•58 toxic differential metabolites were identified from testis using UHPLC-Q-TOF/MS.•Glycerophospholipid metabolism, ether lipid metabolism, and glutathione metabolism were key pathways in ...TGT-induced reproductive toxicity.•Cytotoxicity of 19 components in TGT was assessed using TM3 and TM4 cell lines.•CYP19A1, PIK3CA, and PIK3CG were potential targets of TGT for reproductive toxicity.
Tripterygium glycoside tablets (TGT) is the most common preparation from Tripterygium wilfordii Hook F, which is widely used in clinical for treating rheumatoid arthritis (RA) and other autoimmune diseases. However, its serious reproductive toxicity limits its application.
This study aimed to elucidate the toxic effects of TGT on the reproductive system of male RA rats and its potential toxic components and mechanism.
Collagen-induced arthritis (CIA) rat model was established, and TGT suspension was given at low, medium, and high doses. Gonadal index, pathological changes, and the number of spermatogenic cells were used to evaluate the toxic effects of TGT on the reproductive system. Non-targeted metabolomics of testicular tissue was conducted by UHPLC-QTOF/MS. Combined with network toxicology, the key targets of TGT-induced reproductive toxicity were screened and RT-qPCR was used to validation. In vitro toxicity of 19 components of TGT was evaluated using TM3 and TM4 cell lines. Molecular docking was used to predict the interaction between toxic components and key targets.
TGT reduced testicular and epididymis weight. Pathology analysis showed a lot of deformed and atrophic spermatogenic tubules. The number of spermatogenic cells decreased significantly (P<0.0001). A total of 58 different metabolites including platelet-activating factor (PAF), lysophosphatidylcholine (Lyso PC), phosphatidylinositol (PI), glutathione (GSH), and adenosine monophosphate (AMP) were identified by testicular metabolomics. Glycerophospholipid metabolism, ether lipid metabolism, and glutathione metabolism were key pathways responsible for the reproductive toxicity of TGT. Ten key reproductive toxicity targets were screened by network toxicology. The cytotoxicity test showed that triptolide, triptonide, celastrol, and demethylzeylasteral could significantly reduce the viability of TM3 and TM4 cells. Alkaloids had no apparent toxic effects. Molecular docking showed that the four toxic components had a good affinity with 10 key targets. All binding energies were less than -7 kcal/mol. The RT-qPCR results showed the Cyp19a1 level was significantly up-regulated. Pik3ca and Pik3cg levels were significantly down-regulated.
Through testicular metabolomics, we found that TGT may cause reproductive toxicity through CYP19A1, PIK3CA, and PIK3CG three target, which was preliminarily revealed. This study laid the foundation for elucidating the toxicity mechanism of TGT and evaluating its safety and quality.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Inflammation, fibrosis, and lipid disorder are essential promoters in the pathogenesis of diabetic kidney injury in diabetes mellitus type 2. Berberine (BBR) has been reported to have ...beneficial effects on diabetic nephropathy, but its action mechanism is still unclear. The present study was designed to elucidate the therapeutic mechanism of BBR in a type 2 diabetic nephropathy rat model induced by a high‐fat diet and low‐dose streptozotocin injection. The diabetic rats were treated with or without BBR by gavage for 20 weeks and examined by serology, 24‐h albuminuria, histology, immunohistochemistry, and molecular analyses. Results showed that treatment with BBR significantly reduced serum levels of blood glucose and lipids, inhibited urinary excretion of albumin, and attenuated renal histological injuries in diabetic rats. Berberine treatment also inhibited renal inflammation, which was associated with inactivation of nuclear factor kappa‐light‐chain‐enhancer of activated B‐cell signalling. As a result, the upregulation of pro‐inflammatory cytokines (interleukin‐1β, tumour necrosis factor‐α) and chemokine (monocyte chemotactic protein‐1) was blocked. In addition, BBR treatment also inactivated transforming growth factor‐β/Smad3 signalling and suppressed renal fibrosis, including expression of fibronectin, collagen I, and collagen IV. The present study reveals that BBR is a therapeutic agent for attenuating type 2 diabetic nephropathy by inhibiting nuclear factor kappa‐light‐chain‐enhancer of activated B cell‐driven renal inflammation and transforming growth factor‐β/Smad3 signalling pathway.
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DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Zika virus (ZIKV) infection in pregnant women during the third trimester can cause neurodevelopmental delays and cryptorchidism in children without microcephaly. However, the consequences of ...congenital ZIKV infection on fertility in these children remain unclear. Here, using an immunocompetent mouse model, we reveal that congenital ZIKV infection can cause hormonal disorders of the hypothalamic-pituitary-gonadal axis, leading to reduced fertility and decreased sexual preference. Our study has for the first time linked the hypothalamus to the reproductive system and social behaviors after ZIKV infection. Although the extent to which these observations in mice translate to humans remains unclear, these findings did suggest that the reproductive health and hormone levels of ZIKV-exposed children should receive more attention to improve their living quality.
Fructus Alpiniae oxyphyllae (A. oxyphylla) is a traditional herb which is widely used in East Asian for the treatment of dyspepsia, diarrhea, abdominal pain, poor memory, inflammatory conditions and ...cancer.
The cytotoxic activities of ethanol extract (EE) and five extract layers including petroleum ether (PE), dichloromethane (DCLM), acetoacetate (EtOAc), n-Butanol (n-Bu) and water fractions (WF) of A. oxyphylla were tested on HepG2, SW480, MCF-7, K562 and HUVEC cell lines using MTT assay and LDH release assay. The component analysis was performed on HPLC with gradient elution. Hoechst 33342 staining, DCFH-DA fluorescence microscopy, flow cytometry analysis, western blot and migration assays were carried out to determine the anti-cancer mechanisms of PE.
MTT analysis showed that EE, PE and DCLM could inhibit cell proliferation on HepG2, SW480, MCF-7, K562 and HUVEC cell lines, especially PE fraction. HPLC analysis pointed out five main components which may contribute to the anti-proliferative activity of PE. Further study showed that PE increased LDH release, induced apoptosis, disrupted mitochondrial membrane potential and elevated intracellular reactive oxygen species (ROS) in HepG2 cells, whereas the antioxidant N-acetyl-l-cysteine (NAC) prevented PE-induced ROS generation. The results of western blot revealed that PE induced apoptosis in HepG2 cells by enhancing Bax/Bcl-2 ratio, increasing cytochrome c in cytosol and activating caspase-3/9. Meanwhile, high levels of ROS could induce DNA damage-mediated protein expression, AKT, ERK inactivation and SAPKs activation. Furthermore, PE conspicuously blocked the migration of HUVEC cells.
The present results demonstrated that PE induced apoptosis in HepG2 cells may be via a ROS-mediated signaling pathway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Eucommia ulmoides Oliver is a native plant and valuable tonic Chinese medicine in China with a long history, great economic value and comprehensive development potential. Traditionally, the ...comprehensive utilization rate of E. ulmoides Oliv. is still very low, only bark has been used as medicine and other parts of Eucommia ulmoides Oliv. cannot be fully utilized, even the leaves have been well utilized in food products in Japan in the past decades. In order to improve the comprehensive utilization efficiency of E. ulmoides Oliv., in this review, we summarized the varieties and contents of main active compounds, biological functions and pharmacological effects in different parts of E. ulmoides Oliv. The findings suggest that other parts of E. ulmoides Oliv. could replace the bark of E. ulmoides Oliv. to some extent besides of their respective applications. The unique and extensive physiological functions between different parts of E. ulmoides Oliv. indicate that the comprehensive utilization of E. ulmoides Oliv. has a wide space to develop, which is also an effective way to protect E. ulmoides Oliv. resources and improve its the utilization rate.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Studies have identified platelet-rich plasma (PRP) as a novel adjuvant therapy in androgenetic alopecia (AGA). However, the efficacy of PRP still needs to be improved. The purpose of this study was ...to assess the efficacy of PRP plus basic fibroblast growth factor (PRPF) for the treatment of AGA.
This was a prospective randomized, double-blind, placebo-controlled, half-head study. Eighty patients whose AGA was staged Norwood-Hamilton stages III to VII or Ludwig stages I to III were enrolled in the study from February of 2019 to September of 2019. Patients were divided randomly into two groups of 40 patients each and were given the following treatment: group 1, PRPF was injected in the right half and the left half with placebo; group 2, PRPF was injected in the right half and the left half with PRP. The treatment was processed three times, 1 month apart. Hair growth parameters were evaluated by trichoscope monthly until the sixth month of the study. Patient satisfaction, hair pull test, and side effects were recorded during follow-up.
Of the 80 patients included in the study, 47 were men and 33 were women with a mean age of 28.96 ± 4.82 years (range, 21 to 46 years). Both PRP and PRPF showed positive improvement ( P < 0.05) on hair count, terminal hair, and anagen hair after the treatment. Efficacy of PRPF revealed a significant improvement ( P < 0.05) in hair count, terminal hair, vellus hair, and anagen hair versus PRP. There was no statistical difference among any of the parameters in the placebo group.
PRPF can be a safe and valuable form of AGA treatment, and has proven to be more effective than PRP.
Hybrid therapy of PRP with relative growth factors, such as basic fibroblast growth factor, have prominent efficacy on treatment of AGA.
Therapeutic, II.
Ceftazidime is a third-generation cephalosporin with high activity against many pathogens. But the ambiguity and diversity of the dosing regimens in neonates and young infants impair access to ...effective treatment. Thus, we conducted a population pharmacokinetic study of ceftazidime in this vulnerable population and recommended a model-based dosage regimen to optimize sepsis therapy. Totally 146 neonates and young infants (gestational age (GA): 36–43.4 weeks, postnatal age (PNA): 1–81 days, current weight (CW): 900–4500 g) were enrolled based on inclusion and exclusion criteria. Ceftazidime bloods samples (203) were obtained using the opportunistic sampling strategy and determined by the high-performance liquid chromatography. The population pharmacokinetic-pharmacodynamic analysis was conducted by nonlinear mixed effects model (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic data. Covariate analysis showed the significance of GA, PNA, and CW on developmental pharmacokinetics. Monte Carlo simulation was performed based on above covariates and minimum inhibitory concentration (MIC). In the newborns with PNA ≤ 3 days (MIC=8 mg/L), the dose regimen was 25 mg/kg twice daily (BID). For the newborns with PNA > 3 days (MIC=16 mg/L), the optimal dose was 30 mg/kg three times daily (TID) for those with GA ≤ 37 weeks and 40 mg/kg TID for those with GA > 37 weeks. Overall, on the basis of the developmental population pharmacokinetic-pharmacodynamic analysis covering the whole range of neonates and young infants, the evidence-based ceftazidime dosage regimens were proposed to optimize neonatal early-onset and late-onset sepsis therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In recent years, many synthetic natural gas demonstration projects have been put into operation all over the world, and hydrogen is usually contained in synthetic natural gas. X80 is the most ...commonly used high-grade pipeline steel in the construction of natural gas pipelines. The compatibility between high-grade pipeline steel and hydrogen directly affects safety and reliability of long-distance pipelines. Therefore, in order to study the effect of hydrogen content on fatigue properties of high-grade pipeline steel, fatigue specimens were taken from base metal, spiral welds, and girth weld of submerged arc spiral welded pipes, respectively. Specifically, the total pressure was 12 MPa and hydrogen content was from 0 to 5vol%. Experimental results indicate that the hydrogen significantly increases the fatigue crack growth rate for both base metal, spiral weld, and heat-affected zone of X80 pipeline steel for about ten times compared with reference environment nitrogen, hydrogen would greatly reduce the fatigue life of the X80 pipeline steel, and the fatigue lifetime would decrease with the increase in hydrogen volume fraction. In order to ensure the safe operation of SNG pipeline, the hydrogen content should be controlled as low as possible.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
This study aims to explore the effects of long non-coding RNA H19 (lncRNA H19) and microRNA let7a (miRNA let7a) expression on the prognosis of thyroid cancer (TC). This may aid in the discovery of ...more effective treatment and prognosis approaches for TC. Between January 2008 and January 2011, 131 TC tissues and adjacent tissues were obtained from TC patients. An additional 122 normal thyroid tissues were also collected as normal controls from patients with benign thyroid lesions. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect lncRNA H19 and miRNA let7a mRNA expression. Five-year follow-ups were conducted. A Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic values of lncRNA H19 and miRNA let7a in TC. The Kaplan-Meier method was applied to analyze the 5-year survival rate of TC patients. Univariate and multivariate factor analyses were employed to analyze the prognostic factors of TC. The lncRNA H19 mRNA expression was higher while the miRNA let7a mRNA expression was lower in TC tissues than, in the normal thyroid tissues and adjacent tissues. The area under the ROC curve (AUC) of lncRNA H19 and miRNA let7a were 0.801 and 0.116, with sensitivity at 72.5% and 84%, as well as specificity 75.4% and 77%, respectively. In TC patients with tumor diameters≥1.0cm, lncRNA H19 mRNA expression was elevated, but miRNA let7a mRNA expression was reduced. This was also evident in TC patients with TNM stages III+IV and those with lymph node metastasis. TC patients with a lower 5-year survival rate showed upregulated levels of lncRNA H19 expression and, downregulated levels of miRNA let7a expression. LncRNA H19 and miRNA let7a expression, tumor diameter, TNM stage and lymph node metastasis were independent prognostic factors of TC. This study demonstrated that increased lncRNA H19 and decreased miRNA let7a expression levels are associated with poor prognosis in TC patients. An inverse relationship between lncRNA H19 and miRNA let7a expression levels was exhibited.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
For the two basic epidemic dynamics in the complex networks: susceptible–infectious–susceptible (SIS) and susceptible–infectious–removed (SIR), we present analytical laws about their outbreak ...prevalence. So that the researching line is pushed from the threshold conditions to the determinants of the outbreak prevalence, which can help us understanding better the mechanisms of the propagation. For these two basic epidemics, we give the relationship of the relative infection scales among all subgroups with the degree of their activities; and the determinants of the prevalence on the level of whole population. Comparison of the laws got from two kinds of epidemics illustrates the essential difference between them.
•We get the analytical laws for the outbreak prevalence of the SIS and SIR epidemics in heterogenous networks.•The infection scales among subgroups are got for these two kinds of epidemics.•The determinants of the prevalence on the level of whole population are presented analytically.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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