Current Drug Targets - Volume 23, Issue 1, 2022

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Abstract: Parkinson’s disease (PD) is one of the most common types of neurological disorder prevailing worldwide and is rapidly increasing in the elderly population across the globe. The cause of PD is still unknown, but a number of genetic as well as environmental factors contributing to the pathogenesis of Parkinson’s disease have been identified. The hallmark of PD includes dopamine deficiency (neurotransmitter imbalance) due to the gradual loss of dopaminergic nerves in the substantia nigra in the midbrain. Studying the mutation of associated genes is particularly informative in understanding the fundamental molecular and pathogenic changes in PD. Intracellular accumulation of misfolded or degraded protein due to mutated genes leading to the manifestation of mitochondrial dysfunction, oxidative stress followed by multifaceted patho-physiologic symptoms. Other studies include the appearance of both motor and non-motor responses like resting tremor, muscle stiffness, slow movement and anxiety, anaemia, constipation, rapid eye movement sleep behaviour disorder. Many bioactive natural compounds have shown positive pharmacological results in treating a number of extensive disease models of PD. Despite the availability of end number of potent medicinal plants around the world, limited research has been done associated with various neurological disorders, including PD. The currently available dopamine-based drug treatments have several side-effects, further, not effective enough to combat PD completely. Therefore, various plant-based compounds with medicinal benefits have grabbed lots of attention of researchers to deal with various life-threatening neurodegenerative disorders like PD. On the basis of literature available till date, here, we have discussed and addressed the molecular basis, current scenario, and the best possible treatment of PD for the future with minimal or no side-effects using various key bioactive compounds from natural origin/medicinal plants.

Background: Molecular therapy with sorafenib remains the mainstay for advancedstage hepatocellular carcinoma. Notwithstanding, treatment efficacy is low, with few patients obtaining long-lasting benefits due to the high chemoresistance rate. Objective: To perform, for the first time, an overview of the literature concerning the role of adenosine triphosphate-binding cassette (ABC) transporters in sorafenib therapy for hepatocellular carcinoma. Methods: Three online databases (PubMed, Web of Science, and Scopus) were searched, from inception to October 2020. Study selection, analysis, and data collection were independently performed by two authors. Results: The search yielded 224 results; 29 were selected for inclusion. Most studies were pre-clinical, using HCC cell lines; three used human samples. Studies highlight the effect of sorafenib in decreasing ABC transporters expression. Conversely, it is described the role of ABC transporters, particularly multidrug resistance protein 1 (MDR-1), multidrug resistance-associated proteins 1 and 2 (MRP-1 and MRP-2) and ABC subfamily G member 2 (ABCG2) in sorafenib pharmacokinetics and pharmacodynamics, being key resistance factors. Combination therapy with naturally available or synthetic compounds that modulate ABC transporters may revert sorafenib resistance by increasing absorption and intracellular concentration. Conclusion: A deeper understanding of ABC transporters’ mechanisms may provide guidance for developing innovative approaches for hepatocellular carcinoma. Further studies are warranted to translate the current knowledge into practice and paving the way to individualized therapy.

Background: Chagas disease is a potentially life-threatening illness caused by the protozoan parasite Trypanosoma cruzi and is transmitted to humans through the excreta of infected blood-sucking triatomine bugs. According to the World Health Organization, 6 to 7 million people are infected with T. cruzi worldwide, mainly in Latin America, with more than 10000 deaths annually. Aim of the Study: The present study aims to provide comprehensive literature information on the importance of triazole-containing heterocycles in developing anti-Chagas disease agents. Methodology: The embodied information was acquired without date limitation by December 2020 using various electronic databases including, SciFinder, PubMed (National Library of Medicine), Science Direct, Wiley, ACS (American Chemical Society), SciELO (Scientific Electronic Library Online), Google Scholar, Springer, Scopus, and Web of Science. Results: Upon in vitro studies, more than 100 triazole-containing heterocycles have been predicted as active compounds against the pathogen responsible for the American trypanosomiasis. However, less is known about their in vivo activity in animal models and their clinical studies in humans. Moreover, the pharmacokinetic studies of these bioactive compounds are still pending. Despite the variety of mechanisms of action attributed to most of these molecules, the exact mechanism involved is still controversial. Thus, in vivo experiments, followed by pharmacokinetics, and the mechanism of action of the most active compounds, should be the subject of future investigation. Conclusion: All in all, recent studies have demonstrated the importance of triazole-containing heterocycles in search of potential candidates for drug development against Chagas disease. Nonetheless, the use of new catalysts and chemical transformations is expected to provide avenues for the synthesis of unexplored triazole derivatives, leading to the development of triazole-containing compounds with new properties and trypanocidal activity.

Abstract: Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

Background: Antiviral resistance and inefficiency of available antiviral drugs to effectively treat viral infections have prompted many researchers worldwide to explore medicinal plants and their isolated compounds as alternative antivirals. The rich flora from the Mascarene Islands has also been thoroughly studied for their wide therapeutic activities, including their antiviral properties. Objective: The aim of this review is to highlight the antiviral propensities of Mascarene endemic and indigenous medicinal plants. Methodology: A review of the literature was conducted via major databases and other primary sources of information. The inhibitory concentration/effective dose causing 50% viral inhibition (IC50/ED50), cytotoxic concentration causing 50% reduction in cell viability (CC50), and selectivity index (SI) were reported, and mechanisms of antiviral action were also discussed. Results: Stillingia lineata was the most effective against chikungunya virus (SI: 10.9), and among its isolated compounds, 12-O-acetylphorbol-13(2″-methyl)- butyrate and 12-deoxyphorbol- 13(2″-methyl)butyrate were the most potent and selective inhibitors of chikungunya virus replication (SI: 41 and >240, respectively). 12-O-acetylphorbol-13(2″-methyl)- butyrate, 12β-O-[nona- 2Z,4E,6E-trienoyl]-4α-deoxyphorbol-13-butyrate, 12-deoxyphorbol-13(2″-methyl)butyrate, and 12-deoxyphorbol-13-[8′-oxohexadeca-2E,4E,6E-trienoate showed strong selective antiviral effect on human immunodeficiency virus-I (SI: 36-899) and II (SI: 33-2056). Obetia ficifolia and Erythroxylon laurifolium were most active against the herpes virus (SI: 18.5 and 16, respectively). Labourdonnaisia glauca showed potent anti-poliovirus activity (SI: 40), while Badula insularis, Labourdonnaisia glauca and Myonima violacea were active against rhinovirus (SI: 1.3-2.5). Both anti-zika and anti-dengue virus activities were reported for Aphloia theiformis, Doratoxylon apetalum, Phyllanthus phillyreifolius and Psiloxylon mauritianum. Conclusion: Promising spectrum of antiviral properties notably against zika, dengue, chikungunya, polio-, rhino-, herpes, and human immunodeficiency viruses were presented by the Mascarene plants suggesting them as viable candidates for the potential development of effective natural antiviral drugs.

Abstract: Wound healing is a complex and never-ending process that involves numerous mediators, enzymatic cascades that are directly or indirectly involved in the mechanism. So, it becomes necessary to closely examine critical factors such as gaseous exchange, a moist environment, anti- microbial activity, and exudation liquids' absorption while designing wound dressings. There is a heap of wound dressings available for human use, but they all are way apart from the ideal dressing. The use of biopolymers may be a solution to tackle the difficulties such as combining with growth factors and cells that can trigger wound healing. This article reviews such therapies for wound healing application.

Abstract: The Angiotensin II type 2 Receptor (AT2R) is one of the critical components of the renin- angiotensin system (RAS), which performs diverse functions like inhibiting cell differentiation, cell proliferation, vasodilatation, reduces oxidative stress and inflammation. AT2R is relatively less studied in comparison to other components of RAS despite its uniqueness (sex-linked) and diverse functions. The AT2R is differentially expressed in different tissues, and its gene polymorphisms are associated with several diseases. The molecular mechanism behind the association of AT2R and its gene polymorphisms with the diseases remains to be fully understood, which hinders the development of AT2R as a drug target. Single nucleotide polymorphisms (SNPs) in AT2R are found at different locations (exons, introns, promoter, and UTR regions) and were studied for association with different diseases. There may be different mechanisms behind these associations as some AT2R SNP variants were associated with differential expression, the SNPs (A1675G/ A1332G) affect the alternate splicing of AT2R mRNA, A1332G genotype results in shortening of the AT2R mRNA and subsequently defective protein. Few SNPs were found to be associated with the diseases in either females (C4599A) or males (T1334C). Several other SNPs were expected to be associated with other similar/related diseases, but studies have not been done yet. The present review emphasizes on the significance of AT2R and its polymorphisms associated with the diseases to explore the precise role of AT2R in different diseases and the possibility to develop AT2R as a potential drug target.