derived neurotrophic factor (BDNF) level, acetylcholinesterase activity, oxidative stress, and apoptosis induced by orally administered malathion in a rat model of malathion-induced neurotoxicity.MATERIALS AND METHODS: Thirty-two adult male Wistar albino rats were divided into four groups and exposed to malathion with or without 4 weeks of RGSE treatment, treated with RGSE alone, or left untreated as controls. The animals were euthanized 24 h after last treatment. Brain samples were collected to measure acetylcholinesterase, superoxide dismutase (SOD), and caspase 3 activity, total antioxidant capacity (TAC), and BDNF levels.RESULTS: Malathion significantly reduced acetylcholinesterase and SOD activity and TAC and significantly increased caspase 3 activity. In comparison, acetylcholinesterase and SOC activity, BDNF level, and TAC were improved and caspase 3 activity was decreased in the malathion-RGSE group, indicating that RGSE corrected the alterations detected in these biochemical parameters.CONCLUSION: Oxidative stress and apoptosis in the brains of rats exposed to oral malathion were substantially controlled by RGSE treatment.

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PMID:  Food Chem Toxicol. 2023 Jul ;177:113795. Epub 2023 Apr 26. PMID: 37116776 Abstract Title:  GSPE attenuates CSE-induced lung inflammation and emphysema by regulating autophagy via the reactive oxygen species/TFEB signaling pathway. Abstract:  Cigarette smoke can enhance reactive oxygen species (ROS) production in inflammatory and epithelial cells. Subsequently, ROS enhance autophagy-induced inflammation due to alveolar macrophages (AMs), the primary source of cytokines implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Therefore, we hypothesized that grape seed proanthocyanidin extract (GSPE), an effective antioxidant, could inhibit emphysema and airway inflammation by ameliorating cigarette smoke extract (CSE)-induced autophagy via suppressing oxidative stress in macrophages. We observed that GSPE significantly attenuated histological changes observed in CSE-induced emphysema and airway inflammation in the lungs of mice. Moreover, GSPE ameliorated lung inflammation by reducing the number of cells, macrophages, and neutrophils and the tumor necrosis factor (TNF)-, interleukin (IL)-1, and IL-6 levels measured in bronchioloalveolar lavage fluid. ROS levels increased after CSE instillation and significantly decreased with in vitro GSPE treatment. GSPE decreased transcription factor EB (TFEB) oxidation by reducing ROS, inhibiting TFEB nuclear translocation. Furthermore, GSPE inhibited ROS-induced autophagy in RAW 264.7 cells, bone marrow-derived macrophages, and AMs. Inhibiting autophagy through GSPE treatment diminishes CSE-induced lung inflammation by inhibiting the NLRP3 inflammasome. This study demonstrates that GSPE can ameliorate CSE-induced inflammation and emphysema via autophagy-induced NLRP3 inflammasome regulation through the ROS/TFEB signaling pathway in a COPD mouse model.

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PMID:  Viruses. 2023 Mar 30 ;15(4). Epub 2023 Mar 30. PMID: 37112864 Abstract Title:  Grape Seed Proanthocyanidins Inhibit Replication of the Dengue Virus by Targeting NF-kB and MAPK-Mediated Cyclooxygenase-2 Expression. Abstract:  Dengue virus (DENV) infection is a serious global health issue as it causes severe dengue hemorrhagic fever and dengue shock syndrome. Since no approved therapies are available to treat DENV infection, it is necessary to develop new agents or supplements that can do this. In this study, grape seed proanthocyanidins extract (GSPE), which is widely consumed as a dietary supplement, dose-dependently suppressed the replication of four DENV serotypes. The inhibitory mechanism demonstrated that GSPE downregulated DENV-induced aberrant cyclooxygenase-2 (COX-2) expression, revealing that the inhibitory effect of the GSPE on DENV replication involved targeting DENV-induced COX-2 expression. Mechanistic studies on signaling regulation have demonstrated that GSPE significantly reduced COX-2 expression by inactivating NF-B and ERK/P38 MAPK signaling activities. Administrating GSPE to DENV-infected suckling mice reduced virus replication, mortality, and monocyte infiltration of the brain. In addition, GSPE substantially reduced the expression of DENV-induced inflammatory cytokines associated with severe dengue disease, including tumor necrosis factor-, nitric oxide synthase, interleukin (IL)-1, IL-6, and IL-8, suggesting that GSPE has potential as a dietary supplement to attenuate DENV infection and severe dengue.

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PMID:  Int J Mol Sci. 2023 Apr 6 ;24(7). Epub 2023 Apr 6. PMID: 37047797 Abstract Title:  Stearoyl-CoA Desaturases1 Accelerates Non-Small Cell Lung Cancer Metastasis by Promoting Aromatase Expression to Improve Estrogen Synthesis. Abstract:  Metastases contribute to the low survival rate of non-small cell lung cancer (NSCLC) patients. Targeting lipid metabolism for anticancer therapies is attractive. Accumulative evidence shows that stearoyl-CoA desaturases1 (SCD1), a key enzyme in lipid metabolism, enables tumor metastasis and the underlying mechanism remains unknown. In this study, immunohistochemical staining of 96 clinical specimens showed that the expression of SCD1 was increased in tumor tissues (

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RFK Jr. testified before a U.S. House hearing organized by the Subcommittee on the Weaponization of the Federal Government

Originally published on www.childrenshealthdefense.org by Michael Nevradakis, Ph.D.

In a hearing marred by contentious interruptions and attempts by House Democrats to remove him as a witness, Robert F. Kennedy Jr., CHD chairman on leave from Children's Health Defense testified before a U.S. House hearing organized by the Subcommittee on the Weaponization of the Federal Government.

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PMID:  Shanghai Kou Qiang Yi Xue. 2022 Dec ;31(6):597-601. PMID: 36970794 Abstract Title:  [Effect of grape seed extract on oxidative stress and pathological changes of aorta in rats with chronic periodontitis and arteriosclerosis]. Abstract:  PURPOSE: To investigate the effect of grape seed extract on pathological changes of aorta in rats with chronic periodontitis and arteriosclerosis, and to analyze the possible mechanism.METHODS: Fifteen SPF male rats with chronic periodontitis and arteriosclerosis were randomly divided into three groups, i.e., model group(n=5), low dose of grape seed extract group (n=5), high dose of grape seed extract group (n=5) , and control group (n=10). The rats in the low and high dose groups were treated with 40 mgkg-1d-1 and 80 mgkg-1d-1 for 4 weeks respectively, while the rats in the normal control group and the model group were treated with the same amount of normal saline at the same time. The maximal intima-media thickness(IMT) of abdominal aorta was measured by H-E staining, the activity of SOD and the content of MDA in serum were measured by colorimetry, the content of GSH-px in serum and serum levels of inflammatory factor (TNF-) and interleukin-6(IL-6) were detected by ELISA. p38 mitogen-activated protein kinase/nuclear transcription factor Kappa B p65(p38 MAPK/NF-B p65) pathway was detected by Western blotting. SPSS 20.0 software package was used for statistical analysis.RESULTS: In the model group, the intima of abdominal aorta was irregularly thickened, with a lot of inflammatory cell infiltration, and arterial lesions appeared. In the low-and high-dose groups of grape seed extract, the plaque of abdominal aorta intima decreased and inflammatory cells reduced significantly, arterial vascular disease was improved, and the improvement was more obvious in high dose group than in low dose group. Compared with the control group, the levels of IMT, serum MDA, TNF-, IL-6, p-p38MAPK/p38MAPK, NF-B p65 and serum SOD and GSH-px in the model group were increased, while those in the model group were decreased(P0.05); the levels of IMT, serum MDA, TNF-, IL-6, p-p38MAPK/p38MAPK, NF-B p65 and SOD, GSH-px were decreased in the low and high dose groups(P0.05).CONCLUSIONS: Grape seed extract can inhibit the oxidative stress level and inflammatory reaction in serum of chronic periodontitis with arteriosclerosis rats, thus improving the intimal lesion of aorta, possibly by inhibiting the activation of p38MAPK/NF-B p65 pathway.

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PMID:  Mol Biol Rep. 2023 Jun ;50(6):5455-5464. Epub 2023 May 8. PMID: 37155008 Abstract Title:  Targeting Nrf2 signaling pathway and oxidative stress by resveratrol for Parkinson's disease: an overview and update on new developments. Abstract:  Parkinson's disease (PD) as a prevalent neurodegenerative condition impairs motor function and is caused by the progressive deterioration of nigrostriatal dopaminergic (DAergic) neurons. The current therapy solutions for PD are ineffective because they could not inhibit the disease's progression and they even have adverse effects. Natural polyphenols, a group of phytochemicals, have been found to offer various health benefits, including neuroprotection against PD. Among these, resveratrol (RES) has neuroprotective properties owing to its capacity to protect mitochondria and act as an antioxidant. An increase in the formation of reactive oxygen species (ROS) leads to oxidative stress (OS), which is responsible for cellular damage resulting in lipid peroxidation, oxidative protein alteration, and DNA damage. In PD models, it's been discovered that RES pretreatment can diminish oxidative stress by boosting endogenous antioxidant status and directly scavenging ROS. Several studies have examined the involvement of RES in the modulation of the transcriptional factor Nrf2 in PD models because this protein recognizes oxidants and controls the antioxidant defense. In this review, we have examined the molecular mechanisms underlying the RES activity and reviewed its effects in both in vitro and in vivo models of PD. The gathered evidence herein showed that RES treatment provides neuroprotection against PD by reducing OS and upregulation of Nrf2. Moreover, in the present study, scientific proof of the neuroprotective properties of RES against PD and the mechanism supporting clinical development consideration has been described.

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PMID:  Curr Med Chem. 2023 May 5. Epub 2023 May 5. PMID: 37151061 Abstract Title:  Resveratrol inhibits restenosis through suppressing proliferation, migration and trans-differentiation of vascular adventitia fibroblasts via activating SIRT1. Abstract:  AIM: After the balloon angioplasty, vascular adventitia fibroblasts (VAFs), which proliferate, trans-differentiate to myofibroblasts and migrate to neointima, are crucial in restenosis. Resveratrol (RSV) has been reported to protect the cardiovascular by reducing restenosis and the mechanism remains unclear.METHOD: This study was dedicated to investigate the effect of RSV on VAFs in injured arteries and explore the potential mechanism. In this work, carotid artery balloon angioplasty was performed on male SD rats to ensure the injury of intima and VAFs were isolated to explore the effects in vitro. The functional and morphological results showed the peripheral delivery of RSV decreased restenosis of the injured arteries and suppressed the expression of proliferation, migration and transformation related genes. Moreover, after being treated with RSV, the proliferation, migration and trans-differentiation of VAFs were significantly suppressed and exogenous TGF-1 can reverse this effect.RESULT: Mechanistically, RSV administration activated SIRT1 and decreased the translation and expression of TGF-1, SMAD3 and NOX4, and reactive oxygen species (ROS) decreased significantly after VAFs treated with RSV.CONCLUSION: Above results indicated RSV inhibited restenosis after balloon angioplasty through suppressing proliferation, migration and trans-differentiation of VAFs via regulating SIRT1- TGF-1-SMAD3-NOX4 to decrease ROS.

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PMID:  Eur J Pharmacol. 2023 Jul 15 ;951:175748. Epub 2023 May 5. PMID: 37149277 Abstract Title:  Resveratrol inhibits autophagy against myocardial ischemia-reperfusion injury through the DJ-1/MEKK1/JNK pathway. Abstract:  Resveratrol (RES), a natural polyphenolic compound found in red wine and grape skins, has attracted significant attention due to its cardioprotective properties. DJ-1, a multifunctional protein that participated in transcription regulation and antioxidant defense, was shown to provide a significant protective impact in cardiac cells treated with ischemia-reperfusion. We created a myocardial ischemia-reperfusion (I/R) model in vivo and in vitro by ligating the left anterior descending branch of rats and subjecting H9c2 cells to anoxia/reoxygenation (A/R) to investigate whether RES reduces myocardial ischemia-reperfusion injury by upregulating DJ-1. We discovered that RES dramatically enhanced cardiac function in rats with I/R. Subsequently, we found that RES prevented the rise in autophagy (P62 degradation and LC3-II/LC3-I increase) induced by cardiac ischemia-reperfusion in vitro and in vivo. Notably, the autophagic agonist rapamycin (RAPA) eliminated RES-induced cardioprotective effects. In addition, Further data showed that RES significantly increased the expression of DJ-1 in the myocardium with the treatment of I/R. At the same time, pretreatment with RES reduced phosphorylation of MAPK/ERK kinase kinase 1 (MEKK1) and Jun N-terminal Kinase (JNK) stimulated by cardiac ischemia-reperfusion, and Beclin-1 mRNA and protein levels while decreasing lactate dehydrogenase (LDH) and improving cell viability. However, the lentiviral shDJ-1 and JNK agonist anisomycin disrupted the effects of RES. In summary, RES could inhibit autophagy against myocardial ischemia-reperfusion injury through DJ-1 modulation of the MEKK1/JNK pathway, providing a novel therapeutic strategy for cardiac homeostasis.

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PMID:  Nutr Neurosci. 2023 May 5:1-13. Epub 2023 May 5. PMID: 37144738 Abstract Title:  Protective effect of resveratrol and tannic acid combination on aluminium chloride induced neurotoxicity in rats. Abstract:  OBJECTIVE: Alzheimer's disease is a progressive neurodegenerative disease and one of the most common causes of dementia. Despite recent advancements, there exists an unmet need for a suitable therapeutic option. This study aimed to evaluate the protective effects of the combination of resveratrol (20mg/kg/day p.o.) and tannic acid (50mg/kg/day p.o.) to reduce aluminium trichloride-induced Alzheimer's disease in rats.METHODS: Wistar rats weighing 150-200g were administered with aluminium chloride (100mg/kg/day p.o.) for 90 days to induce neurodegeneration and Alzheimer's disease. Neurobehavioral changes were assessed using novel object recognition test, elevated plus maze test, and Morris water maze test. Histopathological studies were performed using H&E stain and Congo Red stains to check amyloid deposits. Further oxidative stress was measured in brain tissue.RESULTS: Aluminium trichloride treated negative control group showed cognitive impairment in the Morris water maze test, novel object recognition test, and elevated plus maze test. Further, the negative control group showed significant oxidative stress, increase amyloid deposits, and severe histological changes. Treatment with the combination of resveratrol and tannic acid showed significant attenuation in cognitive impairment. The oxidative stress markers and amyloid plaque levels were significantly attenuated with the treatment.CONCLUSION: The present study indicates the beneficial effects of resveratrol-tannic acid combination in AlClinduced neurotoxicity in rats.

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PMID:  Neuroscience. 2023 Jun 15 ;521:134-147. Epub 2023 May 3. PMID: 37142180 Abstract Title:  Resveratrol Attenuates the Disruption of Lipid Metabolism Observed in Amyloid Precursor Protein/Presenilin 1 Mouse Brains and Cultured Primary Neurons Exposed to A. Abstract:  To examine whether resveratrol (RSV), an activator of silent mating-type information regulation 2 homolog 1 (SIRT1), can reverse the disruption of lipid metabolism caused by-amyloid peptide (A), APP/PS1 mice or cultured primary rat neurons were treated with RSV, suramin (inhibitor of SIRT1), ZLN005, a stimulator of peroxisome proliferator-activated receptorcoactivator-1(PGC-1), or PGC-1silencing RNA. In the brains of the APP/PS1 mice, expressions of SIRT1, PGC-1, low-density lipoprotein receptor (LDLR) and very LDLR (VLDLR) were reduced at the protein and, in some cases, mRNA levels; while the levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein E (ApoE), total cholesterol and LDL were all elevated. Interestingly, these changes were reversed by administration of RSV, while being aggravated by suramin. Furthermore, activation of PGC-1, but inhibition of SIRT1, decreased the levels of PCSK9 and ApoE, while increased those of LDLR and VLDLR in the neurons exposed to A, and silencing PGC-1, but activation of SIRT1, did not influence the levels of any of these proteins. These findings indicate that RSV can attenuate the disruption of lipid metabolism observed in the brains of APP mice and in primary neurons exposed to Aby activating SIRT1, in which the mechanism may involve subsequently affecting PGC-1.

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PMID:  Microsc Res Tech. 2023 May 2. Epub 2023 May 2. PMID: 37129001 Abstract Title:  Resveratrol inhibits ferroptosis via activating NRF2/GPX4 pathway in mice with spinal cord injury. Abstract:  Ferroptosis is a newly defined form of cell death involved in neurologic disease. Resveratrol is a non-flavonoid polyphenolic compound with anti-inflammatory and antioxidant properties, but its potential therapeutic mechanism in spinal cord injury (SCI) remains unknown. Therefore, this study evaluates the mechanism by which resveratrol promotes neurological and motor function recovery in mice with SCI. The motor function of mice was evaluated using the Basso Mouse Scale score and footprint test. The effect of resveratrol on the neuronal cell state was observed using NeuN, fluoro-Jade C, and Nissl staining. The expression of iron content in injured segments was observed using Perls blue and Diaminobenzidine staining. The effect of resveratrol on the levels of malondialdehyde, glutathione, Fe, and glutathione peroxidase 4 enzyme activity was also investigated. The mitochondrial ultrastructures of injured segment cells were observed using transmission electron microscope, while the protein levels of ferroptosis-related targets were detected using Western blot. Our findings show that resveratrol improves motor function after SCI and has certain neuroprotective effects; in ferroptosis-related studies, resveratrol inhibited the expression of ferroptosis-related proteins and ions. Resveratrol improved changes in mitochondrial morphology. Mechanistically, the Nrf2 inhibitor ML385 reversed the inhibitory effect of resveratrol on ferroptosis-related genes, indicating that resveratrol inhibits ferroptosis through the Nrf2/GPX4 pathway. Our findings elucidate that resveratrol promotes functional recovery, inhibits ferroptosis post-SCI, and provides an experimental basis for subsequent clinical translational research.

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PMID:  Ecotoxicol Environ Saf. 2023 Jun 15 ;258:114931. Epub 2023 Apr 28. PMID: 37121080 Abstract Title:  Resveratrol reliefs DEHP-induced defects during human decidualization. Abstract:  Di-(2-Ethylhexyl) phthalate (DEHP) is widely used as an additive in many plastic products. Studies have revealed that DEHP persistent exposure can affect embryonic development and lead to adverse female reproductive disorders. The establishment of pregnancy involves extensive changes in the endometrial tissue, including massive extracellular matrix (ECM) remodeling. Decidualization of the endometrium provides a suitable environment for subsequent growth by causing changes in the morphology of the uterine stromal cells, is a key process in human pregnancy. Resveratrol (RSV) is a natural polyphenolic plant antitoxin with a wide range of pharmacological effects. Growing evidence indicates that RSV has therapeutic effects on certain female reproductive disorders. In this study, the effect of DEHP on cell viability was investigated by cell proliferation assay. Cell decidualization was induced in vitro, and the downregulation of molecules associated with decidualization was confirmed through quantitative real-time PCR and western blot analysis. Immunofluorescence analysis revealed alteration in cell morphology, and found that administration of DEHP sufficiently induced ERentry into the nucleus. The effect of DEHP on cells was fully verified by RNA-seq analysis. Interestingly, an upregulation of decidual molecules was observed after rescue with RSV, which was confirmed by RNA-seq transcriptome analysis and quantitative real-time PCR assay. Additionally, the expression of ECM remodeling-related genes was significantly restored by RSV administration. The study revealed the potential mechanisms of DEHP-induced decidualization defects and the functional relieving roles of RSV while providing a perspective therapeutic candidate for alleviating the DEHP-induced deficiencies in decidualization.

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PMID:  J Sci Food Agric. 2023 Apr 28. Epub 2023 Apr 28. PMID: 37115015 Abstract Title:  Resveratrol protects against cadmium-induced cerebrum toxicity through modifications of the cytochrome P450 enzyme system in microsomes. Abstract:  BACKGROUND: Cadmium (Cd), known as a vital contaminant in the environment, penetrates the blood-brain barrier and accumulates in the cerebrum. Acute toxicosis of Cd, which leads to lethal cerebral edema, intracellular accumulation and cellular dysfunction, remains to be illuminated with regard to the exact molecular mechanism of cerebral toxicity. Resveratrol (RES), present in the edible portions of numerous plants, is a simply acquirable and correspondingly less toxic natural compound with neuroprotective potential, which provides some theoretical bases for antagonizing Cd-induced cerebral toxicity.RESULTS: This work was executed to research the protective effects of RES against Cd-induced toxicity in chicken cerebrum. Markedly, these lesions were increased in the Cd group, which also exhibited a thinner cortex, reduced granule cells, vacuolar degeneration, and an enlarged medullary space in the cerebrum. Furthermore, Cd induced CYP450 enzyme metabolism disorders by disrupting the nuclear xenobiotic receptor response (NXRs), enabling the cerebrum to reduce the ability to metabolize exogenous substances, eventually leading to Cd accumulation. Meanwhile, accumulated Cd promoted oxidative damage and synergistically promoted the damage to neurons and glial cells.CONCLUSION: RES initiated NXRs (especially for aromatic receptor and pregnancy alkane X receptor), decreasing the expression of CYP450 genes, changing the content of CYP450, maintaining CYP450 enzyme normal activities, and exerting antagonistic action against the Cd-induced abnormal response of nuclear receptors. These results suggest that the cerebrum toxicity caused by Cd was reduced by pretreatment with RES.2023 Society of Chemical Industry.

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PMID:  Toxics. 2023 Apr 17 ;11(4). Epub 2023 Apr 17. PMID: 37112606 Abstract Title:  Natural Polyphenols-Resveratrol, Quercetin, Magnolol, and-Catechin-Block Certain Aspects of Heroin Addiction and Modulate Striatal IL-6 and TNF-. Abstract:  We have examined the effects of four different polyphenols in attenuating heroin addiction using a conditioned place preference (CPP) paradigm. Adult male Sprague Dawley rats received heroin (alternating with saline) in escalating doses starting from 10 mg/kg, i.p. up to 80 mg/kg/d for 14 consecutive days. The rats were treated with distilled water (1 mL), quercetin (50 mg/kg/d),-catechin (100 mg/kg/d), resveratrol (30 mg/kg/d), or magnolol (50 mg/kg/d) through oral gavage for 7 consecutive days, 30 min before heroin administration, starting on day 8. Heroin withdrawal manifestations were assessed 24 h post last heroin administration following the administration of naloxone (1 mg/kg i.p). Heroin CPP reinstatement was tested following a single dose of heroin (10 mg/kg i.p.) administration. Striatal interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-) were quantified (ELISA) after naloxone-precipitated heroin withdrawal. Compared to the vehicle, the heroin-administered rats spent significantly more time in the heroin-paired chamber (

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PMID:  Pharmaceutics. 2023 Apr 19 ;15(4). Epub 2023 Apr 19. PMID: 37111772 Abstract Title:  Double-Loaded Doxorubicin/Resveratrol Polymeric Micelles Providing Low Toxicity on Cardiac Cells and Enhanced Cytotoxicity on Lymphoma Cells. Abstract:  The anthracycline antibiotic doxorubicin is a well-known antitumour agent, however its cardiotoxicity is a significant obstacle to therapy. The aim of the present study was to improve the safety of doxorubicin through its simultaneous encapsulation with a cardioprotective agent (resveratrol) in Pluronic micelles. The formation and double-loading of the micelles was performed via the film hydration method. Infrared spectroscopy proved the successful incorporation of both drugs. X-ray diffraction analyses revealed that resveratrol was loaded in the core, whereas doxorubicin was included in the shell. The double-loaded micelles were characterised by a small diameter (26 nm) and narrow size distribution, which is beneficial for enhanced permeability and retention effects. The in vitro dissolution tests showed that the release of doxorubicin depended on the pH of the medium and was faster than that of resveratrol. In vitro studies on cardioblasts showed the opportunity to reduce the cytotoxicity of doxorubicin through the presence of resveratrol in double-loaded micelles. Higher cardioprotection was observed when the cells were treated with the double-loaded micelles compared with referent solutions with equal concentrations of both drugs. In parallel, treatments of L5178 lymphoma cells with the double-loaded micelles revealed that the cytotoxic effect of doxorubicin was enhanced. Thus, the study demonstrated that the simultaneous delivery of doxorubicin and resveratrol via the micellar system enabled the cytotoxicity of doxorubicin in lymphoma cells and lowered its cardiotoxicity in cardiac cells.

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PMID:  Mol Cell Biochem. 2023 Apr 19. Epub 2023 Apr 19. PMID: 37074505 Abstract Title:  Cardioprotective role of a magnolol and honokiol complex in the prevention of doxorubicin-mediated cardiotoxicity in adult rats. Abstract:  Doxorubicin (DOXO) induces marked cardiotoxicity, though increased oxidative stress while there are some documents related with cardioprotective effects of some antioxidants against organ-toxicity during cancer treatment. Although magnolia bark has some antioxidant-like effects, its action in DOXO-induced heart dysfunction has not be shown clearly. Therefore, here, we aimed to investigate the cardioprotective action of a magnolia bark extract with active component magnolol and honokiol complex (MAHOC; 100 mg/kg) in DOXO-treated rat hearts. One group of adult male Wistar rats was injected with DOXO (DOXO-group; a cumulative dose of 15 mg/kg in 2-week) or saline (CON-group). One group of DOXO-treated rats was administered with MAHOC before DOXO (Pre-MAHOC group; 2-week) while another group was administered with MAHOC following the 2-week DOXO (Post-MAHOC group). MAHOC administration, before or after DOXO, provided full survival of animals during 12-14 weeks, and significant recoveries in the systemic parameters of animals such as plasma levels of manganese and zinc, total oxidant and antioxidant statuses, and also systolic and diastolic blood pressures. This treatment also significantly improved heart function including recoveries in end-diastolic volume, left ventricular end-systolic volume, heart rate, cardiac output, and prolonged P-wave duration. Furthermore, the MAHOC administrations improved the structure of left ventricles such as recoveries in loss of myofibrils, degenerative nuclear changes, fragmentation of cardiomyocytes, and interstitial edema. Biochemical analysis in the heart tissues provided the important cardioprotective effect of MAHOC on the redox regulation of the heart, such as improvements in activities of glutathione peroxidase and glutathione reductase, and oxygen radical-absorbing capacity of the heart together with recoveries in other systemic parameters of animals, while all of these benefits were observed in the Pre-MAHOC treatment group, more prominently. Overall, one can point out the beneficial antioxidant effects of MAHOC in chronic heart diseases as a supporting and complementing agent to the conventional therapies.

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PMID:  J Asian Nat Prod Res. 2023 Apr 3:1-9. Epub 2023 Apr 3. PMID: 37010929 Abstract Title:  Use of honokiol in lung cancer therapy: a mini review of its pharmacological mechanism. Abstract:  Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,2'-diol) is a biologically active natural product derived fromand has been shown to have excellent biological activities. This paper discusses research progress on the use of honokiol in the treatment of lung cancer, as studies have confirmed that honokiol can exert anti-lung-cancer effects through multiple pathways and multiple signaling pathways, such as inhibiting angiogenesis, affecting mitochondrial function and apoptosis, regulating of autophagy and epithelial-mesenchymal transition (EMT). In addition, honokiol combined with other chemotherapy drugs is also a way in which it can be applied.

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PMID:  Free Radic Biol Med. 2023 Jun ;202:62-75. Epub 2023 Mar 28. PMID: 36997099 Abstract Title:  Honokiol prevents chronic cerebral hypoperfusion induced astrocyte A1 polarization to alleviate neurotoxicity by targeting SIRT3-STAT3 axis. Abstract:  Alzheimer's Dementia (AD) and Vascular Dementia (VaD) are two main types of dementias for which no specific treatment is available. Chronic Cerebral Hypoperfusion (CCH) is a pathogenesis underlying AD and VaD that promotes neuroinflammatory responses and oxidative stress. Honokiol (HNK) is a natural compound isolated from magnolia leaves that can easily cross blood brain barrier and has anti-inflammatory and antioxidant effects. In the present study, the effects of HNK on astrocyte polarization and neurological damage in in vivo and in vitro models of chronic cerebral hypoperfusion were explored. We found that HNK was able to inhibit the phosphorylation and nuclear translocation of STAT3, A1 polarization, and reduce conditioned medium's neuronal toxicity of astrocyte under chronic hypoxia induced by cobalt chloride; STAT3 phosphorylation inhibitor C188-9 was able to mimic the above effects of HNK, suggesting that HNK may inhibit chronic hypoxia-induced A1 polarization in astrocytes via STAT3. SIRT3 inhibitor 3-TYP reversed, while Sirt3 overexpression mimicked the inhibitory effects of HNK on oxidative stress, STAT3 phosphorylation and nuclear translocation, A1 polarization and neuronal toxicity of astrocyte under chronic hypoxic conditions. For in vivo research, continuous intraperitoneal injection of HNK (1 mg/kg) for 21 days ameliorated the decrease in SIRT3 activity and oxidative stress, inhibited astrocytic STAT3 nuclear translocation and A1 polarization, and prevented neuron and synaptic loss in the hippocampal of CCH rats. Besides, HNK application improved the spatial memory impairment of CCH rats, as assessed with Morris Water Maze. In conclusion, these results suggest that the phytochemical HNK can inhibit astrocyte A1 polarization via regulating SIRT3-STAT3 axis, thus improving CCH-induced neurological damage. These results highlight HNK as novel treatment for dementia with underlying vascular mechanisms.

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PMID:  Int Immunopharmacol. 2023 May ;118:109849. Epub 2023 Mar 16. PMID: 36933490 Abstract Title:  Honokiol reduces fungal burden and ameliorate inflammation lesions of Aspergillus fumigatus keratitis via Dectin-2 down-regulation. Abstract:  PURPOSE: To screen and identify the mechanism of honokiol on anti-fungi and anti-inflammation in fungal keratitis (FK) through bioinformatic analysis and biological experiments.METHODS: Transcriptome profile demonstrated differential expression genes (DEGs) of Aspergillus fumigatus keratitis between PBS-treated and honokiol-treated groups via bioinformatics analyses. Inflammatory substances were quantified by qRT-PCR, Western blot and ELISA, and macrophage polarization was examined by flow cytometry. Periodic acid Schiff staining and morphological interference assay were used to detect hyphal distribution in vivo and fungal germination in vitro, respectively. Electron microscopy was to illustrate hyphal microstructure.RESULTS: Illumina sequencing demonstrated that compared with the honokiol group, 1175 up-regulated and 383 down-regulated genes were induced in C57BL/6 mice Aspergillus fumigatus keratitis with PBS treatment. Through GO analysis, some differential expression proteins (DEPs) played major roles in biological processes, especially fungal defense and immune activation. KEGG analysis provided fungus-related signaling pathways. PPI analysis demonstrated that DEPs from multiple pathways form a close-knit network, providing a broader context for FK treatment. In biological experiments, Dectin-2, NLRP3 and IL-1were upregulated by Aspergillus fumigatus to evaluate immune response. Honokiol could reverse the trend, comparable to Dectin-2 siRNA interference. Meanwhile, honokiol could also play an anti-inflammatory role via promoting M2 phenotype polarization. Moreover, honokiol reduced hyphal distribution in the stroma, delayed germination, and destroyed the hyphal cell membrane in-vitro.CONCLUSIONS: Honokiol possesses anti-fungal and anti-inflammatory effects in Aspergillus fumigatus keratitis and may develop a potential and safe therapeutic modality for FK.

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PMID:  Chin Med. 2023 Mar 17 ;18(1):30. Epub 2023 Mar 17. PMID: 36932412 Abstract Title:  Honokiol acts as an AMPK complex agonist therapeutic in non-alcoholic fatty liver disease and metabolic syndrome. Abstract:  BACKGROUND: Non-alcoholic fatty liver (NAFLD) and its related metabolic syndrome have become major threats to human health, but there is still a need for effective and safe drugs to treat these conditions. Here we aimed to identify potential drug candidates for NAFLD and the underlying molecular mechanisms.METHODS: A drug repositioning strategy was used to screen an FDA-approved drug library with approximately 3000 compounds in an in vitro hepatocyte model of lipid accumulation, with honokiol identified as an effective anti-NAFLD candidate. We systematically examined the therapeutic effect of honokiol in NAFLD and metabolic syndrome in multiple in vitro and in vivo models. Transcriptomic examination and biotin-streptavidin binding assays were used to explore the underlying molecular mechanisms, confirmed by rescue experiments.RESULTS: Honokiol significantly inhibited metabolic syndrome and NAFLD progression as evidenced by improved hepatic steatosis, liver fibrosis, adipose inflammation, and insulin resistance. Mechanistically, the beneficial effects of honokiol were largely through AMPK activation. Rather than acting on the classical upstream regulators of AMPK, honokiol directly bound to the AMPK1 subunit to robustly activate AMPK signaling. Mutation of honokiol-binding sites of AMPK1 largely abolished the protective capacity of honokiol against NAFLD.CONCLUSION: These findings clearly demonstrate the beneficial effects of honokiol in multiple models and reveal a previously unappreciated signaling mechanism of honokiol in NAFLD and metabolic syndrome. This study also provides new insights into metabolic disease treatment by targeting AMPK1 subunit-mediated signaling activation.

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PMID:  Acta Pharm Sin B. 2023 Feb ;13(2):577-597. Epub 2022 Aug 10. PMID: 36873166 Abstract Title:  Honokiol alleviated neurodegeneration by reducing oxidative stress and improving mitochondrial function in mutant SOD1 cellular and mouse models of amyotrophic lateral sclerosis. Abstract:  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons (MNs) with large unmet medical needs. Multiple pathological mechanisms are considered to contribute to the progression of ALS, including neuronal oxidative stress and mitochondrial dysfunction. Honokiol (HNK) has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke, Alzheimer's disease and Parkinson's disease. Here we found that honokiol also exhibited protective effects in ALS disease models bothand. Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins (SOD1-G93A cells for short). Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione (GSH) synthesis and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway. Also, honokiol improved both mitochondrial function and morphologyfine-tuning mitochondrial dynamics in SOD1-G93A cells. Importantly, honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function. The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice. Overall, honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.

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PMID:  Life Sci. 2023 May 1 ;320:121543. Epub 2023 Mar 4. PMID: 36871934 Abstract Title:  Nephroprotective effects of honokiol in a high-fat diet-streptozotocin rat model of diabetic nephropathy. Abstract:  AIMS: Diabetic nephropathy (DN) is the foremost basis of end-stage kidney failure implicating endoplasmic reticulum (ER) stress and dysregulation of Rho kinase/Rock pathway. Magnolia plants are used in traditional medicine systems in Southeast Asia owing to bioactive phytoconstituents. Earlier, honokiol (Hon) exhibited therapeutic potential in experimental models of metabolic, renal, and brain disorders. In the present study, we evaluated potential of Hon against DN and possible molecular mechanisms.MAIN METHODS: In the existing experiments, high-fat diet (HFD) (17 weeks) and streptozotocin (STZ) (40 mg/kg once) induced DN rats were orally treated with Hon (25, 50, 100 mg/kg) or metformin (150 mg/kg) for 8 weeks.KEY FINDINGS: Hon attenuated albuminuria, blood biomarkers (e.g., urea nitrogen, glucose, C-reactive protein, and creatinine) and ameliorated lipid profile, electrolytes levels (Na/K), and creatinine clearance against DN. Hon significantly decreased renal oxidative stress and inflammatory biomarkers against DN. Histomorphometry and microscopic analysis revealed nephroprotective effects of Hon marked by a decrease in leukocyte infiltration, renal tissue damage, and urine sediments. RT-qPCR showed that Hon treatment attenuated mRNA expression of transforming growth factor-1 (TGF-1), endothelin-1 (ET-1), ER stress markers (GRP78, CHOP, ATF4, and TRB3), and Rock 1/2 in DN rats. Data from ELISA supported a decrease in levels of TGF-1, ET-1, ER stress markers, and Rock1/2 by Hon.SIGNIFICANCE: Hon attenuated hyperglycemia, redox imbalance, and inflammation and improved renal functions in rats. Hon alleviates DN pathogenesis possibly by attenuating ER stress and Rock pathway.

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PMID:  Cell Death Dis. 2023 Mar 1 ;14(3):174. Epub 2023 Mar 1. PMID: 36859530 Abstract Title:  Honokiol suppresses the aberrant interactions between renal resident macrophages and tubular epithelial cells in lupus nephritis through the NLRP3/IL-33/ST2 axis. Abstract:  Lupus nephritis (LN) is a type of immune-complex nephritis caused by systemic lupus erythematosus and is a major contributor to mortality and morbidity. Honokiol (HNK) has been found to have a therapeutic effect on LN, but its action mechanism remains unclear. In this study, we first demonstrated that HNK attenuates kidney injury in MRL/lpr mice. Results from RNA sequencing combined with ingenuity pathway analysis suggested that HNK plays an anti-LN role through inhibition of the NLRP3 inflammasome and IL33. GEO chip data, single-cell data, and clinical samples from LN patients demonstrated that the pyroptosis and IL-33/ST2 pathways are abnormally activated during the stage of LN. In vivo, similar to the results of the AAV-mediated NLRP3 shRNA MRL/lpr model, HNK downregulated serum and renal IL-33 levels, and suppressed NLRP3 inflammasome and the IL-33/ST2 axis in the kidney. In vitro, co-culturing NLRP3-overexpressing or IL-33 knocked-down rat renal macrophages with NRK-52E cells confirmed that NLRP3 activation in resident macrophages directly upregulates IL-33, which in turn mediates the IL-33/ST2/NF-B pathway to promote the inflammatory response of renal tubular epithelial cells. Furthermore, a molecular docking model and surface plasmon resonance analysis were utilized to demonstrate a direct interaction between HNK and NLRP3. In conclusion, this study provides a novel anti-LN treatment strategy in which HNK plays a preventive and therapeutic role against LN by suppressing the abnormal crosstalk between renal resident macrophages and renal tubular epithelial cells by inhibiting the activation of the NLRP3/IL-33/ST2 axis.

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PMID:  Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2023 Apr ;39(4):332-338. PMID: 37087551 Abstract Title:  [Kiwi fruit essence reduces radiation-induced lung injury by down-regulating TNF-and PDGF-B in rats]. Abstract:  Objective To observe the role of tumor necrosis factor-(TNF-) and platelet-derived growth factor-B (PDGF-B) in kiwi fruit essence-mediated protection of radiation-induced lung injury (RILI) in rats. Methods 96 male healthy Sprague-Dawley rats were divided into normal control group, model group, and kiwi fruit essence treatment group(60 and 240 mg/kg) by the random number table method, with 24 animals in each group. The whole lungs underwent 6 MV X-ray irradiation (18 Gy) to induce RILI animal models in rats of the latter three groups. On the next day after irradiation, rats in the latter two groups were intragastrically administrated with 60 or 240 mg/kg kiwi fruit essence, once a day. The rats in the normal control and model groups were treated with 9 g/L sodium chloride solution. Eight rats in the latter three groups were randomly sacrificed on days 14, 28, and 56, while normal control rats were sacrificed on day 56 as the overall control. Blood samples were collected and separated. Serum concentrations of TNF-and PDGF-B were detected using ELISA. The lung tissues were isolated for HE and Masson staining to evaluate alveolitis and pulmonary fibrosis (PF). The hydroxyproline (HYP) content in lung tissues was detected. The mRNA and protein expression of pulmonary TNF-and PDGF-B were determined by quantitative real-time PCR and immunohistochemistry. Results Compared with the model group, treatment with 60 and 240 mg/kg kiwi fruit essence group significantly reduced alveolitis on days 14 and 28 as well as PF lesions on days 28 and 56. Compared with the normal control group, HYP content in the lung tissue of the model group increased on day 28 and day 56, while TNF-and PDGF-B levels in the serum and lung tissues increased at each time point. Compared with the model group during the same period, 60 and 240 mg/kg kiwi fruit essence element treatment group reported the diminished levels of serum and pulmonary TNF-on day 14 and day 28. Consistently, the lung tissue HYP content and serum and pulmonary PDGF-B levels on day 28 and day 56 were reduced. In addition, the above indicators in the 240 mg/kg kiwi fruit essence treatment group were lower than those for the 60 mg/kg kiwi fruit essence treatment group. Conclusion Kiwi fruit essence can alleviate RILI in rats, which is related to the down-regulation of TNF-expression at the early stage and decreased PDGF-B level at the middle and late stages.

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PMID:  Nat Prod Res. 2023 Jan 9:1-5. Epub 2023 Jan 9. PMID: 36622893 Abstract Title:  Exploration of bioactive molecules fromandas an immunity modulatormolecular docking and molecular dynamics simulation study. Abstract:  andare the widely used plant in Ayurvedic systems of medicine. Both plants are well known for their immunomodulatory activity. In the current study, in silico exploration was performed using advanced computational techniques such as molecular docking and molecular dynamics simulation approach. Bioactive molecules from theandwere docked against the Human IL-2. Out of all the docked bioactive molecules, Pygenic acid-B (PubChem CID:146157192) showed the highest negative binding affinity.

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PMID:  Women Health. 2023 ;63(5):359-369. Epub 2023 Apr 20. PMID: 37080903 Abstract Title:  Effect ofon gestational diabetes mellitus and its complications. Abstract:  Ayurvedic system of medicine uses giloy or guduchi, also known as(TC), to treat diabetes and related diseases like hyperglycemia and hyperlipididemia. However, its usage in gestational diabetes mellitus (GDM) is not well studied. The primary objective of the study was to examine the effects of water extract of TC called satva, essential oil, and hydroalcoholic (HA) extract on GDM and its complications and to explore their mechanism of action using mice model. We used streptozotocin-induced diabetes in pregnant mice as murine model and tested TC preparations for anti-GDM activities. Blood glucose, insulin, litter size, and placental weight were assessed. ELISA method was used to measure plasma insulin level to compute homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and homeostatic model assessment for assessing beta cell function (HOMA-Beta) levels to estimate insulin resistance, insulin sensitivity, and beta cell function respectively. TC-treated groups had significantly higher serum insulin levels, QUICKI, average litter size, and lower placental weight (

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PMID:  Am J Gastroenterol. 2023 Jun 1 ;118(6):1058-1068. Epub 2022 Dec 20. PMID: 36537785 Abstract Title:  Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort-Results of an International Multicenter Randomized Controlled Trial. Abstract:  INTRODUCTION: Consumption of green kiwifruit is known to relieve constipation. Previous studies have also reported improvements in gastrointestinal (GI) comfort. We investigated the effect of consuming green kiwifruit on GI function and comfort.METHODS: Participants included healthy controls (n = 63), patients with functional constipation (FC, n = 60), and patients with constipation-predominant irritable bowel syndrome (IBS-C, n = 61) randomly assigned to consume 2 green kiwifruits or psyllium (7.5 g) per day for 4 weeks, followed by a 4-week washout, and then the other treatment for 4 weeks. The primary outcome was the number of complete spontaneous bowel movements (CSBM) per week. Secondary outcomes included GI comfort which was measured using the GI symptom rating scale, a validated instrument. Data (intent-to-treat) were analyzed as difference from baseline using repeated measures analysis of variance suitable for AB/BA crossover design.RESULTS: Consumption of green kiwifruit was associated with a clinically relevant increase of1.5 CSBM per week (FC; 1.53, P

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PMID:  Genes Environ. 2022 Dec 9 ;44(1):26. Epub 2022 Dec 9. PMID: 36494703 Abstract Title:  Chemopreventive effects and anti-tumorigenic mechanisms of Actinidia arguta, known as sarunashi in Japan toward 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- induced lung tumorigenesis in a/J mouse. Abstract:  BACKGROUND: Previously, we reported the inhibitory effect of Actinidia arguta juice, known as sarunashi juice (sar-j) in Japan, on mutagenesis, inflammation, and mouse skin tumorigenesis. The components of A. arguta responsible for the anti-mutagenic effects were identified to be water-soluble, heat-labile phenolic compounds. We proposed isoquercetin (isoQ) as a candidate anticarcinogenic component. In this study, we sought to investigate the chemopreventive effects of A. arguta juice and isoQ on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, and identify the possible mechanisms underlying the anti-tumorigenic effects of A. arguta.RESULTS: The number of tumor nodules per mouse lung in the group injected with NNK and administered A. arguta juice orally was significantly lower than that in the group injected with NNK only. Oral administration of isoQ also reduced the number of nodules in the mouse lungs. As expected, the mutagenicity of NNK and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) detected using S. typhimurium TA1535 decreased in the presence of sar-j. However, NNK and MNNG mutagenicity detected using S. typhimurium YG7108, a strain lacking the O-methylguanine DNA methyltransferases (ogtand ada) did not decrease in the presence of sar-j suggesting that sar-j may mediate its antimutagenic effect by enhancing the DNA damage repair by ogtand ada. Phosphorylation of Akt, with or without epidermal growth factor stimulation, in A549 cells was significantly decreased following sar-j and isoQ treatment, indicating that components in sar-j including isoQ suppressed the PI3K/AKT signaling pathways.CONCLUSIONS: Sar-j and isoQ reduced NNK-induced lung tumorigenesis. Sar-j targets both the initiation and growth/progression steps during carcinogenesis, specifically via anti-mutagenesis, stimulation of alkyl DNA adduct repair, and suppression of Akt-mediated growth signaling. IsoQ might contribute in part to the biological effects of sar-j via suppression of Akt phosphorylation, but it may not be the main active ingredient.

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PMID:  Cureus. 2022 Dec ;14(12):e32505. Epub 2022 Dec 14. PMID: 36654621 Abstract Title:  Spontaneous Remission of Metastatic Castration-Resistant Prostate Cancer: Coley's Toxin Revisited? Abstract:  Metastatic castration-resistant prostate cancer (mCRPC) is an incurable disease associated with poor survival outcomes. Immunotherapy was first pioneered by William Coley in the early 20th century with the injection of live and heat-killed bacteria. Despite the recent emergence of cancer immunotherapy, mCRPC remains an elusive immune target. Spontaneous remission of mCRPC following microbial infection has not been described in the literature to date. We present evidence of spontaneous biochemical and radiologic regression in a patient with mCRPC following multiple episodes of sepsis.

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PMID:  Environ Pollut. 2023 Aug 1 ;330:121783. Epub 2023 May 8. PMID: 37164221 Abstract Title:  Neonatal exposure to bisphenol analogues disrupts genital development in male mice. Abstract:  The public concern and governmental regulations on bisphenol A (BPA) have stimulated the development and production of alternative analogues to replace BPA in a myriad of applications. Given the endocrine disrupting activities of BPA and potentially other analogues, the present study investigated and compared the effects of neonatal exposure to BPA, BPB, BPE, BPF, and BPS on the genital development in male mice. Pups were injected subcutaneously on the right shoulder in the mornings of postnatal days P0.5, P2, P4, and P6, resulting in a low dose of 0.05 g/g body weight (bw)/day and a high dose of 10 g/g bw/day. Mice were sacrificed at predetermined time and evaluated for gene expression levels (3 days after birth or P3), steroid hormone levels (P5), and morphological changes (P21). The results demonstrated that BPA, BPB, BPE, or BPF significantly shortened glans penis length and anogenital distance, while BPS didn't. Testis weight and anogenital distance were also significantly affected by BPA, BPE or BPF. The results also revealed that bisphenol analogues exposure significantly reduced testosterone levels, and altered the expression levels of developmental genes networks in developing penis of mice. Our data demonstrate that selected bisphenol analogues may possess similar endocrine disrupting effects compared to BPA, and exposure to these analogues could affect reproductive development of male mice. This raises the concern on the environmental and health safety of bisphenol analogues applied as industrial BPA replacements.

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PMID:  J Hazard Mater. 2023 Jul 5 ;453:131410. Epub 2023 Apr 12. PMID: 37088024 Abstract Title:  Prenatal bisphenol S exposure induces hepatic lipid deposition in male mice offspring through downregulation of adipose-derived exosomal miR-29a-3p. Abstract:  The increased usage of bisphenol S (BPS) results in wide distribution in pregnant women. In this study, pregnant mice were given multiple-dose BPS during gestation. Results showed that prenatal BPS exposure (50 g/kg/day) induced increased weight gain, dyslipidemia, higher liver triglyceride (TG), adipocyte hypertrophy, and hepatic lipid deposition in male offspring. Exosomes play important roles in regulating lipid metabolism. Here, serum exosomes and adipose miRNA sequencing of male offspring indicated a remarkable decrease in miR-29a-3p expression. To clarify whether adipocyte-derived exosomes mediate hepatic lipid deposition, exosomes were extracted from BPS-treated adipocytes and co-cultured with hepatocytes. These exosomes could be taken up by hepatocytes and promoted lipid deposition, and notably, exosomal miR-29a-3p was downregulated. Furthermore, miR-29a-3p knockdown in adipocyte-derived exosomes promoted hepatocyte lipid deposition, whereas overexpression led to the opposite effect. Also, the role of miR-29a-3p was demonstrated in hepatocytes by overexpressing or knocking it down. Subsequent studies have shown that miR-29a-3p can promote lipid deposition by directly targeting Col4a1. Taken together, prenatal BPS exposure could lead to lower miR-29a-3p yield in adipocyte-derived exosomes and decrease miR-29a-3p content transported to hepatocytes, which further negatively regulate Col4a1 and promote hepatic lipid deposition. Our findings provided clues to maternal environmental exposure-induced liver metabolic diseases.

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PMID:  Environ Int. 2023 Apr ;174:107926. Epub 2023 Apr 10. PMID: 37075580 Abstract Title:  Occurrence of multiple bisphenol S analogues in children from Shantou, China. Abstract:  Emerging bisphenol S analogues (BPSs) have gained their application perspectives to replace bisphenol A (BPA) and BPA analogues (BPAs). However, the extent of human exposure and potential health risk from BPSs is rarely known yet. We hypothesized that children living in Shantou, China, a well-known e-waste recycling city, may expose to emerging BPSs together with BPA and BPAs. In this study, BPA, six commonly used BPAs and 11 emerging BPSs were determined simultaneously in 240 urine samples collected from children residing in Shantou. BPA, BPS, bisphenol F, bisphenol AF and three BPSs of 2,4'-bis(hydroxyphenyl)sulfone, 4-((4-(allyloxy)phenyl)sulfonyl)phenol and diphenylsulfone (DPS) were the urinary predominant bisphenols with detection frequencies of 67-100% in the children. BPA was found at the highest median concentration (3.36 g/g creatinine) followed by BPS (0.313) and DPS (0.187). It is interesting to find that the girls and children in the younger group (2  age 

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PMID:  Life Sci Alliance. 2023 Aug ;6(8). Epub 2023 May 9. PMID: 37160307 Abstract Title:  Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage. Abstract:  Glaucoma is a common neurodegenerative disorder characterized by retinal ganglion cell death, astrocyte reactivity in the optic nerve, and vision loss. Currently, lowering the intraocular pressure (IOP) is the first-line treatment, but adjuvant neuroprotective approaches would be welcome. Vitamin C possesses neuroprotective activities that are thought to be related to its properties as a co-factor of enzymes and its antioxidant effects. Here, we show that vitamin C promotes a neuroprotective phenotype and increases gene expression related to neurotropic factors, phagocytosis, and mitochondrial ATP production. This effect is dependent on the up-regulation of secreted phosphoprotein 1 (SPP1) in reactive astrocytes via the transcription factor E2F1. SPP1astrocytes in turn promote retinal ganglion cell survival in a mouse model of glaucoma. In addition, oral administration of vitamin C lowers the IOP in mice. This study identifies an additional neuroprotective pathway for vitamin C and suggests a potential therapeutic role of vitamin C in neurodegenerative diseases such as glaucoma.

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PMID:  Front Neurol. 2023 ;14:1130575. Epub 2023 Apr 20. PMID: 37153653 Abstract Title:  The neuroprotective effect of ascorbic acid against imidacloprid-induced neurotoxicity and the role of HO-1 in mice. Abstract:  Imidacloprid (IMI) is not only a neurotoxic agricultural pesticide but also a possible food contaminant. The aims of this study were to (1) explore the relationship between recurrent IMI administration and neuronal toxicity in mice and (2) evaluate the potential neuroprotective effect of ascorbic acid (AA), a substance with significant free radical scavenger and having property to block the inflammatory pathways. Mice were categorized as nave controls (administered vehicles for 28 days); the IMI-treatment animal group (administered po 45-mg/kg body weight of IMI per day for 28 days); and the IMI + AA treatment animal group (administered the same IMI dose + 200 mg/kg of AA orally for 28 days). On day 28, memory losses were assessed using the Y-maze and novel target identification behavioral tests. Mice were sacrificed 24 h after the final IMI treatments, as well as hippocampus tissues, were utilized to determine histological assessments, oxidative stress biomarkers, and Heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression levels. The findings demonstrated that IMI-treated mice had substantial impairment of spatial and non-spatial memory functions, as well as reduced antioxidant enzyme and acetylcholinesterase activity. The AA neuroprotective action was achieved through the suppression of the HO-1 expression as well as the stimulation of Nrf2 expression in hippocampal tissues. In summary, recurrent IMI exposure causes oxidative stress and neurotoxicity in mice, and the administration of AA significantly reduces the IMI toxicity possibly by the activation of the HO-1/Nrf2 pathway.

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PMID:  Front Cell Infect Microbiol. 2023 ;13:1152269. Epub 2023 Apr 19. PMID: 37153159 Abstract Title:  A pro-oxidant property of vitamin C to overcome the burden of latentinfection: A cross-talk review with Fenton reaction. Abstract:  Tuberculosis (TB), caused by the bacillus, is one of the deadliest infectious illnesses of our day, along with HIV and malaria.Chemotherapy, the cornerstone of TB control efforts, is jeopardized by the advent ofstrains resistant to many, if not all, of the existing medications.Isoniazid (INH), rifampicin (RIF), pyrazinamide, and ethambutol are used to treat drug-susceptible TB for two months, followed by four months of INH and RIF, but chemotherapy with potentially harmful side effects is sometimes needed to treat multidrug-resistant (MDR) TB for up to two years. Chemotherapy might be greatly shortened by drugs that killmore quickly while simultaneously limiting the emergence of drug resistance.Regardless of their intended target, bactericidal medicines commonly kill pathogenic bacteria (gram-negative and gram-positive) by producing hydroxyl radicalsthe Fenton reaction.Researchers have concentrated on vitamins with bactericidal properties to address the rising cases globally and have discovered that these vitamins are effective when given along with first-line drugs. The presence of elevated iron content, reactive oxygen species (ROS) generation, and DNA damage all contributed to VC's sterilizing action on. Moreover, it has a pleiotropic effect on a variety of biological processes such as detoxification, protein folding - chaperons, cell wall processes, information pathways, regulatory, virulence, metabolism etc.In this review report, the authors extensively discussed the effects of VC on, such as the generation of free radicals and bactericidal mechanisms with existing treatments, and their further drug development based on ROS production.

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PMID:  J Immunol. 2023 May 5. Epub 2023 May 5. PMID: 37144841 Abstract Title:  Prenol, but Not Vitamin C, of Fruit Binds to SARS-CoV-2 Spike S1 to Inhibit Viral Entry: Implications for COVID-19. Abstract:  Fruit consumption may be beneficial for fighting infection. Although vitamin C is the celebrity component of fruit, its role in COVID-19 is unclear. Because spike S1 of SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) on host cells to enter the cell and initiate COVID-19, using an-screen-based assay, we screened vitamin C and other components of fruit for inhibiting the interaction between spike S1 and ACE2. We found that prenol, but neither vitamin C nor other major components of fruit (e.g., cyanidin and rutin), reduced the interaction between spike S1 and ACE2. Thermal shift assays indicated that prenol associated with spike S1, but not ACE2, and that vitamin C remained unable to do so. Although prenol inhibited the entry of pseudotyped SARS-CoV-2, but not vesicular stomatitis virus, into human ACE2-expressing HEK293 cells, vitamin C blocked the entry of pseudotyped vesicular stomatitis virus, not SARS-CoV-2, indicating the specificity of the effect. Prenol, but not vitamin C, decreased SARS-CoV-2 spike S1-induced activation of NF-B and the expression of proinflammatory cytokines in human A549 lung cells. Moreover, prenol also decreased the expression of proinflammatory cytokines induced by spike S1 of N501Y, E484K, Omicron, and Delta variants of SARS-CoV-2. Finally, oral treatment with prenol reduced fever, decreased lung inflammation, enhanced heart function, and improved locomotor activities in SARS-CoV-2 spike S1-intoxicated mice. These results suggest that prenol and prenol-containing fruits, but not vitamin C, may be more beneficial for fighting against COVID-19.

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PMID:  Eur Rev Med Pharmacol Sci. 2023 Apr ;27(8):3322-3335. PMID: 37140282 Abstract Title:  Vitamin C as a potential ameliorating agent against hepatotoxicity among alcoholic abusers. Abstract:  OBJECTIVE: Drug and substance abuse remains a major medical problem globally. Alcohol consumption, particularly heavy drinking, is an important risk factor for many health problems and is a major contributor to the global burden of disease. Vitamin C has proven to be defensive against toxic substances and provides antioxidant and cytoprotective activity to hepatocytes. The aim of this study was to investigate vitamin C as a potential ameliorating agent against hepatotoxicity among alcohol abusers.PATIENTS AND METHODS: This study was a cross-sectional study that included eighty male hospitalized alcohol abusers and twenty healthy people as a control group. Alcohol abusers received standard treatment plus vitamin C. Total protein, albumin, total Bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and 8-hydroxhguanosine (8-OHdG) were investigated.RESULTS: This study reported that, in the alcohol abuser group, there was a significant increase in the total protein, bilirubin, AST, ALT, ALP, TBARS, SOD and 8-OHdG; on the other hand, there was a significant decrease in albumin, GSH and CAT compared with the control group. The alcohol abuser group treated with vitamin C showed a significant decrease in total protein, bilirubin, AST, ALT, ALP, TBARS, SOD and 8-OHdG; on the other hand, there was a significant increase in albumin, GSH and CAT compared with the control group.CONCLUSIONS: This study's findings suggest that alcohol abuse induces significant alterations in various hepatic biochemical parameters and oxidative stress and that vitamin C has a partial protective role in countering alcohol abuse-induced hepatotoxicity. Using vitamin C as an adjunctive supplement to standard treatment may be helpful in minimizing the toxic side effects of alcohol abuse.

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PMID:  Front Med (Lausanne). 2023 ;10:1121036. Epub 2023 Apr 5. PMID: 37122322 Abstract Title:  Effect of breathing exercises on oxidative stress biomarkers in humans: A systematic review and meta-analysis. Abstract:  BACKGROUND: Breathing exercises improve oxidative stress in healthy young adults and patients with diabetes, hypertension, and chronic obstructive pulmonary disease. Furthermore, the mechanism of respiratory intervention is controversial. Therefore, in this meta-analysis, we aimed to systematically evaluate the effects of breathing exercises on oxidative stress biomarkers in humans and provide evidence for the clinical application of breathing exercises.METHODS: The Embase, PubMed, Cochrane Library, Web of Science, CNKI, and WANFANG databases were searched for studies about the effects of breathing exercises on human oxidative stress levels, with no restraints regarding time, race, or language. The experimental group included various breathing exercises, and the outcome index included malondialdehyde, superoxide dismutase, and glutathione, nitric oxide, vitamin C, or total antioxidant capacity levels from a randomized controlled trial. Data were extracted by more than two authors and reviewed by one author.RESULTS: Ten studies were included from five countries. Data from patients with no disease, chronic obstructive pulmonary disease, hypertension, or diabetes were included. Participants who performed breathing exercises had greater changes in the included biomarkers than those who did not, suggesting that these biomarkers can be used to evaluate oxidative stress after respiratory interventions.CONCLUSION: Breathing exercises increased SOD and GSH activities and decreased MDA content.SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022337119, identifier CRD42022337119.

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PMID:  Arch Phys Med Rehabil. 2023 May 6. Epub 2023 May 6. PMID: 37150427 Abstract Title:  Effects of Breathing Exercises in Patients With Chronic Obstructive Pulmonary Disease: A Network Meta-analysis. Abstract:  OBJECTIVE: A network meta-analysis of randomized controlled trials (RCTs) was conducted to compare and rank the effectiveness of various breathing exercises for patients with chronic obstructive pulmonary disease (COPD).DATA SOURCES: We searched PubMed, Web of Science, Embase, and the Cochrane Library databases to determine the articles.STUDY SELECTION: Publications investigating the effect of breathing exercises on exercise capacity (six-minute walk test [6MWT]), pulmonary function (the ratio of the first second forced expiratory volume of forced vital capacity [FEV/FVC]), quality of life (St George's Respiratory Questionnaire [SGRQ]), inspiratory muscle pressure (maximum inspiratory pressure [PI]), and dyspnea (Borg scale) were searched.DATA EXTRACTION: Data extracted by 2 researchers were entered into predesigned tables for data extraction. The quality of the literature was assessed using the Cochrane Collaboration's tool.DATA SYNTHESIS: A total of 43 RCTs involving 1977 participants were analyzed. To boost exercise capacity, the top 2 exercises were inspiratory muscle training (75%), Chinese traditional fitness exercises (13%); To improve pulmonary function, the top 2 exercises were Chinese traditional fitness exercises (32%), diaphragm breathing (30%); To raise patients' quality of life, the top 2 exercises were yoga (52%), diaphragm breathing (28%); To increase inspiratory muscle pressure, the top 2 exercises were pursed-lip breathing (47%), Chinese traditional fitness exercises (25%); To improve dyspnea, the top 2 exercises were yoga (44%), inspiratory muscle training (22%).CONCLUSIONS: Various breathing exercises for COPD patients confer benefits that manifest in diverse ways. Pulmonary rehabilitation specialists could administer personalized breathing exercises tailored to each patient's condition to attain optimal therapeutic outcomes.

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PMID:  Front Psychiatry. 2023 ;14:1101046. Epub 2023 Apr 17. PMID: 37139325 Abstract Title:  The integration of yoga breathing techniques in cognitive behavioral therapy for post-traumatic stress disorder: A pragmatic randomized controlled trial. Abstract:  INTRODUCTION: In trauma-focused Cognitive Behavioral Therapy (TF-CBT), stabilization techniques are used before confrontation ones to increase stress/affect tolerance and thus effectiveness of CBT. This study investigated the effects of pranayama, meditative yoga breathing and breath holding techniques, as a complimentary stabilization technique in patients with post-traumatic stress disorder (PTSD).METHODS: Seventy-four PTSD-patients (84% female, 44.213years) were randomized to receive either pranayama at the beginning of each TF-CBT session or TF-CBT alone. The primary outcome was self-reported PTSD severity after 10 sessions of TF-CBT. Secondary outcomes included quality of life, social participation, anxiety, depression, distress tolerance, emotion regulation, body awareness, breath-holding duration, acute emotional reaction to stress, and adverse events (AEs). Intention-to-treat (ITT) and exploratory per-protocol (PP) analyses of covariance with 95% confidence intervals (CI) were performed.RESULTS: ITT analyses revealed no significant differences on primary or secondary outcomes, except for breath-holding duration in favor of pranayama-assisted TF-CBT (20.81s, 95%CI=13.05|28.60). PP analyses of 31 patients without AEs during pranayama revealed significantly lower PTSD severity (-5.41, 95%CI=-10.17|-0.64) and higher mental quality of life (4.89, 95%CI=1.38|8.41) than controls. In contrast, patients with AEs during pranayama breath holding reported significantly higher PTSD severity (12.39, 95%CI=5.08|19.71) than controls. Concurrent somatoform disorders were found to be a significant moderator of change in PTSD severity (=0.029).CONCLUSION: In PTSD patients without concurrent somatoform disorders, the integration of pranayama into TF-CBT might reduce post-traumatic symptoms and increase mental quality of life more efficiently than TF-CBT alone. The results remain preliminary until they can be replicated by ITT analyses.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03748121.

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PMID:  Front Pharmacol. 2023 ;14:1167398. Epub 2023 Apr 24. PMID: 37168997 Abstract Title:  Protective effects of ginsenosides Rg1 and Rb1 against cognitive impairment induced by simulated microgravity in rats. Abstract:  Microgravity experienced during space flight is known to exert several negative effects on the learning ability and memory of astronauts. Few effective strategies are currently available to counteract these effects. Rg1 and Rb1, the major steroidal components of ginseng, have shown potent neuroprotective effects with a high safety profile. The present study aimed to investigate the effects of Rg1 and Rb1 on simulated microgravity-induced learning and memory dysfunction and its underlying mechanism in the hindlimb suspension (HLS) rat model. Administration of Rg1 (30 and 60 mol/kg) and Rb1 (30 and 60 mol/kg) for 2 weeks resulted in a significant amelioration of impaired spatial and associative learning and memory caused by 4-week HLS exposure, measured using the Morris water maze and Reward operating conditioning reflex (ROCR) tests, respectively. Furthermore, Rg1 and Rb1 administration alleviated reactive oxygen species production and enhanced antioxidant enzyme activities in the prefrontal cortex (PFC). Rg1 and Rb1 also assisted in the recovery of mitochondrial complex I (NADH dehydrogenase) activities, increased the expression of Mfn2 and decreased the fission marker dynamin-related protein (Drp)-1expression. Additionally, Rg1 and Rb1 treatment increased the SYN, and PSD95 protein expressions and decreased the ratio of Bax:Bcl-2 and reduced the expression of cleaved caspase-3 and cytochrome C. Besides these, the BDNF-TrkB/PI3K-Akt pathway was also activated by Rg1 and Rb1 treatment. Altogether, Rg1 and Rb1 treatment attenuated cognitive deficits induced by HLS, mitigated mitochondrial dysfunction, attenuated oxidative stress, inhibited apoptosis, increased synaptic plasticity, and restored BDNF-TrkB/PI3K-Akt signaling.

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PMID:  Int J Mol Sci. 2023 Apr 16 ;24(8). Epub 2023 Apr 16. PMID: 37108509 Abstract Title:  Ginsenoside Rc from Panax Ginseng Ameliorates Palmitate-Induced UB/OC-2 Cochlear Cell Injury. Abstract:  By 2050, at least 700 million people will require hearing therapy while 2.5 billion are projected to suffer from hearing loss. Sensorineural hearing loss (SNHL) arises from the inability of the inner ear to convert fluid waves into neural electric signals because of injury to cochlear hair cells that has resulted in their death. In addition, systemic chronic inflammation implicated in other pathologies may exacerbate cell death leading to SNHL. Phytochemicals have emerged as a possible solution because of the growing evidence of their anti-inflammatory, antioxidant, and anti-apoptotic properties. Ginseng and its bioactive molecules, ginsenosides, exhibit effects that suppress pro-inflammatory signaling and protect against apoptosis. In the current study, we investigated the effects of ginsenoside Rc (G-Rc) on UB/OC-2 primary murine sensory hair cell survival in response to palmitate-induced injury. G-Rc promoted UB/OC-2 cell survival and cell cycle progression. Additionally, G-Rc enhanced the differentiation of UB/OC-2 cells into functional sensory hair cells and alleviated palmitate-induced inflammation, endoplasmic reticulum stress, and apoptosis. The current study offers novel insights into the effects of G-Rc as a potential adjuvant for SNHL and warrants further studies elucidating the molecular mechanisms.

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PMID:  Int J Mol Sci. 2023 Apr 13 ;24(8). Epub 2023 Apr 13. PMID: 37108384 Abstract Title:  Heat Treatment Enhances the Neuroprotective Effects of Crude Ginseng Saponin by Increasing Minor Ginsenosides. Abstract:  Ginsenoside is the primary active substance of ginseng and has many pharmacological effects, such as anti-cancer, immune, regulating sugar and lipid metabolism, and antioxidant effects. It also protects the nervous and cardiovascular systems. This study analyzes the effects of thermal processing on the bioactivities of crude ginseng saponin. Heat treatment increased the contents of minor ginsenosides in crude saponins, such as Rg3, and heat-treated crude ginseng saponin (HGS) had better neuroprotective effects than non-treated crude saponin (NGS). HGS reduced glutamate-induced apoptosis and reactive oxygen species generation in pheochromocytoma 12 (PC12) cells, significantly more than NGS. HGS protected PC12 cells against glutamate-induced oxidative stress by upregulating Nrf2-mediated antioxidant signaling and downregulating MAPK-mediated apoptotic signaling. HGS has the potential for the prevention and treatment of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease.

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PMID:  Free Radic Biol Med. 2023 Aug 1 ;204:54-67. Epub 2023 Apr 25. PMID: 37105420 Abstract Title:  Ginsenoside Rg1 protects cardiac mitochondrial function via targeting GSTP1 to block S-glutathionylation of optic atrophy 1. Abstract:  Mitochondrial dysfunction is a fundamental challenge in myocardial injury. Ginsenoside Rg1 (Rg1) is a bioactive compound with pharmacological potential for cardiac protection. Optic atrophy 1 (OPA1) acts as a mitochondrial inner membrane protein that contributes to the structural integrity and function of mitochondria. This study investigated the protective role of Rg1 in septic cardiac injury from the perspective of OPA1 stability. Rg1 protected cardiac contractive function against endotoxin injury in mice by maintaining mitochondrial cristae structure. In cardiomyocytes, lipopolysaccharide (LPS) evoked mitochondrial fragmentation and destruction of mitochondrial biogenesis, which were prevented by Rg1, possibly due to the preservation of the integrity of cristae structure. In support, the beneficial effects of Rg1 on cardioprotection and mitochondrial biogenesis were diminished by OPA1 deficiency subjected to the LPS challenge. Mechanistically, LPS stimulation triggered intracellular glutathione destabilization that promoted S-glutathionylation of OPA1 at Cys551, leading to the dissociation of OPA1-Mitofilin. Rg1 interacted with Glutathione S-transferase pi (GSTP1) to inhibit its mediated S-glutathionylation of OPA1, thereby promoting OPA1-Mitofilin interaction and protecting mitochondrial cristae structure. These findings suggest that GSTP1/OPA1 axis may be a beneficial strategy for the treatment of myocardial injury, and expand the clinical application of Rg1.

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PMID:  Front Pharmacol. 2023 ;14:1163638. Epub 2023 Apr 10. PMID: 37101547 Abstract Title:  Ginsenoside Rg1 can reverse fatigue behavior in CFS rats by regulating EGFR and affecting Taurine and Mannose 6-phosphate metabolism. Abstract:  Chronic fatigue syndrome (CFS) is characterized by significant and persistent fatigue. Ginseng is a traditional anti-fatigue Chinese medicine with a long history in Asia, as demonstrated by clinical and experimental studies. Ginsenoside Rg1 is mainly derived from ginseng, and its anti-fatigue metabolic mechanism has not been thoroughly explored.We performed non-targeted metabolomics of rat serum using LC-MS and multivariate data analysis to identify potential biomarkers and metabolic pathways. In addition, we implemented network pharmacological analysis to reveal the potential target of ginsenoside Rg1 in CFS rats. The expression levels of target proteins were measured by PCR and Western blotting.Metabolomics analysis confirmed metabolic disorders in the serum of CFS rats. Ginsenoside Rg1 can regulate metabolic pathways to reverse metabolic biases in CFS rats. We found a total of 34 biomarkers, including key markers Taurine and Mannose 6-phosphate. AKT1, VEGFA and EGFR were identified as anti-fatigue targets of ginsenoside Rg1 using network pharmacological analysis. Finally, biological analysis showed that ginsenoside Rg1 was able to down-regulate the expression of EGFR.Our results suggest ginsenoside Rg1 has an anti-fatigue effect, impacting the metabolism of Taurine and Mannose 6-phosphate through EGFR regulation. This demonstrates ginsenoside Rg1 is a promising alternative treatment for patients presenting with chronic fatigue syndrome.

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PMID:  Adv Clin Exp Med. 2023 Apr 24. Epub 2023 Apr 24. PMID: 37093091 Abstract Title:  Ginsenoside Rb3 reduces ox-LDL-induced injury in human aortic endothelial cells by regulating the miR-513a-5p/ZBTB20 axis. Abstract:  BACKGROUND: Atherosclerosis (AS) is a common vascular disease, and its main influencing factor is endothelial damage caused by oxidized low-density lipoprotein (ox-LDL). As one of the main active ingredients of ginseng, ginsenoside Rb3 has anti-inflammatory and anti-oxidative effects. However, the role of ginsenoside Rb3 in endothelial injury induced by ox-LDL is not clear.OBJECTIVES: This study aimed to evaluate the effect and potential mechanism of ginsenoside Rb3 action on ox-LDL-treated human aortic endothelial cells (HAECs).MATERIAL AND METHODS: The HAECs treated with ox-LDL were used to establish an in vitro AS model. The viability of the HAECs was analyzed with Cell Counting Kit-8 (CCK-8). Flow cytometry was performed to assess the apoptosis. Oxidative stress, inflammation and endothelial dysfunction were evaluated using enzyme-linked immunosorbent assay (ELISA) and western blotting. The levels of miR-513a-5p were assessed using quantitative real-time polymerase chain reaction (qPCR). A dual-luciferase assay was performed to analyze the relationship between miR-513a-5p and a zinc finger and BTB domain-containing protein (ZBTB20).RESULTS: Exposure of HAECs to ox-LDL (50g/mL) reduced cell viability, superoxide dismutase (SOD) activity and endothelial nitric oxide synthase (eNOS) expression, while increasing the levels of malondialdehyde (MDA), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-), and soluble intercellular adhesion molecule-1 (sICAM-1). The pretreatment with Rb3 markedly enhanced cell viability and decreased ox-LDL-induced oxidative stress, inflammation and endothelial dysfunction in HAECs. The ox-LDL decreased the level of miR-513a-5p, which was reversed by Rb3 pretreatment. The ZBTB20 was a target of miR-513a-5p in HAECs, and ox-LDL upregulated ZBTB20 expression, which was reversed by Rb3 pretreatment. The protective effect of Rb3 on ox-LDL-induced HAECs was diminished by miR-513a-5p inhibition, which was reversed by ZBTB20 knockdown.CONCLUSIONS: Ginsenoside Rb3 reduces the effects of ox-LDL on HAECs by regulating the miR-513a-5p/ZBTB20 axis, which provides a theoretical basis for the treatment of AS.

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If you are among the millions of Americans suffering from joint pain and arthritis, there's good news about a favorite summer treat. According to research from Oregon Health & Science University, tart cherries help reduce the chronic inflammation that leads to pain.[1]

In fact, the Oregon researchers declared that tart cherries have the "highest anti-inflammatory content of any food" and can help osteoarthritis patients manage their condition.

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PMID:  Acta Biochim Biophys Sin (Shanghai). 2023 Apr 19 ;55(4):587-600. PMID: 37092860 Abstract Title:  Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells. Abstract:  Ginsenoside Rh3 (GRh3) is a seminatural product obtained by chemical processing after isolation from Chinese herbal medicine that has strong antitumor activity against human tumors. However, its antitumor role remains to be elucidated. The aim of this study is to explore the mechanisms underlying the tumor suppressive activity of GRh3 from the perspective of pyroptosis and ferroptosis. GRh3 eliminates colorectal cancer (CRC) cells by activating gasdermin D (GSDMD)-dependent pyroptosis and suppressing solute carrier family 7 member 11 (SLC7A11), resulting in ferroptosis activation through the Stat3/p53/NRF2 axis. GRh3 suppresses nuclear factor erythroid 2-related factor 2 (NRF2) entry into the nucleus, leading to the decrease of heme oxygenase 1 (HO-1) expression, which in turn promotes NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and caspase-1 expression. Finally, caspase-1 activates GSDMD-dependent pyroptosis. Furthermore, GRh3 prevents NRF2 from entering the nucleus, which suppresses SLC7A11, causing the depletion of glutathione (GSH) and accumulation of iron, lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and eventually leading to ferroptosis in CRC cells. In addition, GRh3 effectively inhibits the proliferation of CRC cellsand in nude mouse models. Collectively, GRh3 triggers pyroptotic cell death and ferroptotic cell death in CRC cells via the Stat3/p53/NRF2 axis with minimal harm to normal cells, showing great anticancer potential.

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PMID:  Am J Chin Med. 2023 ;51(4):883-908. Epub 2023 Apr 17. PMID: 37060192 Abstract Title:  Ginsenosides are Promising Medicine for Tumor and Inflammation: A Review. Abstract:  Ginseng is a valuable medicinal plant in Asian countries with thousands of years of history. Ginsenosides, one of the active components of ginseng, are considered to be of potential value in the treatment of various diseases. The antitumor effects of ginsenosides, such as Rg3, Rh2, Rg5, and CK, are well known, and their potential mechanisms are thought to be related to inducing apoptosis, enhancing the immune response, reversing drug resistance to chemotherapy, and regulating signaling pathways, such as MAPK, PI3K/Akt/mTOR, Wnt/[Formula: see text]-catenin, NF-[Formula: see text]B, ASK-1/JNK, AMPK, and EGFR/Akt/SOX2. On the other hand, ginsenosides also have anti-inflammatory effects, including reducing the release of inflammatory factors, regulating the balance of immune cells, regulating the diversity of intestinal flora, and activating MAPK, NF-[Formula: see text]B, and NLRP3 inflammasomes. These data suggest that ginsenosides may provide new insights as promising drugs for the treatment of malignant tumors and inflammatory diseases.

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PMID:  Molecules. 2023 Mar 30 ;28(7). Epub 2023 Mar 30. PMID: 37049846 Abstract Title:  Ginsenoside Rb1 Interfered with Macrophage Activation by Activating PPARto Inhibit Insulin Resistance in Obesity. Abstract:  Type 2 diabetes (T2D) is characterized by insulin resistance (IR), often accompanied by inflammation. Macrophage activation acts as an inflammatory response, which is characterized by macrophage recruitment in the initial stage. Ginsenoside Rb1 (Rb1) is a main active ingredient, which is known for its fat-reducing, anti-inflammatory effects. To clarify that Rb1 regulates macrophage activation in adipose tissue and improves tissue inflammation, network pharmacology and molecular docking were used for target prediction and preliminary validation. By constructing the co-culture model of adipose-derived stem cells (ADSC) and primary macrophage (PM), the body adipose tissue microenvironment was simulated to observe the adipogenesis degree of adipocytes under the effect of Rb1. The levels of cytokines, macrophage polarization, and protein or RNA expression in the inflammatory signaling pathway were finally detected. The results showed that 89 common targets of T2D-Rb1 were obtained after their intersection. Furthermore, according to the results of the KEGG pathway and PPI analysis, PTGS2 (COX-2) is the downstream protein of PPAR-NF-B. The molecular binding energy of PPAR-Rb1 is -6.8 kcal/mol. Rb1 significantly inhibited the increase in MCP-1, TNF-, and IL-1induced by hypertrophic adipocytes supernatant and promoted the expression of IL-10. Rb1 inhibited the activation of inflammatory macrophages and PM migration and upregulated PPARexpression with the blocking of NF-B activation. Additionally, Rb1 promoted the expression of IRS1 and PI3K in the insulin signal pathway, which had a similar effect with ROS. Therefore, Rb1 might affect macrophage activation through PPAR, which might alleviate obese insulin resistance in T2D early stage.

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PMID:  Nutrients. 2023 Mar 27 ;15(7). Epub 2023 Mar 27. PMID: 37049466 Abstract Title:  Inhibitory Effects of Ginsenoside Compound K on Lipopolysaccharide-Stimulated Inflammatory Responses in Macrophages by Regulating Sirtuin 1 and Histone Deacetylase 4. Abstract:  Inflammation, an innate immune response mediated by macrophages, has been a hallmark leading to the pathophysiology of diseases. In this study, we examined the inhibitory effects of ginsenoside compound K (CK) on lipopolysaccharide (LPS)-induced inflammation and metabolic alteration in RAW 264.7 macrophages by regulating sirtuin 1 (SIRT1) and histone deacetylase 4 (HDAC4). LPS suppressed SIRT1 while promoting HDAC4 expression, accompanied by increases in cellular reactive oxygen species accumulation and pro-inflammatory gene expression; however, the addition of CK elicited the opposite effects. CK ameliorated the LPS-induced increase in glycolytic genes and abrogated the LPS-altered genes engaged in the NAD+ salvage pathway. LPS decreased basal, maximal, and non-mitochondrial respiration, reducing ATP production and proton leak in macrophages, which were abolished by CK. SIRT1 inhibition augmentedexpression along with increased LPS-induced inflammatory and glycolytic gene expression, while decreasing genes that regulate mitochondrial biogenesis; however, its activation resulted in the opposite effects. Inhibition of HDAC4 enhancedexpression and attenuated the LPS-induced inflammatory gene expression. In conclusion, CK exerted anti-inflammatory and antioxidant properties with the potential to counteract the alterations of energy metabolism, including glycolysis and mitochondrial respiration, through activating SIRT1 and repressing HDAC4 in LPS-stimulated macrophages.

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PMID:  Bioorg Chem. 2023 Jun ;135:106537. Epub 2023 Apr 9. PMID: 37043883 Abstract Title:  Ginsenoside Rh4 inhibits breast cancer growth through targeting histone deacetylase 2 to regulate immune microenvironment and apoptosis. Abstract:  High expression of histone deacetylase 2 (HDAC2) is recognized as a marker of invasive breast cancer (BC). HDAC2 is not only responsible for enhancing tumor cell growth, development, and anti-apoptosis, but also plays a significant role in regulating PD-L1 on the surface of tumor cells. Continuous expression of PD-L1 allows tumor cells to escape immune surveillance. There is not much research on how HDAC2 affects the immune system in breast cancer. Ginsenoside Rh4 (Rh4) is a major rare saponin in heat-treated ginseng, which is widely applied in treating and preventing various diseases because of its potent medicinal value and stable safety. However, it is unclear how Rh4 affects the tumor immune microenvironment in breast cancer. Therefore, this paper aims to investigate the effect of Rh4 on HDAC2 in breast cancer, specifically the effect of HDAC2 on apoptosis and the immune microenvironment to inhibit breast cancer growth. According to our study, ginsenoside Rh4 has been shown to significantly suppress breast cancer cell proliferation without any adverse effects. The molecular docking results of Rh4 and HDAC2 indicate a binding energy of -6.06 kcal/mol, suggesting the potential of Rh4 as a targeting modulator of HDAC2. Mechanistically, Rh4 induces apoptosis of breast cancer cells by the HDAC2-mediated caspase pathway and inhibits the HDAC2-mediated JAK/STAT pathway to regulate the immune microenvironment, which inhibits breast cancer growth. Specifically, Rh4 was shown for the first time to blockade immune checkpoints (PD-1/PD-L1) and increase levels of T-lymphocytes in the tumor. In a word, our study establishes a theoretical framework for applying Rh4 as an immune checkpoint inhibitor as part of breast cancer treatment.

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PMID:  Medicine (Baltimore). 2023 Apr 7 ;102(14):e33463. PMID: 37026927 Abstract Title:  The effect of ginsenoside Rg3 combined with chemotherapy on immune function in non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials. Abstract:  BACKGROUND: The occurrence and development of non-small cell lung cancer (NSCLC) are closely related to the immune status of the tumor-host. The immunosuppression caused by tumor cells and toxic side effects produced by chemotherapeutic drugs results in a decrease in immune function, ultimately leading to the failure of clinical chemotherapy treatment. Ginsenoside Rg3 has been clinically reported to have positive effects in enhancing immune function in patients. Thus, we screened and evaluated the quality of the evidence regarding the benefits of ginsenoside Rg3 and conducted a meta-analysis to assess the impact on improving immune function in NSCLC.METHODS: The PubMed, EMBASE, Cochrane Library, CNKI, Weipu (VIP), and Wanfang databases were searched in this study, all from the time of library construction to January 2023.RESULTS: In total,12 trials with a sample size of 1008 cases were included based on the eligible criteria. The results showed that compared with first-line chemotherapy alone, the combination of ginsenoside Rg3 and first-line chemotherapy could better improve level of the CD3+ T lymphocytes [mean difference (MD) = 4.72; 95% confidence intervals (CI): 3.92, 5.53; P

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PMID:  Ren Fail. 2023 Dec ;45(1):2197075. PMID: 37017270 Abstract Title:  Ginsenoside Rg1 treatment alleviates renal fibrosis by inhibiting the NOX4-MAPK pathway in T2DM mice. Abstract:  Diabetic kidney disease (DKD) is a severe complication of type 2 diabetes mellitus (T2DM). However, the pathogenesis of DKD remains unclear, and effective treatment strategies are still lacking. Ginsenoside Rg1 (Rg1) has been reported to improve DKD, but the mechanism is unclear. NADPH oxidase 4 (NOX4) is an essential reactive oxygen species (ROS) source in the kidney. The mitogen-activated protein kinase (MAPK) signaling may exacerbate renal fibrosis. Therefore, we hypothesized that Rg1 might alleviate renal injury and fibrosis by inhibiting NOX4 and MAPK signaling in T2DM-induced DKD. We found that Rg1 significantly improves lipid deposition, fibrosis, and ROS production and reduces NOX4, p22phox, p47phox, p-ERK, p-JNK, and p-P38 MAPK expressions in the T2DM mice kidneys. We also found that the high-fat diet treatment in mice and the palmitate (PA) and PA+HG (high glucose) exposure in human mesangial cells could significantly induce lipid deposition, ROS production, fibrosis, and the activation of NOX4-MAPK signaling. The results suggest that high lipid and glucose may play a significant role in DKD progression, while Rg1 may attenuate renal fibrosis by inhibiting NOX4-MAPK signaling.

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New "Twitter Files" reveal how the White House and Twitter flag social media posts that contradicted the official government narrative on COVID-19

Originally published on www.childrenshealthdefense.org by Michael Nevradakis, Ph.D.

New "Twitter Files" released today by investigative journalist Paul D. Thacker reveal how a "dark money group" helped the White House and Twitter flag social media posts by Robert F. Kennedy Jr. and Children's Health Defense that contradicted the official government narrative on COVID-19.

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PMID:  Food Funct. 2023 Apr 24 ;14(8):3793-3803. Epub 2023 Apr 24. PMID: 37000511 Abstract Title:  Ginsenoside Rb1 alleviated concanavalin A-induced hepatocyte pyroptosis by activating mitophagy. Abstract:  Pyroptosis is characterized as gasdermin-mediated programmed death and has received substantial attention in recent years. Excessive hepatocyte pyroptosis could induce acute liver injury, and there is a lack of efficient natural compounds to alleviate it. Ginsenoside Rb1 is the most prevalent ginsenoside in ginseng with a variety of biological activities and is usually added to functional foods. In spite of the numerous beneficial effects ginsenoside Rb1 exerts, its role in hepatocyte pyroptosis is yet unknown. In this study, we found that ginsenoside Rb1 alleviated concanavalin A-induced hepatocyte pyroptosis and inhibited NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, which is critical for the process of pyroptosis. Furthermore, with the addition of the mitophagy inhibitor cyclosporin A, we proved that ginsenoside Rb1 promoted PINK1/Parkin-mediated mitophagy to alleviate hepatocyte pyroptosis. The further mechanism was that ginsenoside Rb1 activated mitophagy to eliminate damaged mitochondria. With the clearance of damaged mitochondria, reactive oxygen species production decreased, and then NLRP3 inflammasome expression was inhibited. Our finding demonstrated that ginsenoside Rb1 could alleviate hepatocyte pyroptosis by activating mitophagy, which could provide a basis for formulating effective dietary therapy or dietary recommendation.

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PMID:  Int J Endocrinol. 2023 ;2023:3595992. Epub 2023 Mar 14. PMID: 36960388 Abstract Title:  Ginsenoside Rg1 Improves Inflammation and Autophagy of the Pancreas and Spleen in Streptozotocin-Induced Type 1 Diabetic Mice. Abstract:  BACKGROUND: Ginsenoside Rg1 (Rg1) is one of the key bioactive components of the precious Traditional Chinese Medicine that has been used to treat diabetes in China. Ginsenosides have been reported to protect diabetics from tissue damage, inflammation, and insulin resistance. Type 1 diabetes (T1D) is an organ-specific autoimmune disease that occurred frequently among adolescents over the world, its development was related to inflammation and-cells immunodeficiency. The aim of this study is to explore the biological mechanism of Rg1 on inflammation and autophagy of-cells in T1D and its therapeutic potential.METHODS: The model of T1D mice was established by injecting Streptozotocin (STZ) (55mg/kg) or citric acids once a day for 5days and from the fourth day of injection, mice were administered with Rg1 (20mg/kg) or saline by gavage once a day for 12days. Hematoxylin-eosin staining, immunofluorescence, ELISA, quantitative real-time PCR, and Western blot were used to observe the histopathological changes, inflammatory factor levels, and autophagy markers after administration of ginsenoside Rg1.RESULTS: Compared to the T1D mice, Rg1 improved the weight (

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