Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma:Experimental and clinical scenarios

Hepatocellular carcinoma(HCC)is the most common type of liver cancer worldwide.Viral hepatitis is a significant risk factor for HCC,although metabolic syndrome and diabetes are more frequently associated with the HCC.With increasing prevalence,there is expected to be>1 million cases annually by 2025.Therefore,there is an urgent need to establish potential therapeutic targets to cure this disease.Peroxisome-proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor that plays a crucial role in the pathophysiology of HCC.Many synthetic agonists of PPARγsuppress HCC in experimental studies and clinical trials.These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC.However,some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy.Thus natural PPARγagonists can be an alternative to exploit this potential target for HCC treatment.In this review,the regulatory role of PPARγin the pathogenesis of HCC is elucidated.Furthermore,the experimental and clinical scenario of both synthetic and natural PPARγagonists against HCC is discussed.Most of the available literature advocates PPARγas a potential therapeutic target for the treatment of HCC.

Peroxisome proliferator-activated receptor agonists:A new hope towards the management of alcoholic liver disease

In this editorial,we examine a paper by Koizumi et al,on the role of peroxisome proliferator-activated receptor(PPAR)agonists in alcoholic liver disease(ALD).The study determined whether elafibranor protected the intestinal barrier and reduced liver fibrosis in a mouse model of ALD.The study also underlines the role of PPARs in intestinal barrier function and lipid homeostasis,which are both affected by ALD.Effective therapies are necessary for ALD because it is a critical health issue that affects people worldwide.This editorial analyzes the possibility of PPAR agonists as treatments for ALD.As key factors of inflammation and metabolism,PPARs offer multiple methods for managing the complex etiology of ALD.We assess the abilities of PPARα,PPARγ,and PPARβ/δagonists to prevent steatosis,inflammation,and fibrosis due to liver diseases.Recent research carried out in preclinical and clinical settings has shown that PPAR agonists can reduce the severity of liver disease.This editorial discusses the data analyzed and the obstacles,advantages,and mechanisms of action of PPAR agonists for ALD.Further research is needed to understand the efficacy,safety,and mechanisms of PPAR agonists for treating ALD.

Anluohuaxianwan Alleviates Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats through Upregulation of Peroxisome Proliferator-Activated Receptor-Gamma and Downregulation of Nuclear Factor-Kappa B/IκBα Signaling Pathway

Objective:The aim of this study was to investigate the effects of traditional Chinese medicine Anluohuaxianwan(ALHXW)on peroxisome proliferator-activated receptor-gamma(PPARγ)and nuclear factor-kappa B(NF-κB)signaling pathways using a rat model of carbon model groups were gavaged with saline for 6 weeks.Liver function was measured,and liver fibrosis and necroinflammation were assessed.Protein and messenger RNA expression levels of PPARγ,NF-κB,and Inhibitorαof NF-κB(IκBα)were analyzed by Western blot and reverse transcription–quantitative polymerase chain reaction.Results:ALHXW markedly alleviated liver injury compared with the model group,as indicated by the improvements in disease status,the morphology of liver and spleen,the liver and spleen indexes,and liver function.The extent of liver fibrosis was improved,hepatic stellate cell activation was inhibited,the expression of PPARγand IκBαwas significantly higher,and the expression of NF-κB was significantly lower in the treatment group as compared with the model group.Conclusions:ALHXW treatment can alleviate CCl4-induced liver fibrosis in rats, and the potential antifibrogenic mechanisms may occur through the upregulation of PPARγ expression and downregulation of NF-κB/IκBα signaling pathway.

Emerging therapeutic options for non-alcoholic fatty liver disease:A systematic review

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation.In the United States alone,annual medical costs are approximately 100 billion dollars.Unfortunately,there is no Federal Drug Administration(FDA)-approved medication for its treatment.However,various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD.It is valuable to have a compilation of the data available on their efficacy.AIM To assess the efficacy of cyclophilin inhibitors,fibroblast growth factor 21 analogs(FGF21),and dual and pan peroxisome proliferator-activated receptor(PPAR)agonists for treating NAFLD.METHODS A comprehensive literature search using keywords including cyclophilin inhibitor,FGF agonist,pan-PPAR agonists,dual-PPAR agonist,NAFLD,nonalcoholic steatohepatitis,and fatty liver was conducted on October 29,2022,in PubMed,EMBASE,Cochrane Library,Scopus and Web of Science.Animal and human research,case reports,and published articles in English from all countries with patients aged 18 and above were included.Only articles with a National Institutes of Health(NIH)Quality Assessment score of five or higher out of eight points were included.Articles that were narrative or systematic reviews,abstracts,not in English,focused on patients under 18 years old,did not measure outcomes of interest,were inaccessible,or had a low NIH Quality Assessment score were excluded.Each article was screened by two independent researchers evaluating relevance and quality.Resources were scored based on the NIH Quality Assessment Score;then,pertinent data was extracted in a spreadsheet and descriptively analyzed.RESULTS Of the 681 records screened,29 met the necessary criteria and were included in this review.These records included 12 human studies and 17 animal studies.Specifically,there were four studies on cyclophilin inhibitors,four on FGF agonists/analogs,eleven on pan-PPAR agonists,and ten on dual-PPAR agonists.Different investigational products were assessed:The most common cyclophilin inhibitor was NV556;FGF agonists and analogs was Efruxifermin;pan-PPAR agonists was Lanifibranor;and dual-PPAR agonists was Saroglitazar.All classes were found to be statistically efficacious for the treatment of NAFLD,with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan(P<0.05).CONCLUSION The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes,as well as good safety profiles(P<0.05).We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.

Crosstalk between gut microbiota and antidiabetic drug action

Type 2 diabetes (T2D) is a disorder characterized by chronic inflated blood glucose levels (hyperglycemia), at first due to insulin resistance and unregulated insulin secretion but with tendency towards global spreading. The gut microbiota is recognized to have an influence on T2D, although surveys have not formed a clear overview to date. Because of the interactions between gut microbiota and host homeostasis, intestinal bacteria are believed to play a large role in various diseases, including metabolic syndrome, obesity and associated disease. In this review, we highlight the animal and human studies which have elucidated the roles of metformin,α-glucosidase inhibitors, glucagon-like peptide-1 agonists, peroxisome proliferator-activated receptors γ agonists, inhibitors of dipeptidyl peptidase-4, sodium/glucose cotransporter inhibitors, and other less studied medications on gut microbiota. This review is dedicated to one of the most widespread diseases, T2D, and the currently used antidiabetic drugs and most promising new findings. In general, the gut microbiota has been shown to have an influence on host metabolism, food consumption, satiety, glucose homoeostasis, and weight gain. Altered intestinal microbiota composition has been noticed in cardiovascular diseases, colon cancer, rheumatoid arthritis, T2D, and obesity. Therefore, the main effect of antidiabetic drugs is on the microbiome composition, basically increasing the short-chain fatty acids-producing bacteria, responsible for losing weight and suppressing inflammation.

Psoriasis treatment: Unconventional and non-standard modalities in the era of biologics

Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide causing a significant occupational, personal or psychosocial morbidity to these patients for life. The basic aim of psoriasis therapy is to control the disease to maximum possible extent and improve the patient's quality of life. Management of triggers for flareups, lifestyle modifications, and dietary supplements are often recommended. Intermittent or rotational therapy with frequent alterations in treatment options is usually needed to reduce toxicity of anti-psoriatic drugs in the absence of safer alternatives. Currently, several biological agents categorized as either T-cell targeted(e.g., Alefacept, Efalizumab) or cytokine modulating(e.g., Adalimumab, Infliximab, Etanercept) are available for treating severe psoriasis. However, their high cost is often precluding for most patients. The usefulness of systemic(methotrexate, cyclosporine, acitretin or several other therapeutic agents) or topical(tar, anthralin, corticosteroids or calcipotriol ointments, phototherapy with or without psoralens) therapies has been well established for the management of psoriasis. The literature is also replete with benefits of less used non-standard and unconventional treatment modalities(hydroxycarbamide, azathioprine, leflunomide, mycophenolate mofetil, isotretinoin, fumarates, topical calcineurin inhibitors, peroxisome proliferator-activated receptors agonists, statins, sulfasalazine, pentoxifylline, colchicine, grenz ray therapy, excimer laser, climatotherapy and balneophototherapy, peritoneal dialysis, tonsillectomy, ichthyotherapy, etc.). These can be used alternatively to treat psoriasis patients who have mild/minimal lesions, are intolerant to conventional drugs, have developed side effects or achieved recommended cumulative dose, where comorbidities pose unusual therapeutic challenges, or may be as intermittent, rotational or combination treatment alternatives.