New Investigational Drug's Targeting Various Molecular Pathways for Treatment of Cervical Cancer: Current Status and Future Prospects.

Currently, cervical cancer (CC) is the fourth recorded widespread cancer among women globally. There are still many cases of metastatic or recurring disease discovered, despite the incidence and fatality rates declining due to screening identification and innovative treatment approaches. Palliative chemotherapy continues to be the standard of care for patients who are not contenders for curative therapies like surgery and radiotherapy. This article seeks to provide a thorough and current summary of therapies that have been looked into for the management of CC. The authors emphasize the ongoing trials while reviewing the findings of clinical research. Agents that use biological mechanisms to target different molecular pathways such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribosepolymerase (PARP), and epigenetic biological mechanisms epitomize and offer intriguing research prospects.

The combination of histone deacetylase inhibitors and radiotherapy: a promising novel approach for cancer treatment.

HDAC inhibitors (HDACi) play an essential role in various cellular processes, such as differentiation and transcriptional regulation of key genes and cytostatic factors, cell cycle arrest and apoptosis that facilitates the targeting of epigenome of eukaryotic cells. In the majority of cancers, only a handful of patients receive optimal benefit from chemotherapeutics. Additionally, there is emerging interest in the use of HDACi to modulate the effects of ionizing radiations. The use of HDACi with radiotherapy, with the goal of reaching dissimilar, often distinct pathways or multiple biological targets, with the expectation of synergistic effects, reduced toxicity and diminished intrinsic and acquired resistance, conveys an approach of increasing interest. In this review, the clinical potential of HDACi in combination with radiotherapy is described as an efficient synergy for cancer treatment will be overviewed.

Hydroxamic acid derivatives as selective HDAC3 inhibitors: computer-aided drug design strategies.

Histone deacetylases (HDACs) are critical epigenetic drug targets that have gained significant attention in the scientific community for the treatment of cancer. The currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Here, we describe our protocol for the discovery of novel potential hydroxamic acid based HDAC3 inhibitors through pharmacophore modeling, virtual screening, docking, molecular dynamics (MD) simulation and toxicity studies. The ten pharmacophore hypotheses were established, and their reliability was validated by different ROC (receiving operator curve) analysis. Among them, the best model (Hypothesis 9 or RRRA) was employed for searching SCHEMBL, ZINC and MolPort database to screen out hit molecules as selective HDAC3 inhibitors, followed by different docking stages. MD simulation (50 ns) and MMGBSA study were performed to study the stability of ligand binding modes and with the help of trajectory analysis, to calculate the ligand-receptor complex RMSD (root-mean-square deviation), RMSF (root-mean-square fluctuation) and H-bond distance, etc. Finally, in-silico toxicity studies were performed on top screened molecules and compared with reference drug SAHA and established structure-activity relationship (SAR). The results indicated that compound 31, with high inhibitory potency and less toxicity (probability value 0.418), is suitable for further experimental analysis.Communicated by Ramaswamy H. Sarma.

Pharmacophore modeling and virtual screening were performed with hydroxamic acid derivatives as HDAC3 inhibitors.MD simulation was performed for 50 ns time duration for selected protein-ligand complexes.SAR and toxicity studies (using TOPKAT tool) were performed.The results of these studies might be valuable in the further design and development of more potent HDAC3 inhibitors.

The Role of Cytokines in Activation of Tumour-promoting Pathways and Emergence of Cancer Drug Resistance.

Scientists are constantly researching and launching potential chemotherapeutic agents as an irreplaceable weapon to fight the battle against cancer. Despite remarkable advancement over the past several decades to wipe out cancer through early diagnosis, proper prevention, and timely treatment, cancer is not ready to give up and leave the battleground. It continuously tries to find some other way to give a tough fight for its survival, either by escaping from the effect of chemotherapeutic drugs or utilising its own chemical messengers like cytokines to ensure resistance. Cytokines play a significant role in cancer cell growth and progression, and the present article highlights their substantial contribution to mechanisms of resistance toward therapeutic drugs. Multiple clinical studies have even described the importance of specific cytokines released from cancer cells as well as stromal cells in conferring resistance. Herein, we discuss the different mechanism behind drug resistance and the crosstalk between tumor development and cytokines release and their contribution to showing resistance towards chemotherapeutics. As a part of this review, different approaches to cytokines profile have been identified and employed to successfully target new evolving mechanisms of resistance and their possible treatment options.

Microbial Metabolites-Induced Epigenetic Modifications for Inhibition of Colorectal Cancer: Current Status and Future Perspectives.

Globally, one of the most prevalent cancers is colorectal cancer (CRC). Chemotherapy and surgery are two common conventional CRC therapies that are frequently ineffective and have serious adverse effects. Thus, there is a need for complementary and different therapeutic approaches. The use of microbial metabolites to trigger epigenetic alterations as a way of preventing CRC is one newly emerging field of inquiry. Small chemicals called microbial metabolites, which are made by microbes and capable of altering host cell behaviour, are created. Recent research has demonstrated that these metabolites can lead to epigenetic modifications such as histone modifications, DNA methylation, and non-coding RNA regulation, which can control gene expression and affect cellular behaviour. This review highlights the current knowledge on the epigenetic modification for cancer treatment, immunomodulatory and anti-carcinogenic attributes of microbial metabolites, gut epigenetic targeting system, and the role of dietary fibre and gut microbiota in cancer treatment. It also focuses on short-chain fatty acids, especially butyrates (which are generated by microbes), and their cancer treatment perspective, challenges, and limitations, as well as state-of-the-art research on microbial metabolites-induced epigenetic changes for CRC inhibition. In conclusion, the present work highlights the potential of microbial metabolites-induced epigenetic modifications as a novel therapeutic strategy for CRC suppression and guides future research directions in this dynamic field.

Targeting Lysosomes: A Strategy Against Chemoresistance in Cancer.

Chemotherapy is still the major method of treatment for many types of cancer. Curative cancer therapy is hampered significantly by medication resistance. Acidic organelles like lysosomes serve as protagonists in cellular digestion. Lysosomes, however, are gaining popularity due to their speeding involvement in cancer progression and resistance. For instance, weak chemotherapeutic drugs of basic nature permeate through the lysosomal membrane and are retained in lysosomes in their cationic state, while extracellular release of lysosomal enzymes induces cancer, cytosolic escape of lysosomal hydrolases causes apoptosis, and so on. Drug availability at the sites of action is decreased due to lysosomal drug sequestration, which also enhances cancer resistance. This review looks at lysosomal drug sequestration mechanisms and how they affect cancer treatment resistance. Using lysosomes as subcellular targets to combat drug resistance and reverse drug sequestration is another method for overcoming drug resistance that is covered in this article. The present review has identified lysosomal drug sequestration as one of the reasons behind chemoresistance. The article delves deeper into specific aspects of lysosomal sequestration, providing nuanced insights, critical evaluations, or novel interpretations of different approaches that target lysosomes to defect cancer.

Dietary Plant Metabolites Induced Epigenetic Modification as a Novel Strategy for the Management of Prostate Cancer.

Prostate cancer is a widespread malignancy among men, with a substantial global impact on morbidity and mortality. Despite advances in conventional therapies, the need for innovative and less toxic treatments remains a priority. Emerging evidence suggests that dietary plant metabolites possess epigenetic-modifying properties, making them attractive candidates for prostate cancer treatment. The present work reviews the epigenetic effects of dietary plant metabolites in the context of prostate cancer therapy. We first outline the key epigenetic mechanisms involved in prostate cancer pathogenesis, including histone modifications, DNA methylation, and miRNA or Long Noncoding RNA (lncRNA) dysregulation. Next, we delve into the vast array of dietary plant metabolites that have demonstrated promising anti-cancer effects through epigenetic regulation. Resveratrol, minerals, isothiocyanates, curcumin, tea polyphenols, soy isoflavones and phytoestrogens, garlic compounds, anthocyanins, lycopene, and indoles are among the most extensively studied compounds. These plant-derived bioactive compounds have been shown to influence DNA methylation patterns, histone modifications, and microRNA expression, thereby altering the gene expression allied with prostate cancer progression, cell proliferation, and apoptosis. We also explore preclinical and clinical studies investigating the efficacy of dietary plant metabolites as standalone treatments or in combination with traditional treatments for people with prostate cancer. The present work highlights the potential of dietary plant metabolites as epigenetic modulators to treat prostate cancer. Continued research in this field may pave the way for personalized and precision medicine approaches, moving us closer to the goal of improved prostate cancer management.

Exploration of Structure-Activity Relationship Using Integrated Structure and Ligand Based Approach: Hydroxamic Acid-Based HDAC Inhibitors and Cytotoxic Agents.

The present study aimed to establish significant and validated quantitative structure-activity relationship (QSAR) models for histone deacetylase (HDAC) inhibitors and correlate their physicochemical, steric, and electrostatic properties with their anticancer activity. We have selected a dataset from earlier research findings. The target and ligand molecules were procured from recognized databases and incorporated into pivotal findings such as molecular docking (XP glide), e-pharmacophore study and 3D QSAR model designing study (phase). Docking revealed molecule 39 with better docking score and well binding contact with the protein. 3D QSAR analysis, which was performed for partial least squares factor 5 reported good 0.9877 and 0.7142 as R2 and Q2 values and low standard of deviation: 0.1049 for hypothesis AADRR.139. Based on the computational outcome, it has been concluded that molecule 39 is an effective and relevant candidate for inhibition of HDAC activity. Moreover, these computational approaches motivate to discover novel drug candidates in pharmacological and healthcare sectors.

Cortisol as a Target for Treating Mental Disorders: A Promising Avenue for Therapy.

Cortisol, commonly known as the "stress hormone," plays a critical role in the body's response to stress. Elevated cortisol levels have been associated with various mental disorders, including anxiety, depression, and post-traumatic stress disorder. Consequently, researchers have explored cortisol modulation as a promising avenue for treating these conditions. However, the availability of research on cortisol as a therapeutic option for mental disorders is limited, and existing studies employ diverse methodologies and outcome measures. This review article aimed to provide insights into different treatment approaches, both pharmacological and non-pharmacological, which can effectively modulate cortisol levels. Pharmacological interventions involve the use of substances, such as somatostatin analogs, dopamine agonists, corticotropin-releasing hormone antagonists, and cortisol synthesis inhibitors. Additionally, non-pharmacological techniques, including cognitivebehavioral therapy, herbs and supplements, transcranial magnetic stimulation, lifestyle changes, and surgery, have been investigated to reduce cortisol levels. The emerging evidence suggests that cortisol modulation could be a promising treatment option for mental disorders. However, more research is needed to fully understand the effectiveness and safety of these therapies.

Multi-targeted HDAC Inhibitors as Anticancer Agents: Current Status and Future Prospective.

Multi-targeted agents can interact with multiple targets sequentially, resulting in synergistic and more effective therapies for several complicated disorders, including cancer, even with relatively modest activity. Histone deacetylase (HDAC) inhibitors are low molecular weight small compounds that increase the acetylation of histone and nonhistone proteins, altering gene expression and thereby impacting angiogenesis, metastasis, and apoptosis, among other processes. The HDAC inhibitors affect multiple cellular pathways thus producing adverse issues, causing therapeutic resistance, and they have poor pharmacokinetic properties. The designing of HDAC-based dual/multi-target inhibitor is an important strategy to overcome adverse effects, drug resistance and increase the effectiveness in controlling cancer. The selection of target combinations to design multitarget HDAC inhibitor is generally accomplished on the basis of systematic highthroughput screening (HTS), network pharmacology analysis methods. The identification of the pharmacophore against individual targets is performed using rational or computation methods. The identified pharmacophore can combine with merged, fused, or linked with the cleavable or non-cleavable linker to retain the interaction with the original target while being compatible with the other target. The objective of this review is to elucidate the potential targets' design strategies, biological activity, and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. This review elucidates the designing strategies of the potential target along with biological activity and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. The development of HDAC-based dual/multi-target inhibitors is important for overcoming side effects, drug resistance, and effective cancer control.

Combination Therapy for the Treatment of Alzheimer's Disease: Recent Progress and Future Prospects.

BACKGROUND: The management of Alzheimer's disease is challenging due to its complexity. However, the currently approved and marketed treatments for this neurodegenerative disorder revolves around cholinesterase inhibitors, glutamate regulators, or the combination of these agents. Despite the prompt assurance of many new drugs, several agents were unsuccessful, especially in phase II or III trials, not meeting efficacy endpoints. OBJECTIVE: The execution of effective treatment approaches through further trials investigating a rational combination of agents is necessitude for Alzheimer's disease. METHODS: For this review, more than 248 relevant scientific papers were considered from a variety of databases (Scopus, Web of Science, Google Scholar, ScienceDirect, and PubMed) using the keywords Alzheimer's disease, amyloid-ß, combination therapies, cholinesterase inhibitors, dementia, glutamate regulators, AD hypothesis. RESULT AND DISCUSSION: The researcher's intent is to either develop a disease-modifying therapeutic means for aiming in the early phases of dementia and/or optimize the available symptomatic treatments principally committed to the more advanced stages of Alzheimer's. Since Alzheimer's possesses multifactorial pathogenesis, designing a multimodal therapeutic intervention for targeting different pathological processes of dementia may appear to be the most practical method to alter the course of disease progression. CONCLUSION: The combination approach may even allow for providing individual agents in lower doses, with reducible costs and side effects. Numerous studies on combination therapy predicted better clinical efficacy than monotherapy. The literature review highlights the major clinical studies (both symptomatic and disease-modifying) conducted in the past decade on combination therapy to combat cognitive disorder.

Histone deacetylase inhibitor-based oncolytic virotherapy: A promising strategy for cancer treatment.

A significant impediment to the treatment of solid and nonsolid cancers is the decline of drug efficacy and/or occurrence of adverse effects. In recent years, there has been increasing interest in oncolytic viruses (OVs) as a method to treat cancer because of their specificity for cancerous tissue and reduced likelihood of adverse effects. The results of clinical trials suggest that OVs have an acceptable safety profile and are effective in treating certain types of cancer, despite the limited number of these organisms. However, further advances are needed to make oncolytic virotherapy more effective by increasing tumor permeation and improving virus delivery. Combining oncolytic virotherapy with conventional treatments, such as targeted inhibitory drugs (e.g., histone deacetylase inhibitors), could results in safer, more reliable, and more effective therapeutics.

Corticosteroids for treatment of COVID-19: effect, evidence, expectation and extent.

BACKGROUND: The World Health Organization (WHO) announced the COVID-19 occurrence as a global pandemic in March 2020. The treatment of SARS-CoV-2 patients is based on the experience gained from SARS-CoV and MERS-CoV infection during 2003. There is no clinically accepted therapeutic drug(s) accessible yet for the treatment of COVID-19. MAIN BODY: Corticosteroids, i.e., dexamethasone, methylprednisolone, hydrocortisone and prednisone are used alone or in combination for the treatment of moderate, severe and critically infected COVID-19 patients who are hospitalized and require supplemental oxygen as per current management strategies and guidelines for COVID-19 published by the National Institutes of Health. Corticosteroids are recorded in the WHO model list of essential medicines and are easily accessible worldwide at a cheaper cost in multiple formulations and various dosage forms. Corticosteroid can be used in all age group of patients, i.e., children, adult, elderly and during pregnancy or breastfeeding women. Corticosteroids have potent anti-inflammatory and immunosuppressive effects in both primary and secondary immune cells, thereby reducing the generation of proinflammatory cytokines and chemokines and lowering the activation of T cells, monocytes and macrophages. The corticosteroids should not be used in the treatment of non-severe COVID-19 patients because corticosteroids suppress the immune response and reduce the symptoms and associated side effects such as slow recovery, bacterial infections, hypokalemia, mucormycosis and finally increase the chances of death. CONCLUSION: Intensive research on corticosteroid therapy in COVID-19 treatment is urgently needed to elucidate their mechanisms and importance in contributing toward successful prevention and treatment approaches. Hence, this review emphasizes on recent advancement on corticosteroid therapy for defining their importance in overcoming SARS-CoV-2 pandemic, their mechanism, efficacy and extent of corticosteroids in the treatment of COVID-19 patients.

Understanding the role of ACE-2 receptor in pathogenesis of COVID-19 disease: a potential approach for therapeutic intervention.

Angiotensin-converting enzyme (ACE) and its homologue, ACE2, are commonly allied with hypertension, renin-angiotensin-aldosterone system pathway, and other cardiovascular system disorders. The recent pandemic of COVID-19 has attracted the attention of numerous researchers on ACE2 receptors, where the causative viral particle, SARS-CoV-2, is established to exploit these receptors for permitting their entry into the human cells. Therefore, studies on the molecular origin and pathophysiology of the cell response in correlation to the role of ACE2 receptors to these viruses are bringing novel theories. The varying level of manifestation and importance of ACE proteins, underlying irregularities and disorders, intake of specific medications, and persistence of assured genomic variants at the ACE genes are potential questions raising nowadays while observing the marked alteration in response to the SARS-CoV-2-infected patients. Therefore, the present review has focused on several raised opinions associated with the role of the ACE2 receptor and its impact on COVID-19 pathogenesis.

Synthetic and Semi-synthetic Drugs as a Promising Therapeutic Option for the Treatment of COVID-19.

The novel coronavirus disease-19 (COVID-19) is a global pandemic that emerged from Wuhan, China, and has spread all around the world, affecting 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 updates of August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine exists. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID- 19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in clinical uses or studies on COVID-19 and also focuses on the mode of action of drugs being repositioned against COVID-19.