Polycystic ovary syndrome (PCOS) is the most common gynaecological endocrine disease that causes anovulatory infertility. The current study aimed to explore the possible role of diacerein (DIA), an IL-1β inhibitor, in treating letrozole-induced PCOS in rats that exhibit the metabolic and endocrinal criteria of PCOS patients. PCOS was induced in female Wistar rats by the oral administration of letrozole (1 mg/kg, per orally, p.o.) for 21 days. Rats were then treated with DIA (25 mg/kg/day, p.o.), DIA (50 mg/kg/day, p.o.), or metformin (2 mg/100 g/day, p.o.) for 14 days after the PCOS induction. PCOS resulted in a significantly higher body weight, ovarian weight, ovarian size, and cysts, as well as an elevation in serum testosterone, LH, insulin, glycemia, and lipid profile levels. All of these effects were significantly reduced by the DIA administration. Additionally, DIA remarkably inhibited the letrozole-induced oxidative stress in the ovaries, muscles, and liver by reducing the upraised levels of malondialdehyde and total nitrite and increasing the suppressed levels of superoxide dismutase and catalase. DIA enhanced the protective proteins Keap-1, Nrf2, and OH-1 levels. Finally, DIA inhibited the elevated mRNA levels of NLRP3 and caspase-1, the up-regulated inflammatory cytokines IL-6, TNF-α, and the IL-1β/NFκB signaling pathway. Our results proved that DIA ameliorates letrozole-induced PCOS through its antioxidant and anti-inflammatory properties.

Liver ischemia-reperfusion (I/R) injury is an inescapable problem. Diacerein, a chondro-protective drug, has antioxidant and anti-inflammatory effects. Its effect on liver I/R injury has not yet been fully clarified. Therefore, the current study aimed to detect its hepatic protective effect with the explanation of possible underlying mechanisms. Adult male albino rats were assigned to 4 groups: sham group, diacerein pretreated sham group, I/R non-treated group, and I/R diacerein pretreated group. Serum liver enzymes, hepatic tissue oxidative stress parameters, inflammatory biomarkers mainly Toll-like receptors-4 (TLR4), and liver fatty acid binding protein (L-FABP) levels were determined. Histopathological examination of liver tissues and immunohistochemical studies of heat shock protein 70, nuclear factor-kappa B, and Cluster of Differentiation 68 were also done. Diacerein pretreatment has the ability to restore the hepatic I/R damaging effect, proved by the reduction of serum liver enzymes, the decrease of the oxidative stress and hepatic inflammation via down-regulation of TLR4/ NFκ-B signaling pathway together with the restoration of L-FABP level and improvement of the histopathological and immunohistochemical study findings in the hepatic tissue. These results suggested the hepatoprotective effect of diacerein relies on its antioxidant and anti-inflammatory effects reducing TLR4/ NFκ-B signaling pathway.

Malaria is one of the most known vector-borne diseases caused by female Anopheles mosquito bites. According to WHO, about 247 million cases of malaria and 619,000 deaths were estimated worldwide in 2021, of which 95% of the cases and 96% of deaths occurred in the African region. Sadly, about 80% of all malaria deaths were of children under five years old. Despite the availability of different insecticides used to control this disease, the emergence of drug-resistant mosquitoes threatens public health. This, in turn, highlighted the need for new larvicidal agents that are effective at different larval life stages. This study aimed to identify novel larvicidal agents. To this end, a series of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates 8a-i was synthesized using a three-step chemical synthetic approach via a Biginelli reaction employed as a key step. All title compounds were screened against Anopheles arabiensis to determine their larvicidal activities. Among them, two derivatives, ethyl 2-((4-bromophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8b and ethyl 2-((4-bromo-2-cyanophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8f, showed the highest larvicidal activity, with mortality of 94% and 91%, respectively, and emerged as potential larvicidal agents. In addition, computational studies, including molecular docking and molecular dynamics simulations, were carried out to investigate their mechanism of action. The computational results showed that acetylcholinesterase appears to be a plausible molecular target for their larvicidal property.Communicated by Ramaswamy H. Sarma.

The increased use of indomethacin (IND) is associated with gastrointestinal injury. This research aims to investigate the effects of a beta-blocker, carvedilol (CAR) on a rat model of IND-induced a...

Purpose Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide. Ischemic heart diseases, particularly acute myocardial infarction (MI), represent the most common cause of death. MI is influenced by multiple factors, including the release of inflammatory mediators. A significant percentage of individuals with CVD experience psychological effects, such as anxiety and depression, which are linked to an increased risk of coronary heart disease. Certain anti-anxiety medications have demonstrated immunomodulatory and anti-inflammatory effects. Tofisopam, a 2,3-benzodiazepine with anxiolytic properties, has been shown to exert in vitro anti-inflammatory and immunomodulatory effects. The present study investigates the potential of tofisopam as a protective adjuvant against isoprenaline-induced MI in rats and explores the possible underlying mechanisms. Methods: The study included four groups: a control group, a group pretreated with tofisopam, an isoprenaline toxic group, and an isoprenaline toxic group pretreated with tofisopam. Results: The findings demonstrated that isoprenaline significantly increased cardiac enzyme levels, as well as elevated oxidative and inflammatory stress parameters, along with evident apoptosis in cardiac cells. In contrast, the tofisopam-pretreated group showed a significant reversal of the cardiac damage induced by isoprenaline. Conclusions: Tofisopam protects against isoprenaline-induced MI through its antioxidant, anti-inflammatory, and anti-apoptotic properties.

Hepatocellular carcinoma (HCC) accounts for more than 5% of all human cancers. Diacerein (DIA), an interleukin (IL)-1β inhibitor, is used for the treatment of osteoarthritis. DIA is a potential anticancer drug acting on several protein targets in the process of apoptosis. The present study aimed to explore the molecular mechanisms underlying the effect of DIA in the treatment of trichloroacetic acid (TCA)–induced pre-neoplastic changes in rats. Rats were allocated into 5 groups and treated for 4 weeks. Group 1: control; received vehicle, Group 2: TCA group; received TCA (1 g/kg, orally for 5 days). Group 3: DIA-treated group; received TCA +DIA (50 mg/kg/day, orally, for 4 weeks). Group 4: positive control group; received TCA (1 g/kg, orally, for 5 days) + 5-fluorouracil (5-FU) (75 mg/kg) intraperitoneally (i.p.), for 4 weeks as a standard anticancer drug. Group 5: received TCA (1 g/kg, orally for 5 days) + DIA (50 mg/kg/day, orally, for 4 weeks) + 5-FU (75 mg/kg, i.p., for 4 weeks). Serum liver enzymes, oxidative stress parameters, inflammatory parameter (IL-1β), and angiogenesis marker vascular endothelial growth factor (VEGF) were assessed along with histopathological evaluation. An apoptotic marker as caspase-3 expression was measured by western blot analysis. Immunoexpression of proliferating cell nuclear antigen (PCNA) and hypoxia-inducible factor-1α (HIF-1α) was evaluated. Results and conclusion: The outcomes proved that at histological level, DIA ameliorated hepatic precancerous lesion via modulation of IL-1β–HIF-1α–VEGF pathway. Conclusion: IL-1β mediates angiogenesis indirectly, as it has been shown to induce hypoxia-inducible factor-1α (HIF-1α) which upregulates VEGF.