Mini Reviews in Medicinal Chemistry - Volume 23, Issue 19, 2023

Fibrosis is a pathological process characterized by tissue scarring that can occur in various human body organs. The fibrosis of the organ is manifested as an increase in fibrous connective tissue and a decrease in parenchymal cells in the organ tissue, leading to structural damage and functional decline of the organ. At present, the incidence and medical burden of fibrosis are increasing worldwide, which has presented severe negative impacts on human health. Although many of the cellular and molecular processes for underlying fibrosis have been discerned, there are still gaps for effective therapies and target fibrogenesis specifically. Recent studies have shown that the microRNA- 29 family (miR-29a, b, c) plays an essential role in the process of multiorgan fibrosis. It is a class of highly conserved single-stranded noncoding RNAs composed of 20-26 nucleotides. Through its 5' untranslated region (UTR) pairing with the 3'UTR of the target mRNA, the mRNA of the target gene is degraded to complete the physiological process of inhibiting the transcription and translation of the target gene. Here, we summarize the interaction of miR-29 with multiple cytokines, describe the mechanism by which miR-29 regulates major fibrotic pathways such as TGF- β1/Smad, PI3K/Akt/mTOR, DNA methylation, and found that miR-29 is closely linked to epithelial- mesenchymal transition (EMT). These findings point to a common or similar regulatory mechanism by miR-29 in fibrogenesis. Finally, we review the antifibrotic activity of miR-29 mimicked in current studies and highlight miR-29 as a promising therapeutic reagent or target for the treatment of pulmonary fibrosis. Besides, there is an urgent need to screen and identify small compounds to modulate miR-29 expression in vivo.

In the last decades, much attention has been paid to the functioning of receptors to understand better how they work with various chemical motifs. Among different families, G-proteincoupled receptor (GPCR) families have drawn much attention in the twenty-first century. They are the most prominent signal transducer across the cell membrane, comprising thousand-odd proteins. One of the members of GPCRs is the serotonin 2A (5-HT2A) receptor, which has been associated with complex etiological mental illnesses. In this survey, we collected data on 5-HT2A, i.e., the role of 5- HT2A receptors in human and animal analogy, various binding site functionalities, advanced effects, and synthetic aspects.

Hepatocellular carcinoma (HCC) is rapidly spreading around the world with a high mortality rate. In the low- and middle-income nations most impacted by HCV and HBV infections, HCC places a significant strain on the healthcare system and leaches productive capability. An extensive study on HCC to create novel therapeutic approaches was motivated by the lack of adequate preventive or curative therapy methods. Several medications have been put forward and some drug molecules are under investigation by the Food and Drug Administration (FDA) for the treatment of HCC. However, these therapeutic choices fall short of the ideal due to toxicity and the rapid rise in drug resistance which decreases the efficacy of these therapeutics and leads to the severity of hepatocellular carcinoma. Therefore, concerning these problems, there is a critical need for novel systemic combination therapies as well as novel molecular entities that target various signalling pathways, reducing the likelihood that cancer cells may develop treatment resistance. In this review, we discuss the conclusions of several studies suggesting that the N-heterocyclic ring system is a key structural component of many synthetic drugs with a diverse range of biological activities. Following nuclei, such as pyridazine, pyridine, and pyrimidines, along with benzimidazole, indole, acridine, oxadiazole, imidazole, isoxazole, pyrazole, quinolines, and quinazolines, have been included to provide a general overview of the link between structure and activity between heterocyclics and their derivatives against hepatocellular carcinoma. A comprehensive investigation of the structure-activity relationship between the series may be done by the direct comparison of anticancer activities with the reference.

Glycogen synthase kinase-3 (GSK3) is one of the important serine/threonine protein kinases and has two isoforms, namely, GSK3α and GSK3β. GSK3 inhibits glycogen synthase activity through phosphorylation. It plays a key role in various pathophysiological processes, such as differentiation, immunity, metabolism, cell death, and cell survival. Therefore, GSK3 has evolved as an important therapeutic target for treating neurological diseases, inflammatory diseases, and cancer. In addition, GSK3 regulates inflammatory processes through NF-ΚB-induced expression of various cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. Moreover, GSK3 is reported to participate in many signaling pathways related to disease pathology, including PI3K/Akt, Wnt, Hedgehog, cyclic adenosine monophosphate, mitogen-activated protein kinase, and transforming growth factor-β (TGF-β). GSK3 has become a therapeutic target against some inflammatory diseases, including the inclusion body myositis, sepsis, and inflammatory bowel disease. Hence, several GSK3 inhibitors have been under evaluation as new therapeutic strategies in recent years. Two drugs targeting GSK3 have already entered clinical studies, including tideglusib and lithium carbonate. In this study, we analyzed nearly 30 different small-molecule GSK3 inhibitors reported in the past 4 years and classified them into four categories (thiazole, pyridine, F-substituted benzene, and others) according to their structure to conduct further literature research. Moreover, we summarized the optimal compounds and described the process of transformation from the lead compound to the optimal compound. In addition, we aimed to summarize the role of GSK3 in the pathogenesis of inflammatory diseases, with insights into the recent progress in the discovery of GSK3 inhibitors.

With the development of the social economy over the last 30 years, non-alcoholic fatty liver disease (NAFLD) is affected by unhealthy living habits and eating styles and has gradually become an increasingly serious public health problem. It is very important to investigate the pathogenesis and treatment of NAFLD for the development of human health. Probucol is an antioxidant with a bis-phenol structure. Although probucol is a clinically used cholesterol-lowering and antiatherosclerosis drug, its mechanism has not been elucidated in detail. This paper reviews the chemical structure, pharmacokinetics and pharmacological research of probucol. Meanwhile, this paper reviews the mechanism of probucol in NAFLD. We also analyzed and summarized the experimental models and clinical trials of probucol in NAFLD. Although current therapeutic strategies for NAFLD are not effective, we hope that through further research on probucol, we will be able to find suitable treatments to solve this problem in the future.

Background: Neurodegenerative procedures include a large spectrum of disorders with diverse pathological features and clinical manifestations, such as Alzheimer's Disease (AD), Parkinson's disease (PD), Multiple sclerosis, and Amyotrophic lateral sclerosis (ALS). Neurodegenerative diseases (NDs) are indicated by progressive loss of neurons and cognitive function, which is associated with free radical formation, extra and intercellular accumulation of misfolded proteins, oxidative stress, mitochondrial and neurotrophins dysfunction, bioenergetic impairment, inflammation, and apoptotic cell death. Boswellic acid is a pentacyclic triterpene molecule of plant origin that has been applied for treating several inflammatory disorders. Numerous studies have also investigated its’ therapeutic potential against multiple NDs. Objective: In this article, we aim to review the neuroprotective effects of boswellic acid on NDs and the related mechanisms of action. Methods: The databases of PubMed, Google Scholar, Web of Sciences, and Scopus were searched to find studies that reported the effects of boswellic acid on NDs without time limits. Review articles, letters, editorials, unpublished data, and articles not published in the English language were not included in the study. Results: Overall, 17 studies were included in the present study (8 NDs in general, 5 AD, 3 PD, and 1 ALS). According to the reports, boswellic acid exerts anti-inflammatory, antioxidant, antiapoptotic, and neuromodulatory effects against NDs. Boswellic acid decreases Tau phosphorylation and amyloid-β (Aβ) generation in AD. This substance also protects nigrostriatal dopaminergic neurons and improves motor impairments in PD and modulates neurotransmitters, decreases the demyelination region, and improves behavioral functions in ALS. Conclusion: Due to the significant effects of boswellic acid in NDs, more clinical studies are necessary to evaluate the pharmacokinetics of this substance because it seems that boswellic acid can be used as a complementary or alternative treatment in patients with NDs.