Identification, structure elucidation, and isomer differentiation of phenolic compounds of Chinese pepper cultivars by UPLC-ESI-Q-TOF-MS and their antioxidant activity.

A total of 43 compounds, including phenolic acids, flavonoids, lignans, and diterpene, were identified and characterized using UPLC-ESI-Q-TOF-MS coupled with UNIFI software. The identified flavonoids were mostly isomers of luteolin, apigenin, and quercetin, which were elucidated and distinguished for the first time in pepper cultivars. The use of multivariate data analytics for sample discrimination revealed that luteolin derivatives played the most important role in differentiating pepper cultivars. The content of phenolic acids and flavonoids in immature green peppers was generally higher than that of mature red peppers. The pepper extracts possessed significant antioxidant activities, and the antioxidant activities correlated well with phenolic contents and their molecular structure. In conclusion, the findings expand our understanding of the phytochemical components of the Chinese pepper genotype at two maturity stages. Moreover, a UPLC-ESI-Q-TOF-MS in negative ionization mode rapid methods for characterization and isomers differentiation was described.

Aged garlic extract preserves beta-cell functioning via modulation of nuclear factor kappa-B (NF-κB)/Toll-like receptor (TLR)-4 and sarco endoplasmic reticulum calcium ATPase (SERCA)/Ca2+ in diabetes mellitus.

BACKGROUND: Peripheral insulin resistance and compromised insulin secretion from pancreatic ß-cells are significant factors and pathogenic hallmarks of diabetes mellitus (DM). NF-κß/TLR-4 and SERCA/Ca2+ pathways have been identified as potential pathways regulating insulin synthesis by preserving pancreatic ß-cell functioning. The current study aimed to evaluate the therapeutic effect of aged garlic extract (AGE) against DM in a streptozotocin (STZ)-induced rat model with particular emphasis on pancreatic ß-cell functioning. METHODS: AGE was characterized by gas chromatography-mass spectrometry (GC-MS), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) to evaluate its physio-chemical characteristics followed by in-vitro anti-diabetic and antioxidant potential. This was followed by the induction of DM in laboratory animals for investigating the therapeutic action of AGE by evaluating the role of NF-κß/TLR-4 and the SERCA/Ca2+ pathway. The parameters assessed in the present experimental setup encompassed antioxidant parameters, metabolic indicators, insulin concentration, intracellular calcium levels, apoptotic markers (CCK-8 and Caspase Glo-8), and protein expression (P-62 and APACHE-II). RESULTS: AGE characterization by SEM, GC-MS, and X-ray diffraction (XRD) revealed the presence of phenylalanine, alliin, S-allylmercaptocysteine (SAMC), tryptophan, 1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid as major bioactive constituents of AGE. Metabolic studies, including intraperitoneal glucose tolerance test (IPGTT), revealed significantly lower blood glucose levels in the AGE group compared to the disease control group. In contrast, the intraperitoneal insulin tolerance test (ITT) exhibited no significant difference in insulin sensitivity between the AGE supplementation group and the DM control group. Interestingly, AGE was found to have no significant effect on fasting glucose and serum insulin levels. In contrast, AGE supplementation was found to cause significant hypoglycaemia in postprandial blood glucose and insulin levels. Importantly, AGE causes restoration of intracellular Ca2+ levels by modulation of SERCA/Ca2 functioning and inhibition NF-κB/TLR-4 pathway. AGE was found to interact with and inhibit the DR-5/ caspase-8/3 apoptotic complex. Furthermore, microscopic studies revealed degeneration and apoptotic changes in pancreatic ß-cells of the DM control group, while supplementation of AGE resulted in inhibition of apoptotic pathway and regeneration of pancreatic ß-cells. CONCLUSION: The current study suggests that AGE enhance glucose homeostasis by exerting their effects on pancreatic ß-cells, without ameliorating peripheral sensitivity. Moreover, AGEs promote an increase in ß-cell mass by mitigating the apoptosis of pancreatic ß-cells. These findings suggest that AGE could aid in developing a viable alternative therapy for diabetes mellitus (DM).

Molecular Dynamics Simulation of Kir6.2 Variants Reveals Potential Association with Diabetes Mellitus.

Diabetes mellitus (DM) represents a problem for the healthcare system worldwide. DM has very serious complications such as blindness, kidney failure, and cardiovascular disease. In addition to the very bad socioeconomic impacts, it influences patients and their families and communities. The global costs of DM and its complications are huge and expected to rise by the year 2030. DM is caused by genetic and environmental risk factors. Genetic testing will aid in early diagnosis and identification of susceptible individuals or populations using ATP-sensitive potassium (KATP) channels present in different tissues such as the pancreas, myocardium, myocytes, and nervous tissues. The channels respond to different concentrations of blood sugar, stimulation by hormones, or ischemic conditions. In pancreatic cells, they regulate the secretion of insulin and glucagon. Mutations in the KCNJ11 gene that encodes the Kir6.2 protein (a major constituent of KATP channels) were reported to be associated with Type 2 DM, neonatal diabetes mellitus (NDM), and maturity-onset diabetes of the young (MODY). Kir6.2 harbors binding sites for ATP and phosphatidylinositol 4,5-diphosphate (PIP2). The ATP inhibits the KATP channel, while the (PIP2) activates it. A Kir6.2 mutation at tyrosine330 (Y330) was demonstrated to reduce ATP inhibition and predisposes to NDM. In this study, we examined the effect of mutations on the Kir6.2 structure using bioinformatics tools and molecular dynamic simulations (SIFT, PolyPhen, SNAP2, PANTHER, PhD&SNP, SNP&Go, I-Mutant, MuPro, MutPred, ConSurf, HOPE, and GROMACS). Our results indicated that M199R, R201H, R206H, and Y330H mutations influence Kir6.2 structure and function and therefore may cause DM. We conclude that MD simulations are useful techniques to predict the effects of mutations on protein structure. In addition, the M199R, R201H, R206H, and Y330H variant in the Kir6.2 protein may be associated with DM. These results require further verification in protein-protein interactions, Kir6.2 function, and case-control studies.

Computational Analysis of Deleterious nsSNPs in INS Gene Associated with Permanent Neonatal Diabetes Mellitus.

Insulin gene mutations affect the structure of insulin and are considered a leading cause of neonatal diabetes and permanent neonatal diabetes mellitus PNDM. These mutations can affect the production and secretion of insulin, resulting in inadequate insulin levels and subsequent hyperglycemia. Early discovery or prediction of PNDM can aid in better management and treatment. The current study identified potential deleterious non-synonymous single nucleotide polymorphisms nsSNPs in the INS gene. The analysis of the nsSNPs in the INS gene was conducted using bioinformatics tools by implementing computational algorithms including SIFT, PolyPhen2, SNAP2, SNPs & GO, PhD-SNP, MutPred2, I-Mutant, MuPro, and HOPE tools to investigate the prediction of the potential association between nsSNPs in the INS gene and PNDM. Three mutations, C96Y, P52R, and C96R, were shown to potentially reduce the stability and function of the INS protein. These mutants were subjected to MDSs for structural analysis. Results suggested that these three potential pathogenic mutations may affect the stability and functionality of the insulin protein encoded by the INS gene. Therefore, these changes may influence the development of PNDM. Further researches are required to fully understand the various effects of mutations in the INS gene on insulin synthesis and function. These data can aid in genetic testing for PNDM to evaluate its risk and create treatment and prevention strategies in personalized medicine.

Novel Therapeutic Agents for Management of Diabetes Mellitus: A Hope for Drug Designing against Diabetes Mellitus.

Diabetes mellitus (DM) is characterized by an absolute decline in insulin secretion and peripheral resistance and is the most prevalent metabolic and endocrine disorder. However, the pathogenesis of DM also includes adipocyte insulin resistance, increased glucagon secretion, increased renal glomerular glucose absorption, and neurotransmitter dysfunction. Although there is a wide spectrum of therapeutics available for glycemic control, owing to the identification of various pathogenic determinants of DM, management of DM remains challenging and complex. Current therapeutic interventions against DM focus mostly on glycemic control without considering the other pathological determinants that eventually lead to treatment failure and the progression of DM. Furthermore, long-term use of these conventionally available anti-diabetic drugs leads to various side effects, henceforth development of novel drugs against DM remains an unending search strategy for researchers. Various studies conducted in various parts of the world have proposed that these novel therapeutic interventions target multiple and alternate pathogenic hotspots involved in DM. The current review article discusses novel therapeutic options that hold particular promise to support their safety and discuss the side effects resulting from their use so that these novel candidate drugs can be effectively fabricated into potential drugs for the treatment of DM.

In Silico Evaluation of the Potential Association of the Pathogenic Mutations of Alpha Synuclein Protein with Induction of Synucleinopathies.

Alpha synuclein (α-Syn) is a neuronal protein encoded by the SNCA gene and is involved in the development of Parkinson's disease (PD). The objective of this study was to examine in silico the functional implications of non-synonymous single nucleotide polymorphisms (nsSNPs) in the SNCA gene. We used a range of computational algorithms such as sequence conservation, structural analysis, physicochemical properties, and machine learning. The sequence of the SNCA gene was analyzed, resulting in the mapping of 42,272 SNPs that are classified into different functional categories. A total of 177 nsSNPs were identified within the coding region; there were 20 variants that may influence the α-Syn protein structure and function. This identification was made by employing different analytical tools including SIFT, PolyPhen2, Mut-pred, SNAP2, PANTHER, PhD-SNP, SNP&Go, MUpro, Cosurf, I-Mut, and HOPE. Three mutations, V82A, K80E, and E46K, were selected for further examinations due to their spatial positioning within the α-Syn as determined by PyMol. Results indicated that these mutations may affect the stability and function of α-Syn. Then, a molecular dynamics simulation was conducted for the SNCA wildtype and the four mutant variants (p.A18G, p.V82A, p.K80E, and p.E46K). The simulation examined temperature, pressure, density, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg). The data indicate that the mutations p.V82A, p.K80E, and p.E46K reduce the stability and functionality of α-Syn. These findings highlight the importance of understanding the impact of nsSNPs on α-syn structure and function. Our results required verifications in further protein functional and case-control studies. After being verified these findings can be used in genetic testing for the early diagnosis of PD, the evaluation of the risk factors, and therapeutic approaches.

Delayed intestinal obstruction from an unintentionally retained surgical gauze in a 24-year old woman two years after caesarean section: a case report.

BACKGROUND: One of the most common surgical emergencies, intestinal obstruction is rarely the result of an inadvertently retained foreign object (also known as a gossypiboma), which may not present symptoms for a lifetime. It also carries additional legal burdens, which may account for the rarity of its reports. CASE PRESENTATION: We report a 24-year-old Sudanese female with a history of emergency Caesarean section two years before the admission presented with abdominal distension and absolute constipation, which was diagnosed as intestinal obstruction with a retained gauzed found within the small intestine. Moreover, a review of recent African-reported cases was done to find relatively similar cases. CONCLUSION: Adhering to the standard of care in surgical theaters and integrating new methods of prevention like tagged gauze could help to decrease the rate of such cases in the future.

Clinical Characterization and Outcomes of Patients with Hypercreatinemia Affected by COVID-19.

The present study evaluated the clinical presentation and outcome of COVID-19 patients with underlying hypercreatinemia at the time of hospitalization. A retrospective observational study was conducted from the 23rd of March 2020 to the 15th of April 2021 in 1668 patients confirmed positive for COVID-19 in the Chest Disease Hospital in Srinagar, India. The results of the present study revealed that out of 1668 patients, 339 with hypercreatinemia had significantly higher rates of admission to the intensive care unit (ICU), severe manifestations of the disease, need for mechanical ventilation, and all-cause mortality. Multivariable analysis revealed that age, elevated creatinine concentrations, IL-1, D-Dimer, and Hs-Crp were independent risk factors for in-hospital mortality. After adjusted analysis, the association of creatinine levels remained strongly predictive of all-cause, in-hospital mortality (HR-5.34; CI-4.89-8.17; p ≤ 0.001). The amelioration of kidney function may be an effective method for achieving creatinemic targets and, henceforth, might be beneficial for improving outcomes in patients with COVID-19.

Endoscopic mucosal resection of colorectal polyps in typical UK hospitals.

AIM: To evaluate the outcomes of endoscopic mucosal resection (EMR) for colorectal polyps, with particular regard to procedural complications and recurrence rate, in typical United Kingdom (UK) hospitals that perform an average of about 25 colonic EMRs per year. METHODS: A total of 239 colorectal polyps (≥ 10 mm) resected from 199 patients referred to Rochdale Infirmary, Salford Royal Hospital and Royal Oldham Hospital for EMR between January 2003 and January 2009 were studied. RESULTS: The mean size of polyps resected was 19.6 ± 12.4 mm (range 10-80 mm). The overall major complication rate was 2.1%. Complications were less frequent with non-adenomas compared with the other groups (Pearson's χ(2) test, P < 0.0001). Resections of larger-sized polyps were more likely to result in complications (unpaired t-test, P = 0.021). Recurrence was associated with histology, with carcinoma-in-situ more likely to recur compared with low-grade dysplasia [hazard ratio (HR) 186.7, 95% confidence interval (95% CI): 8.81-3953.02, P = 0.001]. Distal lesions were also more likely to recur compared with right-sided and transverse colon lesions (HR 5.93, 95% CI: 1.35-26.18, P = 0.019). CONCLUSION: EMR for colorectal polyps can be performed safely and effectively in typical UK hospitals. Stricter follow-up is required for histologically advanced lesions due to increased recurrence risk.