Current Molecular Pharmacology - Volume 12, Issue 3, 2019

Background: The ancient and highly evolutionarily conserved Wnt signaling pathway is critical in nearly all tissues and organs for an organism to develop normally from embryo through adult. Wnt signaling is generally parsed into “canonical” or Wnt-β-catenin-dependent or “non-canonical” β-catenin-independent signaling. Even though designating Wnt signaling as either canonical or noncanonical allows for easier conceptual discourse about this signaling pathway, in fact canonical and non-canonical Wnt crosstalk regulates complex nonlinear networks. Objective: In this perspective, we discuss the integration of canonical and non-canonical Wnt signaling via differential Kat3 (CBP and p300) coactivator usage, thereby regulating and coordinating gene expression programs associated with both proliferation and cellular differentiation and morphogenesis. Methods: Pharmacologic inhibitors, cell culture, real-time PCR, chromatin immunoprecipitation, protein immunoprecipitation, Western blotting, reporter-luciferase, protein purification, site-directed mutagenesis, in vitro phosphorylation and binding assays, and immunofluorescence were utilized. Conclusion: Coordinated integration between both canonical and non-canonical Wnt pathways appears to be crucial not only in the control of fundamental morphologic processes but also in the regulation of normal as well as pathologic events. Such integration between both canonical and non-canonical Wnt signaling is presumably effected via reversible phosphorylation mechanism (e.g., protein kinase C) to regulate differential β -catenin/Kat3 coactivator usage in order to coordinate proliferation with differentiation and adhesion.

Background: Mescaline (3,4,5-trimethoxyphenethylamine), mainly found in the Peyote cactus (Lophophora williamsii), is one of the oldest known hallucinogenic agents that influence human and animal behavior, but its psychoactive mechanisms remain poorly understood. Objectives: This article aims to fully review pharmacokinetics and pharmacodynamics of mescaline, focusing on the in vivo and in vitro metabolic profile of the drug and its implications for the variability of response. Methods: Mescaline pharmacokinetic and pharmacodynamic aspects were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Biological effects of other compounds found in peyote were also reviewed. Results: Although its illicit administration is less common, in comparison with cocaine and Cannabis, it has been extensively described in adolescents and young adults, and licit consumption often occurs in religious and therapeutic rituals practiced by the Native American Church. Its pharmacodynamic mechanisms of action are primarily attributed to the interaction with the serotonergic 5-HT2A-C receptors, and therefore clinical effects are similar to those elicited by other psychoactive substances, such as lysergic acid diethylamide (LSD) and psilocybin, which include euphoria, hallucinations, depersonalization and psychoses. Moreover, as a phenethylamine derivative, signs and symptoms are consistent with a sympathomimetic effect. Mescaline is mainly metabolized into trimethoxyphenylacetic acid by oxidative deamination but several minor metabolites with possible clinical and forensic repercussions have also been reported. Conclusion: Most reports concerning mescaline were presented in a complete absence of exposure confirmation, since toxicological analysis is not widely available. Addiction and dependence are practically absent and it is clear that most intoxications appear to be mild and are unlikely to produce lifethreatening symptoms, which favors the contemporary interest in the therapeutic potential of the drugs of the class.

Background: Diabetes mellitus and concomitant dyslipidemia, being referred to as ‘diabetic dyslipidemia’, are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated. Conclusion: Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.

Background: Targeting of drugs to the subcellular compartments represents one of the modern trends in molecular pharmacology. The approach for targeting mitochondria was developed nearly 50 years ago, but only in the last decade has it started to become widely used for delivering drugs. A number of pathologies are associated with mitochondrial dysfunction, including cardiovascular, neurological, inflammatory and metabolic conditions. Objective: This mini-review aims to highlight the role of mitochondria in pathophysiological conditions and diseases, to classify and summarize our knowledge about targeting mitochondria and to review the most important preclinical and clinical data relating to the antioxidant lipophilic cations MitoQ and SkQ1. Methods: This is a review of available information in the PubMed and Clinical Trials databases (US National Library of Medicine) with no limiting period. Results and Conclusion: Mitochondria play an important role in the pathogenesis of many diseases and possibly in aging. Both MitoQ and SkQ1 have shown many beneficial features in animal models and in a few completed clinical trials. More clinical trials and research efforts are needed to understand the signaling pathways influenced by these compounds. The antioxidant lipophilic cations have great potential for the treatment of a wide range of pathologies.

Background: Epigenetic alterations comprise key regulatory events that dynamically alter gene expression and their deregulation is commonly linked to the pathogenesis of various diseases, including cancer. Unlike DNA mutations, epigenetic alterations involve modifications to proteins and nucleic acids that regulate chromatin structure without affecting the underlying DNA sequence, altering the accessibility of the transcriptional machinery to the DNA, thus modulating gene expression. In cancer cells, this often involves the silencing of tumor suppressor genes or the increased expression of genes involved in oncogenesis. Advances in laboratory medicine have made it possible to map critical epigenetic events, including histone modifications and DNA methylation, on a genome-wide scale. Like the identification of genetic mutations, mapping of changes to the epigenetic landscape has increased our understanding of cancer progression. However, in contrast to irreversible genetic mutations, epigenetic modifications are flexible and dynamic, thereby making them promising therapeutic targets. Ongoing studies are evaluating the use of epigenetic drugs in chemotherapy sensitization and immune system modulation. With the preclinical success of drugs that modify epigenetics, along with the FDA approval of epigenetic drugs including the DNA methyltransferase 1 (DNMT1) inhibitor 5-azacitidine and the histone deacetylase (HDAC) inhibitor vorinostat, there has been a rise in the number of drugs that target epigenetic modulators over recent years. Conclusion: We provide an overview of epigenetic modulations, particularly those involved in cancer, and discuss the recent advances in drug development that target these chromatin-modifying events, primarily focusing on novel strategies to regulate the epigenome.

Background: Bisphenol A (BPA) is a synthetic plasticizer that is commonly used in the production of polycarbonate plastics and epoxy resins. Human exposure occurs when BPA migrates from food and beverage containers into the contents when heated or even under normal conditions of use. BPA exerts endocrine disruptor action due to its weak binding affinity for the estrogen receptors ERα and ERβ. BPA exerts other effects by activating the membrane receptor GPER (GPR30) and/or other receptors such as the estrogen-related receptors (ERRs). Objective: This review summarizes emerging data on BPA and cancer. These include data linking exposure to BPA with an increased risk of hormone-related cancers such as those of the ovary, breast, prostate, and even colon cancer. BPA can also induce resistance to various chemotherapeutics such as doxorubicin, cisplatin, and vinblastine in vitro. The development of chemoresistance to available therapeutics is an emerging significant aspect of BPA toxicity because it worsens the prognosis of many tumors. Conclusion: Recent findings support a causal role of BPA at low levels in the development of cancers and in dictating their response to cytotoxic therapy. Accurate knowledge and consideration of these issues would be highly beneficial to cancer prevention and management.

Background: Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic target for treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 and CB2, there are non-CB1 and non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, and GPR119. In addition, CB1 and CB2 display allosteric binding and biased signaling, revealing correlations between biased signaling and functional outcomes. Interestingly, new investigations have indicated that CB1 is functionally present within the mitochondria of striated and heart muscles directly regulating intramitochondrial signaling and respiration. Conclusion: In this review, we summarize the recent progress in cannabinoid-related orphan GPCRs, CB1/CB2 structure, Gi/Gs coupling, allosteric ligands and biased signaling, and mitochondria-localized CB1, and discuss the future promise of this research.