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The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Cerebral malaria (CM) induced by Plasmodium falciparum is a devastating neurological complication that may lead the patient to coma and death. This study aimed to protect Plasmodium-infected C57BL6 mice from CM by targeting the angiotensin II type 1 (AT1) receptor, which is considered the common connecting link between hypertension and CM. In CM, AT-1 mediates blood-brain barrier (BBB) damage through the overexpression of β-catenin. The AT-1-inhibiting drugs, such as irbesartan and losartan, were evaluated for the prevention of CM. The effectiveness of these drugs was determined by the down regulation of β-catenin, TCF, LEF, ICAM-1, and VCAM-1 in the drug-treated groups. The expression levels of VE-cadherin and vinculin, essential for the maintenance of BBB integrity, were found to be restored in the drug-treated groups. The pro-inflammatory cytokine levels were decreased, and the anti-inflammatory cytokine levels increased with the treatment. As a major highlight, the mean survival time of treated mice was found to be increased even in the absence of treatment with an anti-malarial agent. The combination of irbesartan or losartan with the anti-malarial agent α/β-arteether has contributed to an 80% cure rate, which is higher than the 60% cure rate observed with α/β-arteether alone treatment., (Copyright © 2024 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by excessive accumulation of extracellular matrix, leading to irreversible fibrosis. Emerging evidence suggests that endoplasmic reticulum (ER) stress, mitochondrial stress, and oxidative stress pathways play crucial roles in the pathogenesis of IPF. ER stress occurs when the protein folding capacity of the ER is overwhelmed, triggering the unfolded protein response (UPR) and contributing to protein misfolding and cellular stress in IPF. Concurrently, mitochondrial dysfunction involving dysregulation of key regulators, including PTEN-induced putative kinase 1 (PINK1), Parkin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and sirtuin 3 (SIRT3), disrupts mitochondrial homeostasis and impairs cellular energy metabolism. This leads to increased reactive oxygen species (ROS) production, release of pro-fibrotic mediators, and activation of fibrotic pathways, exacerbating IPF progression. The UPR-induced ER stress further disrupts mitochondrial metabolism, resulting in altered mitochondrial mechanisms that increase the generation of ROS, resulting in further ER stress, creating a feedback loop that contributes to the progression of IPF. Oxidative stress also plays a pivotal role in IPF, as ROS-mediated activation of TGF-β, NF-κB, and MAPK pathways promotes inflammation and fibrotic responses. This review mainly focuses on the links between ER stress, mitochondrial dysfunctions, and oxidative stress with different signaling pathways involved in IPF. Understanding these mechanisms and targeting key molecules within these pathways may offer promising avenues for intervention., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Pulmonary fibrosis (PF) is characterized by an increase in collagen synthesis and deposition of extracellular matrix. Several factors, including transforming growth factor-β1 (TGF-β1), mothers against decapentaplegic homolog family proteins (Smad), and alpha-smooth muscle actin (α-SMA) trigger extracellular matrix (ECM) accumulation, fibroblast to myofibroblasts conversion, and epithelial-to-mesenchymal-transition (EMT) leading to PF. However, the role of cellular defense mechanisms such as the role of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling during the onset and progression of PF is not understood completely., Aim: The present study aims to analyze the involvement of TGF-β1/Smad signaling, and Nrf2 in the EMT and metabolic alterations that promote fibrosis in a time-dependent manner using bleomycin (BLM)-induced PF model in C57BL/6 mice., Key Findings: Histopathological studies revealed loss of lung architecture and increased collagen deposition in BLM-exposed mice. BLM upregulated TGF-β1/Smad signaling and α-SMA at all time-points. The gradual increase in the accumulation of α-SMA and collagen implied the progression of PF. BLM exposure raises Nrf2 throughout each specified time-point, which suggests that Nrf2 activation might be responsible for TGF-β1-induced EMT and the development of PF. Further, metabolomic studies linked the development of PF to alterations in metabolic pathways. The pentose phosphate pathway (PPP) was consistently enriched across all the time-points. Additionally, alterations in 22 commonly enriched pathways, associated with fatty acid (FA) and amino acid metabolism were observed in 30- and 60-days., Significance: This study elucidates the association of TGF-β1/Smad and Nrf2 signaling in the EMT and metabolic alterations associated with the etiology and progression of PF., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2023. Published by Elsevier Inc.)

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Cytochrome P450 2E1 (CYP2E1) is an enzyme, primarily involved in the metabolism of xenobiotics and procarcinogens. The present study was designed to investigate the potential role of CYP2E1 triggered endoplasmic reticulum stress in the progression of HCC through inhibition of apoptosis. In vitro CYP2E1 promotes HepG2 cell migration, reduced chromatin condensation, enhanced intracellular ROS accumulation and induce cell cycle progression. Conversely this effect was averted by CYP2E1 siRNA, selective inhibitor Diallyl sulphide (DAS) and antioxidants (vitamin C and E). In vivo Diethylnitrosamine (DEN) induced HCC rats showed decreased body weight and increased relative liver weight. Moreover, macro trabecular-massive HCC (MTM-HCC) histological subtyping showed pathological features like well-differentiated tumors, micro-trabecular and pseudo glandular patterns, megakaryocytes and cholestasis. Masson's trichrome staining revealed an intensive accumulation of collagen fibers in the extracellular matrix (ECM). Increased CYP2E1, VEGF and PCNA enhance the carcinogenicity as revealed in immunohistochemistry results. Immunoblot analysis showed reduced expression of copper-zinc superoxide dismutase (CuZnSOD) and manganese superoxide dismutase (MnSOD) in cytosolic as well as mitochondrial fraction of rat liver tissue respectively. Also, increased level of CYP2E1 stimulated the upregulation of unfolded proteins response (UPR) and ER stress-related proteins such as Glucose regulatory protein 78 (GRP78), activating transcription factor 6 (ATF6) and CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP). Meanwhile, CYP2E1 stimulated ER-stress reduces BCL2 and downregulates the cleaved caspase 3 thus suppresses apoptosis. in. Furthermore, immunofluorescence revealed increased expression level of α-SMA in the HCC rat liver tissue. The level of CYP2E1 mRNA was significantly increased. Altogether, these findings indicate that CYP2E1 has a dynamic role in the pathogenesis of HCC and might be a budding agent in liver carcinogenesis therapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is among the deadliest cancer in human malignancies. It is the most common and severe type of primary liver cancer. However, the molecular mechanisms underlying HCC pathogenesis remain poorly understood. Long non-coding RNAs (lncRNAs), a new kind of RNA and epigenetic factors, play a crucial role in tumorigenesis and the progression of HCC. LncRNAs are capable of promoting the autophagy, proliferation, and migration of tumor cells by targeting and modulating the expression of downstream genes in signaling pathways related to cancer; these transcripts modify the activity and expression of various tumor suppressors and oncogenes. LncRNAs could act as biomarkers for treatment approaches such as immunotherapy, chemotherapy, and surgery to effectively treat HCC patients. Improved knowledge regarding the aetiology of HCC may result from an advanced understanding of lncRNAs. Enhanced oxidative stress in the mitochondrial and Endoplasmic reticulum leads to the activation of unfolded protein response pathway that plays a crucial role in the pathophysiology of hepatocellular carcinoma. The mutual regulation between LncRNAs and Endoplasmic reticulum (ER) stress in cancer and simultaneous activation of the unfolded protein response (UPR) pathway determines the fate of tumor cells in HCC. Mitochondria-associated lncRNAs work as essential components of several gene regulatory networks; abnormal regulation of mitochondria-associated lncRNAs may lead to oncogenesis, which provides further insight into the understanding of tumorigenesis and therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Lipopolysaccharide (LPS) is a well-known agent to induce septic conditions. Sepsis-induced cardiomyopathy has an overwhelming death rate. Carvacrol (CVL), a monoterpene phenol, has anti-inflammatory and antioxidant properties. This research aimed to investigate the effect of CVL on LPS-induced dysfunction in the heart. In this study, we evaluated the effect of CVL in LPS-stimulated H9c2 cardiomyoblast cells and Balb/C mice., Main Methods: LPS was used to induce septic conditions in H9c2 cardiomyoblast cells in vitro and in Balb/C mice. A survival study was conducted to assess the survival rate of mice after LPS and/or CVL treatment., Key Findings: In vitro studies indicated that CVL inhibits reactive oxygen species (ROS) generation and abates pyroptosis mediated by NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in H9c2 cells. In mice, CVL intervention improved the survival rate in septic conditions. The CVL administration markedly improved the echocardiographic parameters and alleviated the LPS-induced reduction in the ejection fraction (%) and fraction shortening (%). The CVL intervention restored the myocardial antioxidants and histopathological alterations and decreased the pro-inflammatory cytokine contents in the heart. Further findings disclosed that CVL reduced the protein levels of NLRP3, apoptosis-associated speck-like protein (ASC), caspase 1, interleukin (IL)-18, IL-1β, and the pyroptosis-indicative protein, gasdermin-D (GSDMD) in the heart. The autophagy-indicative proteins, beclin 1 and p62 in the heart were also restored in the CVL-treated group., Significance: Altogether, our findings demonstrated that CVL has a beneficial effect and can be a potential molecule against sepsis-induced myocardial dysfunction., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chondroitin anchored crystalline nano-capsules bearing Imatinib (IMT), and simvastatin (SMV) was developed using Poly (L-lactic acid) (PLLA) by two-step method, i.e., firstly, by synthesizing chondroitin (CSA) anchored simvastatin (SMV) using cystamine as a spacer (SMV-SS-CSA) for disulfide triggered glutathione (GSH) sensitive release and secondly, by developing phenyl boronic ester grafted Pluronic F68 (PEPF) for H 2 O 2 responsive release. By combining these conjugates, we have prepared crystalline nano-capsules (CNs) for preferential targeting of CD44 receptors. The developed CNs were spherical when characterized through SEM, TEM, and AFM for surface morphology, while changes in particle size and crystalline structure were confirmed through Quasi-Elastic light scattering (QELS) and Wide Angle X-ray Scattering (WAXS). The enhanced cellular uptake was noted in chondroitin-modified nano-capsules IMT/SMV-SS-CSA@CNs compared to unmodified nano-capsules IMT+SMV@CNs. IMT/SMV-SS-CSA@CNs displayed significantly higher G2/M phase arrest (76.9%) than unmodified nano-capsules. The prototype formulation (IMT/SMV-SS-CSA@CNs) showed an overall improved pharmacokinetic profile in terms of both half-life and AUC 0-α . When tested in the 4T1 subcutaneously injected tumor-bearing Balb/c mice model, the tumor growth inhibition rate of IMT/SMV-SS-CSA@CNs was significantly higher (91%) than the IMT+SMV combination. Overall, the findings suggest that the proposed dual responsive chondroitin-modified drug delivery could have a step forward in achieving spatial and temporal targeting at the tumor site., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Lung cancer is an aggressive malignancy and the leading cause of cancer-related deaths. Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon, plays a pivotal role in lung carcinogenesis. Uncovering the molecular mechanism underlying the pathophysiology of B[a]P induced malignancy is crucial. Male Sprague Dawley rats were induced with B[a]P to generate a lung cancer model. The B[a]P administered rats show increased body and lung weight, loss of normal pulmonary architecture, and decreased survival. This study demonstrated that B[a]P upregulates activating transcription factor-6 (ATF6) and C/EBP Homologous Protein (CHOP) and induces endoplasmic reticulum (ER) stress. B[a]P also dysregulated mitochondrial homeostasis by upregulating, PTEN-induced putative kinase-1 (PINK1) and Parkin. B[a]P affected the levels of superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA), and increased oxidative stress. B[a]P exposure downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase-1(HO1). The metabolomic study identified that biosynthesis of nucleotide, amino acids, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), and glutathione metabolism were up-accumulated. On the other hand, lower accumulation of fatty acids e.g., palmitic acid, stearic acid, and oleic acid were reported in the B[a]P induced group. Overall, the results of this study indicate that B[a]P treatment affects several signaling and metabolic pathways, whose dysregulation might be involved in lung cancer induction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Bacterial and fungal co-infection leads to polymicrobial keratitis (PMK). The current study produced swellable mucoadhesive biopolymeric films composed of chitosan, HPMC, and glycerol using cast drying method. The film was dual-loaded with fluconazole (FCZ) and ofloxacin (OFX) to treat PMK. The prepared film exhibited excellent thickness, folding endurance, surface pH, tensile strength, and stability characteristics. In addition, it also exhibited good in vitro antimicrobial activity, ex-vivo mucoadhesion, and corneal permeation. AUC (0-∞) and MRT were 6.5 and 5.2-fold higher for a film containing FCZ and 22.5 and 2.5-fold higher for a film containing OFX than their marketed formulations. PK-PD simulation study supports desired efficacy of the proposed dosage form. Thus, the film exhibits longer pre-corneal drug residence time and enhanced ocular bioavailability, most likely resulting in high patient compliance. The proposed film could be a prominent replacement for the existing dosage form and may present a viable alternative for the treatment of PMK., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2022. Published by Elsevier B.V.)

Diabetic retinopathy (DR) is a chronic microvascular complication of diabetes mellitus (DM). It is a worldwide growing epidemic disease considered to be the leading cause of vision-loss and blindness in people with DM. Redox reactions occurring at the extra- and intracellular levels are essential for the maintenance of cellular homeostasis. Dysregulation of redox homeostasis are implicated in the onset and development of DR. Thioredoxin1 (TRX1) and Thioredoxin2 (TRX2) are cytoplasmic and mitochondrially localized antioxidant proteins ubiquitously expressed in various cells and control cellular reactive oxygen species (ROS) by reducing the disulfides into thiol groups. Thioredoxin-interacting protein (TXNIP) binds to TRX system and inhibits the active reduced form of TRX through disulfide exchange reaction. Recent studies indicate the association of TRX/TXNIP with redox signal transduction pathways including activation of Nod-like receptor pyrin domain containing protein-3 (NLRP3) inflammasome, apoptosis, autophagy/mitophagy, epigenetic modifications in a redox-dependent manner. Thus, it is important to gain a more in-depth understanding about the cellular and molecular mechanisms that links redoxisome and ER/Mitochondrial dysfunction to drive the progression of DR. The purpose of this review is to provide a mechanistic understanding of the complex molecular mechanisms and pathophysiological roles associated with redoxisome, the TRX/TXNIP redox signaling complex under oxidative stress in the development of DR. Also, the molecular targets of FDA approved drugs and clinical trials in addition to effective antioxidant strategies for the treatment of diabetic retinopathy are reviewed., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the vaccine effectiveness. Asymptomatic breakthrough infections have been a major problem in assessing vaccine effectiveness in populations globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines since whole virion vaccines generate antibodies against all the viral proteins. Here, we show how a statistical and machine learning (ML) based approach can be used to discriminate between SARS-CoV-2 infection and immune response to an inactivated whole virion vaccine (BBV152, Covaxin). For this, we assessed serial data on antibodies against Spike and Nucleocapsid antigens, along with age, sex, number of doses taken, and days since last dose, for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, our ensemble ML model classified 724 to be infected. For method validation, we determined the relative ability of a random subset of samples to neutralize Delta versus wild-type strain using a surrogate neutralization assay. We worked on the premise that antibodies generated by a whole virion vaccine would neutralize wild type more efficiently than delta strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, neutralization against Delta strain was more effective, indicating infection. We found 71.8% subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period. Our approach will help in real-world vaccine effectiveness assessments where whole virion vaccines are commonly used., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Tubulointerstitial fibrosis, a frequent complication of chronic kidney disease (CKD) is a major public health issue. Biochanin A (BCA), an isoflavone, has numerous pharmacological activities. However, its effect on renal fibrosis and underlying molecular mechanism has not yet been clarified. This study explored the effect of BCA on renal tubulointerstitial fibrosis and inflammation in mice., Main Methods: The mouse model of unilateral ureteral obstruction (UUO) in vivo and transforming growth factor (TGF)-β1 activated renal fibroblast (NRK 49F) cells in vitro model were used to assess the antifibrotic effect of BCA. Biochemical analysis, histopathology, western blotting, and immunofluorescent staining methods were performed to elucidate the mechanism of BCA., Key Findings: In vitro, BCA suppressed the expression of fibrogenic proteins in TGF-β1-activated renal fibroblasts. The treatment with BCA displayed less tubular injury, prevented the aberrant accumulation of extracellular matrix (ECM) components, and inhibited the TGF-β1/Smad2/3 signaling axis in the kidneys. Furthermore, BCA impeded the phosphorylation of NF-kB(p65) and blunted the expression of inflammatory genes in the obstructed kidneys. The UUO induced expressions of nod-like receptor protein 3 (NLRP3), active caspase 1, interleukin(IL)-18, and IL-1β proteins were decreased in the BCA treated groups. We also found the increased expression of redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) proteins in BCA treated groups compared to the UUO control., Significance: These findings indicate that BCA has a therapeutic benefit against renal fibrosis, and the ameliorative effect is mediated via inhibiting the TGF-β1/Smad2/3 and NF-kB/NLRP3 signaling axis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Pathological cardiac hypertrophy is a characteristic feature in many cardiovascular diseases (CVDs). Aloin is an anthraquinone glycoside from Aloe species, and the effect of aloin on cardiac hypertrophy and associated fibrotic changes have not been elucidated. This study investigated the effect of aloin against the isoproterenol (ISO)-induced cardiac hypertrophy in rats., Main Methods: Cardiac hypertrophy experimental model was induced in rats by subcutaneous injection of ISO for 14 days. Meanwhile, the animals were administered orally with aloin at doses of 25 and 50 mg/kg/day. On the 15th day, cardiac echocardiography was performed, the heart was collected and subjected for histopathological, gene expression, and immunoblot studies. Additionally, the effect of aloin on ISO-induced hypertrophic changes in H9c2 cells was investigated., Key Findings: Aloin markedly alleviated ISO-induced heart injury, reduced cardiac hypertrophy, improved cardiac function, and histological alterations in the heart. Mechanistically, aloin attenuated ISO-induced fibrosis via inhibition of the levels of collagen I, α-smooth muscle actin (α-SMA), fibronectin, transforming growth factor-β (TGF-β) and pSmad2/3 proteins in the heart. Aloin alleviated ISO-induced myocardial oxidative damage and up-regulated the levels of antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Moreover, aloin treatment attenuated ISO-induced hypertrophic changes and the generation of reactive oxygen species (ROS) in H9c2 cells in vitro., Significance: Our findings demonstrated that aloin alleviated ISO-induced cardiac hypertrophy and fibrosis via inhibiting TGF-β/pSmad2/3 signaling and restoring myocardial antioxidants, and therefore has promising therapeutic potential against cardiac hypertrophy and fibrosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cassia occidentalis Linn (CO) is an annual/perennial plant having traditional uses in the treatments of ringworm, gastrointestinal ailments and piles, bone fracture, and wound healing. Previously, we confirmed the medicinal use of the stem extract (ethanolic) of CO (henceforth CSE) in fracture healing at 250 mg/kg dose in rats and described an osteogenic mode of action of four phytochemicals present in CSE. Here we studied CSE's preclinical safety and toxicity. CSE prepared as per regulations of Current Good Manufacturing Practice for human pharmaceuticals/phytopharmaceuticals and all studies were performed in rodents in a GLP-accredited facility. In acute dose toxicity as per New Drug and Clinical Trial Rules, 2019 (prior name schedule Y), in rats and mice and ten-day dose range-finding study in rats, CSE showed no mortality and no gross abnormality at 2500 mg/kg dose. Safety Pharmacology showed no adverse effect on central nervous system, cardiovascular system, and respiratory system at 2500 mg/kg dose. CSE was not mutagenic in the Ames test and did not cause clastogenicity assessed by in vivo bone marrow genotoxicity assay. By a sub chronic (90 days) repeated dose (as per OECD, 408 guideline) study in rats, the no-observed-adverse-effect-level was found to be 2500 mg/kg assessed by clinico-biochemistry and all organs histopathology. We conclude that CSE is safe up to 10X the dose required for its osteogenic effect., (Copyright © 2021 Elsevier Inc. All rights reserved.)