Current Drug Targets - Volume 22, Issue 13, 2021

Glycogen synthase kinase-3 (GSK-3) is a protein kinase containing threonine or serine amino acid residues. GSK-3 was first discovered in 1980 as a regulatory protein kinase, Glycogen synthase (GS) enzyme, which is responsible for the conversion of glycogen from glucose with the help of uridine diphosphate glucose (UDP-Glu) residue. GSK-3 has two isoforms present in human beings, namely GSK-3 α (serine residue at 21 position) and GSK-3 β (serine residue at 9 position). GSK-3 has two terminals, namely C- terminal and N- terminal. C-terminal of GSK-3 resembles α- helix conformation, which acts as an activator loop and is responsible for positioning residues in ATP binding and catalysis of substrates. On the other hand, the N- terminal of GSK-3 resembles β- strand conformation, which acts as an inhibitory loop; having a tyrosine molecule at 216 positions, it is essential for the complete GSK-3 activity. N- terminal of GSK-3 is responsible for ATP binding activity and exhibits various biological activities like cell signaling, gene induction following activation of T cell receptor, apoptosis, protein translation, glycogen metabolism, and inflammatory process. Activation of GSK-3 leads to pro-inflammatory actions, i.e. an increase in the binding activity of NF-kB (pro-inflammatory genes), increase in the transactivation activity of NF-kB, increase in the phosphorylation of p105, and a decrease in the transactivation activity of C/EBPβ (anti- inflammatory genes), resulting in a large number of prevalent diseases such as diabetes, cancer, neurodegenerative diseases, psychiatric diseases, mood disorders, etc. Glycogen synthase kinase inhibitors (GSK-3 inhibitors) are various chemotypes and have different mechanisms of actions. They are obtained from different sources such as natural products, synthetic ATP as well as non-ATP competitive inhibitors along with substrate-competitive inhibitors. The inhibitors of GSK3 have proven to possess very potent anti-inflammatory action. GSK-3 inhibitors are useful for treating different prevalent disorders, such as neurodegenerative diseases, including Alzheimer's disease, hyperglycemia, cancer disease, and mood disorders like depression, etc. In this review, we have highlighted the evidence regarding the description and types of GSK, inflammation process, and the factors affecting inflammation, the relationship between inflammation and GSK, GSK3 inhibitors, and finally, the impact of various natural as well as synthetic GSK3 inhibitors having anti-inflammatory activity.

Background: Activation of Poly (ADP-ribose) polymerase 1 (PARP1), a post-translational modifying enzyme, has been shown to be involved with several inflammatory and viral diseases. Objectives: The goal of this review is to highlight the mechanisms underlying PARP1 activation during viral or infectious pathogenesis and to assess potential possibilities of using PARP1 inhibitors as a therapeutic countering of SARS-CoV-2 virus. Methods: An extensive bibliographic search was done using Pubmed, Mendeley and google scholar with key words. Pre-prints are reported with potential caveats and studies without experimental data were excluded. Results: Covid-19, a global pandemic; is associated with systemic surge of inflammatory cytokines resulting in severe inflammation of the lung, heart dysfunction, ischemia, and stroke. PARP1 regulates expression of NFkB and downstream cytokine production and its inhibition is known to attenuate the expression of inflammatory cytokines. PARP1 and other PARP family members regulate viral infection, replication, and virulence. The literature clearly suggests that PARP1 plays an important role in host-pathogen interactions and pathogenesis, with pre-clinical and in vitro studies supporting the idea that PARP1 inhibition may negatively affect viability of several viruses including the replication of the SARS-CoV and SARS-CoV-2 virus. Conclusion: The current review discusses mechanisms of PARP1 activation during viral infection, inflammatory diseases, cytokine expression and possibility of PARP1 in regulating cytokine storm and hyper-inflammation seen with Covid-19. Additionally, in vitro studies showing the negative regulation of SARS-CoV-2 virus replication by PARP inhibitors indicates a potential therapeutic role of PARP inhibitors for Covid-19 or its variants.

Background: Glycogen syntheis kinase (GSK-3) inhibitors are novel therapeutic agents for treating various types of cancer, such as breast, lung, and gastric cancer. No pathological changes have been found by the morphological examination of GSK-3. Objectives: This review describes recent procedures using GSK-3 inhibitors, primarily in treating colon carcinoma. Furthermore, it also explains the mechanism of action of different GSK-3 inhibitors in treating various types of cancers and proposes some additional mechanisms may be useful for further research on GSK-3 inhibitors for cancers, including colon carcinoma. Results: The majority of the cancerous and pre-cancerous lesions are stimulated by the transformation of membrane-bound arachidonic acid (AA) to eicosanoids, a transformation that promotes for the viability, proliferation, and spread of cancer. GSK-3 inhibitors can reinstate hostility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) responsiveness in gastric adenocarcinoma cells. GSK-3, the final enzyme in glycogen synthesis, is a serine/threonine kinase that phosphorylates varied sequences that are more than a hundred in number, within proteins in an array of heterogeneous pathways. It is an essential module of an exceptionally large number of cellular processes, playing a fundamental role in many metabolic processes and diseases. Many patients diagnosed with colon cancer achieve long-term remission with outstanding survival through the GSK-3 inhibitors. Conclusion: Prior to the extensive application of these proposed mechanisms of GSK-3 inhibitor, further evaluation and clinical studies are needed. Only after the completion of appropriate clinical studies and morphological examinations, would extensive application be apprpriate.

Since the discovery of (2α,3β)-2,3-dihydroxyolean-12-en-28-oic acid, also known as maslinic acid, many studies have examined its biological activity, which has been shown to promote health and resist various diseases. This article focuses on previous research on maslinic acid and mainly reviews its reported effects on cardiovascular diseases, neuroprotection, diabetes, cancer, inflammation, and pathogens. Maslinic acid exerts positive effects on both cell and animal models of disease. Although its mechanism of action has not yet been completely elucidated, maslinic acid is feasible as a nutritional additive and has the potential to be developed as a drug.

Psoriasis is an immune-mediated chronic skin inflammation. This disease can be associated with several manifestations like red flakes, silver scales, patches, plaques, and silvery-white squams. Approximately 70% of the patients treated with topical dosage forms have a mild-to-moderate form of psoriasis, whereas a moderate-to-severe form of psoriasis is treated with systemic, photo, and biological therapies. Considering the big fraction that topicals cover, we present the current market potential, clinical relevance, and recent advances in the topical delivery of the drug for psoriasis. Though we witnessed several advancements in the recent few decades, delivering new immunomodulatory and biological molecules for topical psoriatic treatment have been proven to be efficient and safe options for the large percentage of patients for whom systemic therapy is not indicated. This article enumerates the promising topical dosage forms at present under assessment for their clinical pertinence. The competency of conventional topicals to reach and transform the world market is enumerated in terms of their success rate after proving the clinical pertinence against psoriasis. However, the entrance of novel drug delivery systems based on advanced topical products in the global market is highly anticipated as they have immense potential to impact the psoriasis treatment in the near future.

Cancer-associated fibroblasts (CAFs) are senescent fibroblasts in tumor nest, which trigger a signaling center to remodel a desmoplastic tumor niche. CAF’s functions in cancer are closely similar to myofibroblasts during the wound healing process. They can produce cytokines, enzymes, and protein- or RNA-containing exosomes to alter the function of surrounding cells. Non-- coding RNAs, including microRNAs and long non-coding RNAs, modulate pathologic mechanisms in cancer. Dysregulation of these RNAs influences the formation and function of CAFs. Furthermore, it has been demonstrated that CAFs, by releasing non-coding RNAs-containing exosomes, affect the tumor cells’ behavior. CAFs also secrete mediators such as chemokines to alter the expression of non-coding RNAs in the tumor microenvironment. This study aimed to discuss the role of non-coding RNAs in CAF development in cancer. Additionally, we have shed light on the therapeutic approaches to develop the strategies based on the alteration of non-coding RNAs in cancer.

Objective: Early in December 2019, mass sufferers due to Novel Coronavirus Pneumonia (SARS-CoV-2) in Wuhan (China) roused worldwide concern. Hardly any drugs showed the light of hope concerning the depletion in the period of treatment, and virological suppression became ineffective. Furthermore, numerous sufferers have undergone off-label use or compassionate use treatments as well as antiretroviral, antiparasitic agents, anti-inflammatory compounds, and convalescent plasma in either oral/parenteral route. This study aims to compile and analyze the effectiveness of Remdesivir and Hydroxychloroquine and give an insight into their drug profile in the treatment and management of COVID-19 patients. Methods: Relevant literature was searched from PubMed, Crossref, Springer, Bentham Sciences, Google Scholar, DOAJ, ScienceDirect, and MEDLINE by using keywords like COVID-19, SARS-- COV-2, Remdesivir, and Hydroxychloroquine. Appropriate peer-reviewed articles were studied and compiled for this review paper. The figures were prepared by using ChemOffice 2016 (Chem- Draw Professional 2016) and Microsoft Office. Results: This study indicates that 5 out of 10 works of literature find that Remdesivir leads to a reduction in recovery time, and the remaining 5 pieces of literature found Remdesivir to have no variance and have limitations. However, 6 out of 12 articles presented an increased chance of survival or reduction in recovery time due to hydroxychloroquine, while the remaining 6 presented hydroxychloroquine having no effect. Conclusion: There is a need to assess more pharmacokinetics and randomized controlled trials (RCT) for Remdesivir and Hydroxychloroquine. Studies should be conducted in different combinations along with Hydroxychloroquine and Remdesivir to obtain better results.

A serine/threonine-protein kinase, recognized as Glycogen Synthase Kinase-3 (GSK-3), is documented as a regulator of assorted cellular roles. GSK-3 activates by phosphorylation and thereby controls the action of many physiological, messenger, and membrane-bound structures. GSK-3α and GSK-3β are two vastly homologous forms of GSK-3 in mammals. Recent information has recommended that GSK-3β is a constructive controller of cancer cell proliferation and a promising key target against cancer cells. GSK-3 is overexpressed in various tumor types, including ovarian tumors. In human breast carcinoma, it has been revealed that the overexpression of GSK-3β was linked with breast cancer patients. The inhibition of GSK-3 or inhibitors of GSK-3 is a promising therapeutic tactic to overcome breast and ovarian cancer. This article features an important aspect of inhibitors of Glycogen Synthase Kinase-3 as a new lead for treating breast and ovarian Cancer.

In India as well as globally, diabetes is in a state of high risk and next to cardiovascular disease. As per the WHO, the risk of diabetes is expected to rise about 511 million by 2030. In quest of novel targets for type-2 diabetes, many targets were elucidated, such as Glycogen Synthase Kinase-3 (GSK-3), Dipeptidyl Peptidase (DPP-IV), PPAR-γ, α-Glucosidase, α-Amylase, GLP-1, and SGLT. Among the targets, GSK-3 was reported to be an effective target for the treatment of diabetes. In the metabolism of glycogen, GSK is a regulatory enzyme for the biosynthesis of glycogen (glycogenesis). It catalyzes the synthesis of a linear unbranched molecule with 1,4-α-glycosidic linkages. GSK-3 family has two isoenzymes, namely α and β, which differ in their Nand C- terminal sequences and are semi-conservative multifunctional serine/threonine kinase enzymes. In this chapter, we discuss an overview of general diabetic mechanisms and how GSK-3 modulation may influence these processes. Mutation in the GSK-3 complex causes diabetes. Synthetic and natural scaffolds modulate GSK-3 against diabetes and leading to its optimization for the development of GSK-3 inhibitors. This review mainly focuses on the development of GSK-3 inhibitors and highlights current and potential future therapeutic approaches that support the notion of targeting glucose metabolism with novel antidiabetic agents.

Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed serine/threonine kinase and was first identified as a regulator of glycogen synthase enzyme and glucose homeostasis. It regulates cellular processes like cell proliferation, metabolism, apoptosis and development. Recent findings suggest that GSK-3 is required to maintain the normal cardiac homeostasis that regulates cardiac development, proliferation, hypertrophy and fibrosis. GSK-3 is expressed as two isoforms, α and β. The role of GSK-3α and GSK-3β in cardiac biology is well documented. Both isoforms have common as well as isoform-specific functions. Human data also suggests that GSK-3β is downregulated in hypertrophy and heart failure and acts as a negative regulator. Pharmacological inhibition of GSK-3α and GSK-3β leads to endogenous cardiomyocyte proliferation and cardiac regeneration via the upregulation of cell cycle regulators, which results in cell cycle re-entry and DNA synthesis. It was found that cardiac-specific knockout (KO) of GSK-3α retained cardiac function, inhibited cardiovascular remodelling and restricted scar expansion during ischemia. Further, knockout of GSK-3α decreases cardiomyocyte apoptosis and enhances its proliferation. However, GSK-3β KO also results in hypertrophic myopathy due to cardiomyocyte hyper-proliferation. Thus GSK-3 inhibitors are named as a double-edged sword because of their beneficial and off-target effects. This review focuses on the isoform-specific functions of GSK-3 that will help in better understanding the role of GSK-3α and GSK-3β in cardiac biology and pave the way for the development of new isoform-specific GSK-3 modulator for the treatment of ischemic heart disease, cardiac regeneration and heart failure.