Current Drug Targets - Volume 23, Issue 7, 2022

Background: Neglected tropical diseases (NTDs) are infectious diseases that mostly affect people living in tropical and subtropical regions, especially in impoverished areas. Ubiquitously found in plants, flavonoids are a group of compounds that have been reported to exhibit a wide range of biological activities against parasites (Leishmania sp., Trypanosoma cruzi, Trypanosoma brucei, Brugia malayi, etc.) that cause certain NTDs. Aims: The present study aims to highlight and discuss our recent reports on the implication of flavonoids in drug development for NTDs, such as leishmaniasis, Chagas disease, African trypanosomiasis, filariasis, among others. Results: Today, studies show that flavonoids exhibit in vitro antileishmanial, anti-trypanosomiasis, antifilarial activities, among others. Furthermore, the molecular hybridization of flavonoids with the triazole groups has led to the development of compounds with improved biological activity. The incorporation of chemical groups, such as NO2, F, and Cl groups, during the process of design and synthesis, leads to the enhancement of pharmacological activity. Conclusion: Flavonoids are useful metabolites that can be prospected as potential leads for the development of new agents against certain NTDs. However, research opportunities, including cytotoxicity and in vivo studies, mechanisms of action, bioavailability of these compounds, remain to be investigated in the future.

Chronic Obstructive Pulmonary Disease (COPD) is a disorder characterized by narrow alveoli as a result of emphysema. As such, there is no treatment to cure this disorder completely, and existing drugs only delay the progression of the disease. In recent years, the stem cell secretome as a drug is remarkably used as a regenerative therapy. In particular, cell-free therapy approaches offer great opportunities for the treatment of COPD. However, a few issues, such as the delivery of stem cell secretome as a drug to the alveolar region, have obstructed their application in clinical scales. To address these challenges, a combination of stem-cells secretome as a drug with nanotechnology could be a smart solution. We suggest that the combinational approach of delivering nanoparticles loaded with stem cell secretome could be a translational medicine approach for the successful outcome of COPD.

Interferon-simulated gene 15 (ISG15) belongs to the family of ubiquitin-like proteins. ISG15 acts as a cytokine and modifies proteins through ISGylation. This posttranslational modification has been associated with antiviral and immune response pathways. In addition, it is known that the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes proteases critical for viral replication. Consequently, these proteases are also central in the progression of coronavirus disease 2019 (COVID-19). Interestingly, the protease SARS-CoV-2-PLpro removes ISG15 from ISGylated proteins such as IRF3 and MDA5, affecting immune and antiviral defense from the host. Here, the implications of ISG15, ISGylation, and generation of SARS-CoV-2-PLpro inhibitors in SARS-CoV-2 infection are discussed.

The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM), pathological conditions and end-organ complications can be attributed to aberrant mTOR. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to the development of T2DM. This review summarizes our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in the treatment of T2DM.

Intervertebral disc (IVD) degeneration is a leading cause of lower back pain. Although the etiology of IVD degeneration (IVDD) is unclear, excessive oxidative stress, inflammation and apoptosis, and disruption of autophagy play an important role in the pathogenesis of IVDD. Therefore, finding a solution to mitigate these processes could stop or reduce the development of IVDD. Melatonin, a powerful antioxidant, plays an important role in regulating cartilage tissue hemostasis. Melatonin inhibits the destruction of the extracellular matrix (ECM) of the disc. Melatonin preserves ECM contents, including sox-9, aggrecan, and collagen II through inhibiting matrix degeneration enzymes such as MMP-13. These protective effects may be mediated by the inhibition of oxidative stress, inflammation and apoptosis, and regulation of autophagy in IVD cells.

Background: A large number of studies have been conducted on the treatment of glioblastoma multiforme (GBM). Chemotherapeutic drugs cannot penetrate deeply into the brain parenchyma due to the presence of the blood-brain barrier (BBB). Hence, crossing BBB is a significant obstacle in developing new therapeutic methods for GBM. Objective: Cell-penetrating peptides (CPPs) have emerged as new tools that can efficiently deliver various substances across BBB. CPPs beneficial properties, such as BBB penetration capacity, low toxicity, and the ability to achieve active targeting and controllable drug release, have made them worthy candidates for GBM treatment. However, their application is limited by several drawbacks, including lack of selectivity, insufficient transport efficacy, and low stability. In order to overcome the selectivity issue, tumor targeting peptides and sequences that can be activated at the target site have been embedded into the structure of CPPs. To overcome their insufficient transport efficacy into the cells, which is mostly due to endosomal entrapment, various endosomolytic moieties have been incorporated into CPPs. Finally, their instability in blood circulation can be solved through different modifications to their structures. As this field is moving beyond preclinical studies, the discovery of new and more efficient CPPs for GBM treatment has become crucial. Thus, by using display techniques, such as phage display, this encouraging treatment strategy can be developed further. Conclusion: Consequently, despite several challenges in CPPs application, recent progress in studies has shown their potential for the development of the next generation GBM therapeutics.

Neurological disorders are disease conditions related to the neurons and central nervous system (CNS). Any structural, electrical, biochemical, and functional abnormalities in neurons can lead to various types of disorders, like Alzheimer’s disease (AD), depression, Parkinson’s disease (PD), epilepsy, stroke, etc. Currently available medicines are symptomatic and do not treat the disease state. Thus, novel CNS active agents with the potential to completely treat an illness are highly desired. A range of small organic molecules is being explored as potential drug candidates to cure different neurological disorders. In this context, arylpiperazinehas been found to be a versatile scaffold and indispensable pharmacophore in many CNS active agents. Several molecules with arylpiperazine nucleus have been developed as potent leads for the treatment of AD, PD, depression, and other disorders. The arylpiperazine nucleus can be optionally substituted at different chemical structures and offer flexibility for the synthesis of a large number of derivatives. In the current review article, we have explored the role of various arylpiperazine containing scaffolds against different neurological disorders, including AD, PD, and depression. The structure-activity relationship studies were conducted for recognizing potent lead compounds. This review article may provide important insights into the structural requirements for designing and synthesizing effective molecules as curative agents for different neurological disorders.

Background: Nanoparticles play a very important role in our daily lives and have a wide range of applications in agriculture and biology, such as antioxidants and antimicrobial compounds. Among them are gold nanoparticles (AuNPs) that are highly complex and are widely used. In recent years gold nanoparticles have attracted much attention because of their optical properties, electronic, physicochemical, and surface Plasmon resonance (SPR). Gold plated nanoparticles, similar to metal nanoparticles, have many unusual chemical and physical properties due to the effects of their quantum size and location compared to other iron or metal atoms. Gold nanoparticles can be used in pharmaceutical products such as antimicrobial and anti-biofilm agents, targeted delivery of anticancer drugs, biosensors, biocatalysis, bioremediation modification of toxic chemicals exposing the soil and atmosphere, dye reduction, etc. Yet such methods are expensive and out of harmony with nature. In that account, the microbes-mediated synthesis of gold nanoparticles recently changed rapidly when pure microbes becoming ac-friendly, non-toxic, and biocompatible as physiological and chemical methods. This document aims to review the progress made in recent years with the fusion of gold nanoparticles. The microbial source includes bacteria, algae fungi. These works motivate people how to apply and synthesize gold nanoparticles. This review also focuses on the process of classification of gold nanoparticles, structures, and their use in the development of various requirements. Objective: The main goal is to study gold nanoparticles and their application in the future. Methods: We studied different research papers, reviewed papers from “Google Scholar”, “NCBI”, “PubMed”, “Science Direct” made. Conclusion: Metal nanoparticles are suitable for many emerging technologies. Understanding the microorganisms found in nature because the fusion of gold nanoparticles is required.

Background: Diabetes mellitus (DM) is a common metabolic disorder characterized by a persistent increment of blood glucose. Type 2 DM is characterized by insulin resistance and β-cell dysfunction. Thioredoxin-interacting protein (TXNIP) is among the factors that control the production and loss of pancreatic β-cells. Objective: Recent studies have shown that high glucose can significantly up-regulate the expression of the TXNIP. Overexpression of TXNIP in β-cells not only induced apoptosis but also decreased the production of insulin. At the same time, TXNIP deficiency protected the apoptosis of β-cells, leading to increased insulin production. Therefore, finding small molecules that can modulate TXNIP expression and downstream signalling pathways is essential. Thus, the inhibition of TXNIP has beneficial effects on the cardiovascular system and other tissues such as the heart and the kidney in DM. Therefore, DM treatment must target small TXNIP activity, inhibit expression, and promote endogenous cell mass and insulin production. Conclusion: This review briefly describes the effect mechanism, regulatory mechanism, and crystal structure of TXNIP. In addition, we highlight how TXNIP signalling networks contribute to diabetes and interact with drugs that inhibit the development often and its complexes. Finally, the current status and prospects of TXNIP targeted therapy are also discussed.