Current Pharmaceutical Design - Volume 28, Issue 16, 2022

Heart failure (HF) is a common cause of morbimortality with different etiopathogenesis and prognosis between men and women. This review provides a brief overview of gender-based differences in response to pharmacological therapies of heart failure with or without reduced ejection fraction (EF). It focuses on the differences in therapy outcomes with angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), angiotensin neprilysin inhibitors (ARNI), beta-adrenergic blockers, mineralocorticoid/ aldosterone receptor antagonists, diuretics, ivabradine and digoxin. The baseline data originate from randomised controlled trials (RCTs) and large registries. We conclude that current guidelines recommending similar therapeutic approaches for both men and women are appropriate, while additional consideration should be given to different approaches regarding the use of ARBs, ACEi, and digoxin. Based on the available data, the ARBs might be considered a first-line therapy of HR for women instead of ACEi. Moreover, female patients should have stricter digoxin monitoring due to higher sensitivity and increased risk of complications. Finally, women are underrepresented in current clinical trials, and therefore future trials should aim to balance the gender recruitment disparity allowing sub-group analysis and comparisons between genders to guide individualised therapeutic strategies and appropriately targeted preventative steps.

Diabetes mellitus is a metabolic condition that influences the endocrine framework. Hyperglycemia and hyperlipidemia are two of the most widely recognized metabolic irregularities in diabetes and two of the most well-known reasons for diabetic intricacies. Diabetes mellitus is a persistent illness brought about by metabolic irregularities in hyperglycemic pancreatic cells. Hyperglycemia can be brought about by an absence of insulin-producing beta cells in the pancreas (Type 1 diabetes mellitus) or inadequate insulin creation that does not work effectively (Type 2 diabetes mellitus). Present diabetes medication directs blood glucose levels in the systemic circulation to the typical levels. Numerous advanced prescription medicines have many negative results that can bring about unexpected severe issues during treatment of the bioactive compound from a different source that is beneficially affected by controlling and adjusting metabolic pathways or cycles. Moreover, a few new bioactive medications disengaged from plants have shown antidiabetic action with more noteworthy adequacy than the oral hypoglycemic agent that specialists have utilized in clinical treatment lately. Since bioactive mixtures are collected from familiar sources, they have a great activity in controlling diabetes mellitus. This study discusses bioactive compounds, their activity in managing diabetes mellitus, and their prospects. Though bioactive compounds have many health-beneficial properties, adequate clinical studies still need to acknowledge that they effectively manage diabetes mellitus.

Hippo, an evolutionarily conserved kinase cascade reaction in organisms, can respond to a set of signals, such as mechanical signals and cell metabolism, to maintain cell growth, differentiation, tissue/organ development, and homeostasis. In the past ten years, Hippo has controlled the development of tissues and organs by regulating the process of cell proliferation, especially in the field of cardiac regeneration after myocardial infarction. This suggests that Hippo signaling is closely linked to cardiovascular disease. Atherosclerosis is the most common disease of the cardiovascular system. It is characterised by chronic inflammation of the vascular wall, mainly involving dysfunction of endothelial cells, smooth muscle cells, and macrophages. Oxidized Low density lipoprotein (LDL) damages the barrier function of endothelial cells, which enter the middle membrane of the vascular wall, accelerate the formation of foam cells, and promote the occurrence and development of atherosclerosis. Autophagy is associated with the development of atherosclerosis. However, the mechanism of Hippo regulation of atherosclerosis has not meant to be clarified. In view of the pivotal role of this signaling pathway in maintaining cell growth, proliferation, and differentiation, the imbalance of Hippo is related to atherosclerosis and related diseases. In this review, we emphasized Hippo as a hub for regulating atherosclerosis and discussed its potential targets in pathophysiology, human diseases, and related pharmacology.

Epigenetic drugs are novel drug categories with promising effects in different cancers. Tazemetostate is among the drugs that were recently used in clinical settings, especially in the treatment of specific tumors and lymphomas. There are a growing number of ongoing clinical trials evaluating the safety and efficacy of tazemetostate in different cancers. The present review addressed the available preclinical studies evaluating the combination of tazemetostate and other chemotherapy agents in treating different cancers and summarized the limited clinical evidence available regarding the efficacy of this novel Enhancer of Zeste Homolog 2 (EZH2) inhibitor in cancer. Based on the available clinical studies, tazemetostate could be considered a safe epigenetic agent with limited adverse events for treating specific types of lymphomas and solid tumors. However, the superiority of using tazemetostate over other chemotherapy agents in patients with cancer as well as using the drug for other clinical conditions, including non-alcoholic steatohepatitis, needs further investigation. Moreover, the effect of tazemetostate on human germline cells is clearly evaluated as some animal studies demonstrated that the drug can affect germline epigenome suggesting further studies on this issue.

Background: FER-1 family member 4 (FER1L4), a 6.7 kb lncRNA located at 20q11.22, plays an important biological function in a variety of tumor diseases. The purpose of this review is to clarify the pathophysiological mechanism and potential biological function of FER1L4 in different tumors.

Methods: By searching the relevant literature in PubMed, the specific pathophysiological mechanism of FER1L4 in different tumors was summarized.

Results: LncRNA FER1L4 is one of the key factors in tumorigenesis and is abnormally down-regulated in many tumors, including osteosarcoma, lung cancer, laryngeal squamous cell carcinoma, laryngeal cancer, colorectal cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, endometrial cancer, osteoarthritis, rheumatoid arthritis, and so on. However, FER1L4 is downregulated in breast cancer, glioma, oral squamous cell carcinoma, renal clear cell carcinoma, and periodontitis, and plays a protective role in orthodontic teeth. In addition, as a tumor suppressor gene or oncogene, FER1L4 affects tumor proliferation, invasion, migration, and apoptosis.

Conclusion: LncRNA FER1L4 has a good application prospect in the treatment and diagnosis of various tumors.

Background: Nuclear128;enriched abundant transcript 1 (abbreviated as NEAT1) is a long-chain noncoding RNA involved in various physiological and pathological processes. This study aimed to clarify the effect and molecule system of NEAT1 within non-alcoholic fatty liver disease (NAFLD) as well as type 2 diabetes (T2DM).

Methods: In this review, current studies concerning mechanisms of NEAT1l, in the development of type 2 diabetes and its complications have been summarized and analyzed. Also, we searched the papers based on NEAT1 related to NAFLD. The related studies were obtained through a systematic search of Pubmed.

Results: NEAT1 displays a close correlation with how T2DM occurs and develops, and it was confirmed to be significantly up-regulated in T2DM and its various complications (e.g., diabetics nephropathy, diabetics cardiomyopathy, diabetics retinopathy as well as diabetic neuropathy). Besides, NEAT1 is capable of impacting the occurrence, development and prognosis of NAFLD and T2DM.

Conclusion: LncRNA NEAT1 is likely to act as a novel therapeutic target for T2DM and its complications. Moreover, non-alcoholic fatty liver disease is also correlated with NEAT1.

Background: At present, the antitumor effect of metformin is controversial. Previous meta-analyses included observational studies, of which the results can be influenced by many confounders, affecting the result of meta-analyses and weakening the strength of evidence. Therefore, we conducted a meta-analysis to confirm the effect of metformin use on patients with advanced or unresectable cancers, including randomized clinical trials (RCTs).

Methods: We searched for RCTs in accordance with the inclusion and exclusion criteria. A meta-analysis was conducted to combine hazard ratios (HRs) or risk ratios (RRs) and their 95% confidence intervals (CIs) using a random-effects model.

Results: Finally, 7 eligible RCTs were included in the meta-analysis. Overall, the combined results revealed that treatment with metformin did not improve the overall survival (OS) of patients (HR, 1.12; 95% CI, 0.91-1.37, p>0.05), and there was no clear evidence that metformin use was related to improved progression-free survival (PFS) (HR, 1.17; 95% CI, 0.97-1.40; p>0.05). The pooled RR for grade III or IV adverse events was 0.92 (95% CI, 0.52- 1.60; p>0.05), indicating that the use of metformin was not significantly related to increased toxicity.

Conclusion: Metformin does not significantly improve the survival of patients with advanced or unresectable cancer, regardless of cancer type and region.

Background: Remifentanil reduces cough during extubation. Ramosetron, a 5-HT3 receptor antagonist, is a potent antiemetic. Regarding the antitussive property of 5-HT receptor agonists, ramosetron can mediate the cough reflex by increasing the remifentanil requirement. This study evaluated the effect of ramosetron on the optimal effect-site concentration (Ce) of remifentanil for preventing emergence cough from sevoflurane anesthesia in female patients.

Methods: Forty-seven randomly selected female patients undergoing laparoscopic cholecystectomy received either ramosetron 0.3 mg (n = 23) or the same volume of normal saline (n = 24) intravenously at the end of surgery. The remifentanil Ce using target-controlled infusion in 50% of patients (EC50) and 95% of patients (EC95) were assessed using Dixon’s up-and-down or isotonic regression method with a bootstrapping approach.

Results: Using Dixon’s up-and-down method, the EC50 of remifentanil in the control group (1.33 ± 0.38 ng/mL) was comparable to that of ramosetron group (1.50 ± 0.69 ng/mL) (P = 0.615). Using isotonic regression analysis, the EC50 (83% confidence interval) did not differ between the two groups (1.17 [0.86-1.43] ng/mL and 1.13 [0.68-1.56] ng/mL in control and ramosetron groups). However, the EC95 (95% confidence interval) was significantly lower in the control group than in the ramosetron group (1.90 [1.45-1.96] ng/mL and 2.92 [2.35-2.97] ng/mL).

Conclusion: Remifentanil Ce for preventing emergence cough was higher in the ramosetron group than in the control group. It may indicate the lowering effect of ramosetron on the antitussive activity of remifentanil.

Background: Nephropathy diabetes is one of the important causes of death and a more prevalent cause of end-stage renal disease. Objective: The present study investigated the effect of applying spironolactone and captopril and their combination on some renal performance indices and cholesterol-efflux-related gene expression in nephropathy diabetic rats. Methods: Intraperitoneal injection of streptozotocin was used to induce diabetes in rats. FBS, creatinine, and BUN were assayed using the calorimetry technique; also, urine microalbumin was assayed by ELISA. Hepatic gene expressions of ABCA1, ABCG1, and miR-33 were evaluated by the real-time PCR method. Results: FBS levels in the captopril-treated group were significantly decreased compared with the untreated diabetic group. BUN levels of treated groups with captopril and a combination of captopril + spironolactone were significantly increased. GFR of both treated diabetic groups with captopril and spironolactone was significantly lower than an untreated diabetic group. ABCA1 gene expression in hepatic cells of the combination of spironolactone + captopril treated group was significantly increased compared to other treated and untreated diabetic groups. The hepatic expression of the ABCG1 gene in the treated and untreated diabetic groups was significantly lower than in the control group. Treatment of the diabetic group with only combination therapy decreased the hepatic gene expression of miR-33 significantly. Conclusion: Obtained results suggest that S+C combination therapy can improve nephropathy and diabetes disorders by targeting the ABCA1 and miR-33 gene expression. It is suggested that miR-33 and ABCA1 genes evaluation could be a new therapeutic strategy for nephropathy diabetes remediation.