PMID: 

Medicine (Baltimore). 2019 Oct ;98(40):e17126. PMID: 31577702

Abstract Title: 

N-acetyl cysteine inhibits lipopolysaccharide-mediated synthesis of interleukin-1β and tumor necrosis factor-α in human periodontal ligament fibroblast cells through nuclear factor-kappa B signaling.

Abstract: 

BACKGROUND: The aim of this study was to investigate the role of n-acetyl cysteine (NAC) in the lipopolysaccharide (LPS)-mediated induction of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) synthesis by human periodontal ligament fibroblast cells (hPDLFs). In addition, we aimed to determine the involvement of the nuclear factor-kappa B (NF-κB) pathway in any changes in IL-1β and TNF-α expression observed in response to LPS and NAC.METHODS: HPDLFs were obtained by primary culture. The culture medium used in this experiment was Dulbecco's Modified Eagle Medium (DMEM low-glucose). Cells were stimulated with various concentrations of NAC or LPS. Cell proliferation was measured at various time-points with the cell Counting Kit 8 (CCK-8) assay. mRNA levels of IL-1β and TNF-α were determined by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Protein levels of IL-1β and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). Protein and mRNA expression levels of NF-κB were measured by western blot and RT-qPCR.RESULTS: The results showed that LPS treatment in hPDLFs induced mRNA and protein expression of IL-1β, TNF-α, and NF-κB. However, these effects were eliminated by pretreatment with NAC. Pretreatment with both NAC (1 mmol/L) and BAY11-7082 (10 μmol/L) significantly inhibited the NF-κB activity induced by LPS.CONCLUSION: NAC inhibits the LPS-mediated synthesis of tumor TNF-α and IL-1β in hPDLFs, through the NF-κB pathway.

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PMID: 

Surgery. 2019 Sep 11. Epub 2019 Sep 11. PMID: 31521320

Abstract Title: 

Ketogenic diet combined with antioxidant N-acetylcysteine inhibits tumor growth in a mouse model of anaplastic thyroid cancer.

Abstract: 

BACKGROUND: Anaplastic thyroid cancer is an aggressive and fatal malignancy. Many advanced cancers are characterized by glucose dependency, leading to oxidative stress and cellular proliferation. Therefore, we sought to determine if a low glucose environment (in vitro) or a ketogenic diet (in vivo) could inhibit anaplastic thyroid cancer tumor growth when combined with the antioxidant N-acetylcysteine.METHODS: In vivo, nude mice were injected with the anaplastic thyroid cancer cell line 8505C (n = 6/group). Group 1 was fed a standard diet; Group 2 was fed a ketogenic diet; Group 3 was given standard diet with N-acetylcysteine (40 mM in the drinking water); and Group 4 was fed ketogenic diet with N-acetylcysteine. Tumor volumes, ketones, and glucose were measured. H&E stains and immunohistochemistry for Ki-67 and Caspase 3 were performed on the tumors. In vitro, 8505C cells were cultured in high glucose (25 mM), low glucose (3 mM), high glucose plus N-acetylcysteine (200 uM), or low glucose plus N-acetylcysteine for 96 hours. We performed CyQUANT proliferation (Thermo Fisher Scientific, Waltham, MA), Seahorse glycolytic stress (Agilent, Santa Clara, CA), and reactive oxidative stress assays.RESULTS: Ketogenic diet plus N-acetylcysteine decreased in vivo tumor volume compared to standard diet (22.5 ± 12.4 mmvs 147± 54.4 mm, P

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PMID: 

Curr Mol Med. 2019 Sep 17. Epub 2019 Sep 17. PMID: 31530262

Abstract Title: 

N-Acetyl Cysteine attenuates the sarcopenia and muscle apoptosis induced by chronic liver disease.

Abstract: 

Sarcopenia is characterized by the loss of muscle mass and strength (muscle atrophy) because of aging or chronic diseases such as chronic liver disease (CLD). Different mechanisms are involved in skeletal muscle atrophy, including decreased muscle fibre diameter and myosin heavy chain levels and increased ubiquitin-proteasome pathway activity, oxidative stress and myonuclear apoptosis. We recently found that all these mechanisms, except myonuclear apoptosis, which was not evaluated in the previous study, were involved in muscle atrophy associated with hepatotoxin 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced CLD. In the present study, we evaluated the involvement of myonuclear apoptosis in CLD-associated sarcopenia and the effect of N-acetyl cysteine (NAC) treatment on muscle strength and apoptosis, using a DDC-supplemented diet-fed mouse model. Four-month-old male C57BL6 mice were fed a standard or DDC-supplemented diet for six weeks in the absence or presence of NAC treatment. Our results showed that NAC attenuated the decrease in muscle fibre diameter and muscle strength associated with CLD-induced muscle wasting in gastrocnemius (GA) muscle of DDC-supplemented diet-fed mice. In addition, in GA muscle of the mice with DDC-supplemented diet-induced CLD showed increased myonuclear apoptosis compared with the GA muscle of the control diet-fed mice, as evidenced by increased apoptotic nuclei number, caspase-8 and caspase-9 expression, caspase-3 activity and BAX/BCL-2 ratio. NAC treatment inhibited all the mechanisms associated with myonuclear apoptosis in the GA muscle. To our knowledge, the present study is the first to report the redox regulation of muscle strength and myonuclear apoptosis in CLD-induced sarcopenia.

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PMID: 

Chem Res Toxicol. 2019 Sep 16 ;32(9):1871-1879. Epub 2019 Aug 22. PMID: 31402651

Abstract Title: 

Bisdemethoxycurcumin Protection of Cardiomyocyte Mainly Depends on Nrf2/HO-1 Activation Mediated by the PI3K/AKT Pathway.

Abstract: 

Bisdemethoxycurcumin (BDMC) is one of three curcuminoids extracted from turmeric. Unlike the dominant ingredient curcumin with some intensive investigations, BDMC was recently reported to possess potent antitumor, anti-inflammatory, antiatherosclerosis, antiobesity, and antiaging effects. Considering its pharmacological effects in inflammation, atherosclerosis, and obesity, this study was designed to examine if BDMC displays cardioprotective properties. In this study, staurosporine (STS) was used to establish the cardiomyocyte injury model. Our data revealed that BDMC significantly inhibited myocardial apoptosis, improved cell survival, reduced caspase-3 activity, and diminished reactive oxygen species (ROS) production. BDMC enhanced phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) and up-regulated the expression of HO-1. Inhibition of HO-1 activity by using tin-protoporphyrin (SnPPIX) can restrain the antiapoptotic effect of BDMC. Furthermore, translocation of Nrf2 from the cytoplasm to the nucleus was ablated by LY294002, although only partially by PD98059. Up-regulation of HO-1 was weakly suppressed by PD98059 but strongly inhibited by LY294002. Unlike PD98059, LY294002 negated the protective effect of BDMC. These findings indicated that BDMC possessed favorable cardioprotection in a Nrf2/HO-1-dependent manner. Activation of Nrf2/HO-1 mainly depended on PI3K/AKT but not MEK/ERK signaling.

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PMID: 

Chemosphere. 2019 Aug 1 ;237:124469. Epub 2019 Aug 1. PMID: 31549635

Abstract Title: 

Effect of developmental exposure to bisphenol A on steroid hormone and vitamin D3 metabolism.

Abstract: 

High exposure to bisphenol A (BPA) in children has been associated with the outcomes of several diseases, including those related to developmental problems. To elucidate the mechanism of BPA mediated developmental toxicity, plasma and urine from rats exposed to BPA was analyzed with high resolution metabolomics, beginning from post-natal day 9, for 91 days. Female and male rats were orally administered 5 different BPA doses to elucidate dose- and sex-specific BPA effects. Regarding dose-specific effects, multivariate statistical analysis showed that metabolic shifts were considerably altered between 5, 50 and 250 mg BPA/kg bw/day in treated rats. A nonmonotonicity and monotonicity between BPA dose and metabolic response were major trajectories, showing overall metabolic changes in plasma and urine, respectively. Metabolic perturbation in the steroid hormone biosynthesis pathway was significantly associated with dose- and sex-specific BPA effects. Intermediate metabolites in the rate-limiting step of steroid hormone biosynthesis down-regulated steroid hormones in the 250 mg treatment. Further, our study identified that BPA increased urinary excretion of vitamin Dand decreased its concentration in blood, suggesting that perturbation of vitamin Dmetabolism may be mechanistically associated with neurodevelopmental disorders caused by BPA. Three metabolites showed a decrease in sex difference with high BPA dose because female rats were more affected than males, which can be related with early puberty onset in female. In brief, the results demonstrated that BPA induces dose- and sex-specific metabolic shifts and that perturbation of metabolism can explain developmental problems.

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PMID: 

Front Endocrinol (Lausanne). 2019 ;10:620. Epub 2019 Sep 10. PMID: 31551937

Abstract Title: 

Non-alcoholic Fatty Liver Disease Induced by Perinatal Exposure to Bisphenol a Is Associated With Activated mTOR and TLR4/NF-κB Signaling Pathways in Offspring Rats.

Abstract: 

Accumulating evidence suggests a role of bisphenol A (BPA) in non-alcoholic fatty liver disease (NAFLD), and its mechanism may be related to the up-regulation of lipogenic genes, but the mechanism of BPA induced lipogenic gene expression remains unknown. The aim of this study was to investigate the effects of perinatal exposure to BPA on NAFLD and its mechanisms. Pregnant Sprague-Dawley rats had access to drinking water containing 1 or 10μg/ml BPA from gestational day 6 to post-natal day 21. For 5 weeks after weaning, offspring drank normal water without BPA. Body weight, lipid profile and the expression of genes or proteins involved in mTOR mediated lipid metabolism and autophagy, as well as inflammatory response were investigatedin the 8-wk-old offspring of different genders. The results showed that body weight was increased only in females, however, males, and females from dams treated with BPA had significantly excess visceral adipose tissue, which was consistent with adipocyte hypertrophy. Elevated TG levels and up-regulation of lipogenic genes or proteins in liver, such as sterol regulatory element binding protein 1 (SREBP1), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FAS) were consistent with increased liver lipid droplets in offspring exposed to BPA. Compared with controls, the protein levels ofInsR, p-IRS-1, IRS-1, TSC1, and TSC2 were decreased, p-PI3K, p-Akt (S473), p-Akt (T308), p-mTOR, and mTOR were increased, and the impaired autophagic degradation was evidenced by increased protein levels of p62, although the levels of p-ULK1, Beclin1, and LC3B proteins were increased in liver of BPA-exposed offspring. The levels of TLR4 and NF-κB proteins were also significantly increased, and ERα protein was significantly decreased in BPA-exposed offspring. Our findings indicate that perinatal exposure to BPA causes the development of NAFLD in both female and male offspring, which is associated with up-regulation of lipogenic genes, dysregulated autophagy and activated inflammatory response involving the PI3K/Akt/mTOR and TLR4/NF-κB pathways.

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PMID: 

J Biochem Mol Toxicol. 2019 Aug 30:e22389. Epub 2019 Aug 30. PMID: 31468582

Abstract Title: 

Gastrodin alleviates Tourette syndrome via Nrf-2/HO-1/HMGB1/NF-кB pathway.

Abstract: 

The aim is to study the effects of gastrodin (GA) on striatal inflammation and oxidative stress in rats with Tourette syndrome (TS). The rat model of TS was induced by 3,3'-iminodipropionitrile. Behavioral tests were carried out by stereotype experiment. The concentrations of amino acid transmitters glutamic acid (Glu) andγ-aminobutyric acid (GABA) in striatum were determined by high-performance liquid chromatography. Superoxide dismutase (SOD) and malondialdehyde (MDA) in serum and striatum were detected by commercial kits. Cytokines in serum and striatum were detected by enzyme-linked immunosorbent assay kits. Western blot analysis was used to detect striatum nuclear erythroid factor 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1)/high mobility group box 1 protein (HMGB1)/nuclear factor-кB (NF-кB) pathway-related proteins. The expressions of Nrf-2 and P-NF-кBp65 in striatum were detected by immunohistochemistry. Compared with the control group, the stereotype scores of rats in the model group significantly increased, and the contents of Glu and GABA in striatum obviously increased. GA significantly reduced the stereotype scores and decreased the contents of Glu and GABA. The levels of SOD in serum and striatum were decreased and the content of MDA in serum and striatum were increased compared with the control group, while GA significantly restored the changes. GA significantly adjusted Nrf-2/HO-1/HMGB1/NF-кB pathway-related proteins changes consistent with immunohistochemical changes. GA may protect striatum of rats with TS by regulating Nrf-2/HO-1/HMGB1/NF-кB pathway protein changes in striatum.

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PMID: 

Biomed Res Int. 2018 ;2018:7617312. Epub 2018 Nov 4. PMID: 30519583

Abstract Title: 

Simvastatin Impairs the Inflammatory and Repair Phases of the Postinjury Skeletal Muscle Regeneration.

Abstract: 

Background: Recent clinical data have suggested that the chronic use of high-lipophilic statins impairs the regenerative capacity of skeletal muscle. Because this activity of statins is poorly understood, we aimed to investigate the effect of simvastatin (SIM) on postinjury myofibre regeneration.Methods: The porcine model was used in this study. The animals were divided into two groups: nontreated (control;=24) and SIM-treated (40 mg/day;=24). On the 15th day (day 0) of the experiment, a bupivacaine hydrochloride- (BPVC-) induced muscle injury was established, and the animals were sacrificed in the following days after muscle injury. The degree of regeneration was assessed based on histopathological and immunohistochemical examinations. The presence and degree of extravasation, necrosis, and inflammation in the inflammatory phase were assessed, whereas the repair phase was evaluated based on the numbers of muscle precursor cells (MPCs), myotube and young myofibres.Results: In the inflammatory phase, SIM increased the distribution and prolonged the period of extravasation, prolonged the duration of necrosis, and prolonged and enhanced the infiltration of inflammatory cells. In the repair phase, SIM delayed and prolonged the activity of MPCs, delayed myotube formation, and delayed and decreased the formation of young myofibres. Our results indicated that SIM did not improve blood vessel stabilization at the site of the injury, did not exert an anti-inflammatory effect, prolonged and enhanced the inflammatory response, and impaired MPC activity, differentiation, and fusion. Moreover, SIM appeared to reduce M1 macrophage activity, resulting in slower removal of necrotic debris and sustained necrosis.Conclusion: This study shows that SIM negatively affects the inflammatory and repair phases of the postinjury muscle regeneration. These findings are unique, strengthen the available knowledge on the side effects of SIM, and provide evidence showing that statin therapy is associated with an increased risk of impairment of the regenerative capacity of muscle.

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PMID: 

J Cell Physiol. 2019 Jul ;234(7):11047-11059. Epub 2018 Dec 7. PMID: 30536661

Abstract Title: 

Coenzyme Qprotects againstβ-cell toxicity induced by pravastatin treatment of hypercholesterolemia.

Abstract: 

New onset of diabetes is associated with the use of statins. We have recently demonstrated that pravastatin-treated hypercholesterolemic LDL receptor knockout (LDLr) mice exhibit reductions in insulin secretion and increased islet cell death and oxidative stress. Here, we hypothesized that these diabetogenic effects of pravastatin could be counteracted by treatment with the antioxidant coenzyme Q(CoQ), an intermediate generated in the cholesterol synthesis pathway. LDLrmice were treated with pravastatin and/or CoQfor 2 months. Pravastatin treatment resulted in a 75% decrease of liver CoQcontent. Dietary CoQsupplementation of pravastatin-treated mice reversed fasting hyperglycemia, improved glucose tolerance (20%) and insulin sensitivity (>2-fold), and fully restored islet glucose-stimulated insulin secretion impaired by pravastatin (40%). Pravastatin had no effect on insulin secretion of wild-type mice. In vitro, insulin-secreting INS1E cells cotreated with CoQwere protected from cell death and oxidative stress induced by pravastatin. Simvastatin and atorvastatin were more potent in inducing dose-dependent INS1E cell death (10-15-fold), which were also attenuated by CoQcotreatment. Together, these results demonstrate that statins impairβ-cell redox balance, function and viability. However, CoQsupplementation can protect the statins detrimental effects on the endocrine pancreas.

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PMID: 

Toxicol Appl Pharmacol. 2019 02 15 ;365:112-123. Epub 2019 Jan 11. PMID: 30639414

Abstract Title: 

In utero exposure to simvastatin reduces postnatal survival and permanently alters reproductive tract development in the Crl:CD(SD) male rat.

Abstract: 

We showed previously that in utero exposure to the cholesterol-lowering drug simvastatin (SMV) during sex differentiation lowers fetal lipids and testicular testosterone production (T Prod) in Hsd:SD rats. Here, the effects of SMV on fetal lipids and T Prod in Crl:CD(SD) rats were correlated with postnatal alterations in F1 males. The current study was conducted in two parts: 1) a prenatal assessment to confirm and further characterize the dose response relationship among previously reported alterations of SMV on fetal T Prod and the fetal lipid profile and 2) a postnatal assessment to determine the effects of SMV exposure during the periods of major organogenesis and/or sexual differentiation on F1 offspring growth and development. We hypothesized that SMV would have adverse effects on postnatal development and sexual differentiation as a consequence of the disruptions of fetal lipid levels and testicular T Prod since fetal cholesterol is essential for normal intrauterine growth and development and steroid synthesis. In the prenatal assessment, SMV was administered orally at 0, 15.6, 31.25, 62.5, 80, 90, 100, and 110 mg SMV/kg/d from GD 14-18, the period that cover the critical window of sex differentiation in the male rat fetus. T Prod was maximally reduced by ~40% at 62.5 mg/kg/d, and higher doses induced overt maternal and toxicity. In the postnatal assessment, SMV was administered at 0, 15.6, 31.25, and62.5 mg/kg/d from GD 8-18 to determine if it altered postnatal development. We found that exposure during this time frame to 62.5 mg SMV/kg/d reduced pup viability by 92%, decreased neonatal anogenital distance, and altered testis histology and morphology in 17% of the F1 males. In another group, SMV was administered only during the masculinizing window (GD14-18) at 62.5 mg/kg/d to determine if male rat sexual differentiation and postnatal reproductive development were altered. SMV-exposed F1 males displayed female-like areolae/nipples, delayed puberty, and reduced seminal vesicle and levator ani-bulbocavernosus weights. Together, these results demonstrate that in utero exposure to SMV reduces offspring viability and permanently disrupts reproductive tract development in the male offspring. While the effects of high dose, short term in utero exposure to SMV in the adult male are likely androgen-dependent and consistent with the 40% reduction in T Prod in the fetal testes, long-term, lower dose administration induced some effects that were likely not mediated by decreased T Prod.

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