Organotin (IV) Dithiocarbamate Compounds as Anticancer Agents: A Review of Syntheses and Cytotoxicity Studies.

Organotin (IV) dithiocarbamate has recently received attention as a therapeutic agent among organotin (IV) compounds. The individual properties of the organotin (IV) and dithiocarbamate moieties in the hybrid complex form a synergy of action that stimulates increased biological activity. Organotin (IV) components have been shown to play a crucial role in cytotoxicity. The biological effects of organotin compounds are believed to be influenced by the number of Sn-C bonds and the number and nature of alkyl or aryl substituents within the organotin structure. Ligands target and react with molecules while preventing unwanted changes in the biomolecules. Organotin (IV) dithiocarbamate compounds have also been shown to have a broad range of cellular, biochemical, and molecular effects, with their toxicity largely determined by their structure. Continuing the investigation of the cytotoxicity of organotin (IV) dithiocarbamates, this mini-review delves into the appropriate method for synthesis and discusses the elemental and spectroscopic analyses and potential cytotoxic effects of these compounds from articles published since 2010.

The Role of Polyphenol in Modulating Associated Genes in Diabetes-Induced Vascular Disorders.

Diabetes-induced vascular disorder is considered one of the deadly risk factors among diabetic patients that are caused by persistent hyperglycemia that eventually leads to cardiovascular diseases. Elevated reactive oxygen species (ROS) due to high blood glucose levels activate signaling pathways such as AGE/RAGE, PKC, polyol, and hexosamine pathways. The activated signaling pathway triggers oxidative stress, inflammation, and apoptosis which later lead to vascular dysfunction induced by diabetes. Polyphenol is a bioactive compound that can be found abundantly in plants such as vegetables, fruits, whole grains, and nuts. This compound exerts therapeutic effects in alleviating diabetes-induced vascular disorder, mainly due to its potential as an anti-oxidative, anti-inflammatory, and anti-apoptotic agent. In this review, we sought to summarize the recent discovery of polyphenol treatments in modulating associated genes involved in the progression of diabetes-induced vascular disorder.

The Role of PKC-MAPK Signalling Pathways in the Development of Hyperglycemia-Induced Cardiovascular Complications.

Cardiovascular disease is the most common cause of death among diabetic patients worldwide. Hence, cardiovascular wellbeing in diabetic patients requires utmost importance in disease management. Recent studies have demonstrated that protein kinase C activation plays a vital role in the development of cardiovascular complications via its activation of mitogen-activated protein kinase (MAPK) cascades, also known as PKC-MAPK pathways. In fact, persistent hyperglycaemia in diabetic conditions contribute to preserved PKC activation mediated by excessive production of diacylglycerol (DAG) and oxidative stress. PKC-MAPK pathways are involved in several cellular responses, including enhancing oxidative stress and activating signalling pathways that lead to uncontrolled cardiac and vascular remodelling and their subsequent dysfunction. In this review, we discuss the recent discovery on the role of PKC-MAPK pathways, the mechanisms involved in the development and progression of diabetic cardiovascular complications, and their potential as therapeutic targets for cardiovascular management in diabetic patients.

MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin.

RATIONALE: Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been associated with many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood. OBJECTIVE: To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms. METHODS AND RESULTS: Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe-/- and Ldlr-/-, we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR-181b in angiotensin II-infused Apoe-/- and Ldlr-/- mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3-/- mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis. CONCLUSIONS: Our findings suggest that the management of miR-181b and its target genes provides therapeutic potential for limiting the progression of atherosclerosis and aneurysms and protecting them from rupture.

Oral inoculation of Enterococcus faecalis, DNA quantification and histopathological evaluation of gingival, heart and kidney tissue samples in rats.

Background and Objectives: Enterococcus faecalis is known as common pathogen for endodontic infections and cause secondary and refractory pulp periapical periodontitis. The bacteria can opportunistically colonize periodontal pockets and presents a possibility of infection developing in other organs. This research will investigate the dissemination of E. faecalis from the gingival tissue to the heart and kidney. Materials and Methods: Three groups were formed, consisting of twelve male Sprague Dawley rats: a control group designated as 0-day, and experimental groups labeled as 7-days and 14-days. Periodontitis induced by concurrent infection with sterile wire 0.2 mm insertion and E. faecalis inoculation is performed into the gingival sulcus located between the maxillary right 1st and 2nd molar teeth area. After euthanasia, tissue samples around the maxillary gingiva, maxillary jaw samples, kidney and heart tissues were obtained for quantitative Real-Time PCR assay and histopathological analysis. Results: Results showed at 7-days, there was an upregulation of E. faecalis gene expression in the gingiva, heart, and kidney samples as well as infiltration of the inflammatory cells at 7-days post induction, which consequently decreased at 14-days. Conclusion: Thus, the study suggests dissemination of E. faecalis from gingival tissue to the heart, kidney which could be probable link between periodontal disease, heart, and kidney disease.

Therapeutic Potential of Hibiscus sabdariffa Linn. in Attenuating Cardiovascular Risk Factors.

Cardiovascular diseases (CVDs) represent a broad spectrum of diseases afflicting the heart and blood vessels and remain a major cause of death and disability worldwide. CVD progression is strongly associated with risk factors, including hypertension, hyperglycemia, dyslipidemia, oxidative stress, inflammation, fibrosis, and apoptosis. These risk factors lead to oxidative damage that results in various cardiovascular complications including endothelial dysfunctions, alterations in vascular integrity, the formation of atherosclerosis, as well as incorrigible cardiac remodeling. The use of conventional pharmacological therapy is one of the current preventive measures to control the development of CVDs. However, as undesirable side effects from drug use have become a recent issue, alternative treatment from natural products is being sought in medicinal plants and is gaining interest. Roselle (Hibiscus sabdariffa Linn.) has been reported to contain various bioactive compounds that exert anti-hyperlipidemia, anti-hyperglycemia, anti-hypertension, antioxidative, anti-inflammation, and anti-fibrosis effects. These properties of roselle, especially from its calyx, have relevance to its therapeutic and cardiovascular protection effects in humans. This review summarizes the findings of recent preclinical and clinical studies on roselle as a prophylactic and therapeutic agent in attenuating cardiovascular risk factors and associated mechanisms.

Combination Therapy of Navitoclax with Chemotherapeutic Agents in Solid Tumors and Blood Cancer: A Review of Current Evidence.

Combination therapy emerges as a fundamental scheme in cancer. Many targeted therapeutic agents are developed to be used with chemotherapy or radiation therapy to enhance drug efficacy and reduce toxicity effects. ABT-263, known as navitoclax, mimics the BH3-only proteins of the BCL-2 family and has a high affinity towards pro-survival BCL-2 family proteins (i.e., BCL-XL, BCL-2, BCL-W) to induce cell apoptosis effectively. A single navitoclax action potently ameliorates several tumor progressions, including blood and bone marrow cancer, as well as small cell lung carcinoma. Not only that, but navitoclax alone also therapeutically affects fibrotic disease. Nevertheless, outcomes from the clinical trial of a single navitoclax agent in patients with advanced and relapsed small cell lung cancer demonstrated a limited anti-cancer activity. This brings accumulating evidence of navitoclax to be used concomitantly with other chemotherapeutic agents in several solid and non-solid tumors that are therapeutically benefiting from navitoclax treatment in preclinical studies. Initially, we justify the anti-cancer role of navitoclax in combination therapy. Then, we evaluate the current evidence of navitoclax in combination with the chemotherapeutic agents comprehensively to indicate the primary regulator of this combination strategy in order to produce a therapeutic effect.

Clinical Review: Navitoclax as a Pro-Apoptotic and Anti-Fibrotic Agent.

B-cell lymphoma 2 (BCL-2) family proteins primarily work as a programmed cell death regulator, whereby multiple interactions between them determine cell survival. This explains the two major classes of BCL-2 proteins which are anti-apoptotic and pro-apoptotic proteins. The anti-apoptotic proteins are attractive targets for BCL-2 family inhibitors, which result in the augmentation of the intrinsic apoptotic pathway. BCL-2 family inhibitors have been studied extensively for novel targeted therapies in various cancer types, fibrotic diseases, aging-related as well as autoimmune diseases. Navitoclax is one of them and it has been discovered to have a high affinity toward BCL-2 anti-apoptotic proteins, including BCL-2, BCL-W and B-cell lymphoma-extra-large. Navitoclax has been demonstrated as a single agent or in combination with other drugs to successfully ameliorate tumor progression and fibrosis development. To date, navitoclax has entered phase I and phase II clinical studies. Navitoclax alone potently treats small cell lung cancer and acute lymphocytic leukemia, whilst in combination therapy for solid tumors, it enhances the therapeutic effect of other chemotherapeutic agents. A low platelet count has always associated with single navitoclax treatments, though this effect is tolerable. Moreover, the efficacy of navitoclax is determined by the expression of several BCL-2 family members. Here, we elucidate the complex mechanisms of navitoclax as a pro-apoptotic agent, and review the early and current clinical studies of navitoclax alone as well as with other drugs. Additionally, some suggestions on the development of navitoclax clinical studies are presented in the future prospects section.