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Triptolide Induces hepatotoxicity via inhibition of CYP450s in Rat liver microsomes
No full textAbstract
Background
Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological activities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored.
Methods
In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A) were investigated both in vivo and in vitro. We monitored the body weight, survival proportions, liver index, changes in pathology, and biochemical index upon TP administration, in vivo. Using a cocktail probe of CYP450 isoform-specific substrates and their metabolites, we then carried out in vitro enzymatic studies in liver microsomal incubation systems via ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Finally, we verified our results at the messenger ribonucleic acid (mRNA) and protein level through quantitative real-time polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemical detection.
Results
The in vivo toxicity study confirmed that Sprague-Dawley (SD) rats exhibited dose-dependent hepatotoxicity after intragastric administration of TP [200, 400, and 600\ua0\u3bcg/(kg.day)] for 28\ua0days. In case of the CYP450 isoforms 3A, 2C9, 2C19, and 2E1, the in vitro metabolic study demonstrated a decrease in the substrate metabolic rate, metabolite production rate, and Vmax, with an increase in the Km value, compared with that observed in the control group. Additionally, a TP dose-dependent decrease in the mRNA levels was observed in the four major isoforms of CYP3A subfamily (3A1/3A23, 3A2, 3A9, and 3A62) and CYP2C9. A similar effect was also observed with respect to the protein levels of CYP2C19 and CYP2E1.
Conclusions
This study suggests that TP can cause hepatotoxicity by reducing the substrate affinity, activity, and expression at the transcriptional and protein levels of the CYP450 isoforms 3A, 2C9, 2C19, and 2E1. TP also has the potential to cause pharmacokinetic drug interactions when co-administered with drugs metabolized by these four isoforms. However, further clinical studies are needed to evaluate the significance of this interaction
Herbal formula Xian-Fang-Huo-Ming-Yin regulates differentiation of lymphocytes and production of pro-inflammatory cytokines in collagen-induced arthritis mice
No full textAbstract
Background
Xian-Fang-Huo-Ming-Yin (XFHM), a traditional herbal formula, has been used to treat sores and carbuncles for hundreds of years in Asia. Nowadays, its clinical effects in treatment of rheumatoid arthritis (RA) have been validated. In this study, we want to study its possible molecular mechanisms of regulating the differentiation of lymphocytes and production of pro-inflammatory cytokines in collagen-induced arthritis (CIA) mice for RA treatment.
Methods
A high performance liquid chromatography-electrospray ionization/mass spectrometer (HPLC-ESI/MS
n
) system was used to analyze the constituents of XFHM granules. An arthritics mouse model was induced by collagen and leflunomide (LEF) was used as a positive control medicine. Pathological changes at the metatarsophalangeal joint were studied through Safranin O and immunohistochemical staining. The differentiation of T, B and NK cells was examined by flow cytometry and pro-inflammatory cytokines were assayed using an Inflammation Antibody Array assay. The expression of key molecules of the nuclear factor \u3baB (NF-\u3baB) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in spleen were studied by western-blot analysis.
Results
In our study. 21 different dominant chemical constituents were identified in XFHM. Treatment with XFHM suppressed the pathological changes in arthrosis of CIA. Additionally, XFHM down-regulated the proliferation and differentiation of CD3
+
T cells and CD3
\u2212
CD19
+
B cells significantly. However, XFHM had no significant effect on CD3
\u2212
NK1.1
+
NK cells. Further study showed that the production of pro-inflammatory cytokines had been suppressed by inhibiting the activation of NF-\u3baB and JAK/STAT signaling.
Conclusions
XFHM can regulate and maintain the immunologic balance of lymphocytic immunity and inhibit ..
Antimalarial activity of Syzygium guineense during early and established Plasmodium infection in rodent models
No full textAbstract
Background
In Ethiopia, the leaves of Syzygium guineense have been found useful for the prevention and cure of malaria, and demonstrated antiplasmodial activity in vitro. Nevertheless, no scientific study has been conducted to confirm its antimalarial activity in vivo. Therefore, the objective of the study was to evaluate the antimalarial effect of Syzygium guineense leaf extract in mice.
Methods
Inoculation of the study mice was carried out by using the malaria parasite, Plasmodium berghei . The plant extract was prepared at 200, 400 and 600\ua0mg/kg. Chloroquine and distilled water was administered to the positive and negative control groups respectively. Parameters like parasitaemia, survival time and body weight were determined following standard tests (4-day suppressive, Rane\u2019s and repository tests).
Results
Syzygium guineense crude leaf extract displayed considerable ( p \u2009<\u20090.05) parasite suppression at doses of 600 and 400\ua0mg/kg in a 4-day suppressive test with chemosuppressive value of 59.39 and 49.09% respectively. S. guineense crude leaf extract also showed dose-dependent schizontocidal activity in both the repository and curative tests. The extract also prevented body weight loss and prolonged survival date of mice significantly ( P \u2009<\u20090.05) at the highest dose employed in the study. Qualitative chemical assay for S. guineense methanolic leaf extract revealed that the plant is endowed with different plant secondary metabolites exemplified by terpenoids, alkaloids, triterpenes, flavonoids, anthraquinones, tannins, glycosides, saponins and phenols.
Conclusion
Syzygium guineense leaf extract possess antimalarial activity in mice. The test substance was found to be safe with no observable signs of toxicity in the study mice. The results of the present work confirmed the in vitro antiplasmodial finding and traditional claims in vivo in mice. Therefore, Syzygium guineense could be regarded as a potential source to develop safe, effective and affordable antimalarial agent
Evaluation of anti-inflammatory activity of compounds isolated from the rhizome of Ophiopogon japonicas
No full textAbstract
Background
Ophiopogon japonicas (L.f) Ker-Gawl has been used as a traditional Chinese medicine to cure acute and chronic inflammation and cardiovascular diseases including thrombotic diseases for thousands of years. Previous phytochemical studies showed that O. japonicus contained compounds with anti-inflammatory activity. The aim of this study was to identify and isolate compounds with anti-inflammatory activity from the rhizome of O. japonicas .
Methods
Compounds were isolated by various column chromatography and their structures were identified in terms of nuclear magnetic resonance spectrum (NMR) and mass spectrum (MS). To measure the anti-inflammatory effects of thirteen compounds in LPS-induced RAW 264.7 macrophage cells, we used the following methods: cell viability assay, nitric oxide assay, enzyme-linked immunosorbent assay, quantitative real-time PCR analysis and western blotting analysis.
Results
One new and twelve known compounds (mainly homoisoflavonoids) were extracted from O. japonicas , in which 4\u2032- O -Demethylophiopogonanone E (10) was considered as a new compound, additionally, compounds 4- O -(2-Hydroxy-1- hydroxymethylethyl)-dihydroconiferyl alcohol (2) and 5,7-dihydroxy-6-methyl-3-(2\u2032, 4\u2032-dihydroxybenzyl) chroman-4-one (12) were isolated from the rhizome of O. japonicas for the first time. The isolated compounds Oleic acid (3), Palmitic acid (4), desmethylisoophiopogonone B [5,7-dihydroxy-3-(4\u2032-hydroxybenzyl)-8- methyl- chromone] (5), 5,7-dihydroxy-6-methyl-3-(4\u2032-hydroxybenzyl) chromone (7) and 10 significantly suppressed the production of NO in LPS-induced RAW 264.7 cells. Especially compound 10 showed the strongest effect against the production of the pro-inflammatory cytokine IL-1\u3b2 and IL-6 with the IC
50
value of 32.5\u2009\ub1\u20093.5\ua0\u3bcg/mL and 13.4\u2009\ub1\u20092.3\ua0\u3bcg/mL, respectively. Further analysis elucidated that the anti-inflammatory activity of compound 10 might be exerted through inhibiting the phosphorylation of ERK1/2 and JNK in MAPK signaling pathways to decrease NO and pro-inflammatory cytokines production.
Conclusions
Our results indicated that 4\u2032- O -Demethylophiopogonanone E can be considered as a potential source of therapeutic medicine for inflammatory diseases
Impact of medical student origins on the likelihood of ultimately practicing in areas of low vs high socio-economic status
No full textAbstract
Introduction
Medical schools are in general over-represented by students from high socio-economic status backgrounds. The University of Western Australia Medical School has been progressively widening the participation of students from a broader spectrum of the community both through expanded selection criteria and quota-based approaches for students of rural, indigenous and other socio-educationally disadvantaged backgrounds. We proposed that medical students entering medical school from such backgrounds would ultimately be more likely to practice in areas of increased socio-economic disadvantage.
Methods
The current practice address of 2829 medical students who commenced practice from 1980 to 2011 was ascertained from the Australian Health Practitioner Regulation Agency (AHPRA) Database. Logistic regression was utilised to determine the predictors of the likelihood of the current practice address being in the lower 8 socio-economic deciles versus the top 2 socio-economic deciles.
Results
Those who were categorised in the lower 8 socio-economic deciles at entry to medical school had increased odds of a current practice address in the lower 8 socio-economic deciles 5 or more years after graduation (OR 2.05, 95% CI 1.72, 2.45, P \u2009<\u20090.001). Other positive univariate predictors included age at medical degree completion (for those 25\ua0years or older vs those 24\ua0years or younger OR 1.53, 95% CI 1.27, 1.84, P \u2009<\u20090.001), being female (OR 1.26, 95% CI 1.07, 1.48, P \u2009=\u20090.005) and having a general practice versus specialist qualification (OR 4.16, 95% CI 3.33, 5.19, P\u2009<\u20090.001). Negative predictors included having attended an independent school vs a government school (OR 0.77, 95% CI 0.64, 0.92, P \u2009<\u20090.001) or being originally from overseas vs being born in Oceania (OR 0.80, 95% CI 0.67, 0.96, P \u2009=\u20090.017). After adjustment for potential confounders in multivariate logistic regression, those in the lower 8 socio-economic deciles at entry to medical school still had increased odds of having a current practice address in the lower 8 socio-economic deciles (OR 1.63, 95% CI 1.34, 1.99, P \u2009<\u20090.001).
Conclusion
Widening participation in medical school to students from more diverse socio-educational backgrounds is likely to increase the distribution of the medical workforce to ultimate service across areas representative of a broader socio-economic spectrum
Exploring the implementation of an electronic record into a maternity unit: a qualitative study using Normalisation Process Theory
No full textAbstract
Background
To explore the benefits, barriers and disadvantages of implementing an electronic record system (ERS). The extent that the system has become \u2018normalised\u2019 into routine practice was also explored.
Methods
Qualitative semi-structured interviews were conducted with 19 members of NHS staff who represented a variety of staff groups (doctors, midwives of different grades, health care assistants) and wards within a maternity unit at a NHS teaching hospital. Interviews were conducted during the first year of the phased implementation of ERS and were analysed thematically. The four mechanisms of Normalisation Process Theory (NPT) (coherence, cognitive participation, collective action and reflexive monitoring) were adapted for use within the study and provided a theoretical framework to interpret the study\u2019s findings.
Results
Coherence (participants\u2019 understanding of why the ERS has been implemented) was mixed \u2013 whilst those involved in ERS implementation anticipated advantages such as improved access to information; the majority were unclear why the ERS was introduced. Participants\u2019 willingness to engage with and invest time into the ERS (cognitive participation) depended on the amount of training and support they received and their willingness to change from paper to electronic records. Collective action (the extent the ERS was used) may be influenced by whether participants perceived there to be benefits associated with the system. Whilst some individuals reported benefits such as improved legibility of records, others felt benefits were yet to emerge. The parallel use of paper and the lack of integration of electronic systems within and between the trust and other healthcare organisations hindered ERS use. When appraising the ERS (reflexive monitoring) participants perceived the system to negatively impact the patient-clinician relationship, time and patient safety.
Conclusions
Despite expectations that the ERS would have a number of advantages, its implementation was perceived to have a range of disadvantages and only a limited number of \u2018clinical benefits\u2019. The study highlights the complexity of implementing electronic systems and the associated longevity before they can become \u2018embedded\u2019 into routine practice. Through the identification of barriers to the employment of electronic systems this process could be streamlined with the avoidance of any potential detriment to clinical services
MAP4K4 and IL-6 + Th17 cells play important roles in non-obese type 2 diabetes
No full textAbstract
Obesity is a causal factor of type 2 diabetes (T2D); however, people without obesity (including lean, normal weight, or overweight) may still develop T2D. Non-obese T2D is prevalent in Asia and also frequently occurs in Europe. Recently, multiple evidences oppose the notion that either obesity or central obesity (visceral fat accumulation) promotes non-obese T2D. Several factors such as inflammation and environmental factors contribute to non-obese T2D. According to the data derived from gene knockout mice and T2D clinical samples in Asia and Europe, the pathogenesis of non-obese T2D has been unveiled recently. MAP4K4 downregulation in T cells results in enhancement of the IL-6
+
Th17 cell population, leading to insulin resistance and T2D in both human and mice. Moreover, MAP4K4 single nucleotide polymorphisms and epigenetic changes are associated with T2D patients. Interactions between MAP4K4 gene variants and environmental factors may contribute to MAP4K4 attenuation in T cells, leading to non-obese T2D. Future investigations of the pathogenesis of non-obese T2D shall lead to development of precision medicine for non-obese T2D
Blood pressure control in type 2 diabetic patients
No full textAbstract
Diabetes mellitus (DM) and essential hypertension are common conditions that are frequently present together. Both are considered risk factors for cardiovascular disease and microvascular complications and therefore treatment of both conditions is essential. Many papers were published on blood pressure (BP) targets in diabetic patients, including several works published in the last 2\ua0years. As a result, guidelines differ in their recommendations on BP targets in diabetic patients. The method by which to control hypertension, whether pharmacological or non-pharmacological, is also a matter of debate and has been extensively studied in the literature. In recent years, new medications were introduced for the treatment of DM, some of which also affect BP and the clinician treating hypertensive and diabetic patients should be familiar with these medications and their effect on BP. In this manuscript, we discuss the evidence supporting different BP targets in diabetics and review the various guidelines on this topic. In addition, we discuss the various options available for the treatment of hypertension in diabetics and the recommendations for a specific treatment over the other. Finally we briefly discuss the new diabetic drug classes and their influence on BP
Overexpression of trefoil factor 3 (TFF3) contributes to the malignant progression in cervical cancer cells
No full textAbstract
Background
There remains a great need for effective therapies for cervical cancers, the majority of which are aggressive leaving patients with poor prognosis.
Methods and results
Here, we identify a novel candidate therapeutic target, trefoil factor 3 (TFF3) which overexpressed in cervical cancer cells and was associated with reduced postoperative survival. Functional studies demonstrated that TFF3 overexpression promoted the proliferation and invasion of cervical cancer cells, and inhibited the apoptosis by inducing the mRNA changes in SiHa and Hela cell lines. Conversely, TFF3 silencing disrupted the proliferation and invasion of cervical cancer cells, and induced the apoptosis via Click-iT EdU test, flow cytometry analysis and two-dimensional Matrigel Transwell analysis. Western blot analysis showed that overexpression of TFF3 repressed E-cadherin (CDH1) expression to promote the invasion of cervical cancer cells. Furthermore, down-regulated CDH1 via overexpression of TFF3 was significantly up-regulated by virtue of inhibitor of p-STAT3.
Conclusions
These results suggested that TFF3 stimulated the invasion of cervical cancer cells probably by activating the STAT3/CDH1 signaling pathway. Furthermore, overexpression of TFF3 decreased the sensitivity of cervical cancer cells to etoposide by increasing P-glycoprotein (P-gp) functional activity. Overall, our work provides a preclinical proof that TFF3 not only contributes to the malignant progression of cervical cancers and but also is a potential therapeutic target
The occurrence of ESBL-producing Escherichia coli carrying aminoglycoside resistance genes in urinary tract infections in Saudi Arabia
No full textAbstract
Background
The infection and prevalence of extended-spectrum \u3b2-lactamases (ESBLs) is a worldwide problem, and the presence of ESBLs varies between countries. In this study, we investigated the occurrence of plasmid-mediated ESBL/AmpC/carbapenemase/aminoglycoside resistance gene expression in Escherichia coli using phenotypic and genotypic techniques.
Methods
A total of 58 E. coli isolates were collected from hospitals in the city of Makkah and screened for the production of ESBL/AmpC/carbapenemase/aminoglycoside resistance genes. All samples were subjected to phenotypic and genotypic analyses. The antibiotic susceptibility of the E. coli isolates was determined using the Vitek-2 system and the minimum inhibitory concentration (MIC) assay. Antimicrobial agents tested using the Vitek 2 system and MIC assay included the expanded-spectrum (or third-generation) cephalosporins (e.g., cefoxitin, cefepime, aztreonam, cefotaxime, ceftriaxone, and ceftazidime) and carbapenems (meropenem and imipenem). Reported positive isolates were investigated using genotyping technology (oligonucleotide microarray-based assay and PCR). The genotyping investigation was focused on ESBL variants and the AmpC, carbapenemase and aminoglycoside resistance genes . E . coli was phylogenetically grouped, and the clonality of the isolates was studied using multilocus sequence typing (MLST).
Results
Our E. coli isolates exhibited different levels of resistance to ESBL drugs, including ampicillin (96.61%), cefoxitin (15.25%), ciprofloxacin (79.66%), cefepime (75.58%), aztreonam (89.83%), cefotaxime (76.27%), ceftazidime (81.36%), meropenem (0%) and imipenem (0%). Furthermore, the distribution of ESBL-producing E. coli was consistent with the data obtained using an oligonucleotide microarray-based assay and PCR genotyping against genes associated with \u3b2-lactam resistance. ST131 was the dominant sequence type lineage of the isolates and was the most uropathogenic E. coli lineage. The E. coli isolates also carried aminoglycoside resistance genes.
Conclusions
The evolution and prevalence of ESBL-producing E. coli may be rapidly accelerating in Saudi Arabia due to the high visitation seasons (especially to the city of Makkah). The health authority in Saudi Arabia should monitor the level of drug resistance in all general hospitals to reduce the increasing trend of microbial drug resistance and the impact on patient therapy