Impediment of Cancer by Dietary Plant-derived Alkaloids Through Oxidative Stress: Implications of PI3K/AKT Pathway in Apoptosis, Autophagy, and Ferroptosis.

The adverse toxicities and stemness are two major factors that constrained the usage of therapeutic strategies to target several cancer types. Previous studies explored the efficacy of PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-specific inhibitors against several cancer types, and many of them are currently in clinical trials. The current review described the efficacy of alkaloids derived from dietary plant sources in developing a new anti-cancer to reduce the prevalence of cancer through the modulation of apoptosis, autophagy, and ferroptosis. We have substantially collected the information pertinent to several intracellular pathways, including PI3K signaling, apoptosis, ferroptosis, and autophagy in modulating cancer progression mediated by the plantderived alkaloids such as daurisoline, dauricine, vasicine, vasicinone, 2-Acetyl-benzylamine, nuciferine, liensinine, gramine, and berbamine. These alkaloids exhibit significant anti-cancer potential to inhibit cancer cells by enhancing the intracellular ROS level and modulation of several signaling pathways, mainly through the PI3K/AKT pathway. These alkaloids can modulate chemotherapeutic agents' efficacy in various cancer cells, both in vitro and in vivo models. Overall the futures for the continued use of alkaloids from natural sources against cancer have to be extended, with the implementation of significant enhancements in the chemistry of these alkaloids for targeted delivery. In this review, we have selected major bioactive alkaloids of dietary and medicinal plants origin and discussed the anti-cancer and combinatorial therapeutic implications of these compounds with several FDA-approved drugs against various cancer cells.

A Recent Update on the Epigenetic Repertoire and Chromatin Modifying Therapy in Diabetes Mellitus: A Comprehensive Review.

Several epigenome studies reported the ability of genes to modulate the lipogenic and glucogenic pathways during insulin signaling as well as the other pathways involved in cardiometabolic diseases. Epigenetic plasticity and oxidative stress are interrelated in the pathophysiology of insulin resistance (IR) and cardiometabolic disease conditions. This review aims to ascertain the previous research evidence pertaining to the role of the epigenome and the variations of histone and non-histone proteins during cardiometabolic disease conditions and insulin signaling to develop effective disease-based epigenetic biomarkers and epigenetics-based chromatic therapy. Several public databases, including PubMed, National Library of Medicine, Medline, and google scholar, were searched for the peer-reviewed and published reports. This study delineates the consistent body of evidence regarding the epigenetic alterations of DNA/histone complexes pertinent to oxidative stress, insulin signaling, metabolic cardiomyopathy, and endothelial dysfunction in patients with cardiometabolic diseases. It has been described that both DNA methylation and post-translational histone alterations across visceral and subcutaneous adipose tissue could facilitate gene transcription to modulate inflammation, lipogenesis, and adipogenesis as the complex network of chromatin-modifying enzymatic proteins involved in the defensive insulin signaling across vasculature in patients with cardiometabolic diseases. Resveratrol, vorinostat, trichostatin, and apabetalone are reported to have significant implications as epigenetic modulators. Based on the epigenetic alterations, a wide range of protein/gene markers, such as interleukin-4 (IL-4) and interferon-γ (IFNγ) genes, may be considered as biomarkers in these patients due to their ability to the polarization of immune cells involved in tissue inflammation and atherosclerosis. Hence, it is crucial to unravel the cell-specific epigenetic information to develop individual risk assessment strategies for chromatin-modifying therapies in patients with cardiometabolic diseases.

The Role of Mitochondria in Piperine Mediated Cardioprotection in Isoproterenol Induced Myocardial Ischemia.

BACKGROUND: Several pharmacological therapeutic interventions are being used as therapeutic agents against myocardial infarction/ischemia (MI) but their usage is constrained by toxicity and nonselective pharmacological actions. Our preliminary report depicted the cardioprotective effect of piperine against isoproterenol (ISO)-induced MI. AIM: Current study determined the protective efficacy of piperine by modulating mitochondrial function in rat models of isoproterenol (ISO)-induced myocardial ischemia. METHODS: The above aim was achieved by analyzing mitochondrial antioxidant status, mitochondrial calcium, mitochondrial enzyme activity, ATP level, and apoptosis. Ultra-structural alterations in heart tissue were determined by TEM analysis. RT-PCR studies and Western blotting were executed to determine apoptotic and proapoptotic gene expression, and apoptotic protein expression, respectively. RESULTS: The results elucidate that piperine pre-treatment prevents ISO induced alterations in the mitochondrial antioxidant status, Krebs cycle as well as mitochondrial respiratory chain enzyme activities (MRCEs). ISO induced ultrastructural changes of heart mitochondria were significantly reduced in the group that received piperine pretreatment followed by ISO injection. Piperine maintains mitochondrial calcium homeostasis and inhibits ISO-induced myocardial apoptosis. A significant increase in the expression levels of proapoptotic genes such as Bax, caspases (caspase 9, caspase 3), and cytochrome-c with a concomitant decrease in Bcl-2 expression (anti-apoptotic gene) was observed in ISO injected group compared to the control group. The group that received the piperine pretreatment followed by ISO administration showed a significant decrease in the expression profile of proapoptotic genes with a concomitant increase in the anti-apoptotic gene expression than the ISO injected group. Apoptotic protein expressions including Bax, cytochrome-c, caspase-3, and cleaved PARP were upregulated & Bcl-2 was downregulated with ISO treatment, whereas piperine pre-treatment prevented these changes in apoptotic protein expressions during ISO-induced myocardial cell damage. CONCLUSION: Current results demonstrate the efficacy of piperine for attenuating ISO-induced myocardial ischemia by enhancing mitochondria function. This study described that piperine could be used as a nutritional intervention against ISO-induced myocardial ischemia.

The protective effect of piperine against isoproterenol-induced inflammation in experimental models of myocardial toxicity.

Myocardial infarction (MI) eventually exacerbates inflammatory response due to the release of inflammatory and pro-inflammatory factors. The aim of this study is to explore the protective efficacy of piperine supplementation against the inflammatory response in isoproterenol (ISO)-induced MI. Masson Trichome staining was executed to determine myocardial tissue architecture. Immunohistochemistry was performed for IL-6, TNF-α. RT-PCR studies were performed to ascertain the gene expression of IL-6, TNF-α, iNOS, eNOS, MMP-2, MMP-9, and collagen-III. Western blotting was performed to determine expression of HIF-1α, VEGF, Nrf-2, NF-ƙB, Cox-2, p-38, phospho-p38, ERK-1/2, phospho-ERK-1/2, and collagen-I. HIF-1α, VEGF, and iNOS expression were significantly upregulated with concomitant decline in eNOS expression in the heart myocardial tissue of rats received ISO alone whereas piperine pretreatment prevented these changes in ISO administered rats. Current results revealed ROS-mediated activation of MAPKs, namely, p-p38, p-ERK1/2 in the heart tissue of ISO administered group. Piperine pretreatment significantly prevented these changes in ISO treated group. NF-κB is involved in the modulation of gene expressions responsible for tissue repair. ISO-induced NF-κB-p65 expression was significantly reduced in the group pretreated with piperine and mitigated extent of myocardial inflammation. A significant increase in cardiac fibrosis upon ISO treatment was reported due to the increased hydroxyproline content, MMP-2 & 9 and upregulation of collagen-I protein compared to control group. All these cardiac hypertrophy markers were decreased in 'piperine pretreated ISO administered group' compared to group received ISO injection. Current findings concluded that piperine as a nutritional intervention could prevent inflammation of myocardium in ISO-induced MI.

The Cytoprotective and Anti-cancer Potential of Bisbenzylisoquinoline Alkaloids from Nelumbo nucifera.

Natural product therapy has been gaining therapeutic importance against various diseases, including cancer. The failure of chemotherapy due to its associated adverse effects promoted adjunct therapy with natural products. Phytochemicals exert anti-carcinogenic activities through the regulation of various cell signaling pathways such as cell survival, inflammation, apoptosis, autophagy and metastasis. The 'small molecule-chemosensitizing agents' from plants induce apoptosis in drug-resistant and host-immune resistant cancer cells in in vitro as well as in vivo models. For example, alkaloids from Nelumbo nucifera, liensinine, isoliensinine and neferine exert the anticancer activity through enhanced ROS generation, activation of MAP kinases, followed by induction of autophagy and apoptotic cell death. Likewise, these alkaloids also exert their cytoprotective action against cerebrovascular stroke/ischemic stroke, diabetes, and chemotherapy-induced cytotoxicity. Therefore, the present review elucidates the pharmacological activities of these bisbenzylisoquinoline alkaloids which include the cytoprotective, anticancer and chemosensitizing abilities against various diseases such as cardiovascular diseases, neurological diseases and cancer.

Neferine and isoliensinine enhance 'intracellular uptake of cisplatin' and induce 'ROS-mediated apoptosis' in colorectal cancer cells - A comparative study.

Cisplatin (CDDP) is a potent platinum-based chemotherapeutic agent used to treat solid tumors including colorectal cancer via inducing cytotoxicity. CDDP usage is limited due to the chemoresistance and associated adverse effects. A combinatorial regimen of phytochemicals with anticancer activity along with approved anticancer drugs seems to be a hopeful strategy against cancer treatment. Lotus-derived compounds such as neferine and isoliensinine have proven significant chemosensitizing activity in different cancer cells. Present study aims to compare chemosensitizing activity/anticancer potential of neferine/isoliensinine in combinatorial regimen with CDDP. Results documented that neferine/isoliensinine with CDDP augmented 'intracellular uptake of cisplatin' consequently apoptosis in HCT-15 cells exemplified by 'apoptotic morphological changes', 'S phase cell cycle arrest', 'ROS mediated oxidative stress' with the concomitant escalation in intracellular calcium & dissipation of MMP and activation of MAPK/PI3K/AKT pathway'. Furthermore, isoliensinine combination with CDDP exclusively enhanced CDDP uptake and induced more ROS-mediated apoptosis compared to other treatment regimens. Combination regimens induced downregulation of Bcl2 and upregulation of cytochrome c, caspase 3, 9, PARP cleavage indicating apoptosis induction through the intrinsic pathway. Thus, the results of the present study suggest that CDDP combination with neferine/isoliensinine augments the anticancer potential of CDDP in an additive manner and decrease CDDP dose requirement.

Premyelinated central axons express neurotoxic NMDA receptors: relevance to early developing white-matter injury.

Ischemic-type injury to developing white matter is associated with the significant clinical condition cerebral palsy and with the cognitive deficits associated with premature birth. Premyelinated axons are the major cellular component of fetal white matter and loss of axon function underlies the disability, but the cellular mechanisms producing ischemic injury to premyelinated axons have not previously been described. Injury was found to require longer periods of modelled ischemia than at latter developmental points. Ischemia produced initial hyperexcitability in axons followed by loss of function after Na(+) and Ca(2+) influx. N-methyl-D-aspartate- (NMDA) type glutamate receptor (GluR) agonists potentiated axon injury while antagonists were protective. The NMDA GluR obligatory Nr1 subunit colocalized with markers of small premyelinated axons and expression was found at focal regions of axon injury. Ischemic injury of glial cells present in early developing white matter was NMDA GluR independent. Axons in human postconception week 18 to 23 white matter had a uniform prediameter expansion phenotype and postembedded immuno-gold labelling showed Nr1 subunit expression on the membrane of these axons, demonstrating a shared key neuropathologic feature with the rodent model. Premyelinated central axons therefore express high levels of functional NMDA GluRs that confer sensitivity to ischemic injury.