Discovery of a natural small-molecule AMP-activated kinase activator that alleviates nonalcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Unfortunately, there is no approved drug treatment for NASH. AMP-activated kinase (AMPK) is an important metabolic sensor and whole-body regulator. It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity, type 2 diabetes and NASH. In this study, we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator, candidusin A (CHNQD-0803). Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a KD value of 4.728 × 10-8 M and activates AMPK at both molecular and intracellular levels. We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition, LPS-stimulated inflammation, TGF-ß-induced fibrosis cell models and the MCD-induced mouse model of NASH. The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition, negatively regulated the NF-κB-TNFα inflammatory axis to suppress inflammation, and ameliorated liver injury and fibrosis. These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00168-z.

Recent Advances in Molecular Mechanisms of Cancer Immunotherapy.

Cancer is among the current leading causes of death worldwide, despite the novel advances that have been made toward its treatment, it is still considered a major public health concern. Considering both the serious impact of cancer on public health and the significant side effects and complications of conventional therapeutic options, the current strategies towards targeted cancer therapy must be enhanced to avoid undesired toxicity. Cancer immunotherapy has become preferable among researchers in recent years compared to conventional therapeutic options, such as chemotherapy, surgery, and radiotherapy. The understanding of how to control immune checkpoints, develop therapeutic cancer vaccines, genetically modify immune cells as well as enhance the activation of antitumor immune response led to the development of novel cancer treatments. In this review, we address recent advances in cancer immunotherapy molecular mechanisms. Different immunotherapeutic approaches are critically discussed, focusing on the challenges, potential risks, and prospects involving their use.

Evaluation of the in vitro antioxidant and antitumor activity of hydroalcoholic extract from Jatropha mollissima leaves in Wistar rats.

Introduction: Despite modern sciences and advancements in new drugs or chemicals, the new era now rushes natural remedies for various illnesses and diseases that lead to end organ damage. In this study, we investigated Jatropha mollissima ethanolic extract's effect against doxorubicin-induced cardiotoxicity and renal toxicity. Methods: To determine phytochemicals, a phytochemical screening was conducted. Various assays were used to measure the antioxidant activity, including the DPPH (2,2-diphenylpicrylhydrazyl), SOD (superoxide dismutase), NO (nitric oxide), and others. The antiproliferative effect of Jm was assessed by MTT assay; morphological analysis was performed using an inverted and phase contrast microscope, ultra morphological analysis of apoptosis with acridine orange (AO)/propidium iodide (PI) staining. Results: It was seen that doxorubicin caused elevated serum markers and abnormal changes in histological patterns. The significant reduction in cardiac and renal marker levels seen in groups given either 400 or 600 mg/kg of crude extract demonstrates that Jm has a protective effect against doxorubicin-induced cardiotoxicity due to the presence of active phytoconstituents having antioxidant potential. There is a dose-dependent decrease in cell viability when using J. mollissima. Apoptosis was observed in the treated cells. Conclusion: In conclusion, our research lends credence to the idea that J. mollissima could be used for cancer management and have cardioprotective and nephroprotective effects.

Biochemical evaluation and medicinal ability of Jatropha mollissima in hepatic disorders.

OBJECTIVE: Jatropha mollissima is one of the most valuable medicinal plants used for the treatment of hepatic disorders. It is evident that 500 mg/kg of sodium valproate causes the hepatotoxicity, ototoxicity, gastrotoxicity, bone marrow suppression, and inflammation. This study was designed to explore the medicinal uses of Jatropha mollissima in hepatic disorders. METHODS: Hepatotoxicity was induced in Wister albino rats by injecting sodium valproate at the rate of 500 mg/kg once daily for fourteen days. Six male rats, each weighing 220-270 g, were placed into four separate groups for the study. The first group was treated with normal saline. Treatment of the second group was carried out by SVP for four days consecutively together with saline for three weeks. Group three and four were treated with sodium valproate and Jm hydroalcoholic extract applied in the concentrations of the 200 mg/kg and 400 mg/kg for the period of the three weeks. Phytochemical screening and HPLC analysis were conducted to identify the phytochemical nature and polyphenols in extract, respectively. DPPH, SOD, and NO tests were performed to measure the antioxidant activity. RESULTS: With the initial dose of treatments to rats, anatomic, physiological, or histopathologic abnormalities were detected. After three weeks, extract of Jatropha mollissima was used to treat the valproic acid-induced hepatotoxicity (P < 0.05). CONCLUSION: It was concluded that sodium valproate (SVP) and Jm extract were administered together. The hepatoprotective effects were extraordinarily high, with high concentrations of 400 mg/kg.

In vivo antioxidants, chemical characterization and biochemical and medicinal potential of Murraya koenigii in cisplatin-induced nephrotoxicity.

Murraya koenigii (Mk) is an old plant with a significant therapeutic value throughout Africa, Asia, and Latin America. The excessive use of cisplatin (Cis> 50 mg/m2) is associated with nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. Remedial measures are needed for the protection of nephrotoxicity against cisplatin. Thus, we have investigated Mk leaf extract's nephroprotective effects to prevent cisplatin-induced nephrotoxicity in Wistar albino rats. The presence of polyphenols, phenolic compounds, tannins, and saponins was revealed during phytochemical investigation, and antioxidant activity was recorded. There were no toxicological symptoms in the treated rats, and no anatomical, physiological, or histological abnormalities were found compared to the control rats. The results of correcting cisplatin-induced nephrotoxicity revealed that the extract has a significant ability to treat kidney damage, with most parameters returning to normal after only three weeks of therapy. It was concluded that co-administered cisplatin with Mk leaves extract showed exceptional nephroprotective effects at a 400 mg/kg dose ratein Cis-induced nephrotoxicity.

A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer.

Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radiotherapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, are available for BC treatment. However, due to its high occurrence and disease progression, effective therapeutic options for metastatic BC are still lacking. Considering this scenario, there is an urgent need for an effective therapeutic strategy to meet the current challenges of BC. Natural products have been screened as anticancer agents as they are cost-effective, possess low toxicity and fewer side effects, and are considered alternative therapeutic options for BC therapy. Natural products showed anticancer activities against BC through the inhibition of angiogenesis, cell migrations, proliferations, and tumor growth; cell cycle arrest by inducing apoptosis and cell death, the downstream regulation of signaling pathways (such as Notch, NF-κB, PI3K/Akt/mTOR, MAPK/ERK, and NFAT-MDM2), and the regulation of EMT processes. Natural products also acted synergistically to overcome the drug resistance issue, thus improving their efficacy as an emerging therapeutic option for BC therapy. This review focused on the emerging roles of novel natural products and derived bioactive compounds as therapeutic agents against BC. The present review also discussed the mechanism of action through signaling pathways and the synergistic approach of natural compounds to improve their efficacy. We discussed the recent in vivo and in vitro studies for exploring the overexpression of oncogenes in the case of BC and the current status of newly discovered natural products in clinical investigations.

Evaluation of the hepatoprotective activity of hydroalcoholic extract of Alhagi camelorum against valproic acid-induced hepatotoxicity in rats.

BACKGROUND AND PURPOSE: Despite many liver disorders, clinically useful drugs are scarce. Moreover, the available therapies are facing the challenges of efficacy and safety. Alhagi camelorum has been used in folk medicine globally for millennia to treat several ailments. Alhagi camelorum (Ac) is an old plant with a significant therapeutic value throughout Africa, Asia, and Latin America. Our goal was to determine the hepatoprotective activity of Alhagi camelorum against valproic acid induced hepatotoxicity using an animal model. EXPERIMENTAL APPROACH: The animals were segregated in 4-groups (6 male rats each) weighing 250-290 g. Group-1 animals were treated with normal saline, Group-2 animals were treated with VPA at the dose of 500 mg/kg i.p for 14 days consecutively, while Group-3 and 4 were treated with valproic acid (VPA) at the dose of 500 mg/kg i.p for 14 days along with 400 mg/kg and 600 mg/kg of Ac hydroalcoholic extract respectively. Subsequently, blood serum samples and liver tissues were collected for biochemical and histopathological analysis. Phytochemical screening was carried out to screen for phytochemical classes and HPLC analysis was conducted to screen polyphenols. The antioxidant activity was carried by different assays such as DPPH, SOD, NO etc. KEY RESULTS: The administration of Ac showed hepatoprotection at the doses of 400 and 600 mg/kg. Ac significantly reduces the elevated serum levels of liver biomarkers compared to the valproic acid-induced hepatotoxic group. These findings were confirmed with histopathological changes where Ac was capable of reversing the toxic effects of valproic acid on liver cells CONCLUSION: It is concluded that Ac showed significant hepatoprotective effects at different doses in the animal model used in this study.

Nephroprotective Effects of Alhagi camelorum against Cisplatin-Induced Nephrotoxicity in Albino Wistar Rats.

Alhagi camelorum (AC) is an old plant with a significant therapeutic value throughout Africa, Asia, and Latin America. The overuse of cisplatin (Cis > 50 mg/m2) is associated with observed nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. Remedial measures are needed for the protection of nephrotoxicity against cisplatin. Thus, we investigated the nephroprotective effects of AC plant extract to prevent cisplatin-induced nephrotoxicity in albino Wistar rats. The presence of polyphenols, phenolic compounds, tannins, and saponins was revealed during phytochemical investigation, and a significantly intense antioxidant activity was recorded. There were no toxicological symptoms in the treated rats, and no anatomical, physiological, or histological abnormalities were found compared to the control rats. The results of correcting cisplatin-induced nephrotoxicity revealed that the extract has a significant ability to treat kidney damage, with most parameters returning to normal after only three weeks of therapy. It is concluded that co-administration of cisplatin with AC extract showed exceptional nephroprotective effects at a dose of 600 mg/kg for Cis-induced nephrotoxicity.

The nephroprotective effects of Daucus carota and Eclipta prostrata against cisplatin-induced nephrotoxicity in rats.

The overuse of cisplatin (>50 mg/m2) is limited to nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. The objective of this study was to investigate the nephroprotective effects of Daucus carota and Eclipta prostrata extracts on cisplatin-induced nephrotoxicity in Wistar albino rats. The study involved male Wistar albino rats of 8 weeks weighing 220-270 g. A single injection of 5 mg/kg was injected into the rats for nephrotoxicity. Rats were divided into four groups based on dose conentrations. Blood and urine samples of rats were collected on the 0, 7th, 14th, and 21st days for nephrological analysis. The results showed that Cis + DC/Cis + EP (600 mg/kg) significantly (p < 0.001) increased the body weight and reduced the kidney weight of cisplatin-induced nephrotoxicity in rats (p < 0.001) as compared to Cis group. The results showed that 600 mg/kg administration of Cis + DC/Cis +EP successfully (p < 0.005) improved the urine and plasmin creatinine, Na, and K level compared to the Cis group. Histopathological results confirmed that Cis + EP/Cis + DC effectively improved the renal abnormalities. It is concluded that the co-administration of Cis + EP extract showed exceptional nephroprotective effects at a dose rate of 600 mg/kg.