Polycystic ovary syndrome (PCOS) is a unification of endocrine and metabolic disorders and has become immensely prevalent among women of fertile age. The prime organ affected in PCOS is the ovary and ...its distressed functioning elicits disturbed reproductive outcomes. In the ovary, macroautophagy/autophagy performs a pivotal role in directing the chain of events starting from oocytes origin until its fertilization. Recent discoveries demonstrate a significant role of autophagy in the pathogenesis of PCOS. Defective autophagy in the follicular cells during different stages of follicles is observed in the PCOS ovary. Exploring different autophagy pathways provides a platform for predicting the possible cause of altered ovarian physiology in PCOS. In this review, we have emphasized autophagy's role in governing follicular development under normal circumstances and in PCOS, including significant abnormalities associated with PCOS such as anovulation, hyperandrogenemia, metabolic disturbances, and related abnormality. So far, few studies have linked autophagy and PCOS and propose its essential role in PCOS progression. However, detailed knowledge in this area is lacking. Here we have summarized the latest knowledge related to autophagy associated with PCOS. This review's main objective is to provide a background of autophagy in the ovary, its possible connection with PCOS and suggested a novel proposal for future studies to aid a better understanding of PCOS pathogenesis.
Abbreviations: AE: androgen excess; AF: antral follicle; AKT/PKB: AKT serine/threonine kinase; AMH: anti-Mullerian hormone; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BMP: bone morphogenetic protein; CASP3: caspase 3; CL: corpus luteum; CYP17A1/P450C17: cytochrome P450 family 17 subfamily A member 1; CYP19A1: cytochrome P450 family 19 subfamily A member 1; DHEA: dehydroepiandrosterone; EH: endometrial hyperplasia; FF: follicular fluid; FOXO: forkhead box O; FSH: follicle stimulating hormone; GC: granulosa cell; GDF: growth differentiation factor; HA: hyperandrogenemia; HMGB1: high mobility group box 1; IGF1: insulin like growth factor 1; INS: insulin; IR: insulin resistance; LHCGR/LHR: luteinizing hormone/choriogonadotropin receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; MAPK8/JNK: mitogen-activated protein kinase 8; MTOR: mechanistic target of rapamycin kinase; MTORC: mechanistic target of rapamycin complex; NAFLD: nonalcoholic fatty liver disease; NFKB: nuclear factor kappa B; OLR1/LOX-1: oxidized low density lipoprotein receptor 1; oxLDL: oxidized low-density lipoproteins; PA: palmitic acid; PCOS: polycystic ovary syndrome; PF: primary follicle; PGC: primordial germ cell; PI3K: phosphoinositide 3-kinase; PMF: primordial follicle; ROS: reactive oxygen species; RP: resting pool; SIRT1: sirtuin 1; SQSTM1/p62: sequestosome 1; T2DM: type 2 diabetes mellitus; TC: theca cell; TUG1: taurine up-regulated 1
Hesperidin possesses myriads of pharmacological benefits, including anti-inflammatory and antioxidant properties. Herein, we speculated that the described pharmacological benefits of hesperidin might ...be due to its potentiating action on SIRT1; thereby, inhibition of NOX4. We developed diabetic neuropathy in Sprague-Dawley rats by feeding them a high-fat diet (HFD) for 12 weeks. We checked the effect of hesperidin on the level of oxidative stress, inflammatory markers, NOX4, and SIRT1 by biochemical analysis, histopathology, immunoblotting, immunocytochemistry, and real-time qPCR in HFD-fed rats and Palmitate encountered rat glial C6 cells. Hesperidin administration improved mechanical, thermal allodynia, and glucose homeostasis. There was a decrease in oxidative stress and inflammation and an enhanced level of antioxidant enzymes. Besides, the expression of NOX4 was down-regulated, while SIRT1 was upregulated. Interestingly, hesperidin treatment protected them from oxidative and inflammatory damage by upregulating SIRT1 and inhibiting NOX4 expression.
•Hesperidin improves mechanical and thermal sensitivity in diabetic neuropathic rats.•Hesperidin ameliorates hyperglycemia and hyperinsulinemia.•Hesperidin treatment protected from oxidative stress damage by inhibiting NADPH oxidase 4.•Hesperidin safeguards from NOX4 instigated inflammation by upregulating SIRT1 expression.
Recent findings have instituted the role of hyperglycemia-related AGE/RAGE and NF-κB in instigating reactive oxygen species (ROS) mediated mitochondrial dysfunction and apoptosis of hepatocyte, which ...leads to steatohepatitis. Naringin, a flavanone glycoside found to possess myriads of pharmacological benefits along with its antioxidant and anti-inflammatory properties. Consequently, we aimed to decipher the effect of naringin on RAGE/NF-κB mediated mitochondrial apoptosis in type 2 diabetes mellitus (T2DM)-induced steatohepatitis.
Hepatic HepG2 cells were cultured in palmitic acid medium with and without naringin. Lipid content was examined by Oil Red O and Nile Red staining. Cellular apoptosis was determined by Annexin V-FITC/PI staining. An experimental T2DM-induced steatohepatitis was developed in Sprague Dawley rats by high-fat diet (HFD) for 12 weeks. The naringin was administrated orally at a dose of 100 mg/kg, daily for eight weeks. Glucose and insulin tolerance test was performed. Liver sections were stained by hematoxylin-eosin and picrosirius red. The mRNA and protein expression of RAGE and NF-κB were determined by qPCR, Immunofluorescence, and Immunoblotting. Mitochondrial membrane potential (MMP), cellular and mitochondrial ROS were measured by FACS.
Palmitic acid encountered HepG2 cells and HFD fed rats exhibited hyperlipidemia, insulin resistance, abnormal aminotransferases, steatosis, and fibrosis. Besides, the level of AGEs, RAGE, NF-κB, and oxidative stress were exacerbated. Moreover, MMP, cellular and mitochondrial ROS were altered in diabetic rats. Nevertheless, the naringin treatment ameliorated the steatohepatitis by improving the levels of aforementioned parameters.
Collectively, these findings suggested anti-steatohepatitis potential of naringin in diabetics.
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•Naringin alleviates glucose intolerance in T2DM-induced steatohepatitis.•Naringin safeguards from steatosis and hepatic inflammation.•Naringin inhibits AGEs formation, thereby inhibits RAGE activation.•Naringin mitigates oxidative stress by down regulating NF-κB.•Naringin protects from NF-κB mediated mitochondrial apoptosis.
Obesity results in the chronic activation of innate immune system and subsequently sets in diabetes. Aim of the study was to investigate the immunometabolic role of brown adipose tissue (BAT) in the ...obesity. We performed both BAT transplantation as well as extirpation experiments in the mouse model of high-fat diet (HFD)-induced obesity. We carried out immune cell profiling in the stromal vascular fraction (SVF) isolated from epididymal white adipose tissue (eWAT). BAT transplantation reversed HFD-induced increase in body weight gain and insulin resistance without altering diet intake. Importantly, BAT transplantation attenuated the obesity-associated adipose tissue inflammation in terms of decreased pro-inflammatory M1-macrophages, cytotoxic CD8a T-cells and restored anti-inflammatory regulatory T-cells (Tregs) in the eWAT. BAT transplantation also improved endogenous BAT activity by elevating protein expression of browning markers (UCP-1, PRDM16 and PGC1α) in it. In addition, BAT transplantation promoted the eWAT expression of various genes involved in fatty acid oxidation (such as Elvol3 and Tfam,). In contrast, extirpation of the interscapular BAT exacerbated HFD-induced obesity, insulin resistance and adipose tissue inflammation (by increasing M1 macrophages, CD8a T-cell and decreasing Tregs in eWAT). Taken together, our results suggested an important role of BAT in combating obesity-associated metabolic complications. These results open a novel therapeutic option to target obesity and related metabolic disorders like type 2 diabetes.
Chromogranin A (ChgA) is an acidic pro-protein found in neuroendocrine organs, pheochromocytoma chromaffin granules, and tumor cells. Proteolytic processing of ChgA gives rise to an array of ...biologically active peptides such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin, which have diverse roles in regulating cardiovascular functions and metabolism, as well as inflammation. Intricate tissue-specific role of ChgA-derived peptide activity in preclinical rodent models of metabolic syndrome reveals complex effects on carbohydrate and lipid metabolism. Indeed, ChgA-derived peptides, PST and CST, play a pivotal role in metabolic syndrome such as obesity, insulin resistance, and diabetes mellitus
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Additionally, supplementation of specific peptide in ChgA-KO mice have an opposing effect on physiological functions, such as PST supplementation reduces insulin sensitivity and enhances inflammatory response. In contrast, CST supplementation enhances insulin sensitivity and reduces inflammatory response. In this review, we focus on the tissue-specific role of PST and CST as therapeutic targets in regulating carbohydrate and lipid metabolism, along with the associated risk factors.
Metabolic Syndrome is a multifactorial disease associated with increased risk of cardiovascular disorders, type 2 diabetes mellitus, fatty liver disease, etc. Various stress stimuli such as reactive ...oxygen species, endoplasmic reticulum stress, mitochondrial dysfunction, increased cytokines, or free fatty acids are known to aggravate progressive development of hyperglycemia and hyperlipidemia. Although the exact mechanism contributing to altered metabolism is unclear. Evidence suggests stress kinase role to be a crucial one in metabolic syndrome. Stress kinase, c-jun N-terminal kinase activation (JNK) is involved in various metabolic manifestations including obesity, insulin resistance, fatty liver disease as well as cardiometabolic disorders. It emerged as a foremost mediator in regulating metabolism in the liver, skeletal muscle, adipose tissue as well as pancreatic β cells. It has three isoforms each having a unique and tissue-specific role in altered metabolism. Current findings based on genetic manipulation or chemical inhibition studies identified JNK isoforms to play a central role in the regulation of whole-body metabolism, suggesting it to be a novel therapeutic target. Hence, it is imperative to elucidate its role in metabolic syndrome onset and progression. The purpose of this review is to elucidate in vitro and in vivo implications of JNK signaling along with the therapeutic strategy to inhibit specific isoform. Since metabolic syndrome is an array of diseases and complex pathway, carefully examining each tissue will be important for specific treatment strategies.
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Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified ...drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 ± 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 ± 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy.
is a nutrient-rich plant with a history of use in traditional medicine. It boasts a diverse range of polyphenols, including quercetin, resveratrol, β-sitosterol, myricetin, and other compounds. We ...developed and validated a sensitive LC-MS/MS method to quantify quercetin and
-res biomarkers in rat serum and applied this method to pharmacokinetic and stability studies. The mass spectrometer was set to negative ionization mode for the quantification of quercetin and
-res. Phenomenex Luna (C18(2), 100 A, 75 × 4.6 mm, 3 µ) column was utilized to separate the analytes using an isocratic mobile phase consisting of methanol and 0.1% formic acid in water (82:18). Validation of the method was performed using various parameters, including linearity, specificity, accuracy, stability, intra-day, inter-day precision, and the matrix effect. There was no observed significant endogenous interference from the blank serum. The analysis was completed within 5.0 min for each run, and the lower limit of quantification was 5 ng/mL. The calibration curves showed a linear range with a high correlation coefficient (r
> 0.99). The precision for intra- and inter-day assays showed relative standard deviations from 3.32% to 8.86% and 4.35% to 9.61%, respectively. The analytes in rat serum were stable during bench-top, freeze-thaw, and autosampler (-4 °C) stability studies. After oral administration, the analytes showed rapid absorption but underwent metabolism in rat liver microsomes despite being stable in simulated gastric and intestinal fluids. Intragastric administration resulted in higher absorption of quercetin and
-res, with greater C
, shorter half-life, and improved elimination. No prior research has been conducted on the oral pharmacokinetics and stability of anti-diabetic compounds in the Ethanolic extract of
EECQ, making this the first report. Our findings can provide the knowledge of EECQ's bioanalysis and pharmacokinetic properties which is useful for future clinical trials.
Pancreastatin (PST), an anti-insulin peptide derived from chromogranin A. Its levels increase in cases of obesity, which contributes to adipose tissue inflammation and insulin resistance. This study ...aims to investigate the immunometabolic effect of PST inhibitor (PSTi8) against PST by using in vitro and in vivo finding.
3T3-L1 cells were differentiated with or without PSTi8, and Oil Red O staining was performed. J774A.1 cells were used for macrophage polarization study. The diet-induced obesity and T2DM model was developed in C57BL/6 mice through high-fat diet for 8 weeks. Alzet osmotic pumps were filled with PSTi8 (release rate: 2 mg/kg/day) and implanted in mice for eight weeks. Further, insulin and glucose tolerance tests were performed. Liver and eWAT sections were stained with hematoxylin and eosin. FACS was used to measure mitochondrial ROS and membrane potential, while Oroboros O2k was used to measure oxygen consumption rate. Immunocytochemistry and qRT-PCR were done for protein and gene expression, respectively.
PSTi8 inhibited the expression of lipolytic genes and proteins in 3T3-L1 adipocytes. PSTi8 improved the inulin sensitivity, lipid profile, MMP, and OCR levels in the 3T3-L1 adipocyte and eWAT. It also increased the M1 to M2 macrophage polarization in J77A.1 cells and eWAT. Further, PSTi8 attenuated inflammatory CD4+ T, CD8+ T cells and increased the anti-inflammatory T-reg and eosinophil populations in the eWAT. It also reduced the expression of pro-inflammatory genes like Mcp1, Tnfα, and Il-6.
Collectively, PSTi8 exerted its beneficial effect on adipose tissue inflammation and restored energy expenditure against diet-induced obesity.
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•PST enhanced and PSTi8 attenuated the lipid accumulation in the 3T3-L1 adipocyte.•Higher level of PST contributes to development of dyshomeostasis in the DIO mice.•Inhibition of PST through PSTi8 improved the insulin sensitivity and decreased IR.•PSTi8 increased enhanced the macrophages polarization from M1 to M2 macrophages.•PSTi8 enhanced the mitochondrial fitness and improved the energy expenditure.
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