Morin hydrate ameliorates Di-2-ethylhexyl phthalate (DEHP) induced hepatotoxicity in a mouse model via TNF-α and NF-κß signaling.

Di-(2-ethylhexyl) phthalic acid (DEHP) pollutes the environment, and posing a significant risk to human and animal health. Consequently, a successful preventative strategy against DEHP-induced liver toxicity needs to be investigated. Morin hydrate (MH), a flavanol compound, possesses toxic preventive attributes against various environmental pollutants. However, the effects of MH have not been investigated against DEHP-induced liver toxicity. Female Swiss albino mice were divided into four groups: control, DEHP (orally administered with 500 mg/kg, DEHP plus MH 10 mg/kg, and DEHP plus MH 100 mg/kg for 14 days. The results showed that the MH treatment ameliorated the DEHP-induced liver dysfunctions by decreasing the alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin, liver histoarchitecture, fibrosis, and markers of oxidative stress. Furthermore, DEHP increased apoptosis, increased active caspase 3 and decreased B cell lymphoma-2 (Bcl-2) expression. However, the MH treatment showed a differential effect on these proteins; a lower dose increased, and a higher dose decreased the expression. Thus, a lower dose of MH could be involved in the disposal of damaged hepatocytes. Expression of Estrogen receptors alpha (ERα) also showed a similar trend with active caspase 3. Furthermore, the expression of Tumor necrosis factor alpha (TNF-α) and Nuclear factor-κß (NF-κß) were up-regulated by DEHP treatment, and MH treatment down-regulated the expression of these two inflammatory markers. Since this down-regulation of TNF-α and NF-κß coincides with improved liver functions against DEHP-induced toxicity, it can be concluded that MH-mediated liver function involves the singling of TNF-α and NF-κß.

Morin hydrate ameliorates heat-induced testicular impairment in a mouse model.

BACKGROUND: Heat stress is known to adversely affect testicular activity and manifest the pathogenesis of spermatogenesis. Morin hydrate is a plant-derived compound, which contains a wide range of biological activities. Thus, it is hypothesized that morin hydrate might have an ameliorative effect on heat-induced testicular impairment. There has not been any research on the impact of morin hydrate on heat-induced testicular damage. METHODS: The experimental mice were divided into four groups, groups1 as the normal control group (CN), and the second which underwent heat stress (HS) by immersing the lower body for 15 min in a thermostatically controlled water bath kept at 43 °C (HS), and third and fourth heat-stressed followed by two different dosages of morin hydrate 10 mg/kg (HSM10) and 100 mg/kg (HSM100) for 14 days. RESULTS: Morin hydrate treatment at 10 mg/kg improved, circulating testosterone levels (increases 3ßHSD), and oxidative stress along with improvement in the testis and caput and corpus epididymis histoarchitecture, however, both doses of morin hydrate improved sperm parameters. Morin hydrate treatment significantly increases germ cell proliferation, (GCNA, BrdU staining), expression of Bcl2 and decreases expression of active caspase 3. Heat stress also decreased the expression of AR, ER- α, and ER-ß, and Morin hydrate treatment increased the expression of these markers in the 10 mg/kg treatment group. CONCLUSION: Morin hydrate ameliorates heat-induced testicular impairment modulating testosterone synthesis, germ cell proliferation, and oxidative stress. These effects could be manifested by regulating androgen and estrogen receptors. However, the two doses showed differential effects of some parameters, which requires further investigations.

Contemporary approaches in the management of uterine leiomyomas.

BACKGROUND: Leiomyomas (fibroids), the most common benign solid tumours in females, originate from the myometrium and are associated with poor quality of life for patients. The current management of uterine leiomyomas mainly includes surgical interventions such as hysterectomy and myomectomy, either by laparoscopy or laparotomy, which have several complications and are not ideal for preserving fertility. Therefore, there is a need to develop or repurpose medical treatments that do not require surgical intervention. OBJECTIVE: Many drugs are used to treat the symptoms associated with uterine fibroids. The main objective of this systematic review is to give an up-to-date account of potential pharmacological agents (non-surgical methods) for the management of uterine leiomyomas. SEARCH STRATEGY: PubMed was searched for scientific and clinical literature using the keyword 'uterine fibroids' along with the drug names described in each section. For example, 'uterine fibroids' and 'ulipristal acetate' were the keywords used to search for literature on ulipristal acetate (UPA). RESULTS: Various preclinical and clinical studies have shown that some drugs and herbal formulations exhibit activity in the management of uterine leiomyomas. Recent studies found that drugs such as UPA, elagolix, EC313, asoprisnol, nutritional supplements and herbal preparations were helpful in treating the symptoms associated with uterine leiomyomas. CONCLUSION: Many drugs show efficacy in patients with symptomatic uterine fibroids. UPA is one of the most studied and prescribed medicines for uterine fibroids; however, its usage has been restricted due to a few recent incidences of hepatic toxicity. Herbal drugs and natural supplements have also shown promising effects on uterine fibroids. The synergistic effects of nutritional and herbal supplements have been reported in certain cases, and should be studied in detail. Further research is warranted to identify the mode of action of the drugs, and to determine the precise conditions that would explain the causes of toxicity in some patients.

Global genomic and proteomic analysis indicates co-evolution of Neisseria species and with their human host.

Neisseria, a genus from the beta-proteobacteria class, is of potential clinical importance. This genus contains both pathogenic and commensal strains. Gonorrhea and meningitis are two major diseases caused by pathogens belonging to this genus. With the increased use of antimicrobial agents against these pathogens they have evolved the antimicrobial resistance capacity making these diseases nearly untreatable. The set of anti-bacterial resistance genes (resistome) and genes associated with signal processing (secretomes) are crucial for the host-microbial interaction. With the virtue of whole-genome sequences and computational biology, it is now possible to study the genomic and proteomic riddles of Neisseria along with their comprehensive evolutionary and metabolic profiling. We have studied relative synonymous codon usage, amino acid usage, reverse ecology, comparative genomics, evolutionary analysis and pathogen-host (Neisseria-human) interaction through bioinformatics analysis. Our analysis revealed the co-evolution of Neisseria genomes with the human host. Moreover, the co-occurrence of Neisseria and humans has been supported through reverse ecology analysis. A differential pattern of the evolutionary rate of resistomes and secretomes was evident among the pathogenic and commensal strains. Comparative genomics supported the presence of virulent genes in both pathogenic and commensal strains of the select genus. Our analysis also indicated a transition from commensal to pathogenic Neisseria strains through the long run of evolution.

Complete mitogenome of endemic plum-headed parakeet Psittacula cyanocephala - characterization and phylogenetic analysis.

Psittacula cyanocephala is an endemic parakeet from the Indian sub-continent that is widespread in the illegal bird trade. Previous studies on Psittacula parakeets have highlighted taxonomic ambiguities, warranting studies to resolve the issues. Since the mitochondrial genome provides useful information concerning the species evolution and phylogenetics, we sequenced the complete mitogenome of P. cyanocephala using NGS, validated 38.86% of the mitogenome using Sanger Sequencing and compared it with other available whole mitogenomes of Psittacula. The complete mitogenome of the species was 16814 bp in length with 54.08% AT composition. P. cyanocephala mitogenome comprises of 13 protein-coding genes, 2 rRNAs and 22 tRNAs. P. cyanocephala mitogenome organization was consistent with other Psittacula mitogenomes. Comparative codon usage analysis indicated the role of natural selection on Psittacula mitogenomes. Strong purifying selection pressure was observed maximum on nad1 and nad4l genes. The mitochondrial control region of all Psittacula species displayed the ancestral avian CR gene order. Phylogenetic analyses revealed the Psittacula genus as paraphyletic nature, containing at least 4 groups of species within the same genus, suggesting its taxonomic reconsideration. Our results provide useful information for developing forensic tests to control the illegal trade of the species and scientific basis for phylogenetic revision of the genus Psittacula.

An interplay between compositional constraint and natural selection dictates the codon usage pattern among select Galliformes.

Galliformes are believed to be the first avian order that started living in human association and became domesticated. Members of this order ranged from common to rare species. Next-generation sequencing has availed researchers with the whole genome sequences of five Galliformes; chicken, helmeted Guinea fowl, turkey, Japanese quail, and peafowl. Bioinformatic analysis based on codon usage, evolution, and species-specific functional enrichment can provide some crucial information aiding proper understanding of their genomic strategies. In this study, we investigated the genomic features of chicken, helmeted guinea fowl, turkey, and Japanese quail. Their genomes were AT biased although the potentially highly expressed genes contained more GC than AT. Cytosine dominated the third position of frequently used optimal codons. Mutational pressures in the analyzed Galliformes were in the range of 0.2-0.6%. Neutrality plot, translational selection index, and mutational responsive index indicated the dominance of selection pressure over mutational pressure among Galliformes. A pair of di-nucleotides, TpA and CpG, was found to be used less frequently than others in protein-coding genes since both of them are associated with the conversion of euchromatin to heterochromatin. Functional enrichment analysis revealed the dominance of proteins associated with fundamental biological processes. In turkey, chicken and helmeted Guinea fowl proteins with immunity-boosting capacity prevailed along with proteins needed for signal transduction and maintenance of central dogma. Evolutionary analysis indicated a bias towards synonymous substitution than non-synonymous mutation.

CYP4F2 1347 G > A & GGCX 12970 C > G polymorphisms: frequency in north Indians & their effect on dosing of acenocoumarol oral anticoagulant.

BACKGROUND & OBJECTIVES: CYP4F2 and γ-glutamyl carboxylase (GGCX) have small but significant roles in the maintenance dose of coumarinic oral anticoagulants (COAs). CYP4F2 1347 G > A and GGCX 12970 C > G polymorphisms have been used in the pharmacogenetic dosing algorithms of warfarin for Caucasians and Chinese populations. India has a large population with multiple ethnic groups but there are no reports about the frequencies of these polymorphisms in north Indians. In the present study, we aimed to find out the allelic frequencies of CYP4F2 1347 G > A and GGCX 12970 C > G polymorphisms in a north Indian population and relate these to daily maintenance drug dose requirements of COA. METHODS: CYP4F2 1347 G > A and GGCX 12970 C > G polymorphisms were genotyped by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) protocols and Taqman SNP discrimination assays in healthy volunteers (n=102) and patients (n=225) receiving acenocoumarol, an oral anticoagulant, after cardiac valve replacement surgery. RESULTS: In healthy volunteers, the allele frequencies for CYP4F2 1347 G > A and GGCX 12970 C > G were 43.14 and 1.43 per cent, respectively. No significant differences in mean weight normalized doses of acenocoumarol were found for these CYP4F2 and GGCX genotypes. Binary logistic regression analysis revealed no significant association of any of the genotypes or alleles with the dosing phenotypes for both the SNPs. INTERPRETATION & CONCLUSIONS: We report distinct frequencies of CYP4F2 1347 G > A and GGCX 12970 C > G polymorphisms in north Indians but these polymorphisms did not have significant bearing on maintenance dose of acenocoumarol oral anticoagulant in cardiac valve replacement patients.

Therapeutic dosing of acenocoumarol: proposal of a population specific pharmacogenetic dosing algorithm and its validation in north Indians.

OBJECTIVES: To develop a population specific pharmacogenetic acenocoumarol dosing algorithm for north Indian patients and show its efficiency in dosage prediction. METHODS: Multiple and linear stepwise regression analyses were used to include age, sex, height, weight, body surface area, smoking status, VKORC1 -1639 G>A, CYP4F2 1347 G>A, CYP2C9*2,*3 and GGCX 12970 C>G polymorphisms as variables to generate dosing algorithms. The new dosing models were compared with already reported algorithms and also with the clinical data for various performance measures. Odds ratios for association of genotypes with drug sensitive and resistant groups were calculated. RESULTS: The pharmacogenetic dosing algorithm generated by multiple regression analysis explains 41.4% (p-value <0.001) of dosage variation. Validation of the new algorithm showed its predictive ability to be better than the already established algorithms based on similar variables. Its validity in our population is reflected by increased sensitivity, specificity, accuracy and decreased rates of over- and under-estimation in comparison to clinical data. The VKORC1-1639 G>A polymorphism was found to be strongly associated with acenocoumarol sensitivity according to recessive model. CONCLUSIONS: We have proposed an efficient north India specific pharmacogenetic acenocoumarol dosing algorithm which might become a baseline for personalised medicine approach for treatment of patients in future.

Pharmacogenetic aspects of coumarinic oral anticoagulant therapies.

Coumarinic oral-anticoagulants (COAs) are commonly used for treatment of thromboembolic events. However, these medications have a narrow therapeutic range and there are large inter-individual variations in drug response. This is especially important in the initial phases of oral-anticoagulant therapy. Recent advancements in pharmacogenetics have established that clinical outcomes in oral-anticoagulant therapy are affected by genetic factors. The allelic variants of genes like cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are closely associated with maintenance dose of oral anti-coagulants. In addition, GGCX (Gamma-glutamyl carboxylase) polymorphism at position 12970 (rs11676382), CYP4F2 (rs2108622; V433M; 1347 C > T) and Apolipoprotein E (APOE) variants have been shown to explain a small but significant influence on dose requirements. There are large differences in the frequencies of these polymorphisms between different world populations which are also related to the requirements of oral anticoagulants. However, the final drug dosage in an individual is determined by complex sets of genetic and environmental factors and several dosing algorithms which combine clinical and genetic parameters to predict therapeutic COA doses have also been developed. The algorithm based dose prediction shows the importance of pharmacogenetic testing in patients undergoing oral anticoagulant therapies.