Current Pharmaceutical Biotechnology - Volume 19, Issue 3, 2018

Background: The gastrointestinal tract harbours a diverse bacterial community that contributes to health and disease. A number of studies have demonstrated that the gut microbiota plays a critical role in the metabolism of serotonin. Methods: Microbial-derived metabolites, such as bile acids and short-chain fatty acids, are reported to affect the production of serotonin which, in turn, directly or indirectly regulates gut motility. Enterochromaffin cells are important specialized endocrine cells found in the intestine, which is the major location of serotonin biosynthesis. The relationship between microbiota and gut motility are studied depended on microbial-derived metabolites and serotonin. Results and Conclusion: Both bile acids and short-chain fatty acids can modulate serotonin metabolism in hosts by affecting key intermediates of the serotonin pathway. Thus, gut motility may be regulated through microbial modifications of host serotonin biosynthesis, which continues to be evaluated as a target for functional gastrointestinal disorders.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease mainly caused by high-fat diets and sudden feed changes, vitamin and energy deficiency, and inflammatory processes. Fatty liver leads to cirrhosis, hepatocellular carcinoma as well as liver failure. Lifestyle-modifying such as weight loss and a healthy diet have an inverse correlation with the risk of fatty liver. The promising effect of a diet rich in vegetables and fruits against fatty liver has been evidenced by several empirical studies focused on flavonoids. Among naturally occurring flavonoids, naringenin is one of the most important flavonoids which can be isolated from some edible fruits, especially citrus species. Methods: In the present review, we discuss the effects of naringenin and its nano-formulations against fatty liver disease and the proposed molecular mechanism of action. A large number of studies attributed to naringenin anti-inflammatory, antioxidant and insulin-like actions, as well as different types of effects on sex hormone metabolism and lipid metabolism. Naringenin-loaded nanoparticles have been used to solve the limited stability, solubility, bioavailability and pharmacological activity of naringenin and, consequently, to improve its therapeutic effects. Results and Discussion: Naringenin exerts diverse biological actions including the decrease of biomarkers of lipid peroxidation and protein carbonylation, increase of antioxidant defenses, scavenging of reactive oxygen species and modulation of signaling pathways related to fatty acid metabolism which can favor the oxidation of fatty acid, lower lipid accumulation in the liver and thereby prevent fatty liver.

Background: Pentoxifylline (PTX) is a drug commonly used in the treatment of intermittent claudication. However, numerous research groups report that PTX also may potentially be used in the anticancer therapy following one of the main trends in the nowadays medicine – combined anticancer therapy. Scope of Review: The review concentrates on the reports revealing the potential use of PTX in cancer treatment. Major Conclusion: PTX is described to possess several properties which may be exploited in cancer treatment. The drug reportedly not only has anticancer activity itself, but also increases cancer cells susceptibility to radiation therapy and, additionally, reduces long-term side effects of this therapy. Furthermore, numerous research groups report that PTX may increase the anticancer potential of commonly used anticancer drugs such as cisplatin or doxorubicin as well as reduce side effects of these drugs. Significance: PTX should be considered as a potential drug in the combined anticancer therapy.

Background: The purpose of this study was to develop an innovative surfactant-free lipidbased formulation (LF) for improving oral bioavailability of loratadine based on using solid particles colloidal silicon dioxide (CSD) as emulsifier and solid carrier. Methods: Loratadine was dissolved in oil solution with the aid of co-solvent and LF formulations were prepared by a simple adsorption and milling technique. The LF Powder was evaluated in terms of angle of repose and X-ray powder diffraction. After dispersing and emulsifying in water, the particle size and morphology were also characterized. In vitro dissolution and pharmacokinetic behavior in vivo were also studied. Results: Orthogonal design indicated that the amount of CSD in formulations had a major and significant influence on emulsification. The optimal formulation showed LF with good flowability and without crystallization or deposition of loratadine in it. Conclusion: After dispersing in water, an emulsion with the mean droplet size of 1.2μm was obtained. Although the dissolution of drug from LF was slower in vitro in acidic aqueous solution, pharmacokinetic studies in vivo showed that the bioavailability of loratadine increased 2.49-fold by CF compared to a commercial tablet.

Background: Transcriptional regulation is a very important and pivotal function in myriad biological responses. Thus, methods to determine transcriptional activity are required in not only basic medical research but also in drug discovery. We established novel reporter constructs using human secreted embryonic alkaline phosphatase (SEAP) and Epstein-Barr virus nuclear antigen (EBNA) 1, which can maintain constructs synchronized to host cell replication. Methods: We established nuclear factor-kappa B (NFkB) or interferon regulatory factor (IRF) driven SEAP expression constructs and then, introduced them into culture cells. Results: The cells maintain reporter constructs for a long period in the culture and produce SEAP into culture supernatant in response to each specific ligand such as lipopolysaccharide (LPS) and interferon- beta. Measuring SEAP with chemiluminescence makes it possible to get high standard dynamic range applying to high-throughput screening in drug discovery in both 96 and 384 well format. We can also use it to determine transcriptional activity in the cells transfected with expression plasmid or treated with various toll-like receptor (TLR) ligands in a concentration-dependent manner and time-dependent manner. Finally, we demonstrated drug screening using a number of natural products library. Conclusion: We for the first time established the two novel reporter cells and validated their quality and accuracy enough to carry out drug screening.

Background: The effect of milking menaquinone-7 (MK-7) with biocompatible organic solvents on MK-7 production in B. subtilis fermentation was studied. Periodic milking of MK-7 from the fermentation medium by n-hexane significantly enhanced the total MK-7 production ~ 1.7 fold at the end of 72 hours of fermentation (p < 0.05) as compared to the control medium. Methods: Milking of MK-7 with a mixture of n-hexane phase modified with n-butanol was also explored. Although milking of MK-7 by a mixture of n-hexane and n-butanol (1:2, v/v), was found to be appropriate in terms of high extraction capacity, no significant increase in total MK-7 concentration was observed. Biocompatibility between the extraction solvents and B. subtilis was also examined. Results and Conclusion: The results indicated that the mixture of n-hexane and n-butanol exhibited some detrimental effects. However, n-hexane alone exhibited delayed toxicity starting at 84 hours of periodic milking and could, therefore, be considered as the most promising organic solvent for milking MK-7 in B. subtilis fermentation while enhancing the productivity of the system.

Background: Drug metabolizing enzymes and transporters (DMETs) play crucial roles in drug absorption and disposition. Species differences in the interaction of compounds with DMETs may contribute to the accuracy of animal models in predicting human responses in clinical studies. Thus it is important to clarify the expression heterogeneity of DMETs between human and rat, that is commonly used as a model for evaluating drug efficacy and drug safety. Methods: We compared the expression patterns of DMETs based on a rat RNA-seq dataset and the human Genotype-Tissue Expression (GTEx) datasets. A relatively high correlation of expression of DMETs between rat and human was observed in most organs, while a lower correlation was detected in the liver and kidney; however, a greater number of genes were variably expressed in the latter two organs. We characterized the basal expression traits of DMETs in rat in terms of organ, sex, and developmental differences. Results: Co-expressed modules across organs of DMETs were identified to include potential functionally- related genes. Interestingly, most of these modules showed liver- and/or kidney-specific expression. Moreover, we identified DMETs modules that were highly correlated to sex or developmental stages. Finally, we created networks containing sex and/or developmentally-related drugs and diseases with their related DMETs to display the clinical significance of sexually dimorphic and/or developmentally- specific DMET genes. Conclusion: Our study provides a deeper understanding of species differences in not only DMETs but specific susceptibility to adverse drug reactions (ADRs).

Aims: Candida species is the common cause of opportunistic fungal infections all over the world with increased mortality and morbidity especially in immunosuppressed patients. Fluconazole is the first line therapy for candidiasis. The antifungal resistance pattern in high-risk patients is a major concern. The present study was aimed to assess the anticandidal activity of Punica granatum peel against fluconazole resistant Candida species isolated from HIV patients. Materials & Methods: Ethanol, chloroform, petroleum ether and aqueous extracts of the peel of P. granatum were evaluated against standard strains of Candida spp. and fluconazole resistant clinical isolates by agar diffusion and broth dilution techniques. The GC-MS analysis of the extracts was performed to identify the phytochemicals present in it. The predominant phytochemical was subjected to molecular docking study to determine its binding efficacy with lanosterol 14-alpha demethylase. Results: P. granatum peel extracts showed excellent anticandidal activity with ethanol extract exhibiting the most inhibitory activity. C. albicans and C. krusei were the most inhibited and C. parapsilosis was the least inhibited species. The GC-MS analysis of the ethanol extract identified five predominant phytochemicals. On docking studies, the five phytochemicals showed a good binding to the lanosterol 14-alpha demethylase. Conclusion: The present study is the first report on the antifungal activity of various extracts of P. granatum against fluconazole resistant Candida isolates. Ethanol extract of P. granatum peel showed excellent anticandidal activity against fluconazole resistant Candida spp. Hence, it can be explored further to identify a potential drug candidate.

Background and Methods: Oplopanax elatus (Nakai) Nakai is used in folk medicine in China. In this study, the antiproliferative activity of an O. elatus fraction extracted by ethyl acetate (EF) was tested on human breast cancer MCF-7 cells, human colon cancer HCT-116 cells, and human stomach cancer AGS cells. The potential mechanism of antiproliferation was also investigated using an apoptosis assay. Results: The results showed that the EF remarkably suppressed proliferation of human breast, stomach, and colon cancer cells. Further apoptosis tests by flow cytometry and immunoblot analyses showed the EF inhibited HCT-116 cell proliferation by inducing apoptosis. The bioassay-monitored fractionation of the EF resulted in the isolation of two polyacetylenes, falcarindiol (compound 1) and oplopandiol (compound 2), with falcarindiol possessing the strongest antiproliferative activity in colon cancer cells. Conclusion: Together, this study evaluated the anticancer activity of an O. elatus extract against human cancer cells, and provided the basis for further development of this herbal extract for the treatment of cancer.

Background: Myocardial Infarction (MI) is one of the leading causes of morbidity and mortality in Egypt and worldwide. Vitamin D deficiency has long been linked to incidence of cardiovascular diseases. Several factors were reported to contribute to serum vitamin D level including exposure to sunlight. However, genetic variations in the vitamin D metabolic pathways have also been considered as strong determinants of vitamin D levels. CYP2R1 is the major 25-hydroxylase enzyme that is responsible for the 1st activation step of vitamin D. Objective: to investigate the contribution of polymorphisms in CYP2R1 gene to vitamin D deficiency and incidence of MI in Egyptians. Methods: The study included 323 subjects; 185 MI patients and 138 healthy controls. Serum 25OHD3, 25OHD2 and total 25OHD levels were measured using LC-MS/MS. SNPs rs2060793 and rs1993116 were determined by polymerase chain reaction - restriction fragment length polymorphism (PCRRFLP) which is considered one of the most commonly used techniques in genotyping. SNP rs10766197 was detected using TaqMan allele discrimination assay. Results: Serum 25OHD3, 25OHD2 and total 25OHD levels were found to be significantly lower in MI patients than controls. The three studied SNPs were associated with significantly different total 25OHD levels and their genotype distributions differed significantly between MI patients and controls where the high risk genotypes were AG/AA for rs2060793, AG/GG for rs1993116 and AG/AA for rs10766197. Additionally, the concurrent presence of high risk genotypes of the three studied SNPs rendered those individuals at extremely higher risk for MI than each individual SNP (OR 14.1, 95% CI (3.1-64.7), p-value = < 0.0001). Conclusions: Genetic variants of CYP2R1 are key determinants of serum 25OHD levels and are highly associated with MI risk.