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Background: Inflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several chronic inflammatory diseases. However, increased liver fibrosis has been reported in mice lacking IL-15 receptor alpha chain (IL-15Ra), suggesting an anti-fibrogenic role for IL-15. As myeloid cells are key players in liver fibrosis and IL-15 signaling can occur independently of IL-15Ra, we investigated the requirement of IL-15 and IL-15Ra in liver fibrosis. Methods: We induced liver fibrosis in Il15-/-, Il15ra-/- and wildtype C57BL/6 mice by the administration of carbon tetrachloride (CCl4). Liver fibrosis was evaluated by Sirius red and Mason’s trichrome staining and a-smooth muscle acting immunostaining of myofibroblasts. Gene expression of collagens, matrix modifying enzymes, cytokines and chemokines was quantified by RT-qPCR. The phenotype and the numbers of intrahepatic lymphoid and myeloid cell subsets were evaluated by flow cytometry. Results: Both Il15-/- and Il15ra-/- mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content. Il15ra-/- mice showed further reduction in collagen deposition compared to Il15-/- mice. However, Col1a1 and Col1a3 genes were similarly induced in the fibrotic livers of wildtype, Il15-/- and Il15ra-/- mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected, Il15-/- and Il15ra-/- mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45+ immune cells and CD68+ macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and antiinflammatory monocyte subsets compared to wildtype mice. Conclusion: Our findings indicate that IL-15 exerts its profibrogenic role in the liver by promoting macrophage activation and that this requires transpresentation of IL-15 by IL-15Ra. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Since ancient time, Emblica officinalis (E. officinalis) is being used for the management of various ailments. Phytochemical analysis proves that fruit juice of E. officinalis contains high amount gallic acid, which could be responsible for medicinal potentials. Hence in this study, gallic acid and fruit juice of E. officinalis were evaluated for anti-hyperlipidemic potential in various experimental animal models. Experimentally, hyperlipidemia was induced through administration of poloxamer-407, tyloxapol and high-fat-diet supplement in rats. Treatment with gallic acid as well as fruit juice of E. officinalis decreased plasma cholesterol and reduced oil infiltration in liver and aorta. Mechanistically, E. officinalis increased peroxisome proliferator-activated receptors-α (PPARα) expression and increased activity of lipid oxidation through carnitine palmitoyl transferase (CPT) along with decreased activity of hepatic lipogenic enzymes i.e. glucose-6-phosphate dehydrogenase (G6PD), fatty acid synthase (FAS) and malic enzyme (ME). Additionally, E. officinalis increased cholesterol uptake through increased LDL-receptor expressions on hepatocytes and decreased LDL-receptor degradation due to decreased proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Simultaneously, E. officinalis showed ability to restore glucose homeostasis through increased Glut4 and PPARγ protein expression in adipose tissue. These findings exposed central role of gallic acid in E. officinalis arbitrated anti-hyperlipidemic action through upregulation of PPARs, Glut4 and lipogenic enzymes, and decreased expression of PCSK9 and lipogenic enzymes. Findings from this experiment demonstrated that E. officinalis is a potential therapy for management of hyperlipidemia and gallic acid could be a potential lead candidate. [ABSTRACT FROM AUTHOR]

As a novel target for breast cancer, interferon inducers have found its role as antiangiogenic agents with diethylaminoethyl dextran (DEAE-Dextran) being a molecule used for centuries as a transfection agent. Our results herein offer an explanation for the emergence of DEAE-Dextran as an anti-tumor agent for TNBC with indepth mechanistic approach as an anti-angiogenic molecule. DEAE-Dextran has found to possess cytotoxic activity demonstrated during the various in vitro cytotoxicity assays; moreover, as an anti-oxidant, DEAE-Dextran has shown to possess excellent reactive oxygen species scavenging activity. The interferon inducing capacity of DEAEDextran was determined qualitatively as well as quantitatively specifically demonstrating overexpression of β-interferon. As a measure of anti-proliferative activity, DEAE-Dextran exhibited reduced ki67, p53, and PCNA levels. Also, overexpression of CK5/6 and p63 in DEAE-Dextran treated animals indicated improvement in breast cell morphology along with an improvement in cell-;cell adhesion by virtue of upregulation of β-catenin and E-cadherin. Anti-angiogenic property of DEAE-Dextran was concluded by the downregulation of CD31, VEGF, and NOTCH1 both in vivo and in vitro. Further, apoptosis due to DEAE-Dextran, initially determined by downregulation of Bcl2, was confirmed with flow cytometry. Overall, results are defensive of DEAE-Dextran as an emerging anti-tumor agent with mechanisms pertaining to b-interferon induction with probable VEGF and NOTCH1 inhibition as well as apoptosis which still needs to be studied in further depth. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer is defined as one of the utmost prevailing breast cancers worldwide, possessing an inadequate prognosis and treatment option limited to chemotherapy and radiotherapy, creating a challenge for researchers as far as developing a specific targeted therapy is concerned. The past research era has shown several promising outcomes for TNBC such as nano-formulations of the chemotherapeutic agents already used for the management of the malignant tumor. Taking a glance at paclitaxel nano formulations, it has been proven beneficial in several researches in the past decade; nevertheless its solubility is often a challenge to scientists in achieving success. We have henceforth discussed the basic heterogeneity of triple negative breast cancer along with the current management options as well as a brief outlook on pros and cons of paclitaxel, known as the most widely used chemotherapeutic agent for the treatment of the disease. We further analyzed the need of nanotechnology pertaining to the problems encountered with the current paclitaxel formulations available discussing the strategic progress in various nano-formulations till date taking into account the basic research strategies required in terms of solubility, permeability, physicochemical properties, active and passive targeting. A thorough review in recent advances in active targeting for TNBC was carried out whereby the various ligands which are at present finding its way into TNBC research such as hyaluronic acid, folic acid, transferrin, etc. were discussed. These ligands have specific receptor affinity to TNBC tumor cells hence can be beneficial for novel drug targeting approaches. Conversely, there are currently several novel strategies in the research pipeline whose targeting ligands have not yet been studied. Therefore, we reviewed upon the numerous novel receptor targets along with the respective nano-formulation aspects which have not yet been fully researched upon and could be exemplified as outstanding target strategies for TNBC which is currently an urgent requirement. [ABSTRACT FROM AUTHOR]

Medicinal plants, having great elementary and therapeutic importance, are the gift to mankind to acquire healthy lifestyle. Emblica officinalis Gaertn. or Phyllanthus emblica Linn. (Euphorbeaceae), commonly known as Indian gooseberry or Amla, has superior value in entirely indigenous traditional system of medicine, including folklore Ayurveda, for medicinal and nutritional purposes to build up lost vitality and vigor. In this article, numerous phytochemicals isolated from E. officinalis and its ethnomedical and pharmacological potentials with molecular mechanisms are briefly deliberated and recapitulated. The information documented in the present review was collected from more than 270 articles, published or accepted in the last five to six decades, and more than 20 e-books using various online database. Additional information was obtained from various botanical books and dissertations. The extracts from various parts of E. officinalis , especially fruit, contain numerous phytoconstituents viz. higher amount of polyphenols like gallic acid, ellagic acid, different tannins, minerals, vitamins, amino acids, fixed oils, and flavonoids like rutin and quercetin. The extract or plant is identified to be efficacious against diversified ailments like inflammation, cancer, osteoporosis, neurological disorders, hypertension together with lifestyle diseases, parasitic and other infectious disorders. These actions are attributed to either regulation of various molecular pathway involved in several pathophysiologies or antioxidant property which prevents the damage of cellular compartments from oxidative stress. However, serious efforts are required in systemic research to identify, isolate and evaluate the chemical constituents for nutritional and therapeutic potentials. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are generally utilized for numerous inflammatory ailments. The long-term utilization of NSAIDs prompts adverse reactions such as gastrointestinal ulceration, renal dysfunction and hepatotoxicity; however, selective COX-2 inhibitors prevent these adverse events. Various scientific approaches have been employed to identify safer COX-2 inhibitors, as in any case, a large portion of particular COX-2 inhibitors have been retracted from the market because of severe cardiovascular events. This study aimed to develop and synthesize a novel series of indomethacin analogues with potential anti-inflammatory properties and fewer side effects, wherein carboxylic acid moiety was substituted using DCC/DMAP coupling. This study incorporates the docking of various indomethacin analogues to detect the binding interactions with COX-2 protein (PDB ID: 3NT1). MD simulation was performed to measure the stability and flexibility of ligand–protein interactions at the atomic level, for which the top-scoring ligand–protein complex was selected. These compounds were evaluated in vitro for COX enzymes inhibition. Likewise, selected compounds were screened in vivo for anti-inflammatory potential using the carrageenan-induced rat paw oedema method and their ulcerogenic potential. The acute toxicity of compounds was also predicted using in silico tools. Most of the compounds exhibited the potent inhibition of both COX enzymes; however, 3e and 3c showed the most potent COX-2 inhibition having IC50 0.34 µM and 1.39 µM, respectively. These compounds also demonstrated potent anti-inflammatory potential without ulcerogenic liability. The biological evaluation revealed that the compound substituted with 4-nitrophenyl was most active. [ABSTRACT FROM AUTHOR]

Nature has gifted a variety of vital phytochemicals having potential therapeutic application against various ailments. Emblica officinalis (E. officinalis), an ancient plant, has long been used as a remedy for diabetes and cardiovascular complications, and presence of abundant amount of gallic acid could be accountable for its medicinal potential. The study was aimed to determine the in-vivo and in-vitro anti-diabetic potential of gallic acid and fruit juice of E. officinalis. Molecular mechanism of gallic acid as well as fruit juice of E. officinalis for anti-diabetic potential has also been revealed. Anti-diabetic potential of E. officinalis and gallic acid was evaluated in 3T3-L1 preadipocytes and various animal models like db/db mice and fructose administered rats. PPAR-γ expression and glucose translocation were observed using western blot and PCR techniques. Treatment of E. officinalis fruit juice and gallic acid facilitated their glucose homeostasis; improved insulin sensitivity; reduced obesity; abridged elevated blood pressure and declined cholesterol level, and also induced adipogenesis in 3T3-L1 adipocytes. Mechanistically, treatment increased expression of PPAR-γ through activation of C/EBPs and simultaneously increased Glut4 translocation in 3T3-L1 adipocytes. Moreover, gallic acid treatment increased insulin sensitivity through activation of Akt rather than AMPK signaling pathway while fruit juice of E. officinalis showed dual activation, Akt and AMPK as well. These findings reveal the role of gallic acid in E. officinalis mediated antidiabetic potential, and delineate the upregulation of pAkt, PPAR-γ and Glut4 in gallic acid mediated antidiabetic activity, thus providing potential therapy for diabetes and related disorders. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes have been shown to be associated with chronic inflammation. Despite extensive evidence for inflammatory mediators in the obese patients and multiple clinical trials, the outcome has been disappointing. In murine models recruitment of immune cells during inflammation has been shown to contribute to the chronic inflammation. Clearcut evidence for the differential expression of chemokines that mediate this recruitment is not available. In this short review we discuss the observations on CCL2 and CCL5 in human obesity. [ABSTRACT FROM AUTHOR]

Background: Nature has gifted a variety of vital phytochemicals having potential therapeutic application against various ailments. Emblica officinalis (E. officinalis), an ancient plant, has long been used as a remedy for diabetes and cardiovascular complications, and presence of abundant amount of gallic acid could be accountable for its medicinal potential.Purpose: The study was aimed to determine the in-vivo and in-vitro anti-diabetic potential of gallic acid and fruit juice of E. officinalis. Molecular mechanism of gallic acid as well as fruit juice of E. officinalis for anti-diabetic potential has also been revealed.Experimental Study Design: Anti-diabetic potential of E. officinalis and gallic acid was evaluated in 3T3-L1 preadipocytes and various animal models like db/db mice and fructose administered rats. PPAR-γ expression and glucose translocation were observed using western blot and PCR techniques.Results: Treatment of E. officinalis fruit juice and gallic acid facilitated their glucose homeostasis; improved insulin sensitivity; reduced obesity; abridged elevated blood pressure and declined cholesterol level, and also induced adipogenesis in 3T3-L1 adipocytes. Mechanistically, treatment increased expression of PPAR-γ through activation of C/EBPs and simultaneously increased Glut4 translocation in 3T3-L1 adipocytes. Moreover, gallic acid treatment increased insulin sensitivity through activation of Akt rather than AMPK signaling pathway while fruit juice of E. officinalis showed dual activation, Akt and AMPK as well.Conclusion: These findings reveal the role of gallic acid in E. officinalis mediated antidiabetic potential, and delineate the upregulation of pAkt, PPAR-γ and Glut4 in gallic acid mediated antidiabetic activity, thus providing potential therapy for diabetes and related disorders. [ABSTRACT FROM AUTHOR]

The synthesis of 1,2,5-trisubstituted benzimidazole derivatives was carried out using liquid phase combinatorial approach using soluble polymer assisted support (PEG5000). Synthesised compounds were characterised by FTIR, ESI-MS, 1 H NMR and 13 C NMR. The purity of compounds was confirmed with HPLC analysis. Compounds were also docked into the binding site of human dihydroorotate dehydrogenase (hDHODH). The synthesised compounds were screened for hDHODH enzyme inhibition assay using brequinar as standard compound. The synthesised compounds demonstrated comparative biological activity. Synthesised compounds 8d and 8e demonstrated IC 50 value of 81 ± 2 nM and 97 ± 2 nM, respectively. [ABSTRACT FROM AUTHOR]

Drug induced gastrointestinal ulceration, renal side effects and hepatotoxicity are the main causes of numerous Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Cyclooxygenase-2 (COX-2) inhibitors discovered to decrease the gastrointestinal issues, but unfortunately, most of them are associated with major cardiovascular adverse effects. Along these lines, various new strategies and frameworks were developed wherein basic alterations of the present medications were accounted for. The aim of the study was to prepare derivatives of mefenamic acid to evaluate anti-inflammatory activity with fewer adverse reactions. In this study, molecular docking investigations of outlined derivatives were done utilizing Protein Data Bank (PDB ID-4PH9). Synthesis of heterocyclic compounds was carried out utilizing Dicyclohexylcarbodiimide/4-Dimethylaminopyridine (DCC/DMAP) coupling. Acute toxicity prediction was performed using free online GUSAR (General Unrestricted Structure-Activity Relationships) software. The study indicated most of the compounds under safe category. In-vitro pharmacological assessment of heterocyclic compounds was done for COX-1 and COX-2 enzymes for the determination of selectivity. In vivo pharmacological screening for anti-inflammatory activity and ED 50 value were determined utilizing carrageenan induced rat paw edema. Gastro intestinal safety study was carried out on selected compounds and found to be devoid of any gastric ulcer toxicity. Most of the compounds indicated high scores as compared to standard during molecular modelling, analysis and displayed interactions with active amino acids of a COX-2 enzyme. The pharmacological screening uncovered that compound substituted with p-bromophenyl indicated maximum potency. [ABSTRACT FROM AUTHOR]

In the present study, 7-subsituted coumarin derivatives were synthesized using various aromatic and heterocyclic amines, and evaluated in vivo for anti-inflammatory and analgesic activity, and for ulcerogenic risk. The most active compounds were evaluated in vitro for 5-lipoxygenase (5-LOX) inhibition. Docking study was performed to predict the binding affinity, and orientation at the active site of the enzyme. In vivo anti-inflammatory and analgesic activity, and in vitro 5-LOX enzyme inhibition study revealed that compound 33 and 35 are the most potent compounds in all the screening methods. In vitro kinetic study of 35 showed mixed or non-competitive type of inhibition with 5-LOX enzyme. Presence of OCH 3 group in 35 and Cl in 33 at C6-position of benzothiazole ring were found very important substitutions for potent activity. [ABSTRACT FROM AUTHOR]

• SOCS1 and SOCS3 are indispensable tumor suppressor proteins in hepatocytes. • Loss of SOCS1 or SOCS3 accelerates liver regeneration but does not affect hepatostat. • SOCS1 regulates HGF signaling whereas SOCS3 controls IL-6 and EGFR signaling. • SOCS1 and SOCS3 also modulate the tumor suppressors TP53 and CDKN1A. The extraordinary capacity of the liver to regenerate following injury is dependent on coordinated and regulated actions of cytokines and growth factors. Whereas hepatocyte growth factor (HGF) and epidermal growth factor (EGF) are direct mitogens to hepatocytes, inflammatory cytokines such as TNFα and IL-6 also play essential roles in the liver regeneration process. These cytokines and growth factors activate different signaling pathways in a sequential manner to elicit hepatocyte proliferation. The kinetics and magnitude of these hepatocyte-activating stimuli are tightly regulated to ensure restoration of a functional liver mass without causing uncontrolled cell proliferation. Hepatocyte proliferation can become deregulated under conditions of chronic inflammation, leading to accumulation of genetic aberrations and eventual neoplastic transformation. Among the control mechanisms that regulate hepatocyte proliferation, negative feedback inhibition by the 'suppressor of cytokine signaling (SOCS)' family proteins SOCS1 and SOCS3 play crucial roles in attenuating cytokine and growth factor signaling. Loss of SOCS1 or SOCS3 in the mouse liver increases the rate of liver regeneration and renders hepatocytes susceptible to neoplastic transformation. The frequent epigenetic repression of the SOCS1 and SOCS3 genes in hepatocellular carcinoma has stimulated research in understanding the growth regulatory mechanisms of SOCS1 and SOCS3 in hepatocytes. Whereas SOCS3 is implicated in regulating JAK-STAT signaling induced by IL-6 and attenuating EGFR signaling, SOCS1 is crucial for the regulation of HGF signaling. These two proteins also module the functions of certain key proteins that control the cell cycle. In this review, we discuss the current understanding of the functions of SOCS1 and SOCS3 in controlling hepatocyte proliferation, and its implications to liver health and disease. [ABSTRACT FROM AUTHOR]

Highlights: [•] Carboplatin, like cisplatin, induces ROS-dependent nephrotoxicity. [•] Carboplatin induced renal damage resembles Fanconi-like condition. [•] Carboplatin intoxication causes aminoaciduria-specifically tyrosinuria and cysteineuria. [•] ATPases, GSH and TBARS are affected significantly with carboplatin. [•] Pentoxifylline mitigates carboplatin induced renal insult. [ABSTRACT FROM AUTHOR]

Abstract: Polysaccharides have been finding, in the last decades, very interesting and useful applications in the biomedical and, specifically, in the biopharmaceutical field. Galactomannans are a group of storage polysaccharides from various plant seeds that reserve energy for germination in the endosperm. There are four major sources of seed galactomannans: locust bean (Ceratonia siliqua), guar (Cyamopsis tetragonoloba), tara (Caesalpinia spinosa Kuntze), and fenugreek (Trigonella foenum-graecum L.). Through keen references of reported literature on galactomannans, in this review, we have described occurrence of various galactomannans, its physicochemical properties, characterization, applications, and overview of some major galactomannans. [Copyright &y& Elsevier]

Background: Inflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several chronic inflammatory diseases. However, increased liver fibrosis has been reported in mice lacking IL-15 receptor alpha chain (IL-15Rα), suggesting an anti-fibrogenic role for IL-15. As myeloid cells are key players in liver fibrosis and IL-15 signaling can occur independently of IL-15Rα, we investigated the requirement of IL-15 and IL-15Rα in liver fibrosis., Methods: We induced liver fibrosis in Il15 -/- , Il15ra -/- and wildtype C57BL/6 mice by the administration of carbon tetrachloride (CCl 4 ). Liver fibrosis was evaluated by Sirius red and Mason's trichrome staining and α-smooth muscle acting immunostaining of myofibroblasts. Gene expression of collagens, matrix modifying enzymes, cytokines and chemokines was quantified by RT-qPCR. The phenotype and the numbers of intrahepatic lymphoid and myeloid cell subsets were evaluated by flow cytometry., Results: Both Il15 -/- and Il15ra -/- mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content. Il15ra -/- mice showed further reduction in collagen deposition compared to Il15 -/- mice. However, Col1a1 and Col1a3 genes were similarly induced in the fibrotic livers of wildtype, Il15 -/- and Il15ra -/- mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected, Il15 -/- and Il15ra -/- mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45 + immune cells and CD68 + macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and anti-inflammatory monocyte subsets compared to wildtype mice., Conclusion: Our findings indicate that IL-15 exerts its profibrogenic role in the liver by promoting macrophage activation and that this requires trans-presentation of IL-15 by IL-15Rα., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cloutier, Variya, Akbari, Rexhepi, Ilangumaran and Ramanathan.)

Flow cytometry is an imperative tool to characterize alterations in a wide range of immune cell populations during inflammatory conditions and disease states that affect the liver such as the obesity-induced non-alcoholic fatty liver disease and liver fibrosis. Identification and quantification of immune cell subsets from the liver is critically dependent on efficient isolation of intrahepatic leukocytes. The isolation of leukocytes from fatty and fibrotic livers and processing the cells for flow cytometry can be challenging with respect to cell yields, purity and most importantly, the level of autofluorescence resulting from fat deposition. Here, we describe an efficient method for isolating intrahepatic leukocytes from mice fed with high fat diet and propose a strategy to alleviate autofluorescence during phenotyping by multicolor flowcytometry. We also describe a gating strategy for robust identification of granulocytes, pro-inflammatory, anti-inflammatory and transitional state monocyte subsets, dendritic cells, B cell, T lymphocyte subpopulations and NK cell subsets. Overall, the procedures described here will allow simultaneous processing of several samples while ensuring reproducible cell isolation and efficient noise reduction required for reliable characterization of intrahepatic leukocytes from the fatty liver tissues., (© 2022 American Association for Anatomy.)