Exploring the potential of drug repurposing for liver diseases: A comprehensive study.

Drug repurposing involves the investigation of existing drugs for new indications. It offers a great opportunity to quickly identify a new drug candidate at a lower cost than novel discovery and development. Despite the importance and potential role of drug repurposing, there is no specific definition that healthcare providers and the World Health Organization credit. Unfortunately, many similar and interchangeable concepts are being used in the literature, making it difficult to collect and analyze uniform data on repurposed drugs. This research was conducted based on understanding general criteria for drug repurposing, concentrating on liver diseases. Many drugs have been investigated for their effect on liver diseases even though they were originally approved (or on their way to being approved) for other diseases. Some of the hypotheses for drug repurposing were first captured from the literature and then processed further to test the hypothesis. Recently, with the revolution in bioinformatics techniques, scientists have started to use drug libraries and computer systems that can analyze hundreds of drugs to give a short list of candidates to be analyzed pharmacologically. However, this study revealed that drug repurposing is a potential aid that may help deal with liver diseases. It provides available or under-investigated drugs that could help treat hepatitis, liver cirrhosis, Wilson disease, liver cancer, and fatty liver. However, many further studies are needed to ensure the efficacy of these drugs on a large scale.

Quillaja saponin mitigates methotrexate-provoked renal injury; insight into Nrf-2/Keap-1 pathway modulation with suppression of oxidative stress and inflammation.

BACKGROUND: Methotrexate (MTX) is an antineoplastic/immunosuppressive drug, whose clinical use is impeded owing to its serious adverse effects; one of which is acute kidney injury (AKI). Most of MTX complications emerged from the provoked pro-oxidant-, pro-inflammatory- and pro-apoptotic effects. Quillaja saponaria bark saponin (QBS) is a bioactive triterpene that has been traditionally used as an antitussive, anti-inflammatory supplement, and to boost the immune system due to its potent antioxidant- and anti-inflammatory activities. However, the protective/therapeutic potential of QBS against AKI has not been previously evaluated. This study aimed to assess the modulatory effect of QBS on MTX-induced reno-toxicity. METHODS: Thirty-two male rats were divided into 4-groups. Control rats received oral saline (group-I). In group-II, rats administered QBS orally for 10-days. In group-III, rats were injected with single i.p. MTX (20 mg/kg) on day-5. Rats in group-IV received QBS and MTX. Serum BUN/creatinine levels were measured, as kidney-damage-indicating biomarkers. Renal malondialdehyde (MDA), reduced-glutathione (GSH) and nitric-oxide (NOx) were determined, as oxidative-stress indices. Renal expression of TNF-α protein and Nrf-2/Keap-1 mRNAs were evaluated as regulators of inflammation. Renal Bcl-2/cleaved caspase-3 immunoreactivities were evaluated as apoptosis indicators. RESULTS: Exaggerated kidney injury upon MTX treatment was evidenced histologically and biochemically. QBS attenuated MTX-mediated renal degeneration, oxidant-burden enhancement, excessive inflammation, and proapoptotic induction. Histopathological analysis further confirmed the reno-protective microenvironment rendered by QBS. CONCLUSIONS: In conclusion, our results suggest the prophylactic and/or therapeutic effects of QBS in treating MTX-induced AKI. Such reno-protection is most-likely mediated via Nrf-2 induction that interferes with oxidant load, inflammatory pathways, and proapoptotic signaling.

Decoding the role of long non-coding RNAs in gallbladder cancer pathogenesis: A review focus on signaling pathways interplay.

Gallbladder cancer (GBC) is one of the most aggressive types of biliary tree cancers and the commonest despite its rarity. It is infrequently diagnosed at an early stage, further contributing to its poor prognosis and low survival rate. The lethal nature of the disease has underlined a crucial need to discern the underlying mechanisms of GBC carcinogenesis which are still largely unknown. However, with the continual evolution in the research of cancer biology and molecular genetics, studies have found that non-coding RNAs (ncRNAs) play an active role in the molecular pathophysiology of GBC development. Dysregulated long non-coding RNAs (lncRNAs) and their interaction with intracellular signaling pathways contribute to malignancy and disease development. LncRNAs, a subclass of ncRNAs with over 200 nucleotides, regulate gene expression at transcriptional, translational, and post-translational levels and especially as epigenetic modulators. Thus, their expression abnormalities have been linked to malignancy and therapeutic resistance. lnsRNAs have also been found in GBC patients' serum and tumor tissue biopsies, highlighting their potential as novel biomarkers and for targeted therapy. This review will examine the growing involvement of lncRNAs in GBC pathophysiology, including related signaling pathways and their wider clinical use.

Corrigendum: Unveiling the therapeutic potential of exogenous ß-hydroxybutyrate for chronic colitis in rats: novel insights on autophagy, apoptosis, and pyroptosis.

[This corrects the article DOI: 10.3389/fphar.2023.1239025.].

The role of matrix metalloproteinase-2 and miR-196a2 in bronchial asthma pathogenesis and diagnosis.

Background: Bronchial asthma is a persistent inflammatory respiratory condition that restricts the passage of air and causes hyperresponsiveness. Chronic asthma can be classified into three categories: mild, moderate, and severe. Remodeling took place as the extracellular matrix accumulated in the walls of the airways. Inflammation occurs as a result of the damage caused by matrix metalloproteinase-2 (MMP-2) to basement membrane type IV collagen. The severity of asthma may be associated with miR-196a2. The objective of our study was to investigate the underlying mechanisms and clinical relevance of miR-196a2 and MMP-2 serum levels in relation to the severity of asthma. Methods: This study recruited 85 controls and 95 asthmatics classified as mild, moderate, or severe. Expression of miR-196a2 was measured by quantitative reverse transcriptase PCR. Using the enzyme-linked immunosorbent assay (ELISA), MMP-2, IL-6, and total immunoglobulin E (IgE) levels in the serum of asthmatics of various grades were compared to a control group. MMP-2's diagnostic and prognostic potential was determined using ROC curve analysis. This study also measured blood Eosinophils and PFTs. We examined MMP-2's connections with IgE, blood Eosinophils, and PFTs. Results: The current investigation found that miR-196a2 expression was significantly higher in the control group than in asthmatic patients as a whole. The study found that severe asthmatics had higher MMP-2, IL-6, and IgE serum levels than healthy controls. We identified the MMP-2 serum concentration cutoff with great sensitivity and specificity. Significant relationships between MMP-2 serum level and miR-196a2 expression in the patient group with severe asthmatics were found. The MMP-2, IL-6, and IgE serum levels were considerably higher in mild, moderate, and severe asthmatics than controls. The miR-196a2 expression and MMP-2 serum concentration correlated positively with IgE and blood eosinophils % and negatively with all lung function tests in the asthmatic patient group.Conclusion: the study revealed that the elevated miR-196a2 expression and serum concentration of MMP-2, IL-6, and IgE associated with elevated blood eosinophils % is associated with pathophysiology and degree of asthma severity. The miR-196a2 expression and MMP-2 serum concentration have a promising diagnostic and prognostic ability in bronchial asthma.

Cyclosporine-induced kidney damage was halted by sitagliptin and hesperidin via increasing Nrf2 and suppressing TNF-α, NF-κB, and Bax.

Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin.

Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

The potential role of miRNAs in the pathogenesis of schizophrenia - A focus on signaling pathways interplay.

microRNAs (miRNAs) play a crucial role in brain growth and function. Hence, research on miRNA has the potential to reveal much about the etiology of neuropsychiatric diseases. Among these, schizophrenia (SZ) is a highly intricate and destructive neuropsychiatric ailment that has been thoroughly researched in the field of miRNA. Despite being a relatively recent area of study about miRNAs and SZ, this discipline has advanced enough to justify numerous reviews that summarize the findings from the past to the present. However, most reviews cannot cover all research, thus it is necessary to synthesize the large range of publications on this topic systematically and understandably. Consequently, this review aimed to provide evidence that miRNAs play a role in the pathophysiology and progression of SZ. They have also been investigated for their potential use as biomarkers and therapeutic targets.

Tuning into miRNAs: A comprehensive analysis of their impact on diagnosis, and progression in asthma.

Asthma is a diverse inflammatory illness affecting the respiratory passages, leading to breathing challenges, bouts of coughing and wheezing, and, in severe instances, significant deterioration in quality of life. Epigenetic regulation, which involves the control of gene expression through processes such as post-transcriptional modulation of microRNAs (miRNAs), plays a role in the evolution of various asthma subtypes. In immune-mediated diseases, miRNAs play a regulatory role in the behavior of cells that form the airway structure and those responsible for defense mechanisms in the bronchi and lungs. They control various cellular processes such as survival, growth, proliferation, and the production of chemokines and immune mediators. miRNAs possess chemical and biological characteristics that qualify them as suitable biomarkers for diseases. They allow for the categorization of patients to optimize drug selection, thus streamlining clinical management and decreasing both the economic burden and the necessity for critical care related to the disease. This study provides a concise overview of the functions of miRNAs in asthma and elucidates their regulatory effects on the underlying processes of the disease. We provide a detailed account of the present status of miRNAs as biomarkers for categorizing asthma, identifying specific asthma subtypes, and selecting appropriate treatment options.

The emerging role of miRNAs in epilepsy: From molecular signatures to diagnostic potential.

Epilepsy is a medical condition characterized by intermittent seizures accompanied by changes in consciousness. Epilepsy significantly impairs the daily functioning and overall well-being of affected individuals. Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from various dysfunctions in brain activity. The molecular processes underlying changes in neuronal structure, impaired apoptotic responses in neurons, and disruption of regenerative pathways in glial cells in epilepsy remain unknown. MicroRNAs (miRNAs) play a crucial role in regulating apoptosis, autophagy, oxidative stress, neuroinflammation, and the body's regenerative and immune responses. miRNAs have been shown to influence many pathogenic processes in epilepsy including inflammatory responses, neuronal necrosis and apoptosis, dendritic growth, synaptic remodeling, and other processes related to the development of epilepsy. Therefore, the purpose of our current analysis was to determine the role of miRNAs in the etiology and progression of epilepsy. Furthermore, they have been examined for their potential application as biomarkers and therapeutic targets.

Itraconazole halts hepatocellular carcinoma progression by modulating sonic hedgehog signaling in rats: A novel therapeutic approach.

Liver cancer stands as the fourth leading global cause of death, and its prognosis remains grim due to the limited effectiveness of current medical interventions. Among the various pathways implicated in the development of hepatocellular carcinoma (HCC), the hedgehog signaling pathway has emerged as a crucial player. Itraconazole, a relatively safe and cost-effective antifungal medication, has gained attention for its potential as an anticancer agent. Its primary mode of action involves inhibiting the hedgehog pathway, yet its impact on HCC has not been elucidated. The main objective of this study was to investigate the effect of itraconazole on diethylnitrosamine-induced early-stage HCC in rats. Our findings revealed that itraconazole exhibited a multifaceted arsenal against HCC by downregulating the expression of key components of the hedgehog pathway, shh, smoothened (SMO), and GLI family zinc finger 1 (GLI1), and GLI2. Additionally, itraconazole extended survival and improved liver tissue structure, attributed mainly to its inhibitory effects on hedgehog signaling. Besides, itraconazole demonstrated a regulatory effect on Notch1, and Wnt/ß-catenin signaling molecules. Consequently, itraconazole displayed diverse anticancer properties, including anti-inflammatory, antiangiogenic, antiproliferative, and apoptotic effects, as well as the potential to induce autophagy. Moreover, itraconazole exhibited a promise to impede the transformation of epithelial cells into a more mesenchymal-like phenotype. Overall, this study emphasizes the significance of targeting the hedgehog pathway with itraconazole as a promising avenue for further exploration in clinical studies related to HCC treatment.

Unveiling the regulatory role of miRNAs in stroke pathophysiology and diagnosis.

Stroke, a major global cause of mortality, leads to a range of problems for those who survive. Besides its brutal events, stroke also tends to have a characteristic of recurrence, making it a complex disease involving intricate regulatory networks. One of the major cellular regulators is the non-coding RNAs (ncRNA), specifically microRNAs (miRNAs), thus the possible functions of miRNAs in the pathogenesis of stroke are discussed as well as the possibility of using miRNA-based therapeutic approaches. Firstly, the molecular mechanisms by which miRNAs regulate vital physiological processes, including synaptic plasticity, oxidative stress, apoptosis, and the integrity of the blood-brain barrier (BBB) are reviewed. The miRNA indirectly impacts stroke outcomes by regulating BBB function and angiogenesis through the targeting of transcription factors and angiogenic factors. In addition, the tendency for some miRNAs to be upregulated in response to hypoxia, which is a prevalent phenomenon in stroke and various neurological disorders, highlights the possibility that it controls hypoxia-inducible factor (HIF) signaling and angiogenesis, thereby influencing the integrity of the BBB as examples of the discussed mechanisms. Furthermore, this review explores the potential therapeutic targets that miRNAs may offer for stroke recovery and highlights their promising capacity to alleviate post-stroke complications. This review provides researchers and clinicians with valuable resources since it attempts to decipher the complex network of miRNA-mediated mechanisms in stroke. Additionally, the review addresses the interplay between miRNAs and stroke risk factors as well as clinical applications of miRNAs as diagnostic and prognostic markers.

The emerging role of miRNAs in myocardial infarction: From molecular signatures to therapeutic targets.

Globally, myocardial infarction (MI) and other cardiovascular illnesses have long been considered the top killers. Heart failure and mortality are the results of myocardial apoptosis, cardiomyocyte fibrosis, and cardiomyocyte hypertrophy, all of which are caused by MI. MicroRNAs (miRNAs) play a crucial regulatory function in the progression and advancement of heart disease following an MI. By consolidating the existing data on miRNAs, our aim is to gain a more comprehensive understanding of their role in the pathological progression of myocardial injury after MI and to identify potential crucial target pathways. Also included are the primary treatment modalities and their most recent developments. miRNAs have the ability to regulate both normal and pathological activity, including the key signaling pathways. As a result, they may exert medicinal benefits. This review presents a comprehensive analysis of the role of miRNAs in MI with a specific emphasis on their impact on the regeneration of cardiomyocytes and other forms of cell death, such as apoptosis, necrosis, and autophagy. Furthermore, the targets of pro- and anti-MI miRNAs are comparatively elucidated.

miRNAs as modulators of neuroinflammation and excitotoxicity: Implications for stroke therapeutics.

Stroke is a widespread neurological disorder associated with physical disabilities, mortality, and economic burden. In recent decades, substantial progress has been achieved in reducing the impact of this public health problem. However, further understanding of the pathophysiology of stroke and the underlying genetic pathways is required. The pathological mechanisms of stroke comprise multifaceted molecular cascades regulated by various microRNAs (miRNAs). An increasing number of studies have highlighted the role of miRNAs, which have received much attention during the last decades as an important class of post-transcriptional regulators. It was shown that miRNAs exert their role in the etiology of stroke via mediating excitotoxicity and neuroinflammation. Additionally, miRNAs could be helpful as non-invasive or minimally invasive biomarkers and therapeutic agents. Thus, the current review focused on the interplay of these miRNAs in stroke pathology to upgrade the existing therapeutic strategies.

Unraveling the role of miRNAs in the diagnosis, progression, and therapeutic intervention of Alzheimer's disease.

Alzheimer's disease (AD) is a multifaceted, advancing neurodegenerative illness that is responsible for most cases of neurological impairment and dementia in the aged population. As the disease progresses, affected individuals may experience cognitive decline, linguistic problems, affective instability, and behavioral changes. The intricate nature of AD reflects the altered molecular mechanisms participating in the affected human brain. MicroRNAs (miRNAs, miR) are essential for the intricate control of gene expression in neurobiology. miRNAs exert their influence by modulating the transcriptome of brain cells, which typically exhibit substantial genetic activity, encompassing gene transcription and mRNA production. Presently, comprehensive studies are being conducted on AD to identify miRNA-based signatures that are indicative of the disease pathophysiology. These findings can contribute to the advancement of our understanding of the mechanisms underlying this disorder and can inform the development of therapeutic interventions based on miRNA and related RNA molecules. Therefore, this comprehensive review provides a detailed holistic analysis of the latest advances discussing the emerging role of miRNAs in the progression of AD and their possible application as potential biomarkers and targets for therapeutic interventions in future studies.

Unraveling the role of miRNAs in the diagnosis, progression, and therapeutic intervention of Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurological disorder characterized by the impairment of the motor system, resulting in symptoms such as resting tremor, cogwheel rigidity, bradykinesia, difficulty with gait, and postural instability. The occurrence of striatal dopamine insufficiency can be attributed to a notable decline in dopaminergic neurons inside the substantia nigra pars compacta. Additionally, the development of Lewy bodies serves as a pathological hallmark of PD. While current therapy approaches for PD aim to preserve dopaminergic neurons or replenish dopamine levels in the brain, it is important to acknowledge that achieving complete remission of the condition remains elusive. MicroRNAs (miRNAs, miR) are a class of small, non-coding ribonucleic acids involved in regulating gene expression at the post-transcriptional level. The miRNAs play a crucial part in the underlying pathogenic mechanisms of several neurodegenerative illnesses, including PD. The aim of this review is to explore the role of miRNAs in regulating genes associated with the onset and progression of PD, investigate the potential of miRNAs as a diagnostic tool, assess the effectiveness of targeting specific miRNAs as an alternative therapeutic strategy to impede disease advancement, and discuss the utilization of newly developed nanoparticles for delivering miRNAs as neurodegenerative therapies.

Unlocking the miRNA-34a-5p/TGF-ß and HMGB1/PI3K/Akt/mTOR crosstalk participate in the enhanced cardiac protection of liraglutide against isoproterenol-induced acute myocardial injury rat model.

Liraglutide (LIRA), a drug used to treat type 2 diabetes mellitus that belongs to the glucagon-like peptide-1 class, has recently drawn attention for its potential cardioprotective properties because of its anti-oxidative and anti-inflammatory properties. This current investigation was designed to assess the impact of LIRA on myocardial injury induced by isoproterenol (ISO). The experiment included 24 male Wistar rats in total, and they were divided into four groups: Control, LIRA (200 µg/kg/12 hrs., S.C.), ISO (85 mg/kg, S.C.), and ISO + LIRA. To assess the results, various biochemical and histopathological analyses were carried out. The findings showed elevated serum enzyme levels, a sign of cardiac injury. ISO-treated rats showed an upregulation of oxidative stress and inflammatory biomarkers like MDA, MPO, nitrites, NADPH oxidase, TNF-α, IL-1ß, IL-6, 8-Hydroxyguanosine (8-OHdG), and TGF-ß, as well as altered gene expressions like TLR-1 and miRNA-34a-5p. According to western blotting analysis, protein levels of AKT, PI3K, and mTOR were obviously enhanced. Additionally, ISO-treated samples showed altered tissue morphology, elevated caspase 3, and decreased Bcl2 concentrations. The levels of these dysregulated parameters were significantly normalized by LIRA therapy, demonstrating its cardioprotective function against ISO-induced myocardial injury in rats. This protective mechanism was linked to anti-inflammatory properties, redox balance restoration, and modulation of the miRNA-34a-5p/TGF-ß pathway.

Unraveling the role of miRNAs in the diagnosis, progression, and drug resistance of oral cancer.

Oral cancer (OC) is a widely observed neoplasm on a global scale. Over time, there has been an increase in both its fatality and incidence rates. Oral cancer metastasis is a complex process that involves a number of cellular mechanisms, including invasion, migration, proliferation, and escaping from malignant tissue through either lymphatic or vascular channels. MicroRNAs (miRNAs) are a crucial class of short non-coding RNAs recognized as significant modulators of diverse cellular processes and exert a pivotal influence on the carcinogenesis pathway, functioning either as tumor suppressors or as oncogenes. It has been shown that microRNAs (miRNAs) have a role in metastasis at several stages, including epithelial-mesenchymal transition, migration, invasion, and colonization. This regulation is achieved by targeting key genes involved in these pathways by miRNAs. This paper aims to give a contemporary analysis of OC, focusing on its molecular genetics. The current literature and emerging advancements in miRNA dysregulation in OC are thoroughly examined. This project would advance OC diagnosis, prognosis, therapy, and therapeutic implications.

Harnessing the power of miRNAs: The molecular architects of asthma pathogenesis and potential targets for therapeutic innovation.

Asthma is a chronic non-communicable respiratory disease that is characterized by airway inflammation and hyperreactivity. Defective functions of airway smooth muscle and dysregulated signaling pathways play a crucial role in the pathogenesis of asthma. Anti-inflammatories and targeted therapy are mainly used for the treatment of asthma. Recent studies have investigated the role of non-coding RNAs, especially microRNAs (miRNAs; miR) in regulating gene expression and their involvement in the dysfunctional signaling pathways. In immune-mediated diseases, including asthma, miRNAs govern the actions of cells that form the airway structure and those responsible for the defense mechanisms in the bronchi and lungs. miRNAs control cell survival, proliferation, and growth, as well as the cells' capacity to produce and release chemokines and immune mediators. Moreover, miRNAs have an important role in the response to therapeutic interventions. Collectively, this review highlights the regulatory roles of miRNAs in modulating the different signaling pathways and therapeutic responses in asthma. Patients who suffer from asthma, particularly those with severe disease characteristics, may benefit from the prospective treatment options that include targeting miRNAs in order to reduce airway inflammation, hyperreactivity, and mucus production.

Role of Nrf2/HO-1, PPAR-γ, and cytoglobin signals in the pathogenesis of methotrexate-induced testicular intoxication in rats and the protective effect of diacerein.

Methotrexate (MTX) is an inhibitor of folic acid reductase used in managing a variety of malignancies. Testicular injury by MTX is one of its serious adverse effects. The current investigation aims to assess the protective effects of diacerein (DIA) on testicular injury by MTX and clarify the possible underlying mechanisms. Testicular injury in rats was induced by a single injection of 20 mg/kg body weight of MTX. DIA was given in 25 mg/kg body weight/day and 50 mg/kg body weight/day doses for 10 days. Compared to the MTX group, DIA attenuated testicular intoxication as evidenced by improvement of testicular histopathological abnormalities and increased serum testosterone and luteinizing hormone. DIA attenuated testicular oxidative stress changes by lowering testicular MDA and boosting GSH content and SOD activity. Moreover, administration of DIA attenuated MTX-induced testicular inflammation, as proved by decreased TNF-α and IL-6. At the molecular level, DIA induced significant upregulation in Nrf2, HO-1, PPAR-γ, and cytoglobin protein expression. The present results proved that DIA, in a dose-dependent manner, exhibited notable amelioration of testicular toxicity induced by MTX through augmentation of anti-inflammatory and antioxidant effects combined by upregulating Nrf2/HO-1, PPAR-γ, and cytoglobin signaling.