Identification of Novel and Recurrent Variants in BTD, GBE1, AGL and ASL Genes in Families with Metabolic Disorders in Saudi Arabia.

Background and Objectives: Inherited metabolic disorders (IMDs) are a group of genetic disorders characterized by defects in enzymes or transport proteins involved in metabolic processes. These defects result in an abnormal accumulation of metabolites and thus interfere with the body's metabolism. A variety of IMDs exist and differential diagnosis is often challenging. Our objective was to gain insight into the genetic basis of IMDs and the correlations between specific genetic mutations and clinical presentations in patients admitted at various hospitals in the Madinah region of the Kingdom of Saudi Arabia. Material and Methods: Whole exome sequencing (WES) has emerged as a powerful tool for diagnosing IMDs and allows for the identification of disease-causing genetic mutations in individuals suspected of IMDs. This ensures accurate diagnosis and appropriate management. WES was performed in four families with multiple individuals showing clinical presentation of IMDs. Validation of the variants identified through WES was conducted using Sanger sequencing. Furthermore, various computational analyses were employed to uncover the disease gene co-expression and metabolic pathways. Results: Exome variant data analysis revealed missense variants in the BTD (c.1270G > C), ASL (c.1300G > T), GBE1 (c.985T > G) and AGL (c.113C > G) genes. Mutations in these genes are known to cause IMDs. Conclusions: Thus, our data showed that exome sequencing, in conjunction with clinical and biochemical characteristics and pathological hallmarks, could deliver an accurate and high-throughput outcome for the diagnosis and sub-typing of IMDs. Overall, our findings emphasize that the integration of WES with clinical and pathological information has the potential to improve the diagnosis and understanding of IMDs and related disorders, ultimately benefiting patients and the medical community.

Identification of anti-cancer organometallic compounds by inhibition of BCL-2/Bax interactions.

Apoptosis is regulated by the BCL-2 family, which includes the anti-apoptotic and pro-apoptotic proteins (Bax, Bok, Bak, etc.). These proteins often interact in dimers and act as apoptotic switches. Anti-apoptotic proteins, such as BCL-2, block the functions of these pro-apoptotic proteins. The pro-apoptotic and anti-apoptotic protein-protein interactions must be inhibited to prevent tumor cells from escaping apoptosis. This method has been used to develop anticancer drugs by inhibiting BCL-2 with both natural and synthetic compounds. Metal-containing compounds were used as pharmaceuticals for human cancer patients for a long time, and cisplatin was the first candidate of this class. Drug design, however, needs to pay more attention to metal complexes. We have studied the X-ray crystal structure of the BCL-2 protein in detail and identified the hydrophobic nature of the site with two less solvent-accessible sites. Based on the hydrophobic nature of the compounds, 74 organometallic compounds with X-ray crystallographically characterized bioactivity (including anticancer activity) were selected from the Cambridge crystallographic database. For testing, molecular docking was used to determine which compound was most effective against the BCL-2 protein. Organometallic compounds (benzene)-chloro-(1-{[(9H-fluoren-2-yl)imino]methyl}naphthalen-2-olato)-ruthenium (2), (1-((1,1'-biphenyl)-4-yl)-2,3,4,5-tetramethylcyclopentadienyl)-chloro-(4,4'-dimethyl-2,2'-bipyridine)-rhodium hexafluorophosphate (37), (µ-1,1'-(butane-1,4-diyl)bis(3-oxy-2-methylpyridin-4(1H)-one))-dichloro-bis(pentamethyl-cyclopentadienyl)-di-rhodium tetrahydrate (46), (µ-1,1'-(butane-1,4-diyl)bis(3-oxy-2-methylpyridin-4(1H)-one))-dichloro-bis(pentamethyl-cyclopentadienyl)-di-iridium (47) etc are found to be important compounds in this study. The capability of different types of complex interactions was identified using Hirshfeld surface analysis of the complexes. A NCI plot was conducted to understand the nature of the interaction between complex amino acids and active-site amino acids. A DFT study was conducted to examine the stability and chemical reactivity of the selected complexes. Using this study, one suitable hydrophobic lead anti-cancer organometallic pharmaceutical was found that binds at the less solvent-accessible hydrophobic site of BCL-2.

Sciadopitysin mitigates spermatological and testicular damage instigated by paraquat administration in male albino rats.

Paraquat (PQ) is a herbicide that has ability to induce testicular toxicity by producing reactive oxygen species (ROS). Sciadopitysin (SPS) is a promising flavonoid that displays multiple pharmacological properties i.e., anti-inflammatory, anti-oxidant and anti-apoptotic. Therefore, the present study was designed to evaluate the mitigative role of SPS against PQ induced testicular toxicity in male rats. The experiment was performed on male albino rats (n = 48) that were divided into 4 groups. The group-1 was control group. Group-2 was administrated orally with PQ (5 mg/kg). Group-3 was administrated orally with PQ (5 mg/kg) and SPS (2 mg/kg). Group-4 was supplemented with SPS (2 mg/kg) through oral gavage. The experiment was conducted for 56 days. The exposure to PQ significantly lowered the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD) as well as glutathione peroxidase (GPx). Whereas, a substantial increase was observed in dead sperms number, abnormalities in the tail, head as well as midpiece of sperms in PQ intoxicated rats. Moreover, a significant increase in the level of ROS and malondialdehyde (MDA) was noticed in PQ administrated group. Furthermore, steroidogenic enzymes expression was significantly decreased in PQ-intoxicated group, whereas the level of inflammatory markers was increased in PQ administrated rats. Besides, the expression of apoptotic markers was significantly escalated in PQ exposed rats, whereas the expression of anti-apoptotic markers was considerably reduced. A significant reduction in hormonal level was also noticed in the rats that were administrated with PQ. Moreover, the histopathological examination revealed that PQ significantly damaged the testicles. However, the supplementation of SPS with PQ significantly reduced the adverse effects of PQ in the testes of albino rats. Therefore, the current investigation demonstrated that SPS possesses a significant potential to avert PQ-induced testicular dysfunction due to its anti-apoptotic, androgenic, anti-oxidant and anti-inflammatory nature.