Apigenin-6-C-glucoside ameliorates MASLD in rodent models via selective agonism of adiponectin receptor 2.

Adiponectin plays key roles in energy metabolism and ameliorates inflammation, oxidative stress, and mitochondrial dysfunction via its primary receptors, adiponectin receptors -1 and 2 (AdipoR1 and AdipoR2). Systemic depletion of adiponectin causes various metabolic disorders, including MASLD; however adiponectin supplementation is not yet achievable owing to its large size and oligomerization-associated complexities. Small-molecule AdipoR agonists, thus, may provide viable therapeutic options against metabolic disorders. Using a novel luciferase reporter-based assay here, we have identified Apigenin-6-C-glucoside (ACG), but not apigenin, as a specific agonist for the liver-rich AdipoR isoform, AdipoR2 (EC50: 384 pM) with >10000X preference over AdipoR1. Immunoblot analysis in HEK-293 overexpressing AdipoR2 or HepG2 and PLC/PRF/5 liver cell lines revealed rapid AMPK, p38 activation and induction of typical AdipoR targets PGC-1α and PPARα by ACG at a pharmacologically relevant concentration of 100 nM (reported cMax in mouse; 297 nM). ACG-mediated AdipoR2 activation culminated in a favorable modulation of key metabolic events, including decreased inflammation, oxidative stress, mitochondrial dysfunction, de novo lipogenesis, and increased fatty acid ß-oxidation as determined by immunoblotting, QRT-PCR and extracellular flux analysis. AdipoR2 depletion or AMPK/p38 inhibition dampened these effects. The in vitro results were recapitulated in two different murine models of MASLD, where ACG at 10 mg/kg body weight robustly reduced hepatic steatosis, fibrosis, proinflammatory macrophage numbers, and increased hepatic glycogen content. Together, using in vitro experiments and rodent models, we demonstrate a proof-of-concept for AdipoR2 as a therapeutic target for MASLD and provide novel chemicobiological insights for the generation of translation-worthy pharmacological agents.

Metabolomics in Depression: What We Learn from Preclinical and Clinical Evidences.

Depression is one of the predominant common mental illnesses that affects millions of people of all ages worldwide. Random mood changes, loss of interest in routine activities, and prevalent unpleasant senses often characterize this common depreciated mental illness. Subjects with depressive disorders have a likelihood of developing cardiovascular complications, diabesity, and stroke. The exact genesis and pathogenesis of this disease are still questionable. A significant proportion of subjects with clinical depression display inadequate response to antidepressant therapies. Hence, clinicians often face challenges in predicting the treatment response. Emerging reports have indicated the association of depression with metabolic alterations. Metabolomics is one of the promising approaches that can offer fresh perspectives into the diagnosis, treatment, and prognosis of depression at the metabolic level. Despite numerous studies exploring metabolite profiles post-pharmacological interventions, a quantitative understanding of consistently altered metabolites is not yet established. The article gives a brief discussion on different biomarkers in depression and the degree to which biomarkers can improve treatment outcomes. In this review article, we have systemically reviewed the role of metabolomics in depression along with current challenges and future perspectives.

The silent threat of plastics along the coastal frontiers of Bangladesh: Are we concerned enough?

Globally plastic pollution is posing a significant threat to the health and integrity of coastal ecosystems. This study aimed to provide a comprehensive overview of plastic pollution in the coastal areas of Bangladesh by examining land-based macroplastic distribution, exploring microplastic (MP) contamination in the coastal aquatic ecosystem and enhancing our understanding of the potential risks associated with MP contamination. Citizen science based monitoring approach using the android application was applied to understand the land-based plastic pollution in the coastal area of Bangladesh. From December 2022 to December 2023, a total of about 3600 photographs of plastic items from 215 citizen scientists were received from the coastal area of Bangladesh covering 580 km long coast line. Polymer Hazard Index (PHI) and Pollution Load Index (PLI) were also calculated to understand the risk of plastic pollution in sediment, water, aquatic organism, dried fish and sea salt. A total of 43 land-based plastic items reported from the coastal area of Bangladesh. Among these plastic items single use items contributed 58.2 % while disposable plastic items contributed 41.8 %. A strong spatial variability in the distribution of these plastic items was observed. PHI and PLI values suggested hazard category-I for MP contamination in sediment, sea salt, water, commercial fishery resources and dry fish. This study highlighted that coastal land area, sea salt, dried fish, water, sediment and organisms are contaminated with plastics which might have the potential threats to human health. Findings from this study will serve as reference data and also baseline for future research to combat the plastic pollution.

An integrated coastal ecosystem monitoring strategy: Pilot case in Naf-Saint Martin Peninsula, Bangladesh.

Rapid population growth creating an excessive pressure on the marine environment and thus monitoring of marine ecosystem is essential. However, due to high technical and financial involvement, monitoring of coastal ecosystem is always challenging in developing countries. This study aims to develop an integrated coastal ecosystem monitoring system that combines scientific sampling, numerical model simulation and citizen science observations to monitor the coastal ecosystem of Bangladesh. This concept of integrated monitoring approach was piloted from January 2022 to April 2023 at the South East coastal zone of Bangladesh. Scientific sampling and numerical model simulations were performed for temperature and salinity data collection. Citizen science approach was employed to collect data on environmental conditions, fisheries, plankton, other marine resources, and plastic pollution. Numerical model simulations and citizen scientists observations of temperature and salinity showed good agreement with the scientifically collected data. In addition, citizen scientists observations on fisheries, plankton, other marine resources and plastic pollution were also in line with the existing database and previous studies. The proposed integrated monitoring approach presents a viable technique, creating a new avenue for coastal and marine ecosystem monitoring where infrastructural facilities are limited.

Insights on discovery, efficacy, safety and clinical applications of ghrelin receptor agonist capromorelin in veterinary medicine.

Growth hormone and insulin like growth factor-1 plays an important role in the regulation of body composition and metabolism. Growth Hormone is released from the pituitary through a specific G-protein coupled receptor (GPCR) called growth hormone secretagogue receptor 1a expressed in the hypothalamus. Ghrelin is a peptide hormone released from the cells in the stomach, which stimulates appetite and food intake in mammals, regulates gut motility, gastric acid secretion, taste sensation, circadian rhythm, learning and memory, oxidative stress, autophagy, glucose metabolism etc. When the release of the endogenous ligand GHSR-1a, i.e., ghrelin is malfunctioned or stopped, external substitutes are administrated to induce the stimulation of growth hormone and appetite. A class of compound known as ghrelin receptor agonists are developed as an external substitute of ghrelin for regulation and stimulation of growth hormone in frailty, for body weight gain, muscle mass gain, prevention of cachexia and for the treatment of chronic fatigue syndromes. Capromorelin [Entyce™ (Aratana Therapeutics, Leawood, KS, USA)] is the only FDA (Food and Drug Administration) approved (May 2016) drug used for stimulating appetite in dogs and was marketed in the fall of 2017. In 2020, USFDA approved Capromorelin [Elura™ (Elanco US Inc.)] for the management of weight loss in chronic kidney disease of cats. This article reviews the discovery of the ghrelin receptor agonist capromorelin, its efficacy, safety, clinical applications and aims to delineate its further scope of use in veterinary practice.

Ectopic Adrenal Rest in Paratubal Region: A Rare Lesion in a Rare Location.

Ectopic adrenal rests (EAT) are rare lesions comprising predominantly adrenocortical tissue in various locations. Here, we report a case of EAT in the paratubal location which was incidentally detected in a salpingo-oophorectomy specimen from a 21-year-old female. The identification of these lesions is extremely essential as it can be associated with hyperplasia and neoplasia.

Lipid-induced alteration in retinoic acid signaling leads to mitochondrial dysfunction in HepG2 and Huh7 cells.

A surfeit of mitochondrial reactive oxygen species (ROS) and inflammation serve as obligatory mediators of lipid-associated hepatocellular maladies. While retinoid homeostasis is essential in restoring systemic energy balance, its role in hepatic mitochondrial function remains elusive. The role of lecithin-retinol acyltransferase (LRAT) in maintenance of retinoid homeostasis is appreciated earlier; however, its role in modulating retinoic acid (RA) bioavailability upon lipid-imposition is unexplored. We identified LRAT overexpression in high-fat diet (HFD)-fed rats and palmitate-treated hepatoma cells. Elevation in LRAT expression depletes RA production and deregulates RA signaling. This altered RA metabolism enhances fat accumulation, accompanied by inflammation that leads to impaired mitochondrial function through enhanced ROS generation. Hence, LRAT inhibition could be a novel approach preventing lipid-induced mitochondrial dysfunction in hepatoma cells.

ReliefChain: A blockchain leveraged post disaster relief allocation system over smartphone-based DTN.

One of the major concerns in any emergency relief operation is appropriate allocation of scarce emergency relief materials to the affected community. Due to several reasons ranging from lack of mechanism to accurately assess demand and utility of relief materials to malicious participation of some of the stakeholders, such allocation may become ad-hoc. Thus, it becomes imperative to have an unchallengeable and globally accessible record of relief requirement vis-à-vis allocation for efficient relief management. Emergency response organizations (e.g. UNICEF) have recommended the adoption of blockchain technology to create such immutable records. However, the usage of blockchain is restricted by the availability of end-to-end internet connection which may not be available in a post-disaster scenario. This paper proposes ReliefChain, a blockchain leveraged post disaster relief allocation system over delay tolerant network that works in such environments. We validate relief requirements to mitigate resource diversion, forecasting the exact demand and enumerating precise utilities of relief items. We design smart contracts for creating new transactions to upload relief requirements and allocations in the blockchain network. The proposed system executes these smart contracts to create an immutable and globally accessible record of relief requirement and allocation. Effectiveness of the proposed system is evaluated through extensive simulation in Ethereum platform. Results substantiate the efficiency of the system over a system using baseline methodologies, in terms of design parameters like shelter specific deficit and average resource deficit while not compromising the blockchain performance in terms of processing time and gas consumption even in presence of malicious forwarders.

Effect of public sentiment on stock market movement prediction during the COVID-19 outbreak.

Forecasting the stock market is one of the most difficult undertakings in the financial industry due to its complex, volatile, noisy, and nonparametric character. However, as computer science advances, an intelligent model can help investors and analysts minimize investment risk. Public opinion on social media and other online portals is an important factor in stock market predictions. The COVID-19 pandemic stimulates online activities since individuals are compelled to remain at home, bringing about a massive quantity of public opinion and emotion. This research focuses on stock market movement prediction with public sentiments using the long short-term memory network (LSTM) during the COVID-19 flare-up. Here, seven different sentiment analysis tools, VADER, logistic regression, Loughran-McDonald, Henry, TextBlob, Linear SVC, and Stanford, are used for sentiment analysis on web scraped data from four online sources: stock-related articles headlines, tweets, financial news from "Economic Times" and Facebook comments. Predictions are made utilizing both feeling scores and authentic stock information for every one of the 28 opinion measures processed. An accuracy of 98.11% is achieved by using linear SVC to calculate sentiment ratings from Facebook comments. Thereafter, the four estimated sentiment scores from each of the seven instruments are integrated with stock data in a step-by-step fashion to determine the overall influence on the stock market. When all four sentiment scores are paired with stock data, the forecast accuracy for five out of seven tools is at its most noteworthy, with linear SVC computed scores assisting stock data to arrive at its most elevated accuracy of 98.32%.

Estradiol overcomes adiponectin-resistance in diabetic mice by regulating skeletal muscle adiponectin receptor 1 expression.

Adiponectin and insulin resistance creates a vicious cycle that exacerbates type 2 diabetes. Earlier, we observed that female leptin receptor-deficient BLKS mice (BKS-db/db) were more sensitive to an adiponectin mimetic GTDF than males, which led us to explore if E2 plays a crucial role in modulation of adiponectin-sensitivity. Male but not female BKS-db/db mice were resistant to metabolic effects of globular adiponectin treatment. Male BKS-db/db displayed reduced skeletal muscle AdipoR1 protein expression, which was consequent to elevated polypyrimidine tract binding protein 1 (PTB) and miR-221. E2 treatment in male BKS-db/db, and ovariectomized BALB/c mice rescued AdipoR1 protein expression via downregulation of PTB and miR-221, and also directly increased AdipoR1 mRNA by its classical nuclear receptors. Estrogen receptor regulation via dietary or pharmacological interventions may improve adiponectin resistance and consequently ameliorate insulin resistance in type 2 diabetes.

Adiponectin receptors by increasing mitochondrial biogenesis and respiration promote osteoblast differentiation: Discovery of isovitexin as a new class of small molecule adiponectin receptor modulator with potential osteoanabolic function.

Previously, we established adiponectin receptors (AdipoRs) as osteoanabolic target. To discover small molecule agonists of AdipoRs, we studied apigenin and apigenin-6C-glucopyranose (isovitexin) that induced osteoblast differentiation. In-silico, in vitro and omics-based studies were performed. Molecular docking using the crystal structures of AdipoRs showed different interaction profiles of isovitexin and apigenin. In osteoblasts, isovitexin but not apigenin rapidly phosphorylated AMP-activated protein kinase (pAMPK) which is downstream of AdipoRs and a master regulator of cellular energy metabolism, and upregulated expression of AdipoRs. Blocking AMPK abolished the osteogenic effect of isovitexin and its effect on AdipoR expression. Isovitexin upregulated the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the mitochondrial biogenesis factor in osteoblasts, and the effect was blocked by AMPK inhibition. Upregulation of PGC-1α by isovitexin was accompanied by increased mitochondrial membrane proteins and mitochondrial DNA (mtDNA). Isovitexin via AdipoRs and PGC-1α induced oxidative phosphorylation (OxPhos) and ATP synthesis that resulted in osteoblast differentiation. Isovitexin had no agonistic/antagonistic activity and stimulatory/inhibitory effect in screening platforms for G protein-coupled receptors and kinases, respectively. In vivo, isovitexin upregulated AdipoRs and osteogenic genes, and increased mtDNA in rat calvarium. We conclude that isovitexin selectively via AdipoRs induced osteoblast differentiation that was fuelled by mitochondrial respiration.

Leprosy drug clofazimine activates peroxisome proliferator-activated receptor-γ and synergizes with imatinib to inhibit chronic myeloid leukemia cells.

Leukemia stem cells contribute to drug-resistance and relapse in chronic myeloid leukemia (CML) and BCR-ABL1 inhibitor monotherapy fails to eliminate these cells, thereby necessitating alternate therapeutic strategies for patients CML. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone downregulates signal transducer and activator of transcription 5 (STAT5) and in combination with imatinib induces complete molecular response in imatinib-refractory patients by eroding leukemia stem cells. Thiazolidinediones such as pioglitazone are, however, associated with severe side effects. To identify alternate therapeutic strategies for CML we screened Food and Drug Administration-approved drugs in K562 cells and identified the leprosy drug clofazimine as an inhibitor of viability of these cells. Here we show that clofazimine induced apoptosis of blood mononuclear cells derived from patients with CML, with a particularly robust effect in imatinib-resistant cells. Clofazimine also induced apoptosis of CD34+38- progenitors and quiescent CD34+ cells from CML patients but not of hematopoietic progenitor cells from healthy donors. Mechanistic evaluation revealed that clofazimine, via physical interaction with PPARγ, induced nuclear factor kB-p65 proteasomal degradation, which led to sequential myeloblastoma oncoprotein and peroxiredoxin 1 downregulation and concomitant induction of reactive oxygen species-mediated apoptosis. Clofazimine also suppressed STAT5 expression and consequently downregulated stem cell maintenance factors hypoxia-inducible factor-1α and -2α and Cbp/P300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2). Combining imatinib with clofazimine caused a far superior synergy than that with pioglitazone, with clofazimine reducing the half maximal inhibitory concentration (IC50) of imatinib by >4 logs and remarkably eroding quiescent CD34+ cells. In a K562 xenograft study clofazimine and imatinib co-treatment showed more robust efficacy than the individual treatments. We propose clinical evaluation of clofazimine in imatinib-refractory CML.

Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents.

BACKGROUND: Skeletal muscle atrophy is characterized by muscle wasting with partial or complete functional loss. Skeletal muscle atrophy severely affects the quality of life and currently, there is no available therapy except for spinal muscular atrophy. OBJECTIVE: Drug repositioning is a promising strategy that reduces cost and time due to prior availability of safety and toxicity details. Here we investigated myogenic and anti-atrophy effects of glucagon-like peptide-1 (GLP-1) analog liraglutide. METHODS: We used several in vitro atrophy models in C2C12 cells and in vivo models in Sprague Dawley rats to study Liraglutide's efficacy. Western blotting was used to assess cAMP-dependent signaling pathways specifically activated by liraglutide. Therapeutic efficacy of liraglutide was investigated by histological analysis of transverse muscle sections followed by morphometry. Myogenic capacity was investigated by immunoblotting for myogenic factors. RESULTS: Liraglutide induced myogenesis in C2C12 myoblasts through GLP-1 receptor via a cAMP-dependent complex network of signaling events involving protein kinase A, phosphoinositide 3-kinase/protein kinase B, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. Liraglutide imparted protection against freeze injury, denervation, and dexamethasone -induced skeletal muscle atrophy and improved muscular function in all these models. In a therapeutic model, liraglutide restored myofibrillar architecture in ovariectomy-induced atrophy. Anti-atrophy actions of liraglutide involved suppression of atrogene expression and enhancement in expression of myogenic factors. CONCLUSION: Liraglutide imparted protection and restored myofibrillar architecture in diverse models of muscle atrophy. Given its potent anti-atrophy, and recently reported osteoanabolic effects, we propose liraglutide's clinical evaluation in skeletal muscle atrophy and musculoskeletal disorders associated with diverse pathologies.

Functionally significant metabolic differences between B and T lymphocyte lineages.

Activation of B and T lymphocytes leads to major remodelling of the metabolic landscape of the cells enabling their post-activation functions. However, naive B and T lymphocytes also show metabolic differences, and the genesis, nature and functional significance of these differences are not yet well understood. Here we show that resting B-cells appeared to have lower energy demands than resting T-cells as they consumed lower levels of glucose and fatty acids and produced less ATP. Resting B-cells are more dependent on OXPHOS, while T-cells show more dependence on aerobic glycolysis. However, despite an apparently higher energy demand, T lineage cells showed lower rates of protein synthesis than equivalent B lineage stages. These metabolic differences between the two lineages were established early during lineage differentiation, and were functionally significant. Higher levels of protein synthesis in B-cells were associated with increased synthesis of MHC class II molecules and other proteins associated with antigen internalization, transport and presentation. The combination of higher energy demand and lower protein synthesis in T-cells was consistent with their higher ATP-dependent motility. Our data provide an integrated perspective of the metabolic differences and their functional implications between the B and T lymphocyte lineages.

Malignant Melanoma of the External Auditory Canal: A Rare Entity.

INTRODUCTION: Although malignant melanomas (MM) are common in the head and neck region; primary malignant melanoma of the external auditory canal (EAC) is rare. CASE REPORT: We present the case of a 50-year-old symptomatic man with a malignant melanoma of the external auditory canal, which clinically masqueraded as a haemangioma. The patient subsequently developed extensive loco-regional metastasis, requiring extensive surgery. We describe the clinical presentation, differential diagnosis, both clinical and pathological in terms of other pigmented lesions in the external auditory canal, detailed histopathology, and literature review. CONCLUSION: We want to emphasize the importance of immediate and adequate biopsy of any pigmented lesion in the head and neck region to rule out MM. Also, we emphasize the importance of deep biopsy for proper histopathological assessment in addition to distinguishing it from benign melanocytic nevi, in order to initiate treatment.

Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are common clinico-pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH. METHODS & RESULTS: HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1ß and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10µM concentration). Furthermore, these agents reversed PA-mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2-LX2 Coculture studies. In mice with choline-deficient high-fat diet-induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride-induced fibrosis model. CONCLUSIONS: Saroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone.

Small-molecule inhibition of TLR8 through stabilization of its resting state.

Endosomal Toll-like receptors (TLR3, TLR7, TLR8, and TLR9) are highly analogous sensors for various viral or bacterial RNA and DNA molecular patterns. Nonetheless, few small molecules can selectively modulate these TLRs. In this manuscript, we identified the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small-molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation. As a proof of concept of their therapeutic potential, we have demonstrated that these drug-like inhibitors are able to suppress TLR8-mediated proinflammatory signaling in various cell lines, human primary cells, and patient specimens. These results not only suggest a novel strategy for TLR inhibitor design, but also shed critical mechanistic insight into these clinically important immune receptors.

Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice.

Lipid generates reactive oxygen species (ROS) in consequence to mitochondrial fission followed by inflammation in propagating hepatic fibrosis. The interaction of SIRT1/Mitofusin2 is critical for maintaining mitochondrial integrity and functioning, which is disrupted upon excess lipid infiltration during the progression of steatohepatitis. The complex interplay between hepatic stellate cells and steatotic hepatocytes is critically regulated by extracellular factors including increased circulating free fatty acids during fibrogenesis. Melatonin, a potent antioxidant, protects against lipid-mediated mitochondrial ROS generation. Lipotoxicity induces disruption of SIRT1 and Mitofusin2 interaction leading to mitochondrial morphological disintegration in hepatocytes. Further, fragmented mitochondria leads to mitochondrial permeability transition pore opening, cell cycle arrest and apoptosis and melatonin protects against all these lipotoxicity-mediated dysfunctions. These impaired mitochondrial dynamics also enhances the cellular glycolytic flux and reduces mitochondrial oxygen consumption rate that potentiates ROS production. High glycolytic flux generates metabolically unfavorable milieu in hepatocytes leading to inflammation, which is abrogated by melatonin. The melatonin-mediated protection against mitochondrial dysfunction was also observed in high-fat diet (HFD)-fed mice through restoration of enzymatic activities associated with respiratory chain and TCA cycle. Subsequently, melatonin reduces hepatic fat deposition and inflammation in HFD-fed mice. Thus, melatonin disrupts the interaction between steatotic hepatocyte and stellate cells, leading to the activation of the latter to abrogate collagen deposition. Altogether, the results of the current study document that the pharmacological intervention with low dose of melatonin could abrogate lipotoxicity-mediated hepatic stellate cell activation and prevent the fibrosis progression.

Dietary fat proportionately enhances oxidative stress and glucose intolerance followed by impaired expression of the genes associated with mitochondrial biogenesis.

Consumption of food that surpasses the metabolic necessity of the body leads to an epidemic condition termed obesity, which causes several metabolic disorders including oxidative damage. Dietary intervention can enlighten the mechanisms and therapeutics associated with these metabolic disorders. The reported studies related to diet include fat of different kinds and from different sources, however they lack dose response aspects. Our study highlighted the importance of dietary fat modification in modulating oxidative stress-induced glucose intolerance. Animals were maintained on a diet with a varied content of fat (30%/45%/60%) for 12 weeks and the 'withdrawal' group was fed a standard diet for another 10 weeks. The diet containing 60 energy% of fat displayed glucose intolerance, high ALT, low GSH levels and tissue-specific modulation of the prooxidant/antioxidant enzymatic activities in the liver/muscles. Prolonged sustenance of the 60 energy% fat containing diet-fed rats on standard diet led to the alteration of antioxidant activities, reversing the oxidative damage. Notably, the 'withdrawal' group displayed an organ-specific response towards dietary modification where the recovery of the antioxidant activities was observed to be much more pronounced in the liver as compared to the muscle. Further, we identified the differential expression of liver/muscle-specific genes associated with oxidative stress and mitochondrial biogenesis in response to the differing fat content. These genes can serve as markers for HFD-induced metabolic complications involving the liver/muscle. Altogether, our study has highlighted the novel area where obesity-induced oxidative stress linked alterations expressed diet and organ specific responses that are recovered by altering the dietary regimen. Future investigation of dietary modulation will open nascent avenues for developing therapeutic modalities addressing obesity-related metabolic complications.

Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study.

Paclitaxel (Tx) is one of the first-line chemotherapeutic drugs used against lung cancer, but acquired resistance to this drug is a major challenge against successful chemotherapy. In this work, we have focused on the chronological changes of various cellular parameters and associated effect on Tx (10 nM) resistance development in A549 cell line. It was observed, at initial stage, the cell death percentage due to drug treatment had increased up to 20 days, and thereafter, it started declining and became completely resistant by 40 days. Expressions of ßIII tubulin and drug efflux pumps also increased over the period of resistance development. Changes in cellular autophagy and reactive oxygen species generation showed a biphasic pattern and increased gradually over the course of upto 20 days, thereafter declined gradually; however, their levels remained higher than untreated cells when resistance was acquired. Increase in extracellular acidification rates and oxygen consumption rates was found to be directly correlated with acquisition of resistance. The depolarisation of mitochondrial membrane potential was also biphasic; first, it increased with increase of cell death up to 20 days, thereafter, it gradually decreased to normal level along with resistance development. Increase in activity of catalase, glutathione peroxidase and glutathione content over these periods may attribute in bringing down the reactive oxygen species levels and normalisation of mitochondrial membrane potential in spite of comparatively higher reactive oxygen species production by the Tx-resistant cells.