Datamining approaches for examining the low prevalence of N-acetylglutamate synthase deficiency and understanding transcriptional regulation of urea cycle genes.

Ammonia, which is toxic to the brain, is converted into non-toxic urea, through a pathway of six enzymatically catalyzed steps known as the urea cycle. In this pathway, N-acetylglutamate synthase (NAGS, EC 2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme A. NAGS deficiency (NAGSD) is the rarest of the urea cycle disorders, yet is unique in that ureagenesis can be restored with the drug N-carbamylglutamate (NCG). We investigated whether the rarity of NAGSD could be due to low sequence variation in the NAGS genomic region, high NAGS tolerance for amino acid replacements, and alternative sources of NAG and NCG in the body. We also evaluated whether the small genomic footprint of the NAGS catalytic domain might play a role. The small number of patients diagnosed with NAGSD could result from the absence of specific disease biomarkers and/or short NAGS catalytic domain. We screened for sequence variants in NAGS regulatory regions in patients suspected of having NAGSD and found a novel NAGS regulatory element in the first intron of the NAGS gene. We applied the same datamining approach to identify regulatory elements in the remaining urea cycle genes. In addition to the known promoters and enhancers of each gene, we identified several novel regulatory elements in their upstream regions and first introns. The identification of cis-regulatory elements of urea cycle genes and their associated transcription factors holds promise for uncovering shared mechanisms governing urea cycle gene expression and potentially leading to new treatments for urea cycle disorders.

An update on molecular mechanisms of curcumin effect on diabetes.

Owing to its prevalent nature, diabetes mellitus has become one of the most serious endocrine illnesses affecting a patient's quality of life due to the manifestation of side effects such as cardiovascular diseases, retinopathy, neuropathy, and nephropathy. Curcumin ((1E, 6E) 21, 7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a major compound of turmeric, has been used in conventional medicine because of its safe nature and cost-effectiveness to meliorate diabetes and its comorbidities. These effects have also been observed in rodent models of diabetes resulting in a reduction of glycemia and blood lipids. Both the preventive and therapeutic activities of this compound are due to its antioxidant and anti-inflammatory characteristics. Furthermore, preclinical outcomes and clinical investigation demonstrate that the use of curcumin neutralizes insulin resistance, obesity, and hyperglycemia. Despite the many benefits of curcumin, its two limiting factors, solubility and bioavailability, remain a challenge for researchers; therefore, several methods such as drug formulation, nano-drug delivery, and the use of curcumin analogs have been developed to deliver curcumin and increase its bioavailability. PRACTICAL APPLICATIONS: The rise of people with type 2 diabetes has become a major concern at the global healthcare level. The best diabetes treatments today are anti-diabetic drug administration, lifestyle-related interventions (such as healthy eating and daily physical activity), arterial pressure detection, and fat control. The polyphenol curcumin, found in turmeric, can promote health by acting on a variety of cellular signaling pathways. This review article discusses curcumin and its role in the treatment of diabetes.