APAP (Acetaminophen)-induced hepatic injury is a major public health threat that requires continuous searching for new effective therapeutics. KSG (Kaempferol-3-sophoroside-7-glucoside) is a kaempferol derivative that was separated from plant species belonging to different genera. This study explored the protective effects of KSG on ALI (acute liver injury) caused by APAP overdose in mice and elucidated its possible mechanisms. The results showed that KSG pretreatment alleviated APAP-induced hepatic damage as it reduced hepatic pathological lesions as well as the serum parameters of liver injury. Moreover, KSG opposed APAP-associated oxidative stress and augmented hepatic antioxidants. KSG suppressed the inflammatory response as it decreased the genetic and protein expression as well as the levels of inflammatory cytokines. Meanwhile, KSG enhanced the mRNA expression and level of anti-inflammatory cytokine, IL-10 (interleukin-10). KSG repressed the activation of NF-κB (nuclear-factor kappa-B), besides it promoted the activation of Nrf2 signaling. Additionally, KSG markedly hindered the elevation of ASK-1 (apoptosis-signal regulating-kinase-1) and JNK (c-Jun-N-terminal kinase). Furthermore, KSG suppressed APAP-induced apoptosis as it decreased the level and expression of Bax (BCL2-associated X-protein), and caspase-3 concurrent with an enhancement of anti-apoptotic protein, Bcl2 in the liver. More thoroughly, Computational studies reveal indispensable binding affinities between KSG and Keap1 (Kelch-like ECH-associated protein-1), ASK1 (apoptosis signal-regulating kinase-1), and JNK1 (c-Jun N-terminal protein kinase-1) with distinctive tendencies for selective inhibition. Taken together, our data showed the hepatoprotective capacity of KSG against APAP-produced ALI via modulation of Nrf2/NF-κB and JNK/ASK-1/caspase-3 signaling. Henceforth, KSG could be a promising hepatoprotective candidate for ALI.

Cyclin-dependent kinase 5 (CDK5) plays a crucial role in various biological processes, including immune response, insulin secretion regulation, apoptosis, DNA (deoxyribonucleic acid) damage response, epithelial−mesenchymal transition (EMT), cell migration and invasion, angiogenesis, and myogenesis. Overactivation of CDK5 is associated with the initiation and progression of cancer. Inhibiting CDK5 has shown potential in suppressing cancer development. Despite advancements in CDK5-targeted inhibitor research, the range of compounds available for clinical and preclinical trials remains limited. The marine environment has emerged as a prolific source of diverse natural products with noteworthy biological activities, including anti-cancer properties. In this study, we screened a library of 47,450 marine natural compounds from the comprehensive marine natural product database (CMNPD) to assess their binding affinity with CDK5. Marine compounds demonstrating superior binding affinity compared to a reference compound were identified through high-throughput virtual screening, standard precision and extra-precision Glide docking modes. Refinement of the selected molecules involved evaluating molecular mechanics–generalized born surface area (MM/GBSA) free binding energy. The three most promising compounds, (excoecariphenol B, excoecariphenol A, and zyzzyanone B), along with the reference, exhibiting favorable binding characteristics were chosen for molecular dynamics (MD) simulations for 200 nanoseconds. These compounds demonstrated interaction stability with the target during MD simulations. The marine compounds identified in this study hold potential as effective CDK5 inhibitors and warrant subsequent experimental validation.

G protein-coupled receptors are considered the most widely investigated drug discovery targets. They are the largest family of receptors with almost 800 genes in humans. Different types of ligands can activate these receptors, such as catecholamines, nucleotides, lipids, and gut microbiota, where some ligands could be bitopic. Nevertheless, some receptors have internal ligands bound to them. Activated G protein-coupled receptors have complex signaling pathways that are involved in almost all bodily functions. Furthermore, they constitute a large percentage of Food and Drug Administration marketed drugs and global share of drugs, in addition to a great proportion of drugs currently in clinical trials targeting these receptors. The approved G protein-coupled receptors targeted drugs and potential drugs are involved in the management of many diseases including cancer, inflammatory diseases, diabetes mellitus, hypertension, obesity, pain, and diseases of the central nervous system. Only 10% of G protein-coupled receptors are targeted. Different pharmacological approaches have been considered in drug discovery of these receptors including polypharmacology, allosteric modulators, biased agonism, tethered agonism, and pharmacogenomics. Advances in the technologies are promising to help in the discovery of new targets. The review's aim is to discuss the importance of G protein-coupled receptors as drug discovery targets.

The coronavirus has become the most interesting virus for scientists because of the recently emerging deadly SARS-CoV-2. This study aimed to understand the behavior of SARS-CoV-2 through the comparative genomic analysis with the closest one among the seven species of coronavirus that infect humans. The genomes of coronavirus species that infect humans were retrieved from NCBI, and then subjected to comparative genomic analysis using different bioinformatics tools. The study revealed that SARS-CoV-2 is the most similar to SARS-CoV among the coronavirus species. The core genes were shared by the two genomes, but there were some genes, found in one of them but not in both, such as ORF8, which is found in SARS-CoV-2. The ORF8 protein of SARS-CoV-2 could be considered as a good therapeutic target for stopping viral transmission, as it was predicted to be a transmembrane protein, which is responsible for interspecies transmission. This is supported by the molecular interaction of ORF8 with both the ORF7 protein, which contains a transmembrane domain that is essential to retaining the protein in the Golgi compartment, and the S protein, which facilitates the entry of the coronavirus into host cells. ORF1ab, ORF1a, ORF8, and S proteins of SARS-CoV-2 could be immunogenic and capable of evoking an immune response, which means that these four proteins could be considered a potential vaccine source. Overall, SARS-CoV-2 is most related to SARS-CoV. ORF8 could be considered a potential therapeutic target for stopping viral transmission, and ORF1ab, ORF1a, ORF8, and the S proteins of SARS-CoV-2 could be utilized as a potential vaccine source.

Aim: To identify the potential renal protective effect produced by astaxanthin on streptozotocin-produced diabetic kidney disease in rats. Study Design: Male Wistar rats (n=60) were separated into six groups, control, diabetic (streptozotocin 45 mg/kg single intraperitoneal injection), diabetic + ramipril (1 mg/kg oral gavage), diabetic + astaxanthin (10mg/kg oral gavage), diabetic + astaxanthin (50 mg/kg oral gavage), and astaxanthin-alone (50 mg/kg oral gavage) group. Place and Duration of Treatment: Department of Pharmacology, College of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia. Duration of treatment was eight weeks. Methodology: Fasting blood glucose, and symptoms of diabetes were evaluated weekly. Kidneys were evaluated by measuring serum creatinine level, kidney index, and hematoxylin and eosin staining. Results: Eight-week astaxanthin treatment (50 mg/kg) in streptozotocin-produced diabetic kidney disease in rats significantly alleviated the diabetic symptoms (p = 0.05), and the decrease in body weight (P = .05) compared to nontreated diabetic rats. Nonetheless, the same dose produced a nonsignificant decline in fasting blood glucose level contrasted to diabetic rats (P = .45). Kidney index and serum creatinine of diabetic rats were significantly attenuated by both 10 and 50 mg/kg astaxanthin doses (P = .05). Additionally, renal architecture was preserved by high-dose astaxanthin treatment compared to nontreated diabetic rats. Conclusion: Astaxanthin could protect against kidney damage associated with diabetes. Nevertheless, the impact of astaxanthin on biological markers of kidney damage in diabetes and the molecular pathways implicated in diabetic kidney disease requires additional investigation.