Assessing the toxicity of pesticides exposure on hepatic miRNA-target gene alterations in rat liver tissues via molecular and integrated network bioinformatics analysis.

The prevalent use of pesticides, including pirimiphos-methyl (PPM) and bifenthrin (BF), poses a serious health risk, particularly to workers who encounter these chemicals daily. Despite the recognized hepatotoxic effects, the specific molecular mechanisms, especially those involving miRNAs in liver damage caused by PPM and BF, are not fully elucidated. Prior studies have not exhaustively analyzed the hepatic miRNA-target gene dynamics following exposure to these pesticides; thus, this research aims to fill that gap through an extensive miRNA analysis to discern their regulation in PPM or BF-induced hepatic toxicity. In this study, male Sprague-Dawley rats were exposed to BF or PPM for 28 days through oral gavage, simulating the chronic exposure faced by humans. We conducted a thorough assessment of the hepatotoxicity induced by PPM and BF, employing multiple evaluation levels, including histological analysis, liver enzyme measurements, and real-time PCR to detect changes in hepatic miRNA-target gene expressions. Additionally, we utilized DIANA-miRPath prediction tools to delineate the functional implications of these hepatic miRNA target genes. Our findings reveal a significant modulation in the expression of rno-miR-155-5p and rno-miR-122-5p, along with their target genes, following PPM and BF treatment. In contrast, rno-miR-21-5p levels remained unaltered. These observations suggest potential utility of these specific hepatic miRNAs as biomarkers for liver injury resulting from pesticide exposure. Subsequent GO enrichment analysis linked target genes to functions like molecular activity, protein binding, and cellular processes. Additionally, KEGG pathway analysis showed these genes, influenced by varied miRNA expressions, play significant roles in metabolic and signaling pathways In conclusion, this study enhances our comprehension of the biological roles of miRNAs in hepatic toxicity induced by PPM and BF. The insights gained here not only shed light on molecular mechanisms but also open avenues for considering these miRNAs as potential diagnostic biomarkers in conditions of pesticide-induced hepatotoxicity, thereby guiding future therapeutic strategies.

The role of stinging nettle (Urtica dioica L.) in the management of rotenone-induced Parkinson's disease in rats.

Parkinson's disease (PD) is one of the most common neurodegenerative conditions. Alpha-synuclein deposition, Lewy bodies (LBs) formation, disruption of the autophagic machinery, apoptosis of substantia nigra dopaminergic neurons, oxidative stress, and neuroinflammation are all pathologic hallmarks of PD. The leaves of the stinging Nettle (Urtica dioica L.) have a long history as an herbal cure with antioxidant, anti-inflammatory, anti-cancer, immunomodulatory, and neuroprotective properties. The current study aims for the first time to investigate the role of Nettle supplementation on Rotenone-induced PD. Rats were divided into five groups; a Saline control, Nettle control (100 mg/kg/day), Rotenone control (2 mg/kg/day), Rotenone + Nettle (50 mg /kg/day), and Rotenone + Nettle (100 mg/kg). After four weeks, the rats were examined for behavioral tests. The midbrains were investigated for histopathological alteration and immunohistochemical reaction for Tyrosine hydroxylase in the dopaminergic neurons, α-synuclein for Lewy bodies, caspase 3 for apoptotic neurons, LC3 and P62 for autophagic activity. Midbrain homogenates were examined for oxidative stress markers. mRNA expression of TNFα and Il6; inflammatory markers, Bcl-2, BAX and Caspase 3; apoptosis markers, were detected in midbrains. The results showed that Nettle caused recovery of midbrain dopaminergic neurons, by inhibiting apoptosis, inflammation, and oxidative stress and by restoring the autophagic machinery with clearance of α-synuclein deposits. We can conclude that Nettle is a potentially effective adjuvant in the treatment of Parkinson's disease.

Knowledge, Attitudes, and Practices Toward the Prevention of Hepatitis B Virus Infection Among Medical Students in Medina City, Kingdom of Saudi Arabia.

INTRODUCTION: This study focuses on assessing the knowledge, attitudes, and practices related to Hepatitis B virus (HBV) prevention among medical students in Medina, Saudi Arabia. HBV is a significant global health concern, with a high prevalence in Saudi Arabia. Medical students due to their field, are at higher risk of exposure. Prior studies in Saudi Arabia show varied levels of awareness. This research aims to provide insights that can inform educational initiatives for this specific population. METHODS: This was a cross-sectional study conducted from June 2023 to September 2023 by using a pre-designed online questionnaire that was distributed among medical students in Medina. Data was analyzed using IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp. RESULTS: This study included 307 participants. 67.8% of the participants correctly identified the link between HBV and liver cancer, and 77.5% recognized the transmission risk from carriers. 91.9% acknowledged the transmission via contaminated blood and fluids, and 88.9% recognized the risk from unsterilized instruments. Positive attitudes were observed, with 92.2% agreeing that following infection control guidelines would protect them at work. Practice scores were generally positive, including high rates of screening (57.3%) and adherence to infection control measures (90.2%). Knowledge scores correlated positively with attitude (rho = 0.204) and practice scores (rho = 0.390). CONCLUSION: A significant proportion of participants had a strong understanding of HBV transmission and the importance of infection control measures. Positive attitudes towards infection control were prevalent, although some reluctance to provide care to HBV-infected individuals was noted.

How to Differentiate between Resistant and Susceptible Wheat Cultivars for Leaf Rust Fungi Using Antioxidant Enzymes and Histological and Molecular Studies?

Eight wheat cultivars, Sakha-94, Giza-171, Sids-1, Sids-12, Sids-13, Shandweel-1, Misr-1, and Misr-2, were evaluated for leaf rust at the seedling and adult stages in the 2021 and 2022 seasons. Biochemical, histological, and genetic analyses were performed to determine the link between cultivars that were either sensitive or resistant to the disease. Misr-2 and Giza-171 cultivars had the highest levels of resistance to leaf rust races in 2021 (LTCGT, STSJT, and TTTST) and 2022 (MBGJT, TTTKS, and TTTTT) at the seedling stage. However, at the adult stage, Sakha-94, Giza-171, Misr-1, and Misr-2 cultivars had the highest levels of resistance; consequently, they had the lowest final disease severity and the lowest values of AUDPC. The correlation between the seedling reaction and adult reaction was non-significant, with values of 0.4401 and 0.4793 in the 2021 and 2022 seasons, respectively. Throughout the biochemical, histological, and genetic analyses, it was observed that catalase, peroxidase, and polyphenol oxidase activities significantly increased in the resistant cultivars. The discoloration of superoxide (O2-) and hydrogen peroxide (H2O2) significantly decreased in resistant and moderately resistant wheat cultivars (Sakha-94, Giza-171, Misr-1, and Misr-2); higher hydrogen peroxide (H2O2) and superoxide (O2-) levels were recorded for the susceptible cultivars compared to the resistant cultivars. Molecular markers proved that the Lr50 gene was detected in the resistant cultivars. Puccinia triticina infections negatively affected most histological characteristics of flag leaves, especially in susceptible cultivars. The thickness of the blade (µ), the thickness of the upper and lower epidermis (UE and LE), the thickness of mesophyll tissue (MT), and bundle length and width in the midrib were decreased in susceptible cultivars such as Sids-1, Sids-13, and Shandwel-1 compared with resistant cultivars.

Efficacy of resveratrol in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized clinical trials.

Polycystic ovarian syndrome (PCOS) is a metabolic and hormonal condition affecting women of a reproductive age. It causes an abnormal menstrual cycle, anovulation, infertility, acne, hirsutism, obesity, hyperlipidemia, and cardiovascular disorders. Because resveratrol decreases testosterone levels, it may be of value in treating PCOS. We aimed to evaluate the efficacy of resveratrol in treating women with PCOS. We searched for randomized clinical trials (RCTs) in PubMed, Cochrane CENTRAL, Scopus and Web of Science. With 95% confidence intervals, the data was retrieved and analyzed as a mean difference (MD) or a standardized mean difference (SMD). Four RCTs with 218 women were included in the analysis. Resveratrol significantly reduced testosterone (SMD = -0.40; 95% CI [-0.71, -0.10], P = 0.009), luteinizing hormone (LH) (SMD = -0.32; 95% CI [-0.62, 0.01], P = 0.04), and dehydroepiandrosterone sulfate (DHEAS) (MD = -0.85; 95% CI [-1.25, -0.45], P < 0.0001) compared with the placebo. Resveratrol is effective in treating women with PCOS due to reducing the levels of testosterone, LH, and DHEAS. In combination with other treatments, especially for hyperlipidemia, resveratrol is beneficial for women diagnosed with PCOS.

Alpha-Mangostin ameliorates acute kidney injury via modifying levels of circulating TNF-α and IL-6 in glycerol-induced rhabdomyolysis animal model.

Alpha mangostin (AM), isolated from G. mangostana, showed beneficial effects in several disorders due to its antioxidant and anti-inflammatory properties. Acute kidney injury (AKI) due to different etiologies can develop into severe complications, resulting in high mortality rates. In this work, AM is tested for its ability to alleviate AKI in glycerol-induced AKI rat model, where 30 Male Sprague-Dawley rats were assigned to a healthy group, glycerol-treated group and AM-treated group. Glycerol- and AM groups received a single dose of glycerol (per IM, 50% glycerol in saline, 8 ml/kg), whereas control group was injected with saline. AM treatment (a single daily dose, per IP, 175mg/kg) was accomplished for three days. Animals were executed to collect blood samples and kidney tissue for biochemical and histological examination. It was found that glycerol induced increase in serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, serum magnesium, TNF-α and IL-6. It also induced renal edema and hypocalcemia along with histopathological renal damage. AM treatment improved renal histological features and alleviated increase in serum creatinine, BUN, serum magnesium, TNF-α and IL-6 levels, as well as renal edema and lipid peroxidation but did not affect serum calcium levels. This suggests AM as a potential therapeutic agent for treating AKI mainly via its antioxidant and anti-inflammatory properties.

The degree of nicotine dependence among users of different tobacco and nicotine products in Madinah City, Saudi Arabia.

BACKGROUND: Nicotine addiction has many consequences. The World Health Organization has classified nicotine dependence as a disorder of substance use. This study aimed to assess the dependence in users of different tobacco and/or nicotine-containing products (TNPs). MATERIALS AND METHODS: This analytical, cross-sectional study involved 211 TNP users in Madinah, Saudi Arabia. The data was collected using a self-administered questionnaire that consisted of two main sections. The first section included sociodemographic domain, TNP status domain, and the Stages of Change model domain. The second section of the instrument included the ABOUT dependence construct comprising 12 items. Independent t-test, analysis of variance, and correlation analysis were used to assess the relationship between the study variables. RESULTS: Most users of TNPs exclusively used tobacco cigarettes (53.1%). Total dependence score was significantly associated with gender, marital status, age group, monthly income, nicotine concentration in electronic cigarettes (e-cigarettes) liquid, and the number of cigarettes smoked per day (P < 0.05). Total dependence score was correlated with the duration of TNP usage (r = 0.24, P < 0.001), Switching attempts to another TNP (r = 0.16, P = 0.020), attempts of quitting TNPs (r = 0.25, P < 0.001), and willingness to quit (r = -0.37, P < 0.001). CONCLUSION: Dependence was associated with gender, marital status, age group, monthly income, nicotine concentration in e-cigarette liquid, and the number of cigarettes smoked per day. It was also associated with duration of TNP usage, Switching attempts to another TNP, attempts of quitting TNPs and the willingness to quit.

Efficacy of ticagrelor compared to clopidogrel in improving endothelial function in patients with coronary artery disease: a systematic review.

BACKGROUND: Ticagrelor and clopidogrel are antiplatelet drugs that act by binding to the adenosine diphosphate P2Y12 receptor. Previous studies have compared between them regarding the endothelial function effect. OBJECTIVES: This systematic review aims to summarize the evidence comparing the efficacy of ticagrelor vs. clopidogrel in improving endothelial function in patients with coronary artery disease (CAD). METHODS: In August 2021, the Scopus, PubMed, Web of Science, and Cochrane library were searched systematically for eligible trials. We included randomized controlled trials that compared the efficacy of ticagrelor vs. clopidogrel in improving endothelial function in patients with CAD. RESULTS: Seven trials (n = 511) were included in our systematic review. Ticagrelor resulted in a greater elevation of the level of progenitor cells CD34+ KDR+ and CD34+ 133+ (P = 0.036 and P = 0.019, respectively), with a lower rate of endothelial cell apoptosis rate (P < 0.001). Moreover, ticagrelor showed superiority regarding nitric oxide, radical oxygen species, and soluble P-selectin levels (P = 0.03, P = 0.02, and P = 0.019, respectively). Flow-mediated dilation findings differed between the studies (P = 0.004 vs. P = 0.39). CONCLUSION: Ticagrelor appears to exert an additional improvement in endothelial function compared with clopidogrel in patients with coronary heart disease.

Histidine-tryptophan-ketoglutarate solution versus multidose cardioplegia for myocardial protection in cardiac surgeries: a systematic review and meta-analysis.

BACKGROUND: Surgical procedures in the heart requires protection of the heart from ischemia-reperfusion injury. Cardioplegia is the primary myocardial protective method in use. Histidine-tryptophan-ketoglutarate (HTK) solution is an intracellular cardioplegic solution that was initially used to preserve organs for transplantation. METHODS: A systematic electronic search was conducted in July 2021, in four databases; PubMed, Scopus, Web of Science, and Cochrane Library for eligible randomized controlled trials. The results were screened and the eligible trials were identified. Thereafter, the relevant data were extracted and pooled as mean difference or risk ratio, and 95% confidence interval in an inverse variance method using RevMan software. RESULTS: This review included 12 trials (n = 1327). HTK solution has resulted significantly in shorter intensive care unit stay (MD = - 0.09; 95% CI [- 0.15, - 0.03], p = 0.006), and shorter hospital stay (MD = - 0.51; 95% CI [- 0.71, - 0.31], p < 0.00001). Moreover, the patients who received the HTK solution had significantly lower levels of creatine kinase (after 4-7 h (MD = - 157.52; 95% CI [- 272.31, - 42.19], p = 0.007), and 24 h (MD = - 136.62; 95% CI [- 267.20, - 6.05], p = 0.04)), as well as creatine kinase muscle brain band (after 44-48 h (MD = - 3.35; 95% CI [- 5.69, - 1.02], p = 0.005)). CONCLUSION: HTK solution had the same efficacy and safety as other cardioplegic solutions in most of the clinical parameters. Furthermore, the solution showed superiority in fastening the recovery and protecting the myocardium at the biochemical level. HTK solution provides longer myocardial protection; therefore, it limits surgical interruption. HTK solution can be used as an alternative to the currently used cardioplegic solutions.

Higher intestinal and circulatory lactate associated NOX2 activation leads to an ectopic fibrotic pathology following microcystin co-exposure in murine fatty liver disease.

Clinical studies implicated an increased risk of intestinal fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Our previous studies have shown that microcystin-LR (MC-LR) exposure led to altered gut microbiome and increased abundance of lactate producing bacteria and intestinal inflammation in underlying NAFLD. This led us to further investigate the effects of the MC-LR, a PP2A inhibitor in activating the TGF-ß fibrotic pathway in the intestines that might be mediated by increased lactate induced redox enzyme NOX2. Exposure to MC-LR led to higher lactate levels in circulation and in the intestinal content. The higher lactate levels were associated with NOX2 activation in vivo that led to increased Smad2/3-Smad4 co-localization and high alpha-smooth muscle actin (α-SMA) immunoreactivity in the intestines. Mechanistically, primary mouse intestinal epithelial cells treated with lactate and MC-LR separately led to higher NOX2 activation, phosphorylation of TGFßR1 receptor and subsequent Smad 2/3-Smad4 co-localization inhibitable by apocynin (NOX2 inhibitor), FBA (a peroxynitrite scavenger) and DMPO (a nitrone spin trap), catalase and superoxide dismutase. Inhibition of NOX2-induced redox signaling also showed a significant decrease in collagen protein thus suggesting a strong redox signaling induced activation of an ectopic fibrotic manifestation in the intestines. In conclusion, the present study provides mechanistic insight into the role of microcystin in dysbiosis-linked lactate production and subsequently advances our knowledge in lactate-induced NOX2 exacerbation of the cell differentiation and fibrosis in the NAFLD intestines.

Lipocalin 2 induces neuroinflammation and blood-brain barrier dysfunction through liver-brain axis in murine model of nonalcoholic steatohepatitis.

BACKGROUND: Recent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology. METHODS: Using murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis. RESULTS: Results showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box 1 (HMGB1) preferably from brain cells. Released HMGB1 acted as a preferential ligand to toll-like receptor 4 (TLR4) and induced oxidative stress by activation of NOX-2 signaling involving activated p65 protein of the NF-κB complex. Further, the HMGB1-derived downstream signaling cascade activated NLRP3 inflammasome and release of proinflammatory cytokines IL-6 and IL-1ß from brain cells. In addition, to advance our present understanding, in vitro studies were performed in primary brain endothelial cells where results showed high circulatory Lcn2 influenced HMGB1 secretion. Mechanistically, we also showed that elevated Lcn2 level in underlying NASH might be a likely cause for induction of blood-brain barrier dysfunction since the adipokine decreased the expression of tight junction protein Claudin 5 and caused subsequent elevation of pro-inflammatory cytokines IL-6 and IL-1ß. CONCLUSION: In conclusion, the NASH-induced brain pathology might be because of increased Lcn2-induced release of HMGB1 and accompanying neuroinflammation.

Exogenous PP2A inhibitor exacerbates the progression of nonalcoholic fatty liver disease via NOX2-dependent activation of miR21.

Nonalcoholic fatty liver disease (NAFLD) is an emerging global pandemic. Though significant progress has been made in unraveling the pathophysiology of the disease, the role of protein phosphatase 2A (PP2A) and its subsequent inhibition by environmental and genetic factors in NAFLD pathophysiology remains unclear. The present report tests the hypothesis that an exogenous PP2A inhibitor leads to hepatic inflammation and fibrogenesis via an NADPH oxidase 2 (NOX2)-dependent pathway in NAFLD. Results showed that microcystin (MC) administration, a potent PP2A inhibitor found in environmental exposure, led to an exacerbation of NAFLD pathology with increased CD68 immunoreactivity, the release of proinflammatory cytokines, and stellate cell activation, a process that was attenuated in mice that lacked the p47phox gene and miR21 knockout mice. Mechanistically, leptin-primed immortalized Kupffer cells (a mimicked model for an NAFLD condition) treated with apocynin or nitrone spin trap 5,5 dimethyl-1- pyrroline N-oxide (DMPO) had significantly decreased CD68 and decreased miR21 and α-smooth muscle actin levels, suggesting the role of NOX2-dependent reactive oxygen species in miR21-induced Kupffer cell activation and stellate cell pathology. Furthermore, NOX2-dependent peroxynitrite generation was primarily responsible for cellular events observed following MC exposure since incubation with phenylboronic acid attenuated miR21 levels, Kupffer cell activation, and inflammatory cytokine release. Furthermore, blocking of the AKT pathway attenuated PP2A inhibitor-induced NOX2 activation and miR21 upregulation. Taken together, we show that PP2A may have protective roles, and its inhibition exacerbates NAFLD pathology via activating NOX2-dependent peroxynitrite generation, thus increasing miR21-induced pathology.NEW & NOTEWORTHY Protein phosphatase 2A inhibition causes nonalcoholic steatohepatitis (NASH) progression via NADPH oxidase 2. In addition to a novel emchanism of action, we describe a new tool to describe NASH histopathology.

Environmental microcystin targets the microbiome and increases the risk of intestinal inflammatory pathology via NOX2 in underlying murine model of Nonalcoholic Fatty Liver Disease.

With increased climate change pressures likely to influence harmful algal blooms, exposure to microcystin, a known hepatotoxin and a byproduct of cyanobacterial blooms can be a risk factor for NAFLD associated comorbidities. Using both in vivo and in vitro experiments we show that microcystin exposure in NAFLD mice cause rapid alteration of gut microbiome, rise in bacterial genus known for mediating gut inflammation and lactate production. Changes in the microbiome were strongly associated with inflammatory pathology in the intestine, gut leaching, tight junction protein alterations and increased oxidative tyrosyl radicals. Increased lactate producing bacteria from the altered microbiome was associated with increased NOX-2, an NADPH oxidase isoform. Activationof NOX2 caused inflammasome activation as shown by NLRP3/ASCII and NLRP3/Casp-1 colocalizations in these cells while use of mice lacking a crucial NOX2 component attenuated inflammatory pathology and redox changes. Mechanistically, NOX2 mediated peroxynitrite species were primary to inflammasome activation and release of inflammatory mediators. Thus, in conclusion, microcystin exposure in NAFLD could significantly alter intestinal pathology especially by the effects on microbiome and resultant redox status thus advancing our understanding of the co-existence of NAFLD-linked inflammatory bowel disease phenotypes in the clinic.

Sparstolonin B (SsnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent.

SsnB previously showed a promising role to lessen liver inflammation observed in a mouse model of NAFLD. Since NAFLD can progress to fibrosis, studies were designed to unravel its role in attenuating NAFLD associated fibrosis. Using both in vivo and in vitro approaches, the study probed the possible mechanisms that underlined the role of SsnB in mitigating fibrosis. Mechanistically, SsnB, a TLR4 antagonist, decreased TLR4-PI3k akt signaling by upregulating PTEN protein expression. It also decreased MDM2 protein activation and increased p53 and p21 gene and protein expression. SsnB also downregulated pro-fibrogenic hedgehog signaling pathway, inhibited hepatic stellate cell proliferation and induced apoptosis in hepatic stellate cells, a mechanism that was LPS dependent. Further, SsnB decreased fibrosis by antagonizing TLR4 induced TGFß signaling pathway. Alternatively, SsnB augmented BAMBI (a TGFß pseudo-receptor) expression in mice liver by inhibiting TLR4 signaling pathway and thus reduced TGFß signaling, resulting in decreased hepatic stellate cell activation and extracellular matrix deposition. In vitro experiments on human hepatic stellate cell line showed that SsnB increased gene and protein expression of BAMBI. It also decreased nuclear co-localization of phospho SMAD2/3 and SMAD4 protein and thus attenuated TGFß signaling in vitro. We also observed a significant decrease in phosphorylation of SMAD2/3 protein, decreased STAT3 activation, alteration of focal adhesion protein and stress fiber disassembly upon SsnB administration in hepatic stellate cells which further confirmed the antagonistic effect of SsnB on TLR4-induced fibrogenesis.

High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease.

High circulatory insulin and leptin followed by underlying inflammation are often ascribed to the ectopic manifestations in non-alcoholic fatty liver disease (NAFLD) but the exact molecular pathways remain unclear. We have shown previously that CYP2E1-mediated oxidative stress and circulating leptin in NAFLD is associated with renal disease severity. Extending the studies, we hypothesized that high circulatory leptin in NAFLD causes renal mesangial cell activation and tubular inflammation via a NOX2 dependent pathway that upregulates proinflammatory miR21. High-fat diet (60% kcal) was used to induce fatty liver phenotype with parallel insulin and leptin resistance. The kidneys were probed for mesangial cell activation and tubular inflammation that showed accelerated NASH phenotype and oxidative stress in the liver. Results showed that NAFLD kidneys had significant increases in α-SMA, a marker of mesangial cell activation, miR21 levels, tyrosine nitration and renal inflammation while they were significantly decreased in leptin and p47 phox knockout mice. Micro RNA21 knockout mice showed decreased tubular immunotoxicity and proinflammatory mediator release. Mechanistically, use of NOX2 siRNA or apocynin,phenyl boronic acid (FBA), DMPO or miR21 antagomir inhibited leptin primed-miR21-mediated mesangial cell activation in vitro suggesting a direct role of leptin-mediated NOX-2 in miR21-mediated mesangial cell activation. Finally, JAK-STAT inhibitor completely abrogated the mesangial cell activation in leptin-primed cells suggesting that leptin signaling in the mesangial cells depended on the JAK-STAT pathway. Taken together the study reports a novel mechanistic pathway of leptin-mediated renal inflammation that is dependent on NOX-2-miR21 axis in ectopic manifestations underlying NAFLD-induced co-morbidities.