CYP3A4 Research Articles

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Optimization of Benzoxazinorifamycins to Minimize hPXR Activation for the Treatment of Tuberculosis and HIV Coinfection.

Tuberculosis (TB) is one of the most significant world health problems, responsible for 1.5 M deaths in 2020, and yet, current treatments rely largely on 40 year old paradigms. Although the rifamycins (RIFs), best exemplified by the drug rifampin (RMP), represent a well-studied and therapeutically effective chemotype that targets the bacterial RNA polymerase (RNAP), these agents still suffer from serious drawbacks including the following: 3-9 month treatment times; cytochrome P450 (Cyp450) induction [particularly problematic for human immunodeficiency virus-Mycobacterium tuberculosis (MTB) co-infection]; and the existence of RIF-resistant (RIFR) MTB strains. We have utilized a structure-based drug design approach to synthesize and test 15 benzoxazinorifamycins (bxRIFs), congeners of the clinical candidate rifalazil, to minimize human pregnane X receptor (hPXR) activation while improving potency against MTB. We have determined the compounds' activation of the hPXR [responsible for inducing Cyp450 3A4 (CYP3A4)]. Compound IC50s have been determined against the wild-type and the most prevalent RIFR (β-S450L) mutant MTB RNAPs. We have also determined their bactericidal activity against "normal" replicating MTB and a model for non-replicating, persister MTB. We have identified a minimal substitution and have probed larger substitutions that exhibit negligible hPXR activation (1.2-fold over the dimethyl sulfoxide control), many of which are 5- to 10-fold more potent against RNAPs and MTB than RMP. Importantly, we have analogues that are essentially equipotent against replicating MTB and non-replicating persister MTB, a property that is correlated with faster kill rates and may lead to shorter treatment durations. This work provides a proof of principle that the ansamycin core remains an attractive and effective scaffold for novel and dramatically improved RIFs.

Analisis Profil Fisika Kimia dan Farmakokinetik Senyawa Pentagamavunon-1 Secara Komputasi

Pentagamavunon-1 (PGV-1) is a curcumin analog which is known to inhibit the growth of cancer cells, bacteria and inhibit free radicals as an antioxidant agent. The purpose of this study was analyzed the pharmacokinetic profile and physicochemical properties of PGV-1 computationally. The predicted parameters were Lipinski rule of five, bioavailability, Blood Brain Barrier (BBB) ​​absorption, GI absorption, P-gp substrate, and prediction of metabolic enzymes involved in drug ADME processes. The results of this study indicate that the compound PGV-1 complies with the Lipinski rule of five with the characteristics of a molecular weight of 348.43 g/mol, hydrogen donor 2, hydrogen acceptor 3, Log P 4.71 and molar refractory 40-130. PGV-1 could absorb through the GI and can pass the blood brain barrier passively without P-gp protein. Several enzymes involved in the metabolism of PGV-1 are CYP2C19, CYP2C9, CYP 3A4. Thus, our finding suggest that PGV-1 can be developed as a drug target compound for active oral drugs.

Chronic coexposure to arsenic and estrogen potentiates genotoxic estrogen metabolic pathway and hypermethylation of DNA glycosylase MBD4 in human prostate epithelial cells

AbstractBackgroundPreviously we reported that arsenic and estrogen cause synergistic effects in the neoplastic transformation of human prostate epithelial cells. In addition to receptor‐mediated pathways, DNA‐reactive estrogen metabolites have also been shown to play a critical role in mutagenicity and carcinogenicity. Both estrogen and arsenic are known prostate carcinogens, however, the effect of coexposure to these two chemicals on genes involved in estrogen metabolism is not known. Therefore, the objective of this study was to evaluate the role of arsenic and estrogen coexposure on the expression of estrogen receptors and estrogen metabolism‐associated genes. Earlier, we also reported the synergistic effect of arsenic and estrogen on decreased expression of MBD4 genes that play an important role in DNA repair through its DNA glycosylase activity. To further understand the mechanism, the promoter methylation of this gene was also analyzed.MethodsTotal RNA and protein were isolated from RWPE‐1 human prostate epithelial cells that were coexposed to arsenic and estrogen for a chronic duration (6 months). The expression of estrogen receptors, estrogen metabolism associated phase I genes (CYP 1A1, 1A2, 3A4, and 1B1) and phase II gene catechol‐O‐methyltransferase (COMT), as well as antioxidant MnSOD, were analyzed either at the RNA level by quantitative reverse transcriptase‐polymerase chain reaction or at the protein level by western blot. Promoter methylation of MBD4 was analyzed by pyrosequencing.ResultsExpression of MnSOD and phase I genes that convert E2 into genotoxic metabolites 2‐OH‐E2 and 4‐OH‐E2 were significantly increased, whereas the expression of phase II gene COMT that detoxifies estrogen metabolites was significantly decreased in arsenic and estrogen coexposed cells. MBD4 promoter was hypermethylated in arsenic and estrogen coexposed cells. Coexposure to arsenic and estrogen has synergistic effects on the expression of these genes as well as in MBD4 promoter hypermethylation.ConclusionsThese novel findings suggest that coexposure to arsenic and estrogen acts synergistically in the activation of not only the estrogen receptors but also the genes associated with genotoxic estrogen metabolism and epigenetic inactivation of DNA glycosylase MBD4. Together, these genetic and epigenetic aberrations provide the molecular basis for the potentiation of carcinogenicity of arsenic and estrogen coexposure in prostate epithelial cells.

Effect of Curcumin at Various Doses on the Pharmacokinetic Profile of Tacrolimus in Healthy Rabbits

The purpose of present study is to evaluate the effect of co-administration of curcumin (CUR) at various doses on the pharmacokinetic (PK) profile of tacrolimus (TAC), a CYP 3A4 substrate in healthy male rabbits. Healthy male rabbits (n=18) were employed in an in vivo, parallel-randomized study. Three groups of rabbits were selected and separated: The rabbits in the first group (control group) received 1 mg/kg TAC orally. Blood samples (1.5-2 mL) were drawn from rabbits' ear marginal veins at the following time frames: 15.0, 30.0, 45.0, 60.0, 90.0, 120.0, 150.0, 180.0 and 300 minutes after TAC administration post dosing and analyzed by using a TAC chemiluminescent enzyme immunoassay (CLIA) detection kit. In the second and third groups (test groups), rabbits received TAC (1mg/kg) at identical conditions as in the control group with volumes equivalent to (30 and 90 mg/kg/day) of prepared CUR suspension in normal saline for seven continuous days. Blood samples from the control group were obtained on the eighth day. Non-compartmental analysis was used to derive different PK parameters of TAC for the three groups. When CUR was co-administered at both concentrations, insignificant statistically small changes between the control and testing groups were found. Our results revealed that the differences for the three groups in PK parameters as Cmax, tmax, ke, AUC0-6 and AUC0-? were statistically insignificant (P>0.05). In conclusion, it has been found that CUR at the experimented doses does not affect the PK of TAC. Further confirmation of our findings is requiered before these results can be applied in patient care.

Massive adrenocortical carcinoma presenting as peripheral edema: a case report

BackgroundAdrenocortical carcinoma is a rare, but potentially lethal, malignancy that is usually detected as an incidental finding on abdominal imaging studies or owing to hormonal complications. This report recounts an unusual presentation with leg edema due to compression of the inferior vena cava. The dearth of proven effective treatment is also addressed.Case presentationA 65-year-old White male physician presented with severe, bilateral pitting edema that extended from the toes to the thighs. It progressed over several months. He also experienced paroxysmal dyspnea. Evaluation of cardiac, hepatic, and renal function failed to determine a cause. Computed tomography revealed a tumor above the right kidney, with compression of the intrahepatic inferior vena cava and upstream distension. Serum cortisol and dehydroepiandrosterone sulfate concentrations were elevated, 24-hour urinary cortisol level was elevated, and serum adrenocorticotropic hormone and testosterone concentrations were suppressed. A 27-cm tumor, the right lobe of the liver, the right kidney, and 26 lymph nodes were resected. Histological study confirmed the diagnosis of adrenocortical carcinoma. Ki67 proliferation index was 26.7% (worse prognosis associated with index > 10%). Lymph nodes were negative for malignancy, but a separate 2.7-cm tumor was found near the renal hilum. Adjuvant mitotane chemotherapy was prescribed. Serum testosterone concentration returned to normal. High-dose hydrocortisone administration was needed because of adrenal suppression and CYP 3A4 induction by mitotane.ConclusionImaging of the abdomen and pelvis should be conducted in cases of unexplained leg edema. In this case, a large adrenal cancer compressed the vena cava. Iron deficiency followed resection of the large tumor. Advanced stages of adrenocortical carcinoma are associated with poor prognosis. Mitotane chemotherapy is a standard but unproven adjuvant treatment that is associated with many complications, and its induction of hepatic CYP 3A4 enzymes necessitates adjustment of other medications.

Design, synthesis, and biological evaluation of a new series of pyrazole derivatives: Discovery of potent and selective JNK3 kinase inhibitors

The design, synthesis, and biological activities of a new series of pyrazole derivatives are reported. The target compounds 1a-1w were initially investigated against NCI-60 cancer cell lines. Compounds 1f, 1h, 1k, and 1v exerted the highest anti-proliferative activity over the studied panel of cancer cell lines. Compound 1f showed the most potent activity, and it is more potent than sorafenib in 29 cancer cell lines of different types and more potent than SP600125 against almost all the tested cancer cell lines. It also exerted sub-micromolar IC50 values (0.54–0.98 µM) against nine cell lines. Moreover, the 23 target compounds were tested against Hep3B and HepG2 hepatocellular carcinoma cell lines, of which compounds 1b, 1c, and 1h showed the strongest anti-proliferative activity. The most potent anticancer compounds (1b, 1c, 1f, and 1h) demonstrated a high selectivity towards cancer cells vis-à-vis normal cells. Compounds1f and 1h induced apoptosis and mild necrosis upon testing against RPMI-8226 leukemia cells. Kinase profiling of this series led to the discovery of two potent and selective JNK3 inhibitors, compounds 1c and 1f with an IC50 values of 99.0 and 97.4 nM, respectively. Both compounds showed a good inhibitory effect against JNK3 kinase in the whole-cell NanoBRET assay. This finding was further supported through molecular modeling studies with the JNK3 binding site. Moreover, compounds 1c and 1f demonstrated a very weak activity against CYP 2D6, CYP 3A4, and hERG ion channels.

Dietary α-lipoic acid alleviates deltamethrin-induced immunosuppression and oxidative stress in northern snakehead (Channa argus) via Nrf2/NF-κB signaling pathway

The goal of the study was to determine the ameliorative effects of dietary alpha-lipoic acid (α-LA) on deltamethrin (DEL)-induced immunosuppression and oxidative stress in northern snakehead (Channa argus). The northern snakeheads (15.38 ± 0.09 g) were exposed to DEL (0.242 μg/L) and fed with diets supplemented α-LA at 300, 600, and 900 mg/kg. After the 28-day exposure test, we obtained the following results: i) α-LA alleviates DEL-induced liver injury by reversing the increase of the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver cytochrome P450 enzymes (Cytochrome P450 (cyp)1a and cyp1b) expression levels. ii) α-LA can reverse the DEL-induced reduction of serum complement 4 (C4), C3, immunoglobulin M (IgM), and lysozyme (LYS) levels and the increase of liver and intestine nuclear factor kappa B (nf-κb) p65, tumor necrosis factor (tnf)-α, interleukin (il)-1β, il-8, and il-6 gene expressions, while il-10 expression levels showed the opposite result. iii) α-LA reversed the reduction of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione-S-transferase (GST) and glutathione peroxidase (GSH-Px) levels in the liver and intestine induced by DEL, while malondialdehyde (MDA) showed the opposite result. iv) α-LA reversed the reduction of Cu/Zn sod, nuclear factor erythroid 2-related factor 2 (nrf2), NAD (P)H: quinone oxidoreductase (nqo)1, and heme oxygenase (ho)-1 antioxidant gene expression levels in the liver and intestine induced by DEL. Therefore, our study indicated that optimal α-LA (600 mg/kg) could attenuate DEL-induced toxicity (including liver damage, immunotoxicity, and oxidative stress) in northern snakehead via Nrf2/NF-κB signaling pathway. This is the first research that explores the alleviated effects of α-LA on DEL-induced toxicity damage in fish. This study provides a positive measure to reduce the toxicity damage caused by DEL to aquatic animals, and provides a theoretical basis for exploring the regulation mechanism of α-LA in toxic substances.

Kratom: History, pharmacology, current user trends, adverse health effects and potential benefits

Kratom (Mitragyna speciosa Korth.) is a tree native to Southeast Asia with dose-dependent stimulant and opioid-like effects. Dried, powdered leaf material is among the kratom products most commonly consumed in the US and Europe, but other formulations also exist including enriched extracts, resins, tinctures, and edibles. Its prevalence in the US remains debated and the use pattern includes self-treatment of mood disorders, pain, and substance use disorders. Most of the adverse effects of kratom and its alkaloid mitragynine have been reported in the literature as case reports or part of surveys necessitating confirmation by clinical trials. Toxicities associated with kratom consumption have focused on hepatic, cardiac, and CNS effects with the potential to cause fatalities primarily as part of polydrug exposures. Kratom may also present with drug-drug interactions primarily through CYP 3A4 and 2D6 inhibition, although the clinical significance remains unknown to date. The variability in composition of commercially available kratom products complicates generalization of findings and requires further investigation by employing clinical trials. Healthcare professionals should remain cautious in counseling patients on the use of kratom in a therapeutic setting.

Interaction of cytochrome P450s with environmental risk factors increases their expression and risk to head and neck cancer.

To investigate the role of interaction of tobacco metabolizing polymorphic cytochrome P450s (CYPs) and glutathione S-transferase M1 (GSTM1) with environmental risk factors in modifying the susceptibility to head and neck squamous cell carcinoma (HNSCC), a case-control study with 1250 proven cases of HNSCC and equal number of healthy controls was planned. A small but significant increase in the risk to HNSCC (1-2 fold) in the cases with variant genotypes of CYPs (1A1 or 1B1 or 2E1) increased several folds (up to 13 fold) in regular tobacco or alcohol users. This several fold increase in risk could be due to more than multiplicative interaction observed between the risk genotypes of CYPs and tobacco or alcohol. A synergistic effect was also observed between tobacco as well as alcohol users among cases with risk genotypes of CYPs and GSTM1 that resulted in a further increase in risk (up to 29 fold) to HNSCC. Interestingly, the increase in the risk in tobacco users among cases with variant genotypes of CYPs or a combination of CYPs & GSTM1 (-) was associated with a higher mRNA expression of CYPs when compared to nontobacco users in controls with wild type of genotypes of CYPs & GSTM1. The data suggest that the interaction of genetic and environmental risk factors leads to increased expression of CYPs which may increase the levels of tobacco-derived carcinogens thereby modifying the risk to HNSCC.

Quantitative Proteomics of Hepatic Drug-Metabolizing Enzymes and Transporters in Patients With Colorectal Cancer Metastasis.

The impact of liver cancer metastasis on protein abundance of 22 drug‐metabolizing enzymes (DMEs) and 25 transporters was investigated using liquid chromatography‐tandem accurate mass spectrometry targeted proteomics. Microsomes were prepared from liver tissue taken from 15 healthy individuals and 18 patients with cancer (2 primary and 16 metastatic). Patient samples included tumors and matching histologically normal tissue. The levels of cytochrome P450 (CYPs 2B6, 2D6, 2E1, 3A4, and 3A5) and uridine 5′‐diphospho‐glucuronosyltransferases (UGTs 1A1, 1A6, 1A9, 2B15, 2B4, and 2B7) were lower in histologically normal tissue from patients relative to healthy controls (up to 6.6‐fold) and decreased further in tumors (up to 21‐fold for CYPs and 58‐fold for UGTs). BSEP and MRPs were also suppressed in histologically normal (up to 3.1‐fold) and tumorous tissue (up to 6.3‐fold) relative to healthy individuals. Abundance of OCT3, OAT2, OAT7, and OATPs followed similar trends (up to 2.9‐fold lower in histologically normal tissue and up to 16‐fold lower in tumors). Abundance of NTCP and OCT1 was also lower (up to 9‐fold). Interestingly, monocarboxylate transporter MCT1 was more abundant (3.3‐fold) in tumors, the only protein target to show this pattern. These perturbations could be attributed to inflammation. Interindividual variability was substantially higher in patients with cancer. Proteomics‐informed physiologically‐based pharmacokinetic (PBPK) models of 50 drugs with different attributes and hepatic extraction ratios (Simcyp) showed substantially lower drug clearance with cancer‐specific parameters compared with default parameters. In conclusion, this study provides values for decreased abundance of DMEs and transporters in liver cancer, which enables using population‐specific abundance for these patients in PBPK modeling.

Influence of cytochrome P450 and glutathione S transferase polymorphisms on response to nilotinib therapy among chronic myeloidleukemia patients from Pakistan

BackgroundCytochrome P450 (CYP) and glutathione S transferases (GSTs) are important biotransforming enzymes responsible for detoxification of anticancer drugs and carcinogens. Polymorphisms in these enzymes may greatly influence the susceptibility to CML and overall efficacy of tyrosine kinase inhibitors. This study was aimed to estimate the possible influence of the polymorphisms of GSTs and CYP in the occurrence of CML as well as in predicting therapeutic outcome of nilotinib therapy in Pakistani CML patients.MethodsThe polymorphic variability in CYP 1A1*2C, GSTP1 (A3131G), GSTT1 and GSTM1 was assessed either by RFLP or multiplex PCR. The BCR ABL1 transcripts were quantified by qPCR to monitor response to nilotinib.ResultsThe CYP1A1*2C heterozygous and GSTP1 homozygous polymorphisms seemed to be a contributing factor in developing CML. Altogether, there were 12 non-responders, 66 responders and 21 partial responders. The most frequent genotype was null GSTM1 in responders followed by CYP 1A1 and GSTP1 -wild type (p = < 0.05). Whereas, homozygous GSTP1 and GSTT1 null genotype is significantly higher only among nilotinib non-responders.ConclusionHence, it can be concluded that wild type CYP1A1, GSTP1 and null GSTM1 may be frequently linked to favorable outcome in patients treated with nilotinib as depicted by sustained deep molecular response in most CML patients.

Angiotensin II AT2 receptor ligands with phenylthiazole scaffolds

The syntheses and the AT1R and AT2R binding data of a series of new small molecule ligands are reported. These ligands comprise a phenylthiazole scaffold rather than the biphenyl or phenylthiophene scaffolds found in essentially all of the previously described ligands originating from the nonselective AT1R/AT2R ligand L-162,313 and the AT2R selective agonist C21, the latter now in Phase II/III clinical trials. A phenylthiazole rather than the phenylthiophene scaffold that is present in the AT2R selective agonist C21 and in the AT2R selective antagonist C38 had a deleterious effect on the affinity to AT2R. Nevertheless, a significant improvement could be accomplished by introduction of a small bulky alkyl group in the 2-position of the imidazole ring attached through a methylene group bridge to the phenylthiazole scaffold. Hence, a combination of a 2-tert-butyl or a 2-isopropyl group and a butoxycarbonyl furnished potent AT2R selective ligands. Furthermore, a high affinity ligand derived from L-162,313 and exhibiting a > 35 fold selectivity for AT1R was identified (10). The ligand 21 with the 2-tert-butyl group and ∼ 35 fold selectivity for AT2R, demonstrated high stability in human, rat and mouse liver microsomes and a very attractive profile with regard to the inhibition of common drug-metabolizing CYP enzymes. Thus, very low levels of inhibition of CYP 3A (5%), 2D6 (12%), 2C8 (26%), 2C9 (23%) and 2B6 (24%) were observed with the 2-tert-butyl derivative comprising the methoxycarbonyl sulfonamide function, levels that are significantly lower than those obtained with C21 under the same experimental conditions.

Study on regulation of CYP450 enzyme system to reduce liver toxicity through compatibility of Aconiti Kusnezoffii Radix Cocta with Chebulae Fructus and Glycyrrhizae Radix et Rhizoma

Aconiti Kusnezoffii Radix Cocta is one of the most commonly used medicinal materials in Mongolian medicine. Due to the strong toxicity of Aconiti Kusnezoffii Radix Cocta, Mongolian medicine often uses Chebulae Fructus, Glycyrrhizae Radix et Rhizoma to reduce the toxicity, so as to ensure the curative effect of Aconiti Kusnezoffii Radix Cocta while ensuring its clinical curative effect, but the mechanism is not clear. The aim of this study was to investigate the effects of Chebulae Fructus, Glycyrrhizae Radix et Rhizoma and Aconiti Kusnezoffii Radix Cocta on the mRNA transcription and protein translation of cytochrome P450(CYP450) in the liver of normal rats. Male SD rats were randomly divided into negative control(NC) group, phenobarbital(PB) group(0.08 g·kg~(-1)·d~(-1)), Chebulae Fructus group(0.254 2 g·kg~(-1)·d~(-1)), Glycyrrhizae Radix et Rhizoma group(0.254 2 g·kg~(-1)·d~(-1)), Aconiti Kusnezoffii Radix Cocta group(0.254 2 g·kg~(-1)·d~(-1))and compatibility group(0.254 2 g·kg~(-1)·d~(-1),taking Aconiti Kusnezoffii Radix Cocta as the standard). After continuous administration for 8 days, the activities of total bile acid(TBA), alkaline phosphatase(ALP), amino-transferase(ALT) and aspartate aminotransferase(AST)in serum were detected, the pathological changes of liver tissue were observed, and the mRNA and protein expression levels of CYP1 A2, CYP2 C11 and CYP3 A1 were observed. Compared with the NC group, the serum ALP, ALT and AST activities in the Aconiti Kusnezoffii Radix Cocta group were significantly increased, and the ALP, ALT and AST activities were decreased after compatibility. At the same time, compatibility could reduce the liver injury caused by Aconiti Kusnezoffii Radix Cocta. The results showed that Aconiti Kusnezoffii Radix Cocta could inhibit the expression of CYP1 A2, CYP2 C11 and CYP3 A1, and could up-regulate the expression of CYP1 A2, CYP2 C11 and CYP3 A1 when combined with Chebulae Fructus and Glycyrrhizae Radix et Rhizoma. The level of translation was consistent with that of transcription. The compatibility of Chebulae Fructus and Glycyrrhizae Radix et Rhizoma with Aconiti Kusnezoffii Radix Cocta could up-regulate the expression of CYP450 enzyme, reduce the accumulation time of aconitine in vivo, and play a role in reducing toxicity, and this effect may start from gene transcription.

In vitro and In silico studies of interactions of cathinone with human recombinant cytochrome P450 CYP(1A2), CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5

Cathinone is the psychostimulatory major active ingredient of khat (Catha edulis Forsk) and are often co-abused with alcohols and polydrugs. With the increased consumption of khat and cathinones on a global scale, efforts should be channelled into understanding and minimising the excruciating effects of possible khat-drug interactions. This study aimed to determine the in vitro inhibitory effects of cathinone on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 and the in silico identification of their type of interactions and residues involved. The activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2 and CYP3A5 were examined by fluorescence based assays using recombinant cDNA-expressed human CYPs in Vivid® P450 screening kits. Cathinone reversibly inhibited CYP1A2, CYP2A6 and CYP3A5 via competitive, uncompetitive and noncompetitive modes with inhibition constant (Ki) values of 57.12, 13.75 and 23.57 µM respectively. Cathinone showed negligible inhibitory effects on CYP2B6, CYP2C8, CYP2C19, CYP2E1 and CYP2J2. Cathinone showed negligible time dependent inhibition on all 8 CYPs. Docking studies was performed on cathinone with CYP1A2, CYP2A6 and CYP3A5 following their inhibition in vitro. Cathinone is bound to a few key amino acid residues in the active sites while π-π interactions are formed in aromatic clusters of CYP1A2 and CYP3A5. These findings offer valuable reference for the use of cathinones and khat when combined with therapeutic drugs that are metabolised by CYP enzymes especially patients on medications metabolised by CYP1A2, CYP2A6 and CYP3A5.

Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases.

Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases.

PIWI-interacting RNA-23210 protects against acetaminophen-induced liver injury by targeting HNF1A and HNF4A

Acetaminophen (APAP) overdose is one of the leading causes of acute liver failure in the US and other developed countries, the molecular mechanisms of APAP-induced hepatotoxicity remain speculative. PIWI-interacting RNAs (piRNAs), a novel class of small non-coding RNAs, have been identified as epigenetic regulators of transposon silencing, mRNA deadenylation, and elimination. However, the functional role of piRNAs in APAP-induced liver injury remains unclear. In the current study, the piRNA profiles were constructed in HepaRG cells after APAP exposure, and the roles of piR-23210 in regulating nuclear receptors (NRs) expression, metabolizing enzymes expression, and consequently APAP-induced liver injury were systematically investigated. As a result, 57 upregulated piRNAs were identified after APAP exposure, indicating the stress-response characteristic of piRNA molecules. Subsequent in vitro and in vivo experiments proved that piR-23210 is a novel self-protective molecule that targets HNF1A and HNF4A transcripts by interacting with RNA binding protein Nucleolin (NCL), suppresses downstream CYPs (CYP2E1, CYP3A4, and CYP1A2) expression, and protects against APAP-induced liver injury. In conclusion, our findings provided new mechanistic clues revealing potential protective role of a piRNA against the hepatoxicity of APAP.

Kolaviron pre-treatment suppresses 7, 12 dimethylbenzanthracene-induced alterations in estrogen receptor-α, CYP 1A1, oxidative stress and inflammation in female Wistar rats.

Due to the need to develop locally available, cheaper, and efficacious treatment regimens for breast cancer, the chemopreventive effect of kolaviron (KV), an extract of Garcinia kola seeds was examined. Fifty (50) female Wistar rats (120-180g) were assigned to five groups (control group, 7, 12 dimethylbenzanthracene [DMBA] groups, tamoxifen group) of 10 rats each. They were pre-treated with KV thrice a week for four weeks except control. Estrogen receptor-α (ER-α) levels were determined in the pre-treated rats before induction of mammary carcinogenesis. After the four weeks pre-treatment period, 80mg/kg of DMBA was used for induction. A hundred and fifty (150) days after induction, the rats were sacrificed humanely. Significantly higher levels of ER-α, formation of lobular neoplastic cells, epithelial hyperplasia, lymphocyte infiltration, increased cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]), CYP1A1 activity and malondialdehyde (MDA) with a corresponding decrease in superoxide dismutase (SOD), catalase and glutathione peroxidase were observed in DMBA-induced rats. Pre-treatment with KV at 200mg/kg body weight significantly (p<.05) decreased ER-α levels by 19.01% and 37.52%, [IL-6] by 36.37% and 20.55%, TNF-α by 42.2% and 12.33% in serum and mammary tissue respectively. Also, a significant (p<.05) decrease in serum CYP1A1 activity, MDA with concomitant increase in SOD, catalase and glutathione peroxidase activities were observed in serum and mammary tissue respectively. Collectively, the results suggest that KV could be further explored in targeting chemoprevention of DMBA-induced mammary damage. PRACTICAL APPLICATIONS: Garcinia kola is widely cultivated in West and Central Africa with kolaviron (KV) as its major constituents. The seeds which have a bitter astringent taste are widely consumed by people in the region. Locals claim that consumption of the seeds provides relief for the management of several ailments including cancer. However, scientific investigations that provide a basis for these claims are still needed. This study provides evidence that points to the ameliorative potential of KV on breast cancer model. The results will be beneficial to local communities who hitherto had no knowledge on the potential of G. kola in chemoprevention. The results from this study will also attract further research attention from the international scientific community to examine the anti-cancer benefits of G. kola. This will also be beneficial to the global community due to the increasing number of breast cancer cases recorded annually.

NANONIZED CURCUMIN IMPROVED ORAL BIOAVAILABILITY OF BROMOCRIPTINE THROUGH CYP3A ENZYME INHIBITION IN RATS

Curcumin (CUR) a water insoluble dietary flavonoid and is reported to inhibit CYP3A4 enzyme. The objective of present study was to assess the effect of CUR and nanonized curcumin (NC) on bromocriptine (BRO) metabolism in rats. NC was prepared by antisolvent precipitation method and was evaluated for particle size and solubility. CYP3A inhibitory activity of CUR was assessed in vitro using erythromycin-N-demethylase (EMD) assay. CYP3A inhibitory effect of CUR and NC confirmed in vivo using pharmacokinetic study of midazolam. These findings were further confirmed by an in vivo pharmacokinetic study in which BRO was administered (10 mg/kg, p.o) to CUR and NC (60 mg/kg, p.o.) pretreated (10 days) rats and its plasma concentrations were determined by HPLC analysis. CUR significantly (p less than 0.05) inhibited CYP 3A activity in EMD assay. CUR and NC significantly (p less than 0.05) increased plasma concentrations of midazolam in dexamethasone pretreated rats. In addition, in vivo studies revealed that CUR and NC pretreatments significantly (p less than 0.05) increased Cmax and AUC and decreased CL/F of BRO compared with BRO group.NC pretreatment may increase the bioavailability of BRO which could be mediated through the inhibition of CYP 3A enzymes.

Biochemical and molecular study on the beneficial effect of Solubilized coenzyme Q10 on thioacetamide-induced liver fibrosis in adult male rats

The current work aims to evaluate the therapeutic effect of both solubilized Coenzyme Q10 and Silymarin on liver injury. Thirty adult male albino rats, weigh 200±10 g, were allocated into five groups. Hepatic injury was induced by intraperitoneal injection of TAA (20 mg/ kg body weight) twice a week. Solubilized CoQ10 (20 mg/kg) and Silymarin (50 mg/kg) were taken orally for 28 days. The present results showed that the values for aspartate/platelet ratio (APRI) as well as aspartate aminotransferase/alanine aminotransferase ratio (AAR) were increased by TAA treatment. While treatments using coenzyme Q10 and Silymarin decreased these values near the control levels. The solubilized CoQ10 could attenuate TAA liver injury throughout controlling the oxidative stress markers (GSH, GSSG), NO level. Also, down-regulation gene expression of fibrotic markers TGF-β, collagen-1α, and TIMP1 and enhancing the expression for MMP2 and cytochrome P 450 (CYP 2E1& CYP 3A2). Collectively, solubilized CoQ10 singly or combined with Silymarin showed higher therapeutic impacts more than or equivalents to Silymarin treatment for liver fibrosis induced by TAA.