Betaine alleviates doxorubicin-induced nephrotoxicity by preventing oxidative insults, inflammation, and fibrosis through the modulation of Nrf2/HO-1/NLRP3 and TGF-ß expression.

Doxorubicin (Dox) is an anthracycline antibiotic used to treat various cancers and shows severe toxicity in multiple organ systems, including kidneys. Evidence shows that betaine's antioxidant and anti-inflammatory properties could prevent the onset of several disorders. Hence, the present study aims to investigate the therapeutic potential of betaine on Dox-induced nephrotoxicity (DIN). Nephrotoxicity was induced in male Sprague Dawley rats using Dox at a dose of 4 mg/kg (cumulative dose: 20 mg/kg) by the intraperitoneal route and cotreated with betaine through oral gavage (200 and 400 mg/kg) for 28 days. At the end of the experiment, biochemical, oxidative stress parameters, histopathology, and qRT-PCR were performed. DIN was indicated by elevated serum creatinine, urea, and decreased albumin levels representing kidney damage; the histopathological lesions (increased capsular space, renal tubule damage, and fibrosis) in renal tissues supported these biochemical findings. Interestingly, betaine treatment improves these alterations in Dox-treated rats. Further, betaine treatment decreases the lipid peroxidation and nitrite concentration and increases the superoxide dismutases and catalase enzyme concentration in Dox-treated rats. Fascinatingly, at the molecular level, DIN in rats shows upregulation of the Nrf2/HO-1 gene, while betaine treatment attenuated its expression along with the downregulation of inflammatory genes (NLRP3, TLR-4, TNF-α, and IL-6) and fibrosis-related genes (TGF-ß and Acta2) expression in Dox-treated rats. These results showed that betaine has reno-protective properties by reducing inflammatory and fibrotic mediators and enhancing antioxidant capacity in the renal tissue of rats treated with Dox. We believe betaine can be exploited as a dietary supplement to attenuate DIN.

Betaine ameliorates doxorubicin-induced cardiomyopathy by inhibiting oxidative stress, inflammation, and fibrosis through the modulation of AMPK/Nrf2/TGF-ß expression.

Doxorubicin (DOX) is a broad-spectrum antibiotic with potent anti-cancer activity. Nevertheless, despite having effective anti-neoplasm activity, its use has been clinically restricted due to its life-threatening side effects, such as cardiotoxicity. It is evident that betaine has anti-oxidant, and anti-inflammatory activity and has several beneficial effects, such as decreasing the amyloid-ß generation, reducing obesity, improving steatosis and fibrosis, and activating AMP-activated protein kinase (AMPK). However, whether betaine could mitigate DOX-induced cardiomyopathy is still unexplored. Cardiomyopathy was induced in male Sprague Dawley rats using DOX (4 mg/kg dose with a cumulative dose of 20 mg/kg, i.p.). Further, betaine (200 and 400 mg/kg) was co-treated with DOX through oral gavage for 28 days. After the completion of the study, several biochemical, oxidative stress parameters, histopathology, western blotting, and qRT-PCR were performed. Betaine treatment significantly reduced CK-MB, LDH, SGOT, and triglyceride levels, which are associated with cardiotoxicity. DOX-induced increased oxidative stress was also mitigated by betaine intervention as the SOD, catalase, MDA, and nitrite levels were restored. The histopathological investigation also confirmed the cardioprotective effect of betaine against DOX-induced cardiomyopathy as the tissue injury was reversed. Further, molecular analysis revealed that betaine suppressed the DOX-induced increased expression of phospho-p53, phospho-p38 MAPK, NF-kB p65, and PINK 1 with an upregulation of AMPK and downregulation of Nrf2 expression. Interestingly, qRT-PCR experiments show that betaine treatment alleviates the DOX-induced increase in inflammatory (TNF-α, NLRP3, and IL-6) and fibrosis (TGF-ß and Acta2) related gene expression, halting the cardiac injury. Interestingly, betaine also improves the mRNA expression of Nrf2, thus modulating the expression of antioxidant proteins and preventing oxidative damage. Here, we provide the first evidence that betaine treatment prevents DOX-induced cardiomyopathy by inhibiting oxidative stress, inflammation, and fibrosis by regulating AMPK/Nrf2/TGF-ß expression. We believe that betaine can be utilized as a potential novel therapeutic strategy for preventing DOX-induced cardiotoxicity.

Antimicrobial and anti-viral effects of selenium nanoparticles and selenoprotein based strategies: COVID-19 and beyond.

Deficiency of selenium (Se) has been described in a significant number of COVID-19 patients having a higher incidence of mortality, which makes it a pertinent issue to be addressed clinically for effective management of the COVID-19 pandemic. Se nanoparticles (SeNPs) provide a unique option for managing the havoc caused by the COVID-19 pandemic. SeNPs possess promising anti-inflammatory and anti-fibrotic effects by virtue of their nuclear factor kappa-light-chain-stimulator of activated B cells (NFκB), mitogen-activated protein kinase (MAPKs), and transforming growth factor-beta (TGF-ß) modulatory activity. In addition, SeNPs possess remarkable immunomodulatory effects, making them a suitable option for supplementation with a much lower risk of toxicity compared to their elemental counterpart. Further, SeNPs have been shown to curtail viral and microbial infections, thus, making it a novel means to halt viral growth. In addition, it can be administered in the form of aerosol spray, direct injection, or infused thin-film transdermal patches to reduce the spread of this highly contagious viral infection. Moreover, a considerable decrease in the expression of selenoprotein along with enhanced expression of IL-6 in COVID-19 suggests a potential association among selenoprotein expression and COVID-19. In this review, we highlight the unique antimicrobial and antiviral properties of SeNPs and the immunomodulatory potential of selenoproteins. We provide the rationale behind their potentially interesting properties and further exploration in the context of microbial and viral infections. Further, the importance of selenoproteins and their role in maintaining a successful immune response along with their association to Se status is summarized.

A comprehensive overview of CRISPR/Cas 9 technology and application thereof in drug discovery.

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-Cas technology possesses revolutionary potential to positively affect various domains of drug discovery. It has initiated a rise in the area of genetic engineering and its advantages range from classical science to translational medicine. These genome editing systems have given a new dimension to our capabilities to alter, detect and annotate specified gene sequences. Moreover, the ease, robustness and adaptability of the CRISPR/Cas9 technology have led to its extensive utilization in research areas in such a short period of time. The applications include the development of model cell lines, understanding disease mechanisms, discovering disease targets, developing transgenic animals and plants, and transcriptional modulation. Further, the technology is rapidly growing; hence, an overlook of progressive success is crucial. This review presents the current status of the CRISPR-Cas technology in a tailor-made format from its discovery to several advancements for drug discovery alongwith future trends associated with possibilities and hurdles including ethical concerns.

Glucagon-like peptide 1 and fibroblast growth factor-21 in non-alcoholic steatohepatitis: An experimental to clinical perspective.

Non-alcoholic steatohepatitis (NASH) is a progressive form of Non-alcoholic fatty liver disease (NAFLD), which slowly progresses toward cirrhosis and finally leads to the development of hepatocellular carcinoma. Obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome are major risk factors contributing to NAFLD. Targeting these risk factors is a rational option for inhibiting NASH progression. In addition, NASH could be treated with therapies that target the metabolic abnormalities causing disease pathogenesis (such as de novo lipogenesis and insulin resistance) as well with medications targeting downstream processes such as cellular damage, apoptosis, inflammation, and fibrosis. Glucagon-like peptide (GLP-1), is an incretin hormone dysregulated in both experimental and clinical NASH, which triggers many signaling pathways including fibroblast growth factor (FGF) that augments NASH pathogenesis. Growing evidence indicates that GLP-1 in concert with FGF-21 plays crucial roles in the conservation of glucose and lipid homeostasis in metabolic disorders. In line, GLP-1 stimulation improves hepatic ballooning, steatosis, and fibrosis in NASH. A recent clinical trial on NASH patients showed that the upregulation of FGF-21 decreases liver fibrosis and hepatic steatosis, thus improving the pathogenesis of NASH. Hence, therapeutic targeting of the GLP-1/FGF axis could be therapeutically beneficial for the remission of NASH. This review outlines the significance of the GLP-1/FGF-21 axis in experimental and clinical NASH and highlights the activity of modulators targeting this axis as potential salutary agents for the treatment of NASH.

Zebrafish as an emerging tool for drug discovery and development for thyroid diseases.

Zebrafish is a useful model for understanding human genetics and diseases and has evolved into a prominent scientific research model. The genetic structure of zebrafish is 70% identical to that of humans. Its small size, low cost, and transparent embryo make it a valuable tool in experimentation. Zebrafish and mammals possess the same molecular mechanism of thyroid organogenesis and development. Thus, thyroid hormone signaling, embryonic development, thyroid-related disorders, and novel genes involved in early thyroid development can all be studied using zebrafish as a model. Here in this review, we emphasize the evolving role of zebrafish as a possible tool for studying the thyroid gland in the context of physiology and pathology. The transcription factors nkx2.1a, pax2a, and hhex which contribute a pivotal role in the differentiation of thyroid primordium are discussed. Further, we have described the role of zebrafish as a model for thyroid cancer, evaluation of defects in thyroid hormone transport, thyroid hormone (TH) metabolism, and as a screening tool to study thyrotoxins. Hence, the present review highlights the role of zebrafish as a novel approach to understand thyroid development and organogenesis.

Nimbolide abrogates cerulein-induced chronic pancreatitis by modulating ß-catenin/Smad in a sirtuin-dependent way.

Chronic pancreatitis (CP) is one of the leading causes of mortality worldwide with no clinically approved therapeutic interventions. The present study was designed to investigate the protective effect of nimbolide (NB), an active constituent of neem tree (Azadirachta indica), by targeting ß-catenin/Smad/SIRT1 in cerulein-induced CP model. The effects of NB was investigated on cerulein (50 µg/kg/hr*6 exposures /day, 3 days a week for 3 weeks) induced CP in mice. Amylase and lipase activity were measured and histopathological evaluation was performed. Collagen deposition in the pancreatic tissue was estimated by hydroxyproline assay, and collagen specific staining picrosirius red and Masson's trichrome. Cerulein-induced CP was significantly controlled by NB treatment, as shown by the downregulation of ß-catenin/Smad signaling in a SIRT1 dependent manner. NB treatment significantly decreased α-SMA, MMP-2, collagen1a, fibronectin, TGF-ß1, p-Smad-2/3 expression and extracellular matrix (ECM) deposition in pancreatic tissue. However, the protective effects of NB on cerulein-induced CP were undermined by nicotinamide (NMD) or splitomicin, sirtuin 1 (SIRT1) inhibitors treatment. NB treatment modulated protein expression by activating SIRT1 and decreasing the expression of ß-catenin/Smad proteins in CP mice. However, the expression of SIRT1 in pancreatic tissue was elevated by NB treatment and it was decreased by NMD or splitomicin treatment. In summary, our results strongly suggest that NB exerted promising protective effects in cerulein-induced CP model by inhibiting ß-catenin/Smad in a sirtuin-dependent manner, which could be attributed to its anti-inflammatory and antifibrotic effects. Our study suggests that NB could be an effective therapeutic intervention for the treatment of CP.

Crocin, an active constituent of Crocus sativus ameliorates cerulein induced pancreatic inflammation and oxidative stress.

Acute pancreatitis (AP) is a disorder of the pancreas marked by profound inflammation and oxidative stress. Phytoconstituents presents an important toolbox of preventive strategies to combat inflammatory disorders. To this end, we selected the active constituent of Crocus sativus, crocin for evaluation against cerulein-induced AP, owing to its promising antiinflammatory activity in acute as well as chronic inflammatory conditions. The animals were randomly divided into five groups comprising of normal control, cerulein control, crocin low dose (30 mg/kg), crocin high dose (100 mg/kg), and crocin control (100 mg/kg). Various biochemical parameters and the levels of inflammatory cytokines and p65-NFκB were measured. The mechanism was investigated by histology and immunohistochemistry. We found that crocin significantly reduced the pancreatic edema, amylase, and lipase levels. It abrogated the oxidative stress incurred by cerulein challenge. We found that crocin modulated the pancreatic inflammatory cytokine levels. Crocin perturbed the nuclear translocation of p65-NFκB. Crocin reverted the pancreatic histology associated with AP. Furthermore, it upregulated the expression of Nrf-2 and downregulated the expression of IL-6, TNF-α, nitrotyrosine, and NFκB. Cumulatively, these results indicate that crocin has promising potential to prevent cerulein induced AP and regular intake of saffron can prove beneficial for the pancreatic health.

Yttrium oxide nanoparticles reduce the severity of acute pancreatitis caused by cerulein hyperstimulation.

Oxidative stress plays a major role in acute pancreatitis (AP), leading to massive macrophage infiltration. Nanoyttria (NY) possesses potent free radical scavenging activity. As reactive oxygen species and inflammation play major role in AP, we hypothesized that NY may alleviate cerulein induced AP. NY ameliorated LPS induced oxidative stress in vitro. It reduced ROS, superoxide radical generation and restored the mitochondrial membrane potential in macrophages. Interestingly, NY reduced plasma amylase and lipase levels and attenuated the mitochondrial stress and inflammatory markers. NY suppressed the recruitment of inflammatory cells around the damaged pancreatic acinar cells. Furthermore, NY intervention perturbed the course of AP via reduction of endoplasmic reticulum (ER) stress markers (BiP, IRE1 and Ero1-Lα), and molecular chaperones (Hsp27 and Hsp70). We, to the best of our knowledge, report for first time that NY can attenuate experimental AP by restoration of mitochondrial and ER homeostasis through Nrf2/NFκB pathway modulation.

Modulation of cerulein-induced pancreatic inflammation by hydroalcoholic extract of curry leaf (Murraya koenigii).

This study was performed to study the in vitro and in vivo efficacy of hydroalcoholic extract of curry leaf (CLE) rich in carbazole alkaloids, against LPS-induced inflammation in Raw 264.7 macrophages and cerulein-induced acute pancreatitis, respectively. CLE was characterized by Fourier-transform infrared (FTIR) and liquid chromatography-mass spectrometry. Raw 264.7 cells were stimulated with LPS (2 µg/ml) and treated with CLE. The animals were treated with two doses of CLE (100 and 300 mg/kg). Plasma biochemistry, tissue lipid peroxidation, cytokines, and histological examination were evaluated. CLE was found to decently scavenge the activity of DPPH radical. It dose dependently suppressed nitrite production and oxidative stress in macrophages. CLE alleviated LPS-induced inflammation in macrophages as evident from the results of various inflammatory cytokines (IL-1ß, IL-6, and TNF-α). In vivo, CLE reduced cerulein-induced pancreatic edema. CLE significantly abrogated the cerulein-induced lipid peroxidation, nitrite, MPO, and GSH levels. The inflammatory cytokines and p65-NFκB activity were significantly reduced by CLE. Mechanistically, CLE reduced the expression of NT, MPO, IL-1ß, ICAM-1, and COX-2, and increased the expression of Nrf2. It reduced distant organ damage markers as well. We report for the first time that CLE holds substantial potential for the prevention of acute pancreatitis.

Oropharyngeal administration of silica in Swiss mice: A robust and reproducible model of occupational pulmonary fibrosis.

Pulmonary fibrosis (PF) is a lethal end stage of interstitial lung disease with increasing prevalence. The disease burden of PF has seen a sharp surge in the past two decades owing to entry of heavy amount of particulate matter due to industrialization and urbanization. In this work, we developed an oropharyngeal aspiration model of silica (1.5 mg/mice) induced pulmonary fibrosis as a homogeneous, reproducible, simple and alternative strategy in Swiss albino mice. Various BALF (protein, albumin, cell count), biochemical parameters (MDA, GSH, hydroxyproline), cytokines (IL-1ß, IL-6, TNF-α and TGF-ß1), histological (H&E and PSR staining) and protein expression (N-cadherin, vimentin, α-SMA, CTGF, collagen-1) studies were conducted to validate the model. Oropharyngeal administration of silica in Swiss mice produced significantly changes in lung morphology with statistically higher lung weights compared to normal control animals. The silica treated mice showed profoundly elevated BALF soluble and cytological parameters and enhanced oxidative and nitrosative stress in lungs. The levels of hydroxyproline were increased by 2.6 fold in the silica treated mice. The expression of pro-inflammatory cytokines were profoundly increased in silica treated mice. The histology and PSR staining indicated increased inflammatory infiltration and staggering fibrosis in silica treated group. In addition, the expression of EMT markers (N-cadherin, vimentin, α-SMA and CTGF) were significantly increased indicating their role in silica induced pulmonary fibrosis. Our work clearly demonstrates the superiority of stress free oropharyngeal instillation of silica with dose reduction over the conventional invasive and non-homogeneous intratracheal route.

Isoproterenol-induced cardiac ischemia and fibrosis: Plant-based approaches for intervention.

Heart is the most active and incumbent organ of the body, which maintains blood flow, but due to various pathological reasons, several acute and chronic cardiac complications arise out of which myocardial infarction is one of the teething problems. Isoproterenol (ISP)-induced myocardial ischemia is a classical model to screen the cardioprotective effects of various pharmacological interventions. Phytochemicals present a novel option for treating various human maladies including those of the heart. A large number of plant products and their active ingredients have been screened for efficacy in ameliorating ISP-induced myocardial ischemia including coriander, curcumin, Momordica, quercetin, and Withania somnifera. These phytochemicals constituents may play key role in preventing disease and help in cardiac remodeling. Reactive oxygen species scavenging, antiinflammatory, and modulation of various molecular pathways such as Nrf2, NFкB, p-21 activated kinase 1 (PAK1), and p-smad2/3 signaling modulation have been implicated behind the claimed protection. In this review, we have provided a focused overview on the utility of ISP-induced cardiotoxicity, myocardial ischemia, and cardiac fibrosis for preclinical research. In addition, we have also surveyed molecular mechanism of various plant-based interventions screened for cardioprotective effect in ISP-induced cardiotoxicity, and their probable mechanistic profile is summarized.

Withaferin A, a novel compound of Indian ginseng (Withania somnifera), ameliorates Cerulein-induced acute pancreatitis: Possible role of oxidative stress and inflammation.

Acute pancreatitis is an inflammatory disorder of the pancreas that may precipitate due to various reasons such as chronic alcoholism, gall stone obstruction, and life style. Current treatment options offer limited efficacy, as they provide only symptomatic relief. This study is an attempt to study the effects of Withaferin A (WFA) against Cerulein-induced acute pancreatitis in mice. Animals were pretreated with WFA via intraperitoneal route, for 7 days. Plasma amylase and lipase, tissue malondialdehyde (MDA), and glutathione were evaluated for all groups. Western blot analysis; haematoxylin and eosin staining of the liver, lung, and pancreas; immunohistochemistry for nitrotyrosine; and myeloperoxidase activity were performed. Haematoxylin and eosin stained sections significantly revealed the altered architecture and thereby damage in the pancreas, lungs, and liver that has been low in treatment groups. Increased myeloperoxidase and nitrotyrosine have also been reduced upon treatment with WFA. Increased levels of MDA, NO, and expression of myeloperoxidase and nitrotyrosine in the parameters estimated add evidence to the role of oxidative stress and inflammation in acute pancreatitis. WFA evidently altered these conditions upon pretreatment. Our study shows that this novel steroidal compound has potent anti-inflammatory property. Natural compounds can therefore be good remedies against many diseases if incorporated in routine diet as dietary supplement.

The Role of Plant-derived Products in Pancreatitis: Experimental and Clinical Evidence.

Pancreatitis is a gastrointestinal disease with a worldwide sharp surge during the past decade. Pancreatitis includes acute and chronic subtypes, which are graded based on the amount of pancreatic inflammation. Phytoconstituents represent a promising class of therapeutic agents with wide acceptability not only based on folk practices but sound presence of pharmacological and molecular evidences. Growing research evidence indicates that different molecular mechanisms are involved in their protective effect. Many phytoremedies have been tried for the treatment of pancreatic injuries and have shown success in preclinical animal models of pancreatitis. The literature was largely collected through PubMed and Google scholar database. A large proportion of phytochemicals targets the inflammatory cascade and modulates the overtly acting redox balance among which nuclear factor kappa-light-chain-enhancer of activated B cells is the key molecule. Inhibition of apoptosis (artemisinin, embelin), inflammasome (withaferin A), neutrophil rolling (fucoidan), Ca+2 release (caffeine), mitogen activated protein kinase (guggulsterone) and many other novel mechanisms apart from antioxidant effect have been postulated behind the protective effect of phytoconstituents. The present review deals to fill the gap of hitherto unavailable comprehensive review on various plant products screened for the treatment of pancreatitis. The possible mechanistic profile of these phytochemicals is summarized. Copyright © 2017 John Wiley & Sons, Ltd.

Therapeutic potential of stem cells in regeneration of liver in chronic liver diseases: Current perspectives and future challenges.

The deposition of extracellular matrix and hyperplasia of connective tissue characterizes chronic liver disease called hepatic fibrosis. Progression of hepatic fibrosis may lead to hepatocellular carcinoma. At this stage, only liver transplantation is a viable option. However, the number of possible liver donors is less than the number of patients needing transplantation. Consequently, alternative cell therapies based on non-stem cells (e.g., fibroblasts, chondrocytes, keratinocytes, and hepatocytes) therapy may be able to postpone hepatic disease, but they are often ineffective. Thus, novel stem cell-based therapeutics might be potentially important cutting-edge approaches for treating liver diseases and reducing patient' suffering. Several signaling pathways provide targets for stem cell interventions. These include pathways such as TGF-ß, STAT3/BCL-2, NADPH oxidase, Raf/MEK/ERK, Notch, and Wnt/ß-catenin. Moreover, mesenchymal stem cells (MSCs) stimulate interleukin (IL)-10, which inhibits T-cells and converts M1 macrophages into M2 macrophages, producing an anti-inflammatory environment. Furthermore, it inhibits the action of CD4+ and CD8+ T cells and reduces the activity of TNF-α and interferon cytokines by enhancing IL-4 synthesis. Consequently, the immunomodulatory and anti-inflammatory capabilities of MSCs make them an attractive therapeutic approach. Importantly, MSCs can inhibit the activation of hepatic stellate cells, causing their apoptosis and subsequent promotion of hepatocyte proliferation, thereby replacing dead hepatocytes and reducing liver fibrosis. This review discusses the multidimensional therapeutic role of stem cells as cell-based therapeutics in liver fibrosis.

Effects of ashwagandha (Withania somnifera) root extract on aging-related changes in healthy geriatric dogs: A randomized, double-blinded placebo-controlled study.

BACKGROUND AND AIM: This study aimed to explore the clinical potential of Withania somnifera/ashwagandha root extract (ARE) to mitigate age-related changes in healthy geriatric dogs. We hypothesized that ARE can reduce the effects of advancing age, including physiological changes, immune response decline and susceptibility to diseases, by its immunomodulatory effects. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in Telangana, India, from July 2022 to September 2022. Twenty apparently healthy dogs, aged 8 years or older, were enrolled. The dogs were divided into two groups to receive ARE (15 mg/kg, once daily, orally) or a placebo control. Various parameters, including serum cortisol levels, haematological profiles, biochemical markers, antioxidant indicators and anti-inflammatory responses, were assessed at the initiation of study, day 30, and day 60. RESULTS: The erythrocyte count and haemoglobin levels were significantly increased with ARE (p < 0.001), whereas leukocyte count decreased (p < 0.05). Moreover, significant decreases in important markers of liver function (alanine aminotransferase, aspartate aminotransferase, albumin and globulin; p < 0.001 at day 60), as well as kidney function markers (creatinine and blood urea nitrogen; p < 0.001 at days 30 and 60), were observed in ARE-treated dogs compared to the placebo control group. In addition, the levels of markers of oxidative stress (superoxide dismutase, catalase, glutathione and malondialdehyde) were significantly modulated by ARE intervention, indicating strong antioxidant effects. Interestingly, serum cortisol levels reduced significantly with ARE (p < 0.001). Compared to baseline, ARE significantly decreased key inflammatory markers, including interferon-γ, tumour necrosis factor-α, nuclear factor kappa light chain enhancer of activated B cells and interleukin-10 (p < 0.001) levels at day 60. CONCLUSION: In conclusion, the findings of this study suggest that ARE has adaptogenic properties in healthy geriatric dogs by improving haematological and biochemical profiles, enhancing antioxidant defence, reducing stress and modulating inflammatory responses.

Therapeutic potential and pharmacological mechanism of visnagin.

Visnagin is a furanochromone and one of the most important compound in the Ammi visnaga (L.) Lam (a synonym of Visnaga daucoides Gaertn.) plant, which is used to cure various ailments. Many investigations into the bioactive properties of visnagin have been studied to date. The literature on visnagin demonstrates its biological properties, including anti-inflammatory, anti-diabetic, and beneficial effects in cardiovascular and renal diseases. Moreover, visnagin improves sperm quality parameters, stimulates steroidogenesis, and increases serum gonadotropins and testosterone levels, while decreasing pro-inflammatory cytokines, oxidative damage, genomic instability, and it modulates apoptosis. Thus, visnagin has emerged as an exciting lead for further research, owing to its potential in various unmet clinical needs. The current review summarized its basic structure, pharmacokinetics, and pharmacological effects, focusing on its mechanisms of action. The review will help to understand the potential of visnagin as an alternative treatment strategy for several diseases and provide insight into research topics that need further exploration for visnagin's safe clinical use. Please cite this article as: Yadav P, Singh SK, Datta S, Verma S, Verma A, Rakshit A, Bali A, Bhatti JS, Khurana A, Navik U. Therapeutic potential and pharmacological mechanism of visnagin. J Integr Med. 2024; 22(4): 399-412.

Rare earth cerium oxide nanoparticles attenuated liver fibrosis in bile duct ligation mice model.

Liver fibrosis is one of the major liver complications which eventually progresses to liver cirrhosis and liver failure. Cerium oxide nanoparticles, also known as nanoceria (NC) are nanoparticles with potential antioxidant and anti-inflammatory activities. Herein, we evaluated the hepatoprotective and anti-fibrotic effects of nanoceria (NC) against bile duct ligation (BDL) induced liver injury. NC were administered i.p. for 12 days (0.5 and 2 mg/kg) to C57BL/6J mice. The biochemical markers of liver injury, oxidative and nitrosative stress markers, inflammatory cytokines were evaluated. Fibrosis assessment and mechanistic studies were conducted to assess the hepatoprotective effects of NC. Administration of NC proved to significantly ameliorate liver injury as evident by reduction in SGOT, SGPT, ALP and bilirubin levels in the treated animals. NC treatment significantly reduced the hydroxyproline levels and expression of fibrotic markers. In summary, our findings establish the hepatoprotective and anti-fibrotic effects of NC against BDL induced liver injury and liver fibrosis. These protective effects were majorly ascribed to their potential ROS inhibition and antioxidant activities through catalase, superoxide dismutase (SOD)-mimetic properties and auto-regenerating capabilities.

Yttrium Oxide Nanoparticles Attenuate L-Arginine Induced Chronic Pancreatitis.

In this work, we tested the efficacy of yttrium oxide nanoparticles (NY), a promising antioxidant and anti-inflammatory agent, in L-arginine (L-Arg) induced chronic pancreatitis (CP) model. The nanoparticles were characterized using multiple techniques including transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (pXRD), and Energy dispersive X-ray analysis (EDX). The rats were divided into three groups: normal control, L-Arg control, L-Arg + NY (1 mg/kg). We probed the mechanistic effects of the NY by ELISA, multiplex analysis of TGF-ß pathway and inflammatory cytokines and immunoblotting. NY treatment significantly reduced pancreatic oxidative-nitrosative stress. In addition, NY intervention also reduced inflammatory cytokines and chemokines resulting in the inhibition of fibrosis signaling. Further, NY treatment suppressed the TGF-ß signaling and epithelial-mesenchymal transition (EMT). We conclude that NY shows potential antioxidant, anti-inflammatory, and anti-fibrotic effects against CP and associated fibrosis.

Nanoceria Ameliorates Fibrosis, Inflammation, and Cellular Stress in Experimental Chronic Pancreatitis.

Chronic pancreatitis (CP) is an inflammatory, irreversible disorder of the pancreas which leads to organ atrophy and poses high risk for the development of pancreatic cancer. Given the lack of clinically approved therapy, we explored the pharmacological potential of the nanoparticles of cerium oxide (nanoceria, NC) against animal models of CP. Nanoceria ameliorated the features of CP as evident from biochemical parameters. It inhibited the inflammatory cytokines and chemokines by abrogation of macrophage signaling. Further, NC attenuated the fibrogenesis by inhibition of TGF-ß signaling, endoplasmic reticulum stress, and epithelial-to-mesenchymal transition. Our findings reveal the anti-CP potential of the novel redox regenerative nanoceria against two models of CP.