Current Drug Metabolism - Volume 20, Issue 1, 2019

Background: The gut microbes have a close symbiotic relationship with their host. Interactions between host and the microbiota affect the nutritional, immunological, and physiological status of the host. The Aryl Hydrocarbon Receptor (AHR) is a ligand activated transcription factor that mediates the toxicity of xenobiotics. Recently, the relationship between the gut microbiota and AHR has attracted the attention of many researchers. Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature. Results: We found and reviewed 49 peer-reviewed papers dealing with the major aspects related to the crosstalk between AHR and microbiota. The AHR influences the intestinal microbiota population and mediates host-microbe homeostasis. Interestingly, the gut microbiota also produces ligands of AHR from bacterial metabolism and thereby activates the AHR signaling pathway. Concusion: This review presents current knowledge of the cross-regulatory circuit between the AHR and intestinal microbiota. The findings of this review confirm the importance of AHR-microbiota interactions in health and disease.

Background: Kisspeptin and its receptor, GPR54, are regarded as key regulators of and catalysts for male puberty onset, and also fundamental gatekeepers of spermatogenesis in mammals. Consequently, the loss function of kisspeptin or GPR54 leads to a symptom of Hypogonadotropic Hypogonadism (HH) in human and HH accompanied by lower gonadotrophic hormone levels, smaller testes, impaired spermatogenesis and abnormal sexual maturation in mice. Besides its well-recognized functions in hypothalamus before and during puberty, accumulating data strongly support kisspeptin production in testis, and participation in somatic and germ cell development and sperm functions as well. This review aims to summarize recent findings regarding kisspeptin activity in the testes and sperm function. Methods: We undertook a keyword search of peer-reviewed research literature including data from in vivo and in vitro studies in humans and genetically modified animal models to identify the roles of kisspeptins in male reproduction. Results: A plethora of studies detail the role of kisspeptins and GPR54 in mammalian spermatogenesis in vivo and in vitro. This review identified recent findings regarding the kisspeptin system in male gonads, and regulation of kisspeptin in testicular physiology and male reproductive defects and disorders. Conclusion: The findings of this review confirm the importance role of kisspeptins in male fertility. Understanding their biphasic roles in testis may help to consider kisspeptins as potential pharmacological targets for treating human infertility.

Background: Diabetes, with an increased prevalence and various progressive complications, has become a significant global health challenge. The concrete mechanisms responsible for the development of diabetes still remain incompletely unknown, although substantial researches have been conducted to search for the effective therapeutic targets. This review aims to reveal the novel roles of Xenobiotic Nuclear Receptors (XNRs), including the Peroxisome Proliferator-Activated Receptor (PPAR), the Farnesoid X Receptor (FXR), the Liver X Receptor (LXR), the Pregnane X Receptor (PXR) and the Constitutive Androstane Receptor (CAR), in the development of diabetes and provide potential strategies for research and treatment of metabolic diseases. Methods: We retrieved a large number of original data about these five XNRs and organized to focus on their recently discovered functions in diabetes and its complications. Results: Increasing evidences have suggested that PPAR, FXR, LXR ,PXR and CAR are involved in the development of diabetes and its complications through different mechanisms, including the regulation of glucose and lipid metabolism, insulin and inflammation response and related others. Conclusion: PPAR, FXR, LXR, PXR, and CAR, as the receptors for numerous natural or synthetic compounds, may be the most effective therapeutic targets in the treatment of metabolic diseases.

Background: Helicobacter pylori (H. pylori)-related gastric diseases are a series of gastric mucosal disorders associated with H. pylori infection. Gastric cancer (GC) is widely believed to evolve from gastritis and gastric ulcer. As an important adhesion molecule of epithelial cells, E-cadherin plays a key role in the development of gastric diseases. In this review, we aim to seek the characteristic of E-cadherin expression at different stages of gastric diseases. Methods: We searched plenty of databases for research literature about E-cadherin expression in H. pylori-related gastric diseases, and reviewed the relationship of E-cadherin and H. pylori, and the role of E-cadherin at different stages of gastric diseases. Results: H. pylori was shown to decrease E-cadherin expression by various ways in vitro, while most of clinical studies have not found the relationship between H. pylori and E-cadherin expression. It is defined that poor outcome of GC is related to loss expression of E-cadherin, but it is still unclear when qualitative change of E-cadherin expression in gastric mucosa emerges. Conclusion: Expression level of E-cadherin in gastric cells may be a consequence of injury factors and body's selfrepairing ability. More studies on E-cadherin expression in gastric mucosa with precancerous lesions need to be performed, which may be potential and useful for early detection, prevention and treatment of GC.

Background: PXR (Pregnane X Receptor) and CAR (Constitutive Androstane Receptor) are termed as xenobiotic receptors, which are known as core factors in regulation of the transcription of metabolic enzymes and drug transporters. However, accumulating evidence has shown that PXR and CAR exert their effects on energy metabolism through the regulation of gluconeogenesis, lipogenesis and β-oxidation. Therefore, in this review, we are trying to summary recent advances to show how xenobiotic receptors regulate energy metabolism. Methods: A structured search of databases has been performed by using focused review topics. According to conceptual framework, the main idea of research literature was summarized and presented. Results: For introduction of each receptor, the general introduction and the critical functions in hepatic glucose and lipid metabolism have been included. Recent important studies have shown that CAR acts as a negative regulator of lipogenesis, gluconeogenesis and β -oxidation. PXR activation induces lipogenesis, inhibits gluconeogenesis and inhabits β-oxidation. Conclusion: In this review, the importance of xenobiotic receptors in hepatic glucose and lipid metabolism has been confirmed. Therefore, PXR and CAR may become new therapeutic targets for metabolic syndrome, including obesity and diabetes. However, further research is required to promote the clinical application of this new energy metabolism function of xenobiotic receptors.

Background: Reducing dietary Crude Protein (CP) and supplementing with certain Amino Acids (AAs) has been known as a potential solution to improve Nitrogen (N) efficiency in dairy production. Thus understanding how AAs are utilized in various sites along the gut is critical. Objective: AA flow from the intestine to Portal-drained Viscera (PDV) and liver then to the mammary gland was elaborated in this article. Recoveries in individual AA in PDV and liver seem to share similar AA pattern with input: output ratio in mammary gland, which subdivides essential AA (EAA) into two groups, Lysine (Lys) and Branchedchain AA (BCAA) in group 1, input: output ratio > 1; Methionine (Met), Histidine (His), Phenylalanine (Phe) etc. in group 2, input: output ratio close to 1. AAs in the mammary gland are either utilized for milk protein synthesis or retained as body tissue, or catabolized. The fractional removal of AAs and the number and activity of AA transporters together contribute to the ability of AAs going through mammary cells. Mammalian Target of Rapamycin (mTOR) pathway is closely related to milk protein synthesis and provides alternatives for AA regulation of milk protein synthesis, which connects AA with lactose synthesis via α-lactalbumin (gene: LALBA) and links with milk fat synthesis via Sterol Regulatory Element-binding Transcription Protein 1 (SREBP1) and Peroxisome Proliferatoractivated Receptor (PPAR). Conclusion: Overall, AA flow across various tissues reveals AA metabolism and utilization in dairy cows on one hand. While the function of AA in the biosynthesis of milk protein, fat and lactose at both transcriptional and posttranscriptional level from another angle provides the possibility for us to regulate them for higher efficiency.

Background: Soy isoflavones, such as genistein and daidzein, are bioflavonoids found in soy products that are able to interact with various hormones such as estrogen. Epidemiological studies reveal a proper level of isoflavones in diet can prevent many diseases like cancers or diabetes. Therefore, it is important to study the biotransformation and xenobiotic metabolism of soy isoflavones. Methods: A systematic review of published studies was carried out to investigate the characterization of isoflavones and their metabolites, sample pretreatment and quantitative analysis of isoflavones, and the influence of soy isoflavones on drug and xenobiotic metabolism. Results: Aglycones with weak estrogen-like activities are the biologically active forms of the soy isoflavones in mammals. The most recent advances including extraction, purification and detection of isoflavones in soybean and soy products are discussed. The effects of soy isoflavones on drug and xenobiotic metabolism involve in regulation of phase I cytochrome P450 (CYPs) enzyme and phase I detoxifying enzymes expression and activity. At the molecular level, soy isoflavones have proved capable of estrogenic/antiestrogenic with tissue-selective, anti-cancer, antiobesity, anti-oxidation, and tyrosine kinase inhibition activities. Conclusion: This review summarized different aspects of soy isoflavones and their molecular mechanisms of pharmacological action on xenobiotic, which demonstrated that soy isoflavones can decrease the incidence of many diseases and benefit for human health. However, since the lack of clinical research for evaluation of the proper dosage of intake of soy isoflavones in diet or adjunctive therapy, there is a need for further studies on the selection of doses, biomedical applications and adverse effects of isoflavones for human health.

Background: Misuse of synthetic antibiotics in livestock leads to the transfer of antibiotic resistant pathogens into humans and deposits toxic residues in meat and milk. There is therefore an urgent need for safe and viable alternative approaches to improve the nutrition and wellbeing of farm animals. An alternative source that has been widely exploited is Traditional Chinese Herbal Medicine (TCHM). These herbs contain several but less toxic bioactive compounds which are generally regarded as biodegradable. Recently, advances in the knowledge of the importance of TCHM have led to a rapid increase in its production and hence, increasing the amount of by-products generated. Such by-products have become a serious environmental challenge because producers regard them as industrial waste and discard them directly. This review summarizes scientific findings on the bioactive compounds in TCHM and TCHM by-products, discusses functional dietary patterns and outlines challenges that may hinder full utilization of TCHM by-products in animal production. Methods: Information for this review was obtained through scientific databases and websites such as Pubmed and Google scholar from 2004 to 2017 using experimental studies on bioactive compounds in TCHM and their effects in animal production. Results: Studies have shown that TCHM by-products contain high amounts of bioactive compounds which confer several nutritional and health benefits to animals and thus could be incorporated as feed additives. Conclusion: The findings for this review indicate that TCHM by-products apart from being a good alternative for synthetic antibiotics could also minimize the current environmental challenges associated with its disposal.

Background: Advanced Glycation End products (AGEs) are basically the end result of glycation of proteins and/or lipids in the presence of sugars. Specific cases of hyperglycemia have been reported with increased propensity of generation of AGEs. Many chronic and deadly diseases such as diabetes, cancer and neurodegenerative disorders have been known to be caused as a result of generation of AGEs. The role of glutathione (GSH) metabolism and its intricate association with AGEs have also been well established in breast cancer prognosis and treatment. To understand the etiology, mechanism and production of AGEs along with clinical relevance of Receptors for Advanced Glycation End-products (RAGE) and RAGE ligands, their interplay with GSH is of paramount importance especially in relation to breast cancer. Methods: The available literature using PubMed, National Library of Medicine database, Web of Science and SCOPUS indexed, Science Direct and other prestigious journals have been systematically reviewed using the keywords: advanced glycation end-products, breast cancer, glutathione RAGE, and AGEs inhibitors. This narrative review of all the relevant papers with significant citations has led us to have greater insight into the action mechanism and potential therapeutic significance of AGEs inhibitors. Results: Targeting breast cancer with the specific immunoglobulins and with other therapeutic interventions is needed to inhibit the generation of AGEs and manage glutathione expression, thus having strong implications in the management of breast cancer. Many RAGE ligands such as HMGB1, S100P, S100A8, S100A9 etc. have been known to enhance RAGE expression which may further lead to increased proliferation, migration and metastatic nature of tumor cells. Hence, RAGE and RAGE ligands in a close linkup with GSH may prove to be effective therapeutic markers of severity of breast cancer and for angiogenesis of tumor. Conclusion: This review provides a strong platform to comprehend the etiology, mechanism and production of AGEs and glutathione along with the agents which can block their production, paving a way for the therapeutic intervention and an amicable solution to treat and manage breast cancer.

Background: Statins have been a major keystone in the management of patients with atherosclerotic cardiovascular disease. The benefits of inhibiting HMG CoA reductase, via statins, were translated into reduction in LDL-c with proportionate decrease in cardiovascular events in response to the magnitude of LDL-c reduction. Despite major advances in pharmacological treatments, including the use of high-dose statins, there are urgent need to further reduce future cardiovascular risk. This is in particularly important since 1 out of 5 high-risk atherosclerotic patients who achieve low LDL-c return with a second cardiovascular event within five years. Although this residual risk post-statin is largely heterogeneous, lowering LDL-c beyond ‘normal’ or guidelines-recommended level using novel therapies has resulted in further reduction in cardiovascular events. Objective: The current review will discuss the use of PCSK9 inhibitors in patients with atherosclerotic disease. PCSK9 inhibitors are a new class of lipid-lowering drugs that are either fully human monoclonal antibodies (evolocumab and alirocumab) or humanised monoclonal antibodies (bococizumab) that effectively reduce LDL-c to unprecedented level. By blocking circulating PCSK9, these drugs would preserve LDL receptors and prevent them from cellular degradation. This process promotes recycling of LDL receptors back to hepatocytes surface, leading into further reduction of LDL-c. Combining PCSK9 inhibitors with statin have led into lower LDL-c, reduction in plaque volume and more importantly reduction in future cardiovascular events. Conclusion: These drugs are very promising, nonetheless, the unselective approach of applying these monoclonal antibodies may not prove to be cost-effective and potentially exposing some patients to unnecessary side effects.