Current Drug Metabolism - Volume 19, Issue 6, 2018

Background: The gut-brain axis is considered a neuroendocrine system, which connects the brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for health conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. Method: We selected recent papers analysing the association among alterations in the homeostasis of the gut-brain axis and neurological disorders. In addition, we described how bioactive natural molecules - such as polyphenols – by influencing gut microbiota composition may help rescue neural signalling pathways impaired in neurodegenerative diseases. Results: Recent studies show that gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Gut bacterial community plays a key role in maintaining normal brain functions. Metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a “microbiota-gut-brain” axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both the gut bacterial composition and brain biochemistry. Conclusion: This review highlights the role of gut microbiota in regulating regulates brain biochemistry and the role of microbiota metabolites on neuropathologies. Dietary ingestion of probiotics, prebiotics and polyphenols affect gut microbiota composition underlining the key role played by specific metabolites not only in the gut microbiota composition but also in the brain health maintenance.

Background: UDP-glucuronosyltransferases (UGTs) are a class of important phase II drug metabolizing enzymes (DMEs), playing essential roles in the homeostasis of endobiotics as well as the dispositional behavior of exogenous compounds. The expression and enzyme activity of UGTs are regulated by multiple dimensions of mechanisms and can be influenced by diverse factors. Thus, the intensive research of its regulatory network is pivotal for better understanding about the physiological, pathological, and therapeutic significance of UGTs. Despite the lag to the research in cytochrome P450s, extensive efforts have been made to advance the understanding of the regulatory network of UGTs in recent years. Method: This review presents a comprehensive summary and intensive discussion about the recent advancement on the regulatory network of UGTs. Results: UGTs can be regulated at the epigenetic level via DNA methylation and histone modification. Various nuclear receptors can influence the mRNA levels of UGTs in a ligand dependent manner. Some general transcriptional factors such as AP-1, NF-ΚB, and p53, and some tissue specific transcriptional factors including HFN1α and HNF4α can also regulate UGTs at the transcriptional level. Multiple miRNAs have been found to be involved in the regulation of UGTs at post-transcriptional level. UGT proteins can be directly regulated via various post-translational modifications, protein-protein interactions, and protein-chemicals interactions, leading to the alternation of enzyme activities. Conclusion: In addition to the well-defined genetic polymorphism that induce individual variation of UGTs, this review reinforces the importance of other mechanisms that are critical for the regulation of UGTs.

Background: The proteomics approach is the new mantra in disease biomarker research in areas such as major depression (MD). Current protocols for investigating biomarkers in biological fluid often employ both immuno- based and non-immuno-based technologies. Method: The immuno-based method is used normally in measuring well-known disease biomarkers, and commercial kits are often available. Immuno-based methods such as radio-immunoassay and enzyme-linked immunosorbent assay are sensitive and specific. However, tedious sample preparations such as filtration and centrifugation are required. Non-immuno-based technologies, such as matrix-assisted laser desorption/ionization- time of flight mass spectrometry has been proven to be useful techniques to rapidly screen disease biomarkers in human biological fluids. The mass spectrometer provides a powerful research tool in the proteomics field, not only in biomarker discovery but also in biomarker validation. A bioinformation tool like principal component analysis is a statistical procedure that utilizes proteomics data. Conclusion: In this article, we review the proteomics approaches in MD biomarker research and the data after the antidepressants treatment. And it covers a selection of advances in the realm of proteomics and its promise for major depression biomarker discovery and antidepressant effects. These technologies have opened new approaches to identifying signaling biomarkers associated with the cellular metabolism, cell life cycle, and detection of disease.

Background: Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immunosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynamics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug. Method: We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms. Results: The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac. Conclusion: The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse effects or drug inefficacy.

Background: Malignant tumors are the leading cause of death in humans. Due to the tedious efforts and investigations made in the field of marine drug discovery, there is now a scientific bridge between marine and pharmaceutical sciences. However, currently only few marine drugs have been lined towards anticancer direction yet many more to are be established in future as well. Method: This review gives an overview of present status of marine natural products MNPs both at the level of research and clinical stages. The authors haved summarized the detail information of diverse marine organisms that were reportedto be active or potentially active in cancer treatment in the last two decades. Interstingly, marine organisms are abundant producer of plenty of structurally incomparable bioactive metabolites that have unusual mode of actions and diverse biosynthetic pathways. Results: This review summarizes the associated anticancer properties of different classes of marine natural compounds based on their structural diversity, biological activity, and the molecular mechanisms of action. Emphasis has also be given to recent advances in clinical development of marine agents used in clinical trials. Conclusions: The present review is summarising the various sources of marine chemicals and their exploration of anticancerous potential. There is justified hope for the discovery and development of new anticancer agents from the marine environment.

Background: The popular drink, coffee (Coffea arabica) is under the great attention of late because of its promising pharmacological potential. Caffeine (the major constituent of coffee) is known for its prominent psychoactive impact. This review aims at highlighting the therapeutic potentials of caffeine and other five coffee components viz. caffeic acid, chlorogenic acids, cafestol, ferulic acid and kahweol and their mechanisms of action. Methods: An up-to-date search was made with selected keywords in PubMed, Science Direct, Web of Science, Scopus, The American Chemical Society and miscellaneous databases (e.g., Google Scholar) for the published literature on the selected topic. Results: A number of pharmacological activities are attributed to these components that include anti-oxidant, antiinflammatory, immunomodulatory, anti-microbial, anti-cancer, cardioprotective and neuroprotective effects. In addition, osteogenesis (kahweol), anti-diabetic (caffeine, chlorogenic acid and ferulic acid) and hepatoprotective (chlorogenic acid) activities have also been reported by some of these components in the scientific literature. Caffeine has also been noted for adverse effect on the development of the brain at early stages and reproductive systems. Conclusion: A more advanced pre-clinical and clinical trials are recommended to investigate the safety profiles of these coffee components before their use as possible therapeutics.