An insight into the mechanisms of action of selected bioactive compounds against epigenetic targets of prostate cancer: implications on histones modifications.

Prostate cancer is a leading cause of morbidity and mortality among men globally. In this study, we employed an in silico approach to predict the possible mechanisms of action of selected novel compounds reported against prostate cancer epigenetic targets and their derivatives, exhausting through ADMET profiling, drug-likeness, and molecular docking analyses. The selected compounds: sulforaphane, silibinin, 3, 3'-diindolylmethane (DIM), and genistein largely conformed to ADMET and drug-likeness rules including Lipinski's. Docking studies revealed strong binding energy of sulforaphane with HDAC6 (- 4.2 kcal/ mol), DIM versus HDAC2 (- 5.2 kcal/mol), genistein versus HDAC6 (- 4.1 kcal/mol), and silibinin against HDAC1 (- 7.0 kcal/mol) coupled with improved binding affinities and biochemical stabilities after derivatization. Findings from this study may provide insight into the potential epigenetic reprogramming mechanisms of these compounds against prostate cancer and could pave the way toward more success in prostate cancer phytotherapy.

Comparative G-Protein-Coupled Estrogen Receptor (GPER) Systems in Diabetic and Cancer Conditions: A Review.

For many patients, diabetes Mellitus and Malignancy are frequently encountered comorbidities. Diabetes affects approximately 10.5% of the global population, while malignancy accounts for 29.4 million cases each year. These troubling statistics indicate that current treatment approaches for these diseases are insufficient. Alternative therapeutic strategies that consider unique signaling pathways in diabetic and malignancy patients could provide improved therapeutic outcomes. The G-protein-coupled estrogen receptor (GPER) is receiving attention for its role in disease pathogenesis and treatment outcomes. This review aims to critically examine GPER' s comparative role in diabetes mellitus and malignancy, identify research gaps that need to be filled, and highlight GPER's potential as a therapeutic target for diabetes and malignancy management. There is a scarcity of data on GPER expression patterns in diabetic models; however, for diabetes mellitus, altered expression of transport and signaling proteins has been linked to GPER signaling. In contrast, GPER expression in various malignancy types appears to be complex and debatable at the moment. Current data show inconclusive patterns of GPER expression in various malignancies, with some indicating upregulation and others demonstrating downregulation. Further research should be conducted to investigate GPER expression patterns and their relationship with signaling pathways in diabetes mellitus and various malignancies. We conclude that GPER has therapeutic potential for chronic diseases such as diabetes mellitus and malignancy.

Potential epigenetic modifications implicated in triple- to quadruple-negative breast cancer transition: a review.

Current research on triple-negative breast cancer (TNBC) has resulted in delineation into the quadruple-negative breast cancer (QNBC) subgroup. Epigenetic modifications such as DNA methylation, histone posttranslational modifications and associated changes in chromatin architecture have been implicated in breast cancer pathogenesis. Herein, the authors highlight genes with observed epigenetic modifications that are associated with more aggressive TNBC/QNBC pathogenesis and possible interventions. Advanced literature searches were done on PubMed/MEDLINE, Scopus and Google Scholar. The results suggest that nine epigenetically altered genes/differentially expressed proteins in addition to the downregulated androgen receptor are associated with TNBC aggressiveness and could be implicated in the TNBC to QNBC transition. Thus, restoring the normal expression of these genes via epigenetic reprogramming could be therapeutically beneficial to TNBC and QNBC patients.

When the androgen hormone receptor becomes inactive in triple-negative breast cancer (TNBC) patients, it results in another subtype of breast cancer called quadruple-negative breast cancer (QNBC). This is because these patients already lack the biological activities of three other important hormone receptors. The functions of these receptors are targeted by some drugs used in the management of breast cancers, so the lack of these receptors in TNBC and QNBC patients is thought to be linked with poor response to treatment. Some epigenetic modifications are involved in a more severe disease that is very difficult to control in TNBC patients and could facilitate its transition to the more aggressive QNBC subtype. Treatment response could be improved by restoring the normal function of the altered genes by reversing the observed epigenetic alterations.

Epigenetic modifications associated with genes implicated in cytokine storm: The potential biotherapeutic effects of vitamins and minerals in COVID-19.

Cytokine storm is a phrase used to refer to an abrupt upsurge in the circulating levels of various pro-inflammatory cytokines, causing increased stimulation and activity of immune cells during disease conditions. The binding of pattern recognition receptors to pathogen-associated molecular patterns during COVID-19 infection recruits response machinery involving the activation of transcription factors and proteins required for a robust immune response by host cells. These immune responses could be influenced by epigenetic modifications as evidenced by significant variations in COVID-19 pathophysiology and response to therapy observed among patients across the globe. Considering that circulating levels of interleukin 1, tumor necrosis factor-α, and interleukin 6 are significantly elevated during cytokine storm in COVID-19 patients, genetic and epigenetic variations in the expression and function of these proteins could enhance our understanding of the disease pathogenesis. Treatment options that repress the transcription of specific cytokine genes during COVID-19 infection could serve as possible targets to counteract cytokine storm in COVID-19. Therefore, the present article reviews the roles of cytokines and associated genes in the COVID-19 cytokine storm, identifies epigenetic modifications associated with the disease progression, and possible ameliorative effects of some vitamins and minerals obtained as epigenetic modifiers for the control of cytokine storm and disease severity in COVID-19 patients. PRACTICAL APPLICATIONS: COVID-19 causes mortality and morbidity that adversely affect global economies. Despite a global vaccination campaign, side effects associated with vaccination, misconceptions, and a number of other factors have affected the expected successes. Cytokine storm in COVID-19 patients contributes to the disease pathogenesis and response to therapy. Epigenetic variations in the expression of various cytokines could be implicated in the different outcomes observed in COVID-19 patients. Certain vitamins and minerals have been shown to interfere with the expression and activity of cytokines implicated in cytokine storm, thereby counteracting observed pathologies. This review examines cytokines implicated in cytokine storm in COVID-19, epigenetic modifications that contribute to increased expression of identified cytokines, specific foods rich in the identified vitamins and minerals, and suggests their possible ameliorative benefits. The article will be beneficial to both scientists and the general public who are interested in the role of vitamins and minerals in ameliorating COVID-19.

Metabolic Implications of Oxidative Stress and Inflammatory Process in SARS-CoV-2 Pathogenesis: Therapeutic Potential of Natural Antioxidants.

COVID-19 is a zoonotic disease with devastating economic and public health impacts globally. Being a novel disease, current research is focused on a clearer understanding of the mechanisms involved in its pathogenesis and viable therapeutic strategies. Oxidative stress and inflammation are intertwined processes that play roles in disease progression and response to therapy via interference with multiple signaling pathways. The redox status of a host cell is an important factor in viral entry due to the unique conditions required for the conformational changes that ensure the binding and entry of a virus into the host cell. Upon entry into the airways, viral replication occurs and the innate immune system responds by activating macrophage and dendritic cells which contribute to inflammation. This review examines available literature and proposes mechanisms by which oxidative stress and inflammation could contribute to COVID-19 pathogenesis. Further, certain antioxidants currently undergoing some form of trial in COVID-19 patients and the corresponding required research gaps are highlighted to show how targeting oxidative stress and inflammation could ameliorate COVID-19 severity.

Vitex doniana Leaves Extract Ameliorates Alterations Associated with 7, 12-Dimethyl Benz[a]Anthracene-Induced Mammary Damage in Female Wistar Rats.

Vitex doniana leaves are used traditionally in West Africa for the treatment of swellings and cancer. We investigated if Vitex doniana leaves extract could ameliorate 7, 12-dimethylbenz[a]anthracene (DMBA)-induced mammary damage. Female Wistar rats aged 52 ± 2 day were administered 80 mg/kg DMBA. After monitoring for 150 day, rats were administered 0, 50, 100, 200 mg/kg Vitex doniana and 20 mg/kg Tamoxifen for 14 day. Serum estrogen receptor-α, IL-1ß and TNF -α levels were determined using ELISA kits. Oxidative stress markers in mammary tissue homogenates were determined using standard spectrophotometric methods. Histopathological examination was done using hematoxylin and eosin staining and cyclooxygenase-2 (COX-2) expression using immunohistochemistry. Liquid chromatography-mass spectrometry was used to determine components present in the extract. Although tumors were not observed, significantly (p < 0.05) lower estrogen receptor-α, malondialdehyde, IL-1ß and TNF -α levels, significantly (p < 0.05) higher glutathione and catalase activity, attenuation of malignant epithelial hyperplasia and mild COX-2 expression were observed in rats administered Vitex doniana when compared to DMBA-induced untreated control. Liquid chromatography-mass spectrometry analysis of the V. doniana extract revealed the presence of 4,5-dihydroxy-7-methoxy-6-methylflavone and vanillylamine, which are compounds with reported antioxidant and anti-inflammatory effects. Collectively, treatment with Vitex doniana ameliorated some derangement observed in DMBA-induced rats.

In silico predictions on the possible mechanism of action of selected bioactive compounds against breast cancer.

ABSTRACT: Breast cancer is one of the leading causes of death among women. We employed in silico model to predict the mechanism of actions of selected novel compounds reported against breast cancer using ADMET profiling, drug likeness and molecular docking analyses. The selected compounds were andrographolide (AGP), dipalmitoylphosphatidic acid (DPA), 3-(4-Bromo phenylazo)-2,4-pentanedione (BPP), atorvastatin (ATS), benzylserine (BZS) and 3ß,7ß,25-trihydroxycucurbita-5,23(E)-dien-19-al (TCD). These compounds largely conform to ADMETlab and Lipinki's rule of drug likeness criteria in addition to their lesser hepatotoxic and mutagenic effects. Docking studies revealed a strong affinity of AGP versus NF-kB (- 6.8 kcal/mol), DPA versus Cutlike-homeobox (- 5.1 kcal/mol), BPP versus Hypoxia inducing factor 1 (- 7.7 kcal/mol), ATS versus Sterol Regulatory Element Binding Protein 2 (- 7.2 kcal/mol), BZS versus Ephrin type-A receptor 2 (- 4.4 kcal/mol) and TCD versus Ying Yang 1 (- 9.4 kcal/mol). Likewise, interaction between the said compounds and respective gene products were evidently observed with strong affinities; AGP versus COX-2 (- 9.6 kcal/mol), DPA versus Fibroblast growth factor receptor (- 5.9 kcal/mol), BPP versus Vascular endothelial growth factor (- 5.8 kcal/mol), ATS versus HMG-COA reductase (- 9.1 kcal/mol), BZS versus L-type amino acid transporter 1 (- 5.3 kcal/mol) and TCD versus Histone deacytylase (- 7.7 kcal/mol), respectively. The compounds might potentially target transcription through inhibition of promoter-transcription factor binding and/or inactivation of final gene product. Thus, findings from this study provide a possible mechanism of action of these xenobiotics to guide in vitro and in vivo studies in breast cancer.

Sickling-preventive effects of rutin is associated with modulation of deoxygenated haemoglobin, 2,3-bisphosphoglycerate mutase, redox status and alteration of functional chemistry in sickle erythrocytes.

Sickle cell anaemia is a hereditary disease branded by an upsurge in generation of ROS, irregular iron release and little or no antioxidant activity which can lead to cellular injuries due to oxidative stress resulting in severe symptoms including anaemia and pain. The disease is caused by a mutated version of the gene that helps make haemoglobin, the protein that carries oxygen in red blood cells. We used in silico and in vitro experiments to examine the antisickling effects of rutin for the first time by means of before and after induction approaches in sickle erythrocytes. Rutin was docked against deoxy-haemoglobin and 2,3-bisphosphoglycerate mutase, revealing binding energies (-27.329 and -25.614 kcal/mol) and Ki of 0.989µM and 0.990 µM at their catalytic sites through strong hydrophobic and hydrogen bond interactions. Sickling was thereafter, induced at 3 h with 2% metabisulphite. Rutin prevented sickling maximally at 12.3µM and reversed same at 16.4µM, by 78.5% and 69.9%, one-to-one. Treatment with rutin significantly (P < 0.05) reinvented the integrity of erythrocytes membrane as evident from the practical % haemolysis compared to induced erythrocytes. Rutin also significantly (P < 0.05) prevented and reversed lipid peroxidation relative to untreated. Likewise, GSH, CAT levels were observed to significantly (P < 0.05) increase with concomitant significant (P < 0.05) decrease in SOD activity based on administration of rutin after sickling induction approach. Furthermore, FTIR results showed that treatment with rutin favourably altered the functional chemistry, umpiring from shifts and functional groups observed. It can thus be deduced that, antisickling effects of rutin may be associated with modulation of deoxy-haemoglobin, 2,3-bisphosphoglycerate mutase, alteration of redox homeostasis and functional chemistry of sickle erythrocytes.

Oxidative Stress and Carcinogenesis: Potential of Phytochemicals in Breast Cancer Therapy.

Breast cancer remains a burden in both developed and developing countries, with higher mortality in developing countries. Attempts to eradicate cancer have not been successful despite the progress made in the development of more novel chemotherapeutic drugs. Reactive-oxygen-species-mediated oxidative stress is known to play a role in breast cancer pathogenesis via genetic and epigenetic modifications, resulting in uncontrolled cell proliferation. Phytochemicals could provide leads for the development of alternative therapeutic agents due to their antioxidant activity, as well as their ability to induce apoptosis in cancer cells. However, most of the studies carried out using in vitro models do not continue with further studies in estrogen-receptor-positive in vivo breast cancer models, or fail to examine the possible biochemical mechanisms of phytochemical-based amelioration. This review examines oxidative-stress-mediated carcinogenesis and the potential of phytochemicals as anticancer agents.