Resveratrol relieves HFD-induced insulin resistance in skeletal muscle tissue through antioxidant capacity enhancement and the Nrf2-Keap1 signaling pathway.

BACKGROUND: Resveratrol has received much attention due to its beneficial effects including antioxidant activity. The purpose of this study was to investigate the therapeutic effects of resveratrol treatment on oxidative stress and insulin resistance in the skeletal muscle of high-fat diet (HFD)-fed animals. METHODS AND RESULTS: A total of 30 six-week-old C57BL/6J mice were randomly allocated to three groups (10 animals in each group): The control group in which mice were fed a normal chow diet (NCD); the HFD group in which mice were fed an HFD for 26 weeks; and the HFD-resveratrol group in which HFD was replaced by a resveratrol supplemented-HFD (400 mg/kg diet) after 10 weeks of HFD feeding. At the end of this period, gastrocnemius muscle samples were examined to determine insulin resistance and the oxidative status in the presence of HFD and resveratrol. Resveratrol supplementation in HFD-fed mice reduced body and adipose tissue weight, improved insulin sensitivity, and decreased oxidative stress as indicated by lower malonaldehyde (MDA) levels and higher total antioxidant capacity. The supplement also increased the expression and activity of antioxidative enzymes in gastrocnemius muscle and modulated Nrf2 and Keap1 expression levels. CONCLUSIONS: These results suggest that resveratrol is effective in improving the antioxidant defense system of the skeletal muscle in HFD-fed mice, indicating its therapeutic potential to combat diseases associated with insulin resistance and oxidative stress.

Crosstalk between autophagy and insulin resistance: evidence from different tissues.

Insulin is a critical hormone that promotes energy storage in various tissues, as well as anabolic functions. Insulin resistance significantly reduces these responses, resulting in pathological conditions, such as obesity and type 2 diabetes mellitus (T2DM). The management of insulin resistance requires better knowledge of its pathophysiological mechanisms to prevent secondary complications, such as cardiovascular diseases (CVDs). Recent evidence regarding the etiological mechanisms behind insulin resistance emphasizes the role of energy imbalance and neurohormonal dysregulation, both of which are closely regulated by autophagy. Autophagy is a conserved process that maintains homeostasis in cells. Accordingly, autophagy abnormalities have been linked to a variety of metabolic disorders, including insulin resistance, T2DM, obesity, and CVDs. Thus, there may be a link between autophagy and insulin resistance. Therefore, the interaction between autophagy and insulin function will be examined in this review, particularly in insulin-responsive tissues, such as adipose tissue, liver, and skeletal muscle.

Alpha-Lipoic Acid, Auraptene, and Particularly Their Combination Prevent the Metastasis of U87 Human Glioblastoma Cells.

Background: The primary malignant brain tumor glioblastoma multiforme (GBM) is most commonly detected in individuals over 60 years old. The standard therapeutic approach for GBM is radiotherapy combined with temozolomide. Recently, herbal products, such as alpha-lipoic acid (ALA) and auraptene (AUR), have shown promising anticancer effects on various cancer cells and animal models. However, it is not well understood how ALA, AUR, and their combination in GBM work to combat cancer. Thus, the purpose of this study was to investigate the antimetastatic effects of the ALA-AUR combination on U87 human glioblastoma cells. Methods: The inhibitory effects of ALA, AUR, and the ALA/AUR combination on the migration and metastasis of U87 cells were evaluated using a wound healing test and gelatin zymography. The expression levels of matrix metalloproteinase MMP-2 and MMP-9 were assessed at the transcriptional and translational levels using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Results: Our findings revealed that combination therapy reduced cell migration and metastasis, which was indicated by the reduction in MMP-2/-9 expression both at mRNA and protein levels, as well as their enzymatic activity in U87 cells. Conclusion: This study demonstrated that the combination of ALA and AUR effectively inhibited the migration and metastasis of U87 cells. Thus, given their safety and favorable specifications, the combination of these drugs can be a promising candidate for GBM treatment as primary or adjuvant therapy.

In vitro and Molecular Docking Analysis of Quercetin as an Anti-inflammatory and Antioxidant.

INTRODUCTION: Quercetin (3,3',4',5,7-pentahydroxyflavone) is a dietary flavonoid with good antioxidant and anti-inflammatory properties. AIMS: The present study aims to determine these effects in peripheral blood mononuclear cells (PBMCs) evoked by lipopolysaccharides (LPS). METHODS: The mRNA expression and protein secretion of inflammatory mediators were evaluated by enzyme- linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (PCR), respectively. Western blotting was utilized for assessing p65-NF-κB phosphorylation. Ransod kits evaluated the glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity in the cell lysates. Ultimately, the molecular docking approach was performed to investigate the biological activity of Quercetin against NF-κB pathway proteins and antioxidant enzymes. RESULTS: The findings revealed that quercetin significantly attenuated the expression and secretion of inflammatory mediators and p65-NF-κB phosphorylation in LPS-induced PBMCs. Additionally, quercetin dose-dependently improved the activities of SOD and GPx enzymes and decreased LPS-mediated oxidative stress in PBMCs. Moreover, quercetin has a considerable binding affinity to IκKb, the core element of the NF-κB pathway and the antioxidant enzyme SOD. CONCLUSION: The data show that quercetin plays a vital role in ameliorating inflammation and oxidative stress caused by LPS in PBMCs.

Carbon Quantum Dots as Multi-Purpose Nanomaterial in Stem Cell Therapy.

Some issues, such as their obscure fate or low survival rate into the body during stem cell therapy, should be addressed to boost efficiency. Nanotechnology offers a suitable solution to combat such limitations. Carbon quantum dots (CQDs) are carbon-based nanomaterials and may be used as multi-purpose compounds in stem cell therapy. CQDs are excellent choices for stem cell labeling thanks to their special features such as optical properties and good biocompatibility. Besides, they can modulate the biological function of stem cells, such as their proliferation, homing ability, and differentiation properties. Considering the charismatic feature of CQDs and their broad unique effect on stem cells, the current review aims to summarize the advancements in this field. Hence, we first focused on CQDs synthesis and their applications. In the next section, the stem cell categories will be discussed, and the final part is dedicated to the recent research evaluating the impact of CQDs on stem cell therapy.

Ellagic acid ameliorates aging-induced renal oxidative damage through upregulating SIRT1 and NRF2.

BACKGROUND: Aging is associated with impaired renal function and structural alterations. Oxidative stress plays a vital role in renal senescence and damage. Sirtuin 1 (SIRT1) is thought to protect cells from oxidative stress through nuclear factor erythroid 2-related factor 2 (NRF2). Ellagic acid (EA), a natural antioxidant, has been demonstrated to have renoprotective roles in vitro and in vivo. This study investigated if SIRT1 and NRF2 mediate the protective effects of EA in aged kidneys. METHODS: Male Wistar rats were divided into three groups including young (4 months), old, and old + EA (25 months). Young and old groups received EA solvent, while the old + EA group was treated with EA (30 mg/kg) by gavage for 30 days. Then, the level of renal oxidative stress, SIRT1 and NRF2 expression, kidney function parameters, and histopathological indices were measured. RESULTS: Treatment with EA significantly increased the level of antioxidant enzymes and reduced malondialdehyde concentration (P < 0.01). Moreover, EA administration remarkably upregulated mRNA and protein levels of SIRT1 and NRF2 as well as deacetylated NRF2 protein (P < 0.05). Additionally, EA treated rats improved kidney function and histopathological scores (P < 0.05). CONCLUSIONS: These findings suggest that ellagic acid exerts protective effects on aged kidneys by activating SIRT1 and NRF2 signaling.

Investigating the effects of Citrullus colocynthis on cognitive performance and anxiety-like behaviors in STZ-induced diabetic rats.

Background: Diabetes can impair cognitive performance and lead to dementia. Patients with type 1 diabetes mellitus (T1DM) are reported with different levels of cognitive dysfunctions in various cognitive domains ranging from general intellectual testing to specific deficits with visuospatial abilities, motor speed, writing, attention, reading, and psychomotor efficiency. The present study aimed to investigate the effect of Citrullus colocynthis on cognitive functions.Methods: A total of 42 male Wistar rats (3-4 months old and weighing 200-250 g) were tested in the current study. Rats were randomly allocated into 3 groups of control, Diabetes, and Diabetes + Drug. The diabetic rats received Citrullus colocynthis extraction orally. The behavioral tests included the open field, elevated plus maze (EPM), novel object recognition (NOR), passive avoidance tests, and Morris Water Maze (MWM) tests. Data were analyzed using student and paired t-tests via SPSS software version 16.Results: Our results showed the protective effects of Citrullus colocynthis administration against cognitive impairments. This is followed by STZ-induced diabetes in the MWM, novel object recognition, and passive avoidance tasks. Also, it was found that Citrullus colocynthis improved anxiety in diabetic rats.Conclusion According to the findings of this study, the administration of 200 mg/kg C. colocynthis once per day for 40 days can lead to ameliorated cognitive impairments and antidiabetic effects such as increasing body weight and decreasing FBS.

Plasma Complement C1q/tumor necrosis factor-related protein 15 concentration is associated with polycystic ovary syndrome.

Polycystic ovarian syndrome (PCOS) is a common poignant endocrine disorder affecting women, posing a close association with metabolic syndrome and obesity. Existing literature characterizes PCOS with deranged levels of several adipokines and myokines. CTRP15 is a paralogue of adiponectin, mainly expressed by skeletal muscles, and plays a key role in insulin, glucose, and lipid metabolism. In the current study, we aim to determine the circulating levels of CTRP15 and evaluate its association with cardiometabolic and inflammatory parameters in PCOS women. This case-control study included 120 PCOS patients (60 Recurrent pregnancy loss (RPL) and 60 infertile (inf) PCOS) and 60 healthy non-PCOS controls. Serum levels of hs-CRP were measured by commercial kits, while serum levels of adiponectin and CTRP15 were determined using the ELISA technique. Serum levels of CTRP15 were significantly elevated in PCOS-RPL and PCOS-inf subgroups when compared to controls (94.80 ± 27.08 and 87.77 ± 25.48 vs. 54.78 ± 15.45, both P < 0.001). Moreover, serum adiponectin was considerably lower in the PCOS group and subgroups (P < 0.001), while serum hs-CRP, fasting insulin, HOMA-IR, and free testosterone were significantly higher when compared to the non-PCOS group (P < 0.05). Furthermore, CTRP15 closely associated with FSH, HOMA-IR, hs-CRP, and BMI. These results highlight a possible involvement of CTRP15 in the pathogenesis of PCOS. The elevated levels of CTRP15 might be a compensatory mechanism for the metabolic dysregulations (excess adiposity, insulin resistance, metaflammation) associated with the syndrome. Nevertheless, future studies are necessary to unravel the underlying mechanism.

Effects of trehalose on NFE2L2, catalase, and superoxide dismutase in the kidney of aged rats.

Aging is associated with an increase in oxidative stress, which damages organs such as the kidney. Trehalose has abundant beneficial activities including antioxidative effects. This study aimed to investigate the effects of trehalose on several antioxidant parameters of the aged kidney. Wistar rats were divided into three groups: young (4 months), aged (24 months), and aged-trehalose. The third group was treated with 2% trehalose for one month. The expression of target genes and enzyme activities in the kidney of the animals were evaluated by quantitative polymerase chain reaction (qPCR) and enzyme colorimetric procedures, respectively. Protein levels of NFE2L2 showed a 50% reduction in aged rats compared to young rats (P<0.001), which was restored by trehalose intervention. In addition, the activity and mRNA levels of catalase (CAT) increased in aged rats while treatment with trehalose reversed this trend. On the other hand, superoxide dismutase (SOD) activity was reduced in the kidneys of aged rats but was not affected by trehalose intervention .It is concluded that trehalose supplementation alleviates the antioxidant system impairments in the kidneys of aged rats. However, further investigations are needed to thoroughly describe the antioxidative impacts of trehalose on the kidneys during aging.

Trehalose and N-Acetyl Cysteine Alleviate Inflammatory Cytokine Production and Oxidative Stress in LPS-Stimulated Human Peripheral Blood Mononuclear Cells.

BACKGROUND: Evidence has shown that inflammation and oxidative stress are implicated in the development of a great number of human diseases. Trehalose possesses various biological effects including antioxidant and anti-inflammatory activities. However, there is little data on the effects of trehalose on human cells including peripheral blood mononuclear cells (PBMCs). Here, we aimed to investigate whether trehalose could attenuate oxidative stress and inflammation induced by lipopolysaccharides (LPS) in PBMCs. METHODS: The enzyme-linked immunosorbent assay (ELISA) and RT-PCR were used to assess the levels of inflammatory cytokines. To investigate the phosphorylation of c-Jun N-terminal kinase (JNK) and NF-κB, western blot analysis was utilized. Oxidant-antioxidant markers were assessed using ELISA and colorimetric procedures. RESULTS: The results revealed that trehalose significantly mitigated the effect of LPS on the phosphorylation of JNK and NF-κB-P65 (p < .00). This mitigation was associated with significantly reduced levels of inflammatory cytokines IL-6, TNF-α, and IL-1ß and increased levels of anti-inflammatory cytokine IL-10 (P < .05). The antioxidant N-acetyl cysteine (NAC) also showed similar effects on JNK and NF-κB-P65 phosphorylation and inflammatory cytokines (p < .00). Furthermore, trehalose alleviated oxidative stress in LPS-stimulated PBMCs as it reversed the altered levels of malondialdehyde and total thiols (p ≤ .05) and restored the activity of antioxidant enzymes glutathione peroxidase and manganese superoxide dismutase (p < .001). CONCLUSION: The results of this study indicated that trehalose prevented inflammation and oxidative stress in the LPS-stimulated PBMCs, providing evidence for the benefits of trehalose as a potential therapeutic agent in inflammatory conditions. ABBREVIATIONS: LPS: Lipopolysaccharide; NAC: N-Acetyl cysteine; ROS: Reactive oxygen species; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; SOD: Superoxide dismutase; GPx: Glutathione peroxidase; MDA: Malondialdehyde; MAPK: Mitogen-activated protein kinases; JNK: c-Jun N-terminal kinase; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells.

Metformin Therapy Attenuates Pro-inflammatory Microglia by Inhibiting NF-κB in Cuprizone Demyelinating Mouse Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disorder characterized by reactive gliosis, inflammation, and demyelination. Microglia plays a crucial role in the pathogenesis of MS and has the dynamic plasticity to polarize between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Metformin, a glucose-lowering drug, attenuates inflammatory responses by activating adenosine monophosphate protein kinase (AMPK) which suppresses nuclear factor kappa B (NF-κB). In this study, we indirectly investigated whether metformin therapy would regulate microglia activity in the cuprizone (CPZ)-induced demyelination mouse model of MS via measuring the markers associated with pro- and anti-inflammatory microglia. Evaluation of myelin by luxol fast blue staining revealed that metformin treatment (CPZ + Met) diminished demyelination, in comparison to CPZ mice. In addition, metformin therapy significantly alleviated reactive microgliosis and astrogliosis in the corpus callosum, as measured by Iba-1 and GFAP staining. Moreover, metformin treatment significantly downregulated the expression of pro-inflammatory associated genes (iNOS, H2-Aa, and TNF-α) in the corpus callosum, whereas expression of anti-inflammatory markers (Arg1, Mrc1, and IL10) was not promoted, compared to CPZ mice. Furthermore, protein levels of iNOS (pro-inflammatory marker) were significantly decreased in the metformin group, while those of Trem2 (anti-inflammatory marker) were increased. In addition, metformin significantly increased AMPK activation in CPZ mice. Finally, metformin administration significantly reduced the activation level of NF-κB in CPZ mice. In summary, our data revealed that metformin attenuated pro-inflammatory microglia markers through suppressing NF-κB activity. The positive effects of metformin on microglia and remyelination suggest that it could be used as a promising candidate to lessen the incidence of inflammatory neurodegenerative diseases such as MS.

The effects of malvidin on oxidative stress parameters and inflammatory cytokines in LPS-induced human THP-1 cells.

Malvidin is an anthocyanin which is involved in inhibiting inflammatory-related mediators in inflammatory diseases; however, its mechanism of action in THP-1 cells is not yet known. THP-1 is a human monocytic cell line that is derived from patients with acute monocytic leukemia. The present study aimed to investigate the effect of malvidin on inflammatory responses and oxidative stress in lipopolysaccharide (LPS)-induced THP-1 cells. THP-1 cells were stimulated with LPS (50 ng/ml) to induce inflammation in the presence or absence of malvidin. The anti/proinflammatory cytokines were evaluated by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Total protein levels/phosphorylation of c-Jun N-terminal kinase (JNK), P65-NF-κB, and IKKα/IKKß were evaluated by western blot analysis. Malondialdehyde (MDA) and nitric oxide (NO) metabolite levels, ferric reducing antioxidant power (FRAP), total thiol (T-SH) content, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity were measured to evaluate the antioxidant activity of malvidin in THP-1 cells. Treatment of LPS-stimulated THP-1 cells with malvidin (100 and 200 µM) led to the significant inhibition of interleukin-6 (IL-6), tumor necrosis factor-α, and IL-1ß messenger RNA (mRNA) expression and protein levels as well as a significant increase in the IL-10 mRNA expression and protein secretion. Moreover, 200 µM malvidin treatment reduced the phosphorylation of JNK, IKKα/IKKß, and P65-NF-κB. These findings showed that malvidin not only decreased the MDA and NO metabolite levels but also increased the FRAP and T-SH content as well as SOD and GPx activities. The findings of the present study demonstrated the potential role of malvidin in blocking inflammation and oxidative stress induced by LPS in THP-1 cell line, suggesting that malvidin is likely to be a therapeutic agent for inflammatory diseases.

Evaluation of lipid ratios and triglyceride-glucose index as risk markers of insulin resistance in Iranian polycystic ovary syndrome women.

BACKGROUND: Insulin resistance has a vital role in the pathophysiology of polycystic ovary syndrome (PCOS). Previous investigations have shown that some lipid ratios could be a simple clinical indicator of insulin resistance (IR) in some disorders and ethnicities. The present study was conducted to evaluate the correlation between triglyceride to HDL-cholesterol (TG/HDL-C), total cholesterol to HDL-cholesterol (TC/HDL-C), as well as fasting triglyceride-glucose (TyG) indices with IR (as measured by homeostasis model assessment of IR (HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and fasting glucose to insulin ratio (FGIR)) among the Iranian women diagnosed with PCOS. METHODS: In the current study, a total of 305 women with PCOS were evaluated. TG/HDL-C, TC/HDL-C, and TyG indices were calculated. Fasting insulin level was measured using ELISA technique. IR was defined as a HOMA-IR value of ≥2.63, FG-IR value of < 8.25, and QUICKI value of < 0.33. RESULTS: The insulin-resistant (IR) and insulin-sensitive (IS) groups, established by the HOMA-IR, FG-IR, and QUICKI values were different in terms of TG/HDL-C, TC/HDL-C, and TyG indices. These indices were associated with IR even after adjusting for age and BMI. ROC curve analyses showed that TyG, TG/HDL-C, and TC/HDL-C strongly predicted HOMA-IR with area under the curve (AUC) of 0.639, 0.619, and 0.623, respectively (P < 0.05). Further, TC/HDL-C was a good predictor of FG-IR with AUC of 0.614 (P = 0.04). CONCLUSION: TyG, TG/HDL-C, and TC/HDL-C indices might be good indicators of IR among Iranian women diagnosed with PCOS.

Evaluation of angiopoietin-like protein 3 (ANGPTL3) levels in polycystic ovary syndrome.

AIM: Angiopoietin-like protein 3 (ANGPTL3) is recognized as a regulator of lipid metabolism. However, little is known about its association with insulin resistance in polycystic ovary syndrome (PCOS) setting. The present study aimed to investigate the serum levels of ANGPTL3 and adiponectin in PCOS women compared to healthy controls. MAIN METHOD: In this study, a total of 175 premenopausal women (117 PCOS and 58 non-PCOS) were enrolled. Serum concentrations of ANGPTL3, adiponectin, fasting insulin, and other hormonal variables were measured using ELISA technique. KEY FINDINGS: Results showed that adiponectin levels were significantly lower in PCOS group than those of non-PCOS group. However, serum levels of ANGPTL3, high-sensitivity C-reactive protein (hs-CRP), and homocysteine (Hcy) were found to be higher in PCOS patients, when compared to non-PCOS ones. Moreover, serum ANGPTL3 positively correlated with BMI and serum triglyceride, while it inversely correlated with serum HDL-C in PCOS patients. SIGNIFICANCE: Our results demonstrated that increased levels of ANGPTL3 correlated with insulin resistance and dyslipidemia in PCOS patients, highlighting the need for future studies targeting its role in the pathogenesis of this disease.

The effects of rosmarinic acid on oxidative stress parameters and inflammatory cytokines in lipopolysaccharide-induced peripheral blood mononuclear cells.

Rosmarinic acid (RA) is a potential herbal medicine and has received considerable attention due to its strong antioxidant properties. The aim of this study is to investigate the impact of RA on inflammation and oxidative stress induced by lipopolysaccharide (LPS) in peripheral blood mononuclear cells (PBMCs). PBMCs were pre-treated with various contents of RA (20, 40, 80 µM) for 24 h, then, stimulated with LPS (10 ng/ml) for more 6 h. ELISA and Real-time PCR were done to detect the levels of IL-6, TNF-α, COX-2, IL-1ß and IL-10. Western blot was done to investigate the phosphorylated amounts of P65-NF-κB and JNK. Inflammatory cytokines and oxidant-antioxidant parameters were determined by colorimetric and ELISA methods. The results indicated that LPS augmented the protein levels of IL-6, TNF-α, and IL-1ß cytokines as well as the mRNA levels of IL-6, TNF-α, IL-1ß, COX-2, and IL-10 cytokines in in PBMCs. However, pretreatment with RA could reduce the impact of LPS on inflammatory markers. In addition, RA inhibited P65-NF-κB and JNK phosphorylation. LPS also caused a decrease in antioxidant enzymes, total thiol, and total antioxidant capacity as well as an increment in malondialdehyde and nitric oxide metabolite contents that RA abrogated them. Collectively, our finding demonstrated that RA ameliorates LPS-induced inflammation in PBMCs. RA reduces oxidative stress by preventing lipid peroxidation and nitric oxide production as well as restarting the activity of the GPx and SOD enzymes. Furthermore, our findings indicated that RA was able to protect PBMCs from inflammation via inhibiting the NF-κB and JNK MAPK pathways. This evidence shows a promising therapeutic role for RA in inflammatory status.

Malvidin prevents lipopolysaccharide-induced oxidative stress and inflammation in human peripheral blood mononuclear cells.

It is indicated that malvidin has anti-inflammatory and antioxidant effects on various cells, although the function of malvidin in preventing inflammatory reactions caused by lipopolysaccharide (LPS) in peripheral blood mononuclear cells (PBMCs) is still not known. The objective of this study was to examine the impact of malvidin on inflammatory responses and oxidative stress in PBMCs as caused by LPS. The present findings showed that LPS significantly increased the expression of IL-6, TNF-α, IL-1ß, and COX-2 mRNA and protein release from PBMCs 22 hr after treatments. It was also revealed that increased levels in cytokine expression coincided with increased phosphorylation of JNK, P65-NF-κB, and IKKα/IKKß. Also, the expression of IL-6, TNF-α, IL-1ß, and COX-2 mRNA induced by LPS as well as secretion of protein in PBMC has been significantly decreased by pretreatment of malvidin. Importantly, pretreatment of the cells with malvidin completely abrogated the phosphorylation of P65-NF-κB, JNK, and IKKα/IKKß in LPS treated cells. Malvidin protection against LPS-induced inflammation was coupled with a decline in the levels of nitric oxide metabolite and malondialdehyde, along with an increase in the ferric reducing antioxidant power, total thiol activity, and also superoxide dismutase and glutathione peroxidase activity. In accordance with this finding, malvidin may represent a promising therapeutic agent for the prevention of inflammation in PBMCs.

Resveratrol alleviates obesity-induced skeletal muscle inflammation via decreasing M1 macrophage polarization and increasing the regulatory T cell population.

Resveratrol was reported to inhibit inflammatory responses; however, the role of this polyphenol in obesity-induced skeletal muscle inflammation remains unknown. Mice fed a high fat diet (HFD) were treated with resveratrol for 16 weeks. Resveratrol treatment decreased macrophage infiltration into skeletal muscle of HFD-fed mice. Resveratrol also led to the polarization of macrophages to the M2 direction, as well as decreasing the expression of a number of M1 pro-inflammatory cytokines [tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß) and interleukin 6 (IL-6)]. In addition, increased infiltration of regulatory T cells (Treg cells) was found following resveratrol treatment in skeletal muscle of mice. Decreased intramyocellular lipid deposition was associated with reduced expression levels of toll-like receptors 2 (TLR2) and TLR4 in resveratrol treated mice. We also found that diminished inflammation in skeletal muscle following resveratrol treatment was accompanied by increasing phosphorylation of 5'-adenosine monophosphate-activated protein kinase (AMPK) and decreasing phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Taken together, these findings suggest that resveratrol ameliorates inflammation in skeletal muscle of HFD-induced model of obesity. Therefore, resveratrol might represent a potential treatment for attenuation of inflammation in skeletal muscle tissue.

Circulating levels of C1q/TNF-α-related protein 6 (CTRP6) in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting females of reproductive age. It has been associated with cardiometabolic disorders including diabetes mellitus and cardiovascular disorders, and increases the risk of developing fecundity pathologies including recurrent pregnancy loss (RPL) and infertility. C1q/tumor necrosis factor-α-related protein-6 (CTRP6) is a novel adipokine involved in glucose and lipid metabolism, host inflammation, and organogenesis. In the present study, we aimed to determine the association of serum CTRP6 levels with some components of metabolic syndrome in PCOS patients (infertile PCOS [inf-PCOS] and PCOS-RPL). This case-control study included 120 PCOS patients (60 inf-PCOS and 60 PCOS-RPL) and 60 healthy controls. Serum high-sensitivity C-reactive protein (hs-CRP) and homocysteine were measured using commercial kits, while adiponectin and CTRP6 levels were assessed using ELISA technique. Inf-PCOS and PCOS-RPL individuals had higher levels of serum CTRP6 than controls (546.15 ± 125.02 ng/ml and 534.04 ± 144.19 ng/ml vs. 440.16 ± 159.24 ng/ml; both p < .001). Moreover, serum adiponectin levels were significantly reduced, while fasting insulin, homeostasis model assessment of insulin resistance, free testosterone, and hs-CRP levels were significantly elevated in PCOS group, when compared with controls. Furthermore, serum CTRP6 positively associated with body mass index in all subjects. It showed an inverse correlation with adiponectin in PCOS group and subgroups. However, it had a direct association with hs-CRP in PCOS group and inf-PCOS subgroup, but not PCOS-RPL subgroup. These findings unravel a probable role of CTRP6 in PCOS pathogenesis, which poses a possibility to be a good diagnostic target. However, further investigation is needed.

Interplay between oxidative stress and autophagy function and its role in inflammatory cytokine expression induced by palmitate in skeletal muscle cells.

Autophagy is a cellular process activated in response to various stresses such as starvation, hypoxia, and oxidative stress. Autophagy was reported to modulate the inflammatory pathways. However, whether autophagy is involved in regulation of palmitate-induced inflammation of skeletal muscle C2C12 cells is still unknown. The present study aimed to investigate the autophagic pathway in C2C12 cells treated with 0.5 mM palmitate. The results showed that the protein levels of LC3BII and P62 were increased in C2C12 cells after 12 h palmitate treatment. Besides, inhibition of autophagy by chloroquine or 3-methyladenin and its activation by rapamycin were associated with elevated mRNA and protein levels of IL-6 and TNF-α inflammatory cytokines in C2C12 cells. To study the mechanism by which autophagy impairment leads to activation of inflammatory responses, reactive oxygen species (ROS) levels in palmitate-treated cells were measured. The results showed that while palmitate stimulates ROS production, pretreatment of the cells with N-acetyl cysteine (NAC), a ROS scavenger, reduced inflammatory responses and also improved LC3-BII and P62 protein in the C2C12 cells exposed to palmitate. These findings suggest that palmitate-induced defect of autophagic flux leads to elevated inflammatory cytokine expression in the skeletal muscle cells by regulating the oxidative stress process.

Evidence for the link between defective autophagy and inflammation in peripheral blood mononuclear cells of type 2 diabetic patients.

Autophagy was shown to modulate inflammation in immune cells. This study was designed to evaluate the association between autophagy and inflammation in peripheral blood mononuclear cells (PBMCs) of type 2 diabetic (T2D) and non-diabetic (ND) subjects. The autophagy markers were measured by real-time PCR and western blot. The gene expression of pro- and anti-inflammatory cytokines was assessed by real-time PCR. Reduced transcription of BECN1 and LAMP2 and unchanged expression of MAP1LC3B and ATG5 were observed in PBMCs of T2D patients. Decreased LC3B-II and increased p62/SQSTM1 levels were found in PBMCs of diabetic patients. The p-mTOR level was higher in PBMCs of diabetic patients. An increase in both IL-1ß and TNF-α gene expression, along with a decrease in the expression of IL-10, was observed in PBMCs of T2D patients. TNF-α mRNA expression was inversely correlated with the mRNA expression of BECN1 and LAMP2. TNF-α and IL-1ß expression were negatively correlated with the protein levels of LC3B-II. TNF-α and IL-1ß expression had also a positive correlation with protein level of p62. IL-10 mRNA expression was positively correlated with the mRNA expression of BECN1 and LAMP2 and protein levels of LC3B-II and negatively correlated with protein level of p62. In addition, p-mTOR level was positively correlated with IL-1ß and TNF-α mRNA expression. The results revealed a reduced autophagy in PBMCs of T2D patients that is liked with an enhanced inflammation. The suppression of autophagy in PBMCs of diabetic patients may be associated with the activation of the mTOR signaling.