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PURPOSE: Pregnancy-mediated physiological and biochemical changes contribute to alterations in the pharmacokinetics of certain drugs. There is a paucity of data on the systematic evaluation of the underlying mechanisms. The objective of the current study was to examine the impact of changes in circulating and tissue hormonal concentration during the late stage of pregnancy on the activity and expression of hepatic cytochrome P450 (CYP) enzymes using a cocktail probe approach. METHODS: Freshly isolated primary human hepatocytes were incubated with third trimester physiologic (plasma) and projected liver (ten-fold higher) concentrations of female hormones: progesterone (2 µM), estradiol (0.3 µM), estriol (0.8 µM), estrone (0.2 µM), 17α-hydroxyprogesterone (0.1 µM), and human growth hormone (0.005 µM). The metabolic activity of the hepatocytes was assessed using a cocktail of isozyme-specific P450 probe substrates (CYP1A2 (phenacetin), CYP2C9 (diclofenac), CYP2C19 (S-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4 (testosterone)). A validated LC-MS/MS assay was used to measure the corresponding metabolite concentrations. CYP450 protein and mRNA levels were measured using western blot and qRT-PCR, respectively. RESULTS: Female hormones at projected third-semester hepatic concentrations significantly enhanced mRNA and protein expression and increased the metabolic activity of CYP3A4. The expression and activity of other CYP450 enzymes studied were not affected by mixtures of female hormones at concentrations used. CONCLUSION: The increased activity of CYP3A4 is consistent with the clinically observed increase in clearance of CYP3A4 substrates during pregnancy. Overall expression and activity of CYP450 isozymes are differentially regulated during pregnancy.
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Citocromo P-450 CYP3A , Espectrometría de Masas en Tándem , Humanos , Femenino , Embarazo , Citocromo P-450 CYP3A/metabolismo , Cromatografía Liquida , Sistema Enzimático del Citocromo P-450/metabolismo , Hepatocitos/metabolismo , Hormonas/metabolismo , Hormonas/farmacología , Microsomas HepáticosRESUMEN
Weekly intramuscular (250 mg/week) or subcutaneous (275 mg/week) injections of 17-hydroxyprogesterone caproate (17-OHPC) is the only treatment option for the prevention of preterm birth in women with a prior history of preterm delivery.The objective of the current study was to determine the relative distribution of 17-OHPC in selected tissues in adult female SD rats after IM (oily formulation or solution), IV (solution), PO (solution), or intravaginal (suppository) administration.Plasma, uterus, adipose, and liver samples were collected at various times and analysed by LC-MS-MS.The highest concentrations of 17-OHPC were observed in the adipose tissue, after IM (oily formulation), and intravaginal administration.Substantial concentrations of 17-OHPC were also observed in the uterus after IM, intravaginal and IV administration.17-OHPC was not detected in the liver and in any of the tissues tested after PO administration.17-OHPC levels in plasma after intravaginal suppository administration were low despite substantial concentrations in the adipose and the uterus.The distribution of 17-OHPC depends on the formulation, the route of administration, and the sampling time.Low systemic concentrations and substantial distribution in the tissues of interest after intravaginal administration warrants future studies to evaluate the potential of the daily intravaginal route of administration of 17-OHPC.
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Hidroxiprogesteronas , Nacimiento Prematuro , Recién Nacido , Humanos , Femenino , Ratas , Animales , Caproato de 17 alfa-Hidroxiprogesterona , 17-alfa-Hidroxiprogesterona , Nacimiento Prematuro/prevención & control , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: To determine the prevalence of antibiotic use by pregnant women in Najran, Saudi Arabia. METHODS: A total of 125 women aged 18 to 45 with a full-term pregnancy participated from October to December 2019. Age, order of current pregnancy, body mass index (BMI), history of miscarriage, and comorbidity were used to estimate antibiotic use. RESULTS: The majority were Saudis (67.2%), aged 30-35 (39.2%) years, with no history of miscarriage (53.6%), second order of pregnancy (26.4%), and going through weeks 20-25 of pregnancy (21.6%). A total of 26.4% of pregnant women had antibiotic prescriptions in the study population. Pregnant women under 30 years were less likely to receive antibiotics. CONCLUSION: The results found an association between maternal age, order of pregnancy and antibiotic use during pregnancy. An association was observed between maternal BMI and the occurrence of adverse drug reactions after antibiotic use. In addition, a history of miscarriage was negatively associated with the use of antibiotics during pregnancy. These predictors of antibiotic administration have the potential to serve as general health indicators and to direct preventative strategies aimed at increasing the rational use of antibiotics.
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Aborto Espontáneo , Mujeres Embarazadas , Femenino , Embarazo , Humanos , Antibacterianos/efectos adversos , Arabia Saudita/epidemiología , Aborto Espontáneo/epidemiología , HospitalesRESUMEN
OBJECTIVES: To test the antidiabetic potential of Gardenia latifolia extract (GLE) in rats with type 2 diabetes mellitus (T2DM) induced by a high-fat diet (HFD) + streptozotocin (STZ). METHODS: The study was carried out in June 2021. Gardenia latifolia powdered leaves were subjected to Soxhlet extraction using ethanol. Male rats were administered a low dose-40 mg/kg STZ by intraperitoneal route following 2 weeks of HFD to induce type-2 diabetic rats (T2DR). Rats were randomized into 5 groups (n=6). Group 1 (normal control; 10 ml/kg normal saline); Group 2 (diabetic control: DC); Group 3 (standard; DR + metformin, 100 mg/kg per oral); Group 4 (DR + GLE 250 mg/kg); Group 5 (DR + GLE 500 mg/kg). The treatment period extended for 2 weeks. Body weight and fasting blood glucose were determined on days 0, 7, and 14. Fasting serum insulin (FSI) levels, fasting blood glucose (FBG), HOMA-IR, antioxidant enzyme level, Insulin tolerance test (ITT), and intraperitoneal glucose tolerance test (IPGTT) tests were estimated. RESULTS: Gardenia latifolia extract exhibited a marked decrease (p<0.001) in fasting blood glucose levels. T2DR receiving a higher dose of GLE showed a greater improvement in metabolic indices (FSI, FBG, Homeostatic Model Assessment of insulin resistance). The ITT and IPGTT results demonstrated that GLE could significantly enhance insulin tolerance, glucose tolerance, and antioxidant enzyme levels in T2DR. CONCLUSION: Gardenia latifolia can be an ideal medicinal plant candidate for treating T2DM, and it should be investigated further for its therapeutic potential.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Gardenia , Insulinas , Animales , Antioxidantes/metabolismo , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dieta Alta en Grasa/efectos adversos , Gardenia/metabolismo , Hipoglucemiantes/uso terapéutico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas , EstreptozocinaRESUMEN
Background: Epilepsy is a neurodegenerative condition characterized by uncontrollable convulsions caused by a misalignment of the central nervous system's inhibitory and excitatory branches. Vateria indica is a medicinal herb with anti-inflammatory, anthelmintic, antiulcer, antitumor, and anticancer properties. Objectives: To investigate the antiepileptic activity of Vateria indica using maximal electrical shock (MES), pentylenetetrazole (PTZ), and isoniazid (INH) induced experimental animal models. Methodology: Vateria indica bark was subjected to Soxhlet extraction using ethanol and quantitative and qualitative analysis was performed. The antiepileptic activity of Vateria indica bark extract (VIE) was investigated using different animal models in mice. GABA levels in the brain and antioxidant capacity in vitro were estimated. Results: Treatment of mice with VIE significantly reversed the MES-induced convulsions, which was reflected by the decrease in the duration (sec) of all the phases of MES-induced convulsions, with an increment in the GABA levels. In the PTZ and INH models, pretreatment with VIE delayed the latency to clonic convulsions (p 0.001), reduced the intensity and duration of clonic convulsions, and reduced the mortality rate in the treatment groups in a dose-dependent manner. VIE intervention dose-dependently restored brain GABA levels. VIE also exhibited significant in-vitro antioxidant activity. Conclusion: Overall, the findings imply that Vateria indica has substantial antiepileptic activities, mediated by positive GABAergic neurotransmission and antioxidant capabilities. To summarize, Vateria indica may provide adequate protection against epileptic seizures, suggesting that it could be used to treat petitmal and grandmal epilepsy. We plan to provide pure lead compounds derived from Vateria indica in the future in order to better understand the role it could play in the development of natural anticonvulsant drugs.
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Introduction: Pharmacovigilance (PV) is critical in determining the risk-benefit ratio of medicines and encouraging their safe, rational, and effective use, hence enhancing patient safety and care. Pharmacists, as drug experts, share responsibility for ensuring that medicines remain safe. Objective: The study aimed to assess the knowledge, attitude, and practice of hospital pharmacists towards PV and adverse drug reaction (ADR) reporting and to know factors that discourage them from reporting ADRs in Najran, Saudi Arabia. Methods: A pre-tested self-administered questionnaire was distributed to all the pharmacists working in government hospitals who consented to participate in the study. Data was collected over three months, from 01 June 2018 to 31 Aug 2018. Data were analyzed using Statistical Package for Social Science (SPSS) software for Windows, version 23. Descriptive statistics such as frequency and percentages, mean ± standard deviation (SD) were calculated, and the Pearson's Chi-square test was used to examine the relationship between different variables. Results: A total of 145 questionnaires were distributed, and the response rate obtained was 70.3%. The definition of PV and ADR were correctly identified by 42% and 68.3% of participants, respectively. A noteworthy finding is that 95% of participants were aware of the existence of the ADR reporting system, and 88.9% knew the responsible regulatory agency. Participants showed a positive attitude towards PV and ADR reporting; 90.1% considered ADR reporting a part of professional obligation, and 94.1% believed that there should be collaboration between pharmacists and other healthcare professionals. A majority of participants (86.1%) had identified an ADR during their practice, and 71.3% had reported an ADR. The unavailability of a professional environment to discuss ADR and insufficient pharmacotherapy/clinical knowledge was cited as the main factors discouraging from reporting ADRs. Conclusions: Overall, the pharmacists had an average to good knowledge of and positive attitude towards PV and ADR reporting and a good ADR reporting practice. The concept of PV and ADR reporting should be further strengthened, and there is a vast potential for the same.
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Background: The drug hydroxychloroquine (HCQ) is widely used to treat rheumatoid arthritis (RA) and has been repurposed for the treatment of COVID-19. This study aims to determine whether HCQ concentration levels in individuals with RA alter the incidence of COVID-19 or its complications. Methods: We collected plasma samples from 13 individuals with confirmed rheumatoid arthritis (RA) to measure HCQ concentration levels. The study included individuals at least 18 years old who had been taking HCQ for at least six months at daily doses ranging from 200 to 400 mg. Results: The study enrolled a total of 13 RA patients. All patients were chronic HCQ users. Among the 13 patients, 7 patients were receiving HCQ at a dose of 200 mg per day, and 6 patients were receiving HCQ at a dose of 400 mg per day. COVID-19 confirmed cases accounted for approximately 46% of all patients. Half of the infected patients (n = 3) were taking a daily dose of 200 mg daily, while the other half were taking 400 mg daily. COVID-19 symptoms ranged from mild to moderate, and the intensity of the symptoms was not severe enough to necessitate hospitalization. COVID-19 symptoms in RA patients included headache, fever, fatigue, dry cough, and loss of taste or smell. Conclusions: Our findings indicated that there was no correlation between HCQ concentrations in rheumatoid arthritis patients and the occurrence of COVID-19 or its complications.
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OBJECTIVE: Hydroxychloroquine (HCQ) has been used during the coronavirus disease 2019 (COVID-19) pandemic because of its reported anti-viral activity. This study examined the association of chronic HCQ use with the incidence and complications of COVID-19. METHODS: This retrospective cohort study included adults with rheumatoid arthritis and/or systemic lupus erythematosus who visited rheumatology clinics in three tertiary hospitals in Riyadh, Saudi Arabia between January 2019 and December 2020. Patients were categorized into two groups based on HCQ use. Data were obtained from the electronic health record and by interviews with patients. The primary study objective was the incidence of COVID-19 and its complications from March 2020 to February 2021. RESULTS: Almost 11% of the study cohort was positive for COVID-19, and the incidence of COVID-19 was similar between HCQ users (11.11%) and nonusers (10.86%). Disease complication rates were similar in the study arms, and they mainly included fever, dry cough, fatigue, and breathing difficulty. CONCLUSIONS: This study revealed no significant association between chronic HCQ use and the incidence of COVID-19, and disease complications were similar in the study arms.
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Antirreumáticos , Artritis Reumatoide , Tratamiento Farmacológico de COVID-19 , COVID-19 , Lupus Eritematoso Sistémico , Adulto , Antirreumáticos/efectos adversos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , COVID-19/epidemiología , Humanos , Hidroxicloroquina/efectos adversos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/epidemiología , Estudios RetrospectivosRESUMEN
Antinociceptive activity of honey and Nigella sativa (N. sativa) oil are well known. Therefore, aim of this study was to investigate the antinociceptive effect of N. sativa oil and its concurrent administration with honey in rats. The tested animals were randomized into 5 groups: Group (1) Normal saline (0.2ml, p.o.); Group (2) N. sativa oil (1gm/kg, p.o.); Group (3) honey (1gm/kg, p.o.); Group (4) N. sativa oil (1gm/kg, p.o.) + honey (1gm/kg, p.o.): Group (5) pethidine (20mg/kg, S.C.) as positive standard. The antinociceptive activity was tested using radiant heat and tail immersion tests. Antioxidant potential was determined by using in-vitro antioxidant assays. Our findings showed that N. sativa oil and honey have antinociceptive effect, the antinociceptive effect appeared after 30 and 60min of administration and declined after 120 and 180 min. Combined administration of N. sativa oil with Honey increased the antinociceptive effect by 20 to 30% in all models. In addition, the antinociceptive effect of the combination reduced the time for onset of action as well as prolonged its duration of action. In conclusion, combined treatment of N. sativa oil with honey increased its antinociceptive activity, showed faster onset of action and prolonged its duration, the fact that can be utilized in the management of painful conditions in humans.
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Analgésicos/uso terapéutico , Miel , Dolor/tratamiento farmacológico , Aceites de Plantas/uso terapéutico , Animales , Masculino , Fitoterapia , Ratas , Ratas WistarRESUMEN
The application of plant extracts or plant-derived compounds in the green synthesis of metal nanoparticles (NPs) was researched. Determining the exact metabolite implicated in the formation of NPs would necessitate comprehensive investigations. Copper nanoparticles (CuNPs) are gaining a lot of attention because of their unique properties and effectiveness against a wide range of bacteria and fungi, as well as their potential for usage in catalytic, optical, electrical, and microelectronics applications. In the course of this study, we aimed to formulate CuNPs utilizing pure tamarixinin A (TA) ellagitannin isolated from Tamarix aphylla galls. The main particle size of the formed CuNPs was 44 ± 1.7 nm with zeta potential equal to -23.7 mV, which emphasize the stability of the CuNPs. The X-ray diffraction spectroscopy showed a typical centered cubic crystalline structure phase of copper. Scanning electron microscopy images were found to be relatively spherical and homogeneous in shape. The antimicrobial properties of TA, as well as its mediated CuNPs, have been evaluated through well diffusion assays against four bacterial, Bacillus subtilis NCTC 10400, Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853, and two fungal, Candida albicans and Aspergillus flavus, strains. The distinctive antimicrobial activities were noted against the fungal strains and the Gram-negative bacterial strains P. aeruginosa ATCC 27853, and E. coli ATCC 25922. In conclusion, CuNPs mediated by TA can be applied for combating a wide range of bacterial and fungal species especially C. albicans, Asp. flavus, and P. aeruginosa in a variety of fields.
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This study aims to evaluate the anti-Leishmania major and the lung adenocarcinoma (A549) cytotoxicity of Withania somnifera root and fruit. The total extracts were obtained by homogenisation in aqueous MeOH, and the sub-extracts [n-hexane, ethyl acetate (EtOAc), n-butanol (n-BuOH), and methanol (MeOH)] were obtained by flash chromatography. The activity evaluation showed that n-BuOH sub-extracts from root and fruit exhibited noticeable antileishmanial promastigote properties. The n-hexane and EtOAc sub-extracts from both organs, and the MeOH sub-extract from the fruit exerted mild to moderate effects on the promastigotes. In-vitro growth-inhibitory test results on axenic amastigote and cytotoxicity testing on macrophages (RAW264.7), the parasite-host at the amastigote stage, revealed that the activity was mainly concentrated in the root EtOAc and n-BuOH sub-extracts and to a lesser extent the fruit MeOH and EtOAc, and the root n-hexane sub-extracts. Only the roots' EtOAc and n-BuOH sub-extracts demonstrated low cytotoxicity on the A549 cell line.
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Adenocarcinoma del Pulmón , Antiprotozoarios , Withania , Frutas , Metanol , Extractos Vegetales/química , Raíces de Plantas/química , Withania/químicaRESUMEN
OBJECTIVES: To determine the influence of caffeine on pharmacokinetics and pharmacodynamics of pioglitazone (PIO) in diabetic rats. METHODS: This was a preclinical study conducted in the College of Pharmacy, Najran University, Saudi Arabia, using 5 groups of Wistar rats: normal rats, untreated diabetic rats, diabetic rats + caffeine (20 mg/kg), diabetic rats + PIO (10 mg/kg), and diabetic rats + PIO (10 mg/kg) + caffeine (20 mg/kg). The drugs were administered for 14 days, and fasting plasma glucose concentrations were determined on the first day, and thereafter at weekly intervals. On day 14, rat sacrifice was followed with assay of levels of biomarkers. To estimate the pharmacokinetic parameters, the diabetic animals were assigned to 2 groups: one group received PIO (10 mg/kg), while the other received PIO + caffeine (20 mg/kg). Blood samples were drawn from the retro-orbital plexus at different time intervals, and pharmacokinetic parameters were measured using high performance liquid chromatography. RESULTS: Caffeine caused statistically marked increases in area under the curve, Cmax, Tmax, and half-life of PIO, and decreased clearance. Combination of PIO and caffeine produced a synergistic effect on percentage reduction in blood glucose, with 67.1% reductions observed on day 7 and 68.9% reductions observed on day 14. Liver and cardiac biomarkers were significantly decreased, suggesting cardioprotective and hepatoprotective effects. CONCLUSION: Co-administration of PIO with caffeine enhances its antidiabetic effect, probably due to enhanced bioavailability of PIO, leading to clinical benefits in diabetic patients.
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Cafeína , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Pioglitazona , Tiazolidinedionas , Animales , Cafeína/farmacología , Humanos , Hipoglucemiantes/farmacocinética , Pioglitazona/farmacocinética , Ratas , Ratas Wistar , Arabia SauditaRESUMEN
OBJECTIVES: The fact that methotrexate (MTX) is hepatotoxic is an important reason to limit its clinical use. Rebamipide (REB) has antioxidant and anti-inflammatory properties and is useful for the treatment of gastro-duodenal ulcers. This study investigated the impact and protective mechanisms of REB against MTX-induced hepatotoxicity in rats. MATERIALS AND METHODS: Animals were divided into four groups of six rats each: a control group, REB group (REB 100 mg/kg/day, orally), MTX control group (20 mg/kg, single i.p.), and MTX + REB group. RESULTS: The administration of MTX induced marked hepatic injury in the form of hepatocyte inflammatory swelling, degeneration, apoptosis, and focal necrosis. In parallel, our biochemical investigations revealed a marked hepatic dysfunction associated with the disturbance of the oxidant/antioxidant balance in the group treated with only MTX. Moreover, MTX led to the down-regulation of the hepatic Nrf2 and Bcl-2 expressions along with a marked elevation in the hepatic NF-κß-p65, GSK-3ß, JAK1, STAT3, PUMA, and Bax expressions. On the other hand, co-treatment with REB significantly ameliorated the aforementioned histopathological, biochemical, and molecular defects caused by MTX treatment. CONCLUSION: the outcomes of the present study showed REB's ability to protect from hepatic injury induced by MTX, possibly through its antioxidant, anti-inflammatory, and anti-apoptotic properties. These effects could be attributed to REB's ability to modulate, at least in part, the Nrf2/GSK-3ß,NF-κß-p65/JAK1/STAT3, and PUMA/Bax/Bcl-2signaling pathways.
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Alanina/análogos & derivados , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Janus Quinasa 1/metabolismo , Hígado/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Quinolonas/farmacología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción ReIA/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Alanina/farmacología , Animales , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Modelos Animales de Enfermedad , Hígado/enzimología , Hígado/patología , Masculino , Metotrexato , Necrosis , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Transducción de SeñalRESUMEN
: Breast cancer (BRCA) remains the leading cause of cancer morbidity and mortality worldwide. In the present study, we identified novel biomarkers expressed during estradiol and tamoxifen treatment of BRCA. The microarray dataset of E-MTAB-4975 from Array Express database was downloaded, and the differential expressed genes (DEGs) between estradiol-treated BRCA sample and tamoxifen-treated BRCA sample were identified by limma package. The pathway and gene ontology (GO) enrichment analysis, construction of protein-protein interaction (PPI) network, module analysis, construction of target genes-miRNA interaction network and target genes-transcription factor (TF) interaction network were performed using bioinformatics tools. The expression, prognostic values, and mutation of hub genes were validated by SurvExpress database, cBioPortal, and human protein atlas (HPA) database. A total of 856 genes (421 up-regulated genes and 435 down-regulated genes) were identified in T47D (overexpressing Split Ends (SPEN) + estradiol) samples compared to T47D (overexpressing Split Ends (SPEN) + tamoxifen) samples. Pathway and GO enrichment analysis revealed that the DEGs were mainly enriched in response to lysine degradation II (pipecolate pathway), cholesterol biosynthesis pathway, cell cycle pathway, and response to cytokine pathway. DEGs (MCM2, TCF4, OLR1, HSPA5, MAP1LC3B, SQSTM1, NEU1, HIST1H1B, RAD51, RFC3, MCM10, ISG15, TNFRSF10B, GBP2, IGFBP5, SOD2, DHF and MT1H) , which were significantly up- and down-regulated in estradiol and tamoxifen-treated BRCA samples, were selected as hub genes according to the results of protein-protein interaction (PPI) network, module analysis, target genes-miRNA interaction network and target genes-TF interaction network analysis. The SurvExpress database, cBioPortal, and Human Protein Atlas (HPA) database further confirmed that patients with higher expression levels of these hub genes experienced a shorter overall survival. A comprehensive bioinformatics analysis was performed, and potential therapeutic applications of estradiol and tamoxifen were predicted in BRCA samples. The data may unravel the future molecular mechanisms of BRCA.
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Neoplasias de la Mama/metabolismo , Biología Computacional/métodos , MicroARNs/metabolismo , Neoplasias de la Mama/genética , Chaperón BiP del Retículo Endoplásmico , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , MicroARNs/genética , Mutación/genética , Unión Proteica/genética , Unión Proteica/fisiologíaRESUMEN
Adrenocortical carcinoma (ACC) is an end-stage hormonal syndrome. Although profound attempts have been made to illuminate the pathogenesis, the molecular mechanisms of ACC remain to be clarified. To identify the important genes in the progression of ACC, microarray datasets GSE19775 was downloaded from the gene expression omnibus database. The differentially-expressed genes (DEGs) were identified, and pathway and GO enrichment analyses were performed. The protein-protein interaction (PPI) network was constructed and the module analysis was performed using the protein interaction network analysis and Cytoscape. Also constructed target genes-miRNA regulatory network and target genes-TF regulatory network. Correlation of the hub genes were analyzed in The Cancer Genome Atlas. The prognostic values of hub genes were further validated by online tool UALCAN. Mutation analysis was done by online tool CBio Cancer Genomics Portal. A total of 884 DEGs were identified, with 441 in up regulation and 443 in down regulation. Pathways in catecholamine biosynthesis, aldosterone synthesis and secretion, pyrimidine deoxyribonucleosides salvage and systemic lupus erythematosus were the most significantly enriched for DEGs (up and down regulated). Blood vessel morphogenesis and cell cycle phase transition were the most significantly enriched term in biological processes, while extracellular matrix and chromosome, centromeric region were in cellular component and heparin binding and protein dimerization activity were in molecular function. Among the PPI networks and its module, target genes-miRNA regulatory network and target genes-TF regulatory network, hub genes were YWHAZ, FN1, GRK5, VCAM1, GATA6, TXNIP, HSPA1A, and F11R. Hub genes such as YWHAZ, STAT1, ICAM1, SH3BP5, CD83, FN1, TK1, HIST1H1C, CABLES1, and MCM3 were associated with poor overall survival, while hub genes such as STAT1, ICAM1, CD83, FN1, TK1, HIST1H1C, and MCM3 were highly expressed in stage 4. In conclusion, DEGs and hub genes diagnosed in this study may deepen our understanding of molecular mechanisms underlying the progression of ACC, and provide important targets for diagnosis and treatment of ACC.
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Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/patología , Genes Relacionados con las Neoplasias/genética , Invasividad Neoplásica/genética , Biomarcadores de Tumor/genética , Proliferación Celular/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Humanos , MicroARNs/genética , Pronóstico , Mapas de Interacción de Proteínas , Análisis de Supervivencia , Factores de Transcripción/genéticaRESUMEN
The present study aimed to investigate the molecular mechanisms underlying glioblastoma multiform (GBM) and its biomarkers. The differentially expressed genes (DEGs) were diagnosed using the limma software package. The ToppGene (ToppFun) was used to perform pathway and Gene Ontology (GO) enrichment analysis of the DEGs. Protein-protein interaction (PPI) networks, extracted modules, miRNA-target genes regulatory network and TF-target genes regulatory network were used to obtain insight into the actions of DEGs. Survival analysis for DEGs was carried out. A total of 590 DEGs, including 243 up regulated and 347 down regulated genes, were diagnosed between scrambled shRNA expression and Lin7A knock down. The up-regulated genes were enriched in ribosome, mitochondrial translation termination, translation, and peptide biosynthetic process. The down-regulated genes were enriched in focal adhesion, VEGFR3 signaling in lymphatic endothelium, extracellular matrix organization, and extracellular matrix. The current study screened the genes in the PPI network, extracted modules, miRNA-target genes regulatory network, and TF-target genes regulatory network with higher degrees as hub genes, which included NPM1, CUL4A, YIPF1, SHC1, AKT1, VLDLR, RPL14, P3H2, DTNA, FAM126B, RPL34, and MYL5. Survival analysis indicated that the high expression of RPL36A and MRPL35 were predicting longer survival of GBM, while high expression of AP1S1 and AKAP12 were predicting shorter survival of GBM. High expression of RPL36A and AP1S1 were associated with pathogenesis of GBM, while low expression of ALPL was associated with pathogenesis of GBM. In conclusion, the current study diagnosed DEGs between scrambled shRNA expression and Lin7A knock down samples, which could improve our understanding of the molecular mechanisms in the progression of GBM, and these crucial as well as new diagnostic markers might be used as therapeutic targets for GBM.
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Neoplasias Encefálicas/genética , Redes Reguladoras de Genes , Glioblastoma/genética , Transcriptoma , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Nucleofosmina , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
AIMS: Buprenorphine (BUP) is approved by the US Food and Drug Administration for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is based on recommendations designed for nonpregnant adults. However, physiological changes during pregnancy may alter BUP exposure and efficacy. The objectives of this study were to develop a physiologically-based pharmacokinetic (PBPK) model for BUP in pregnant women, to predict changes in BUP exposure at different stages of pregnancy, and to demonstrate the utility of PBPK modelling in optimizing BUP pharmacotherapy during pregnancy. METHODS: A full PBPK model for BUP was initially built and validated in healthy subjects. A fetoplacental compartment was included as a combined compartment in this model to simulate pregnancy induced anatomical and physiological changes. Further, gestational changes in physiological parameters were incorporated in this model. The PBPK model predictions of BUP exposure in pregnancy and during the postpartum period were compared to published data from a prospective clinical study. RESULTS: The predicted BUP plasma concentration-time profiles in the virtual pregnant populations are consistent with the observed data in the 2nd and 3rd trimesters, and the postpartum period. The differences in the predicted means of dose normalized area under the plasma drug concentration-time curve up to 12 h, average concentration and maximum concentration were within ±25% of the corresponding observed means with the exception of average concentration in the 3rd trimester (-26.3%). CONCLUSION: PBPK model-based simulation may be a useful tool to optimize BUP pharmacotherapy during pregnancy, obviating the need to perform pharmacokinetic studies in each trimester and the postpartum period that normally require intensive blood sampling.
Asunto(s)
Buprenorfina/farmacocinética , Modelos Biológicos , Antagonistas de Narcóticos/farmacocinética , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/rehabilitación , Complicaciones del Embarazo/rehabilitación , Administración Sublingual , Adulto , Área Bajo la Curva , Buprenorfina/administración & dosificación , Buprenorfina/efectos adversos , Simulación por Computador , Femenino , Humanos , Intercambio Materno-Fetal/efectos de los fármacos , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/efectos adversos , Tratamiento de Sustitución de Opiáceos/efectos adversos , Placenta/metabolismo , Embarazo , Estudios Prospectivos , Distribución TisularRESUMEN
OBJECTIVE: The aim of this study was to examine the effects of 17-alpha-hydroxyprogesterone caproate (17OHP-C) on the activity and expression of several common hepatic cytochrome P450 (CYP) enzymes. STUDY DESIGN: Primary human hepatocytes were pretreated with vehicle or 17OHP-C (0.1 and 1 µmol/L) for 72 hours, then incubated for 1 hour with a cocktail of CYP substrates. The activity of various CYP enzymes was determined by measuring the formation of the metabolites of specific CYP substrates, using liquid chromatography-tandem mass spectrometry. The messenger RNA expression of various CYP enzymes was determined by real-time polymerase chain reaction. RESULTS: In primary cultures of human hepatocytes, 17OHP-C minimally altered the activity or messenger RNA levels of CYP1A2, CYP2C9, CYP2D6, and CYP3A. However, 17OHP-C at 1 µmol/L increased CYP2C19 activity by 2.8-fold (P < .01) and CYP2C19 expression by 2.4-fold (P < .001), compared with vehicle-treated cells. A strong positive correlation between activity and expression of CYP2C19 was also observed (r = 0.9, P < .001). CONCLUSION: The activity and expression of hepatic CYP2C19 was significantly increased by 17OHP-C in primary cultures of human hepatocytes. This suggests that exposure to medications that are metabolized by CYP2C19 may be decreased in pregnant patients receiving 17OHP-C. Metabolism of substrates of CYP1A2, CYP2C9, CYP2D6, and CYP3A are not expected to be altered in patients receiving 17OHP-C.