Prostate cancer (PCa) is among the most common malignancies and remains a leading cause of cancer-related mortality in men worldwide. One of the main drivers is the dysregulation of the downstream signalling machinery. The PI3K, AKT, and mTOR signalling pathways play a pivotal role in cellular sustenance, growth, metabolism, and proliferation. In prostate cancer this pathway is generally altered due to the mutation or deletion of the PTEN (phosphatase and tensin homolog) gene and unnecessary activities of some components of PI3K, AKT, or mTOR. Extracellular communication of the androgen receptor (AR) with a wide array of oncogenic signatures is a primary evasion mechanism of cancer therapy and metastasis. This review focuses on the structure and function of the PI3K/AKT/mTOR pathway to better understand its role in prostate tumor biology. Furthermore, current therapeutic strategies that combinatorically target individual components of this pathway, such as allosteric and ATP-competitive AKT inhibitors, isoform-selective PI3K inhibitors, first- and second-generation mTOR inhibitors, are under consideration. The study particularly focuses on the combined use of immunotherapy (checkpoint inhibitors), chemotherapy (docetaxel), and androgen deprivation therapy (ADT), which are designed to break through the resistance-generating mechanisms and increase clinical efficacy. Overall, the findings support the need to conduct comprehensive preclinical and clinical studies on these alternative treatment regimens, and the eventual goal is to develop new treatment options for prostate cancer. The evidence of the pathway-specific therapy approach for the treatment of prostate cancer in recent clinical trials still failed to give a conclusive result. The current discussion also investigates the emerging areas of focus and perfection of combination regimens. The combination of all these developments makes it clear that the PI3K/AKT/mTOR signalling pathway is a key strategic point for developing therapeutics.

Polycystic ovarian syndrome (PCOS) is one of the known causes of anovulatory fertility in the world. Previous research has linked oxidative stress could contribute to PCOS, and vanillic acid has shown antioxidant potential. Hence, the present study evaluated the effect of vanillic acid on letrozole-induced polycystic ovarian syndrome in female rats. PCOS was induced in Wistar female rats with letrozole (1 mg/kg, orally) in carboxymethoxycellulose (1 % w/v), administered for 21 days. After induction, the standard group received clomiphene citrate (1 mg/kg, orally) while other treatment groups were administered with vanillic acid at doses 25, 50, and 100 mg/kg, orally for 15 days, and without treatment was considered a negative control group. Different parameters studied were body weight, ovary weight, blood glucose, lipid profile, hormonal levels [luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone], markers for oxidative stress (superoxide dismutase, reduced glutathione, catalase, and malonaldehyde), and histopathology of the ovary. Statistical analysis was done for the results and p < 0.05 was considered to indicate the significance. Vanillic acid-treated animals showed a concentration-dependent activity on the tested parameters. The highest tested dose (100 mg/kg) produced a more prominent effect in significantly (P < 0.001) decreasing the body weight, and ovary weight and improving the hormonal imbalance. Also, vanillic acid significantly (P < 0.01) reduced elevated blood sugar and lipid levels. Additionally, vanillic acid reduced oxidative stress significantly (P < 0.001) in the ovaries of female rats. Histopathological reports showed a reduction in cystic follicles and appearance of normal healthy follicles at different stages of development after the administration of vanillic acid. Furthermore, these effects were observed to be comparable with those recorded for standard drug, clomiphene. The current study data suggests that vanillic acid has protected the letrozole-induced polycystic ovarian syndrome. In the event of several side effects associated with conventional treatments used for PCOS, the findings of this study suggest the promising role of vanillic acid. More research in this direction might identify the true potency of vanillic acid in the treatment of PCOS.

Alzheimer’s disease (AD) is a severe, varied, and complex brain condition that gradually impairs memory and cognitive function. Epidemiological studies have shown that patients who have a history of long-term NSAID use have a decreased risk of developing AD. The objective of this study is to conduct the structural analysis of a novel ibuprofen prodrug and test its anti-Alzheimer’s properties. Computational and docking studies were conducted using AMBER 18 package. The in-vivo studies were performed using aluminum chloride-induced experimental AD in rats. Adult Wistar rats of either sex were used and treated with aluminum chloride (32.5 mg/kg, p.o) and ibuprofen prodrug (50 mg/kg, p.o) daily for 30 days. The hole-board test and elevated plus maze were conducted on 10th, 20th and 30th day. Further, on 31st day, animals were euthanized and the brain tissue was used for histopathology. The results obtained were subjected to statistical analysis by one-way ANOVA and Dunnet’s test, p < 0.05 was considered to indicate the significance. The structural configuration of the novel compound indicated the presence of several structures such as aliphatic, aromatic, and asymmetry in the compound. The geometrical analysis indicated that the ibuprofen conjugate has dreiding energy of 51.22 kcal/mol with a van der waals radius of 62.56 A. The Huckel analysis confirmed the presence of aromatic rings in the compound. The molecular docking studies suggested affinity towards beta-secretase and acetylcholinesterase, besides indicating that the compound has ideal characteristics for the oral route (Log P = 2.33), cellular absorption (TPSA = 95.50), and oral bioavailability (number of rotatable bonds = 10). The toxicity profile indicated devoid of major systemic toxicity with mild possibility of cytotoxicity. The in-vivo analysis showed that the Ibu-prodrug significantly (P < 0.001) reversed the changes induced by aluminum chloride and restored histomorphological features in brain tissue. The findings suggested that the ibuprofen conjugate might possess the potential to manage the complications of AD. The action appears to be mediated through inhibition of beta-secretase and acetylcholinesterase activities. More studies might aid in identifying a specific therapeutic intervention that is still lacking in the treatment of AD.

During the early stages of the COVID-19 pandemic, infection rates were high and symptoms were severe. Medical resources, including healthcare experts and hospital facilities, were put to the test to ensure their readiness to deal with this unique event. An intensive care unit (ICU) is expected to be required by many hospitalized patients. Many hospitals worldwide lacked resources during the pandemic’s peak stages, particularly in critical care treatment. Because of this, there were issues with capacity, as well as an excessive influx of patients. Additionally, even though the research location provides medical care to a sizable population, there is a paucity of scientific data detailing the situation as it pertains to COVID-19 patients during the height of the outbreak. Therefore, this study aimed to identify and describe the features of COVID-19 patients hospitalized in the ICU of one of the multispecialty hospitals in Riyadh, Saudi Arabia. An observational retrospective study was conducted using a chart review of COVID-19 patients admitted to the ICU between March 2020 and December 2020. To characterize the patients, descriptive statistics were utilized. An exploratory multivariate regression analysis was carried out on the study cohort to investigate the factors that were shown to be predictors of death and intubation. Only 333 (29.33%) of the 1135 samples from the hospital’s medical records were used for the final analysis and interpretation. More than 76% of the patients in the study were male, with a mean BMI of 22.07 and an average age of around 49 years. The most frequent chronic condition found among the patients who participated in the study was diabetes (39.34%), followed by hypertension (31.53%). At the time of admission, 63 of the total 333 patients needed to have intubation performed. In total, 22 of the 333 patients died while undergoing therapy. People with both diabetes and hypertension had a 7.85-fold higher risk of death, whereas those with only diabetes or hypertension had a 5.43-fold and 4.21-fold higher risk of death, respectively. At admission, intubation was necessary for many male patients (49 out of 63). Most intubated patients had hypertension, diabetes, or both conditions. Only 13 of the 63 patients who had been intubated died, with the vast majority being extubated. Diabetes and hypertension were significant contributors to the severity of illness experienced by COVID-19 participants. The presence of multiple comorbidities had the highest risk for intubation and mortality among ICU-admitted patients. Although more intubated patients died, the fatality rate was lower than in other countries due to enhanced healthcare management at the ICU of the study center. However, large-scale trials are needed to determine how effective various strategies were in preventing ICU admission, intubation, and death rates.

Researchers have recently focused on the biological and synthetic effects of 1, 2, and 4-triazole fused heterocyclic molecules because they have tremendous medicinal value. The objective of the present study was to carry out the 3D QSAR evaluation on the substituted 1,2, and 4 triazole derivatives for anticancer potential using k-Nearest Neighbor-Molecular Field Analysis (kNN-MFA) method. Using the molecular design suite, a three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis was undertaken on a series of 4-amino-5-(pyridin3yl)-4H-1, 2, and 4-triazole-3-thiol anticancer drugs (Vlife MDS). This study used a genetic algorithm and a manual selection approach on 20 substituted 1, 2, and 4-triazole derivatives. Based on the genetic algorithm (GA), the 3D-QSAR model was generated. Statistical significance and predictive capacity were evaluated using internal and external validation. The most significant model has a correlation coefficient of 0.9334 (squared correlation coefficient r2 = 0.8713), showing that biological activity and descriptors have a strong relationship. The model exhibited internal predictivity of 74.45 percent (q2 = 0.2129), external predictivity of 81.09 percent (pred r2 = 0.8417), and the smallest error term for the predictive correlation coefficient (pred r2se = 0.1255). The model revealed steric (S 1047––0.0780––0.0451S 927) and electrostatic (E 1002) data points that contribute remarkably to anticancer activity. A molecular field study demonstrates a link between the structural features of substituted triazole derivatives and their activities. The good-to-moderate anticancer potential of compounds confirms the significant pharmacological role of 1,2,4-triazole derivatives. These results could lead to the identification of potential chemical compounds with optimal anticancer activity and minimal side effects.

Background/Objectives: Lipid metabolism dysregulation contributes to cancer progression. Monoacylglycerol lipase (MAGL) breaks down 2-arachidonoylglycerol (2-AG) into glycerol and arachidonic acid, a substrate for cyclooxygenase-2 (COX-2) to produce pro-inflammatory mediators such as prostaglandin E2 (PGE2). Lipopolysaccharide (LPS) activation of Toll-like receptor 4 (TLR4) triggers inflammatory pathways, including COX-2/PGE2 signaling, implicated in diseases such as melanoma. MAGL inhibition reduces prostaglandins and other inflammatory mediators, but its role in inflammation-driven melanoma progression remains unexplored. This study investigated how JZL184, a selective MAGL inhibitor, and 2-AG affect LPS-induced inflammation, proliferation, and migration in B16 melanoma cells. Methods: Cells received LPS alone or with JZL184 or 2-AG. We measured inflammatory transcripts by qRT-PCR, COX-2 protein by Western blot, PGE2 release by ELISA, proliferation by CCK-8, and migration by scratch assay. Results: LPS increased COX-2, PGE2, VEGF, N-cadherin, and inflammatory cytokine expression. JZL184 suppressed these LPS-induced changes and reduced cell proliferation and migration. In contrast, 2-AG did not alter LPS-induced proliferation or inflammatory signals. JZL184’s effects on inflammatory gene expression and proliferation were independent of CB1 receptor signaling, suggesting its anti-melanoma activity may result from reduced inflammatory mediators rather than enhanced endocannabinoid signaling. Conclusions: These findings provide initial evidence that MAGL may regulate inflammation-triggered melanoma progression and could be a plausible therapeutic target.