Current Pharmaceutical Design - Volume 28, Issue 26, 2022

Coronary artery disease, autonomic neuropathy, and diabetic cardiomyopathy are the most common cardiovascular complications of diabetes. However, emerging evidence demonstrates that diabetes also affects the heart’s electrical conduction system, culminating in lethal arrhythmias and sudden cardiac death. Diabetes and rhythm disturbances have a complex relationship, and arrhythmias cannot only be attributed to ischemia and autonomic neuropathy. Hypoglycemia, hyperglycemia, and glucose fluctuations can potentially induce arrhythmias by activating various pathways. Structural remodeling can accelerate and exacerbate disease development. Mitochondrial dysfunction can also alter the structure and metabolism of cardiomyocytes and contribute to disease progression through oxidative stress and inflammation.

Diabetic nephropathy is one of the chronic microvascular complications of diabetes and is a leading cause of end-stage renal disease. Fortunately, clinical trials have demonstrated that sodium-glucose cotransporter type 2 inhibitors could decrease proteinuria and improve renal endpoints and are promising agents for the treatment of diabetic nephropathy. The renoprotective effects of sodium-glucose cotransporter type 2 inhibitors cannot be simply attributed to their advantages in aspects of metabolic benefits, such as glycemic control, lowering blood pressure, and control of serum uric acid, or improving hemodynamics associated with decreased glomerular filtration pressure. Some preclinical evidence suggests that sodium-glucose cotransporter type 2 inhibitors exert their renoprotective effects by multiple mechanisms, including attenuation of oxidative and endoplasmic reticulum stresses, anti-fibrosis and anti-inflammation, protection of podocytes, suppression of megalin function, improvement of renal hypoxia, restored mitochondrial dysfunction and autophagy, as well as inhibition of sodium-hydrogen exchanger 3. In the present study, the detailed molecular mechanisms of sodium-glucose cotransporter type 2 inhibitors with the actions of diabetic nephropathy were reviewed, with the purpose of providing the basis for drug selection for the treatment of diabetic nephropathy.

The advanced era has invited a plethora of chronic and autoimmune infirmities unmistakably dominated by rheumatoid arthritis, occurring because of equivocal causes, including ecological factors, genetic variations, etc. Unfortunately, it is winning pretty much in every stratum of the society in the undefined age group of the population. Engineered drugs are accessible for the treatment; however, they do experience adverse effects as the treatment requires a prolonged duration worsened by noncompliance. To overwhelm it, certain pharmacological and molecular pathways are explored in the wake of Chinese herbs that prompted the prevention of this deteriorating autoimmune disease. The alcoholic extracts and decoctions are procured from Chinese herbs, such as Paeonia lactiflora, Glycyrrhiza uralensis, Tripterygium wilfordii, etc., which have been proved to manifest constructive pharmacological actions. The activities that were exhibited by extracts are significantly innocuous, non-toxic, and potent to fix the affliction in contrast with the chemosynthetic drugs. Therefore, these Chinese herbs bring forth potent anti-inflammatory, immune-suppressing, anti-nociceptive, anti-neovascularizing, free radical scavenging activities, and various other benefits to withstand several pathological events that usually endure infirmity. It can be abridged that Chinese herbs possess assorted and selective therapeutic properties with profound safety and viability to treat this rheumatic disorder. Thus, this review aims to shed light on naturally originated treatment that is pertinent to providing invulnerable therapy exonerating from adverse effects by restraining joint deformities, production of auto-antibodies, and inflammation.

Artificial intelligence is the leading branch of technology and innovation. The utility of artificial intelligence in the field of medicine is also remarkable. From drug discovery and development to introducing products to the market, artificial intelligence can play its role. As people age, they are more prone to be affected by eye diseases around the globe. Early diagnosis and detection help minimize the risk of vision loss and provide a quality life. With the help of artificial intelligence, the workload of humans and manmade errors can be reduced to an extent. The need for artificial intelligence in the area of ophthalmic is also significant. In this review, we elaborated on the use of artificial intelligence in the field of pharmaceutical product development, mainly with its application in ophthalmic care. AI in the future has a high potential to increase the success rate in the drug discovery phase has already been established. The application of artificial intelligence for drug development, diagnosis, and treatment is also reported with the scientific evidence in this paper.

Objective: This study aims to examine the synergetic augmentation of calycosin-7-O-β-D-glucoside (CG) on cisplatin (CDDP) to induce apoptosis of human epithelial ovarian SK-OV-3 cancer cells. Methods: The SK-OV-3 cells were divided into four groups: control, CDDP monotherapy, CG monotherapy, and combined CDDP and CG treatment. The cell counting kit-8 method detected cell proliferation at different times and under different treatments. Hoechst 33258 staining and annexin V-FITC/propidium iodide double staining methods were used to observe the apoptosis of the SK-OV-3 cells. The caspase-3 enzyme activity detection method, quantitative reverse transcription-polymerase chain reaction, and western blot were used to detect the apoptosis-related factors and the activities of the enzyme in SK-OV-3 cells. Results: The inhibition rates of SK-OV-3 cell proliferation when exposed to 10 μM of CDDP, 50 μM of CG, and a combination of 10 μM of CDDP and 50 μM of CG were 23.2% ± 1.1%, 26.7% ± 2.0%, and 46.7% ± 1.3% after 48 h, respectively. Following the use of the drug combination, the apoptosis rate and caspase-3 enzyme activity were significantly higher than in the single-drug treatment group; the data differences were also significant (p < 0.05). At the protein and ribonucleic acid levels, CG significantly enhanced the effect of CDDP on p53, caspase-3, caspase-9, Bax, and Bcl-2. Conclusion: In vitro, CG significantly increases the CDDP-induced apoptosis of the SK-OV-3 cells through the p53 pathway at the cellular level. In addition, using the drugs in combination reduces the toxicity and side effects caused by using CDDP alone.

Background: Cardio-cerebrovascular disease is an important public health challenge worldwide, and its complex etiology has not been elucidated fully. The study investigated the relationship between two common polymorphisms, C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, baseline lipids and the lipid-lowering efficacy of simvastatin in a Chinese hyperlipidemic population. Methods: All participants were recruited from Anhui, China. By the extreme sampling method, we selected subjects with a low response (n=108) and high response (n=106) based on their adjusted lipid-lowering response to simvastatin administrated for 8 consecutive weeks. Both MTHFR C677T and A1298C loci were genotyped by the MALDI-TOF MS platform. Serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were measured at baseline and after 8 weeks of oral 20 mg/d tablets of simvastatin. Results: Patients with the 677TT genotype had significantly higher baseline TC, HDL-C, and change in HDL-C (ΔHDL-C) levels after treatment than those with 677CC+CT genotypes (β = 0.207, P = 0.045; β = 0.182, P = 0.026; and β = 0.16, P = 0.002, respectively). Patients with 1298AC+CC genotypes had significantly higher baseline LDL-C and change in LDL-C (ΔLDL-C) levels (β = 0.276, P =0.043; β = 0.359, P = 0.025, respectively) than those with 1298AA genotype. We found statistical interactions between the two SNPs in association with baseline HDL-C (P for interaction = 0.034), TC (P for interaction = 0.069), and TG (P for interaction = 0.034). Baseline TC (P = 0.027) and HDL-C (P = 0.046) and change in HDL-C (P = 0.019) were different among those with the MTHFR A-T haplotype compared with A-C. Conclusion: Our major findings suggest that both MTHFR C677T and A1298C polymorphisms could be important genetic determinants of lipid traits and drug efficacy of simvastatin. This will contribute to a better understanding of strategies for personalized medication in Chinese patients with dyslipidemia.

Background: Managing bacterial infections caused by multidrug-resistant (MDR) and biofilmforming bacteria is a global health concern. Therefore, enormous efforts were directed toward finding potential alternative antimicrobial agents, such as antimicrobial peptides (AMPs). Aim: We aimed to synthesize a novel modified hybrid peptide designed from natural parents’ peptides with enhanced activity and reduced toxicity profile. Methods: Rational design was used to hybridize the two antimicrobial peptides, in which the alpha-helical parts of BMAP-28 and LL-37 were combined. Then, several amino acid modifications were applied to generate a modified hybrid peptide named MAA-41. The physicochemical properties were checked using in silico methods. The MAA-41 was evaluated for its antimicrobial and anti-biofilm activities. Synergistic studies were performed with five conventional antibiotics. Finally, the cytotoxicity on mammalian cells and the hemolytic activity were assessed. Results: The MAA-41 revealed a broad-spectrum activity against Gram-positive and Gram-negative bacteria, including standard and MDR bacterial strains. The concentration against planktonic cells ranged between 10 and 20 μM, with higher potency against Gram-negative bacteria. The MAA-41 displayed potent activity in eradicating biofilm-forming cells, and the MBECs were equal to the MIC values reported for planktonic cells. This new peptide exhibited reduced toxicity profiles against erythrocyte cells but not against Vero cells. Combining MAA-41 peptides with conventional antibiotics improved the antimicrobial activity of the combined agents. Either synergistic or additive effects were shown as a significant decrease in MIC to 0.25 μM. Conclusion: This study proposes the validity of a novel peptide (MAA-41) with enhanced antimicrobial activity and reduced toxicity, especially when used as conventional antibiotic combinations.

Background: Glioma is the most common malignant intracranial tumor with high lethality. Despite surgery combined with chemoradiotherapy, the prognosis for patients with glioma remains poor. This is primarily due to acquired chemoradiotherapy resistance. Therefore, to improve the prognosis of glioma, further study into the mechanism of chemoradiotherapy resistance is needed. Objective: This study aimed to (1) evaluate the prognosis of patients with glioma by using a prognostic risk score model constructed by chemoradiotherapy resistance genes, (2) provide new targets and directions for precise treatment of glioma, and (3) discuss the tumor heterogeneity of tumor cells. Methods: According to therapy class and overall survival (OS), we identified 53 genes associated with glioma chemoradiotherapy resistance in The Cancer Genome Atlas Glioblastoma (TCGA GBM) database. Considering the important role of chemoradiotherapy resistance-related genes in the prognosis of glioma, we preliminarily screened and identified vital prognostic factors among these genes by using the Cox regression model of absolute contraction and selection operators in the TCGA GBM lower-grade glioma (TCGA GBMLGG) dataset. Next, the heterogeneity of the chemoradiotherapy resistance-associated genes in different glioma cells was revealed by single-cell sequencing in the GSE117891 cohort. Results: A prognostic risk score model consisting of three genes (ARL4C, MSN, TNFAIP6) was constructed. The expression of this model was high in glioma neural progenitor cells (NPCs) and low in glioma oligodendrocytes. The OS rates were significantly lower in the high- vs. low-risk group. Conclusion: Our 3 gene risk score complements the current glioma diagnosis and provides a novel insight into chemoradiotherapy resistance mechanisms for the prognosis of patients with glioma.