The promising antioxidant effects of lignans: Nrf2 activation comes into view.

Lignans are biologically active compounds widely distributed, recognized, and identified in seeds, fruits, and vegetables. Lignans have several intriguing bioactivities, including anti-inflammatory, antioxidant, and anticancer activities. Nrf2 controls the expression of many cytoprotective genes. Activation of Nrf2 is a promising therapeutic approach for treating and preventing diseases resulting from oxidative injury and inflammation. Lignans have been demonstrated to stimulate Nrf2 signaling in a variety of in vitro and experimental animal models. The review summarizes the findings of fourteen lignans (Schisandrin A, Schisandrin B, Schisandrian C, Magnolol, Honokiol, Sesamin, Sesamol, Sauchinone, Pinoresinol, Phyllanthin, Nectandrin B, Isoeucommin A, Arctigenin, Lariciresinol) as antioxidative and anti-inflammatory agents, affirming how Nrf2 activation affects their pharmacological effects. Therefore, lignans may offer therapeutic candidates for the treatment and prevention of various diseases and may contribute to the development of effective Nrf2 modulators.

The enteroprotective effect of nifuroxazide against methotrexate-induced intestinal injury involves co-activation of PPAR-γ, SIRT1, Nrf2, and suppression of NF-κB and JAK1/STAT3 signals.

Methotrexate (MTX) has long manifested therapeutic efficacy in several neoplastic and autoimmune disorders. However, MTX-associated intestinal toxicity restricts the continuation of treatment. Nifuroxazide (NIF) is an oral antibiotic approved for gastrointestinal infections as an effective antidiarrheal agent with a high safety profile. The current study was designed to explore the potential efficacy of NIF in alleviating intestinal toxicity associated with MTX chemotherapy with the elucidation of the proposed molecular mechanisms. Rats were administered NIF (50 mg/kg; p.o.) for ten days. On day five, a single i.p. injection of MTX (20 mg/kg) was given to induce intestinal intoxication. At the end of the experiment, duodenal tissue samples were isolated for biochemical, Western blotting, immunohistochemical (IHC), and histopathological analysis via H&E, PSA, and Alcian blue stains. NIF showed antioxidant enteroprotective effects against MTX intestinal intoxication through enhanced expression of the redox-sensitive signals of PPAR-γ, SIRT1, and Nrf2 estimated by IHC. Moreover, NIF down-regulated the pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), NF-κB protein expression, and the phosphorylation of JAK1/STAT3 proteins, leading to mitigation of intestinal inflammation. In accordance, the histological investigation revealed that NIF ameliorated the intestinal pathological changes, preserved the goblet cells, and reduced the inflammatory cells infiltration. Therefore, NIF could be a promising candidate for adjunctive therapy with MTX to mitigate the associated intestinal injury and increase its tolerability.

Baicalin and lung diseases.

Studies focusing on natural products have been conducted worldwide, and the results suggest that their natural ingredients effectively treat a wide range of illnesses. Baicalin (BIA) is a glycoside derived from the flavonoid baicalein present in Scutellaria baicalensis of the Lamiaceae family. Interestingly, BIA has been shown to protect the lungs in several animal models used in numerous studies. Therefore, we fully analyzed the data of the studies that focused on BIA's lung protective function against various injuries and included them in this review. Interestingly, BIA exhibits promising effects against acute lung injury, lung fibrosis, pulmonary embolism, and lung remodelling associated with COPD, LPS, and paraquat insecticide. BAI exhibits anticancer activity against lung cancer. Additionally, BIA potently attenuates lung damage associated with infections. BIA primarily exerts its therapeutic effects by suppressing inflammation, oxidative stress immune response, and apoptosis pathways. Nrf2/HO-1, PI3K/Akt, NF-κB, STAT3, MAPKs, TLR4, and NLRP3 are important targets in the pulmonary therapeutic effects of BIA on different lung disease models. Consequently, we recommend using it in future potential clinical applications, its contribution to treatment guidelines, and translating its promising effects to clinical practice in lung diseases.

Pharmacological update of mirtazapine: a narrative literature review.

Mirtazapine (MTZ) is an antidepressant drug with an exceptional pharmacological profile. It also has an excellent safety and tolerability profile. The present review provides a pharmacological update on MTZ and summarizes the research findings of MTZ's effects on different diseases. MTZ is hypothesized to have antidepressant effects because of the synergy between noradrenergic and serotonergic actions and is effective in treating major depressive disorder and depression associated with epilepsy, Alzheimer's disease, stroke, cardiovascular disease, and respiratory disease. In cancer patients, MTZ significantly reduced sadness, nausea, sleep disruption, and pain and improved quality of life. Also, it has promising effects on Parkinson's disease, schizophrenia, dysthymia, social anxiety disorder, alcohol dependency, posttraumatic stress disorder, panic disorder, pain syndromes, obsessive-compulsive disorder, and sleep disorders. Additionally, MTZ is potentially therapeutic in different situations associated with depression, such as liver, kidney, cardiovascular, respiratory, infertility, heavy metal-induced neurotoxicity, and pruritus. Potent antioxidative, anti-inflammatory, and anti-apoptotic bioactivities mediate these promising effects. These positive outcomes of the scientific investigations motivate more and more clinical trials for a golden exceptional antidepressant in different conditions.

Targeting necroptosis in fibrosis.

Necroptosis, a type of programmed cell death that resembles necrosis, is now known to depend on a different molecular mechanism from apoptosis, according to several recent studies. Many efforts have reported the possible influence of necroptosis in human disorders and concluded the crucial role in the pathophysiology of various diseases, including liver diseases, renal injuries, cancers, and others. Fibrosis is the most common end-stage pathological cascade of several chronic inflammatory disorders. In this review, we explain the impact of necroptosis and fibrosis, for which necroptosis has been demonstrated to be a contributing factor. We also go over the inhibitors of necroptosis and how they have been applied to fibrosis models. This review helps to clarify the role of necroptosis in fibrosis and will encourage clinical efforts to target this pathway of programmed cell death.

Nrf2/HO-1 as a therapeutic target in renal fibrosis.

Chronic kidney disease (CKD) is one of the most prevalent chronic diseases and affects between 10 and 14 % of the world's population. The World Health Organization estimates that by 2040, the disease will be fifth in prevalence. End-stage CKD is characterized by renal fibrosis, which can eventually lead to kidney failure and death. Renal fibrosis develops due to multiple injuries and involves oxidative stress and inflammation. In the human body, nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in the expression of antioxidant, anti-inflammatory, and cytoprotective genes, which prevents oxidative stress and inflammation damage. Heme oxygenase (HO-1) is an inducible homolog influenced by heme products and after exposure to cellular stress inducers such as oxidants, inflammatory chemokines/cytokines, and tissue damage as an outcome or downstream of Nrf2 activation. HO-1 is known for its antioxidative properties, which play an important role in regulating oxidative stress. In renal diseases-induced tissue fibrosis and xenobiotics-induced renal fibrosis, Nrf2/HO-1 has been targeted with promising results. This review summarizes these studies and highlights the interesting bioactive compounds that may assist in attenuating renal fibrosis mediated by HO-1 activation. In conclusion, Nrf2/HO-1 signal activation could have a renoprotective effect strategy against CKD caused by oxidative stress, inflammation, and consequent renal fibrosis.

The molecular mechanisms underlying anti-inflammatory effects of galangin in different diseases.

When used as an alternative source of drugs to treat inflammation-associated diseases, phytochemicals with anti-inflammatory properties provide beneficial impacts. Galangin is one of the most naturally occurring flavonoids. Galangin has many biological activities, such as anti-inflammatory, antioxidant, antiproliferative, antimicrobial, anti-obesity, antidiabetic, and anti-genotoxic activities. We observed that galangin was well tolerated and positively impacted disease underlying inflammation for the renal, hepatic, central nervous system, cardiovascular, gastrointestinal system, skin, and respiratory disorders, as well as ulcerative colitis, acute pancreatitis, retinopathy, osteoarthritis, osteoporosis, and rheumatoid arthritis. Galangin anti-inflammatory effects are mediated mainly by suppressing p38 mitogen-activated protein kinases, nuclear factor-kappa B, and nod-like receptor protein 3 signals. These effects are confirmed and supported by molecular docking. Clinical translational research is required to accelerate the bench-to-bedside transfer and determine whether galangin can be utilised as a safe, natural source of pharmaceutical anti-inflammatory medication for humans.

Pharmacological updates of nifuroxazide: Promising preclinical effects and the underlying molecular mechanisms.

Nifuroxazide (NFX) is a safe nitrofuran antibacterial drug used clinically to treat acute diarrhea and infectious traveler diarrhea or colitis. Recent studies revealed that NFX displays multiple pharmacological effects, including anticancer, antioxidant, and anti-inflammatory effects. NFX has potential roles in inhibiting thyroid, breast, lung, bladder, liver, and colon cancers and osteosarcoma, melanoma, and others mediated by suppressing STAT3 as well as ALDH1, MMP2, MMP9, Bcl2 and upregulating Bax. Moreover, it has promising effects against sepsis-induced organ injury, hepatic disorders, diabetic nephropathy, ulcerative colitis, and immune disorders. These promising effects appear to be mediated by suppressing STAT3 as well as NF-κB, TLR4, and ß-catenin expressions and effectively decreasing downstream cytokines TNF-α, IL-1ß, and IL-6. Our review summarizes the available studies on the molecular biological mechanisms of NFX in cancer and other diseases and it is recommended to translate the studies in experimental animals and cultured cells and repurpose NFX in various diseases for scientific evidence based on human studies.

Therapeutic interventions target the NLRP3 inflammasome in ulcerative colitis: Comprehensive study.

One of the significant health issues in the world is the prevalence of ulcerative colitis (UC). UC is a chronic disorder that mainly affects the colon, beginning with the rectum, and can progress from asymptomatic mild inflammation to extensive inflammation of the entire colon. Understanding the underlying molecular mechanisms of UC pathogenesis emphasizes the need for innovative therapeutic approaches based on identifying molecular targets. Interestingly, in response to cellular injury, the NLR family pyrin domain containing 3 (NLRP3) inflammasome is a crucial part of the inflammation and immunological reaction by promoting caspase-1 activation and the release of interleukin-1ß. This review discusses the mechanisms of NLRP3 inflammasome activation by various signals and its regulation and impact on UC.

Flavonoids-mediated TLR4 Inhibition as a Promising Therapy for Renal Diseases.

Toll-like receptors (TLRs) control both innate and adaptive immunity with a wide expression on renal epithelial cells and leukocytes. Activation of TLRs results in the production of cytokines, chemokines and interferons along with activation of the transcription factor NF-κB, resulting in inflammatory perturbations. TLR4 signaling pathway is the most extensively studied of TLRs. TLR4 is expressed on renal microvascular endothelial and tubular epithelial cells. So, targeting TLR4 modulation could be a therapeutic approach to attenuate kidney diseases that are underlined by inflammatory cascade. Medicinal plants with anti-inflammatory activities display valuable effects and are employed as alternative sources to alleviate renal disease linked with inflammation. Flavonoids and other phytochemicals derived from traditional medicines possess promising pharmacological activities owing to their relatively cheap and high safety profile. Our review focuses on the potent anti-inflammatory activities of twenty phytochemicals to verify if their potential promising renoprotective effects are related to suppression of TLR4 signaling in different renal diseases, including sepsis-induced acute kidney injury, renal fibrosis, chemotherapy-induced nephrotoxicity, diabetic nephropathy and renal ischemia/reperfusion injury. Additionally, molecular docking simulations were employed to explore the potential binding affinity of these phytochemicals to TLR4 as a strategy to attenuate renal diseases associated with activated TLR4 signaling.

Promising hepatoprotective effects of lycopene in different liver diseases.

The incidence of liver diseases such as hepatitis, fibrosis, cirrhosis, and liver cancer is one of the world's most significant health challenges. Liver diseases can be caused by a variety of circumstances, including viral infection, exposure to xenobiotics, environmental pollutants, metabolic disorders, and others. Lycopene (LYC) is a potent antioxidant of the carotenoid family in red fruits and vegetables. LYC has been found to have multiple biological activities, including antioxidative, anti-inflammatory, and antiapoptotic effects. Notably, LYC has promised hepatoprotective properties against various liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, hepatic ischemia/reperfusion injury, hepatocellular carcinoma, fulminant hepatic failure, and radiation-induced liver damage. It also protects against drug-induced liver injury caused by tramadol, cisplatin, methotrexate, oestrogen, sulfamethoxazole, and others. Moreover, promising hepatoprotective effects of LYC in environmental toxins such as Di(2-ethylhexyl) phthalate, atrazine, aflatoxins, 2,3,7,8-tetrachlorodibenzo-p-dioxin, bisphenol A, dichlorvos as well as heavy metals. Our review aims to discuss LYC's hepatoprotective properties and explore the mechanisms behind this effect. It highlights several research directions for further investigating the potential benefits of LYC consumption in treating human liver diseases.

The importance of natural chalcones in ischemic organ damage: Comprehensive and bioinformatic analysis review.

Over the last few decades, extensive research has been conducted, yielding a detailed account of thousands of newly discovered compounds of natural origin and their biological activities, all of which have the potential to be used for a wide range of therapeutic purposes. There are multiple research papers denoting the central objective of chalcones, which have been shown to have therapeutic potential against various forms of ischemia. The various aspects of chalcones are discussed in this review regarding molecular mechanisms involved in the promising anti-ischemic potential of these chalcones. The main mechanisms involved in these protective effects are Nrf2/Akt activation and NF-κB/TLR4 suppression. Furthermore, in-silico studies were carried out to discover the probable binding of these chalcones to Keap-1 (an inhibitor of Nrf2), Akt, NF-κB, and TLR4 protein molecules. Besides, network pharmacology analysis was conducted to predict the interacting partners of these signals. The obtained results indicated that Nrf2, Akt, NF-κB, and TLR4 are involved in the beneficial anti-ischemic actions of chalcones. Conclusively, the present findings show that chalcones as anti-ischemic agents have a valid rationale. The discussed studies will provide a comprehensive viewpoint on chalcones and can help to optimize their effects in different ischemia. PRACTICAL APPLICATIONS: Ischemic organ damage is an unavoidable pathological condition with a high worldwide incidence. According to the current research progress, natural chalcones have been proved to treat and/or prevent various types of ischemic organ damage by alleviating oxidative stress, inflammation, and apoptosis by different molecular mechanisms. This article displays the comprehensive research progress and the molecular basis of ischemic organ damage pathophysiology and introduces natural chalcones' mechanism in the ischemic organ condition.

Protective effects of berberine on various kidney diseases: Emphasis on the promising effects and the underlined molecular mechanisms.

Berberine (BBR) is a pentacyclic benzylisoquinoline alkaloid that can be found in diversity of medicinal plants. BBR has a wide range of pharmacological bioactivities, in addition when administrated orally, it has a broad safety margin. It has been used as an antidiarrheal, antimicrobial, and anti-diabetic drug in Ayurvedic and Chinese medicine. Several scholars have found that BBR has promising renoprotective effects against different renal illnesses, including diabetic nephropathy, renal fibrosis, renal ischemia, renal aging, and renal stones. Also, it has renoprotective effects against nephrotoxicity induced by chemotherapy, heavy metal, aminoglycosides, NSAID, and others. These effects imply that BBR has an evolving therapeutic potential against acute renal failure and chronic renal diseases. Hence, we report herein the beneficial therapeutic renoprotective properties of BBR, as well as the highlighted molecular mechanism. In conclusion, the studies discussed throughout this review will afford a comprehensive overview about renoprotective effect of BBR and its therapeutic impact on different renal diseases.