Efficacy and prognostic value of peripheral blood CD4+ T cells and serum IL-6 and IL-8 in tuberculous meningitis.

Objective: To investigate the value of peripheral blood clusters of differentiation 4 (CD4+) T-lymphocyte (T cells) count and serum interleukin-6 (IL-6) and interleukin-8 (IL-8) in the treatment and prognosis of tuberculous meningitis (TBM). Methods: Sixty-five patients with TBM were prospectively included in the observation group. Sixty-five patients with pulmonary TB and a group of 65 healthy individuals served as the control groups. The differences in peripheral blood CD4+ T-cell count, serum IL-6, and IL-8 levels were compared, and changes in these indices after anti-TB treatment in the observation group were analysed. The observation group was divided into effective and ineffective groups based on their response after 24 weeks of anti-TB treatment. The study also evaluated the influence of peripheral blood CD4+ T-cell count, serum IL-6, and IL-8 levels on the adverse prognosis of TBM during anti-TB treatment. Results: Before treatment, the CD4+ T-cell count in the peripheral blood of the observation group was lower than in both the control and healthy groups, and serum IL-6 and IL-8 levels were higher than in the control group (P < 0.001). After 24 weeks of anti-TB treatment, the CD4+ T-cell count in the peripheral blood of the observation group increased, whereas the levels of IL-6 and IL-8 decreased significantly (P < 0.001). The levels of CD4+ T cells and IL-6 in the peripheral blood of patients before treatment were identified as independent factors influencing the efficacy of anti-TB treatment (odds ratio [OR] = 0.989, 95 % confidence interval [CI]: 0.980-0.997; OR = 1.010, 95 % CI: 1.003-1.017). Conclusion: In patients with TBM, the CD4+ T-cell count in the peripheral blood is decreased, whereas serum IL-6 and IL-8 are increased. The combination of CD4+ T cells and IL-8 shows a degree of predictive value for the prognosis of anti-TB treatment.

Effect of genetic polymorphisms on the pharmacokinetics of gefitinib in healthy Chinese volunteers.

Gefitinib is the first-generation drug of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) metabolised by the cytochrome P450 and transported by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). In the present study, the pharmacokinetics of gefitinib in healthy Chinese volunteers was investigated and the effect of genetic polymorphisms on its variability was evaluted.Forty-five healthy volunteers were administered a single dose of gefitinib and the blood samples were used for quantifying the concentration of gefitinib and genotyping fifteen single-nucleotide polymorphisms of cytochrome P450 enzymes (CYP3A4, CYP3A5, CYP2D6, CYP2C9 and CYP2C19) and drug transporters (ABCB1 and ABCG2).CYP3A5*3 (rs776746) polymorphism showed a significant influence, with higher gefitinib AUC0-t in carrier of CC genotype than in CT/TT genotype (BH-adjusted p value <0.05). For CYP2C9*3 (rs1057910), significant differences in pharmacokinetics of gefitinib were detected between carriers of AA and AC genotypes, with higher AUC0-t, AUC0-∞ and Cmax in carrier of AC genotype than in AA gen-otype (BH-adjusted p value <0.05). No associations were found between SNPs in CYP3A4, CYP2D6, CYP2C19, ABCB1, ABCG2 and the pharmacokinetics of gefitinib.The SNPs in CYP3A5*3 (rs776746) and CYP2C9*3 (rs1057910) were found to be associated with altered gefitinib pharmacokinetics in healthy Chinese volunteers.

Effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension in mice and its mechanism / 中国药理学通报

Aim To study the effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension and explore the underlying mechanism in mice. Methods 10 to 12 weeks old wild type (WT) mice and TRPM8 gene knockout (TRPM8

Novel Associations of Dyslipidaemia with Vitamin D and Bone Metabolism in Elderly Patients with Diabetes: A Cross-Sectional Study.

Objective: Little is known about whether diabetic dyslipidaemia contributes to increased bone fragility in patients with diabetes. This study aimed to explore the potential effects of dyslipidaemia on vitamin D and bone metabolism in elderly subjects with type 2 diabetes (T2D). Methods: A total of 1479 male patients and 1356 female patients 50 years or older with T2D were included in Shanghai, China. Lipid profiles, 25-hydroxyvitamin D (25(OH)D), serum procollagen type I N-terminal propeptide (P1NP), ß-C-terminal telopeptide (ß-CTX) and other parameters were measured. Principal component regression (PCR) and mediation analysis were used to estimate the associations of lipid profile, 25(OH)D and bone turnover levels. Results: Female patients presented with higher blood lipids, lower 25(OH)D, and higher P1NP and ß-CTX levels than male patients with T2D. TC was associated with P1NP in males and females (ß=0.056, P<0.05; ß=0.095, P<0.01, respectively), and 25(OH)D fully mediated the associations in males and mediated approximately 17.89% of the effects in females. LDL-C was associated with P1NP in males and females (ß=0.072 and 0.105 respectively, all P<0.01), and 25(OH)D mediated the relationships approximately 20.83% in males and 14.29% in females. TG was negatively associated with P1NP (in males, ß= -0.063, P<0.05; in females, ß= -0.100, P<0.01) and ß-CTX (in males, ß= -0.108; in females, ß= -0.128, all P<0.01) independent of 25(OH)D, while HDL-C was not associated with P1NP or ß-CTX in diabetic patients. Conclusion: Hypercholesterolemia and hypertriglyceridaemia might affect bone metabolism by distinguishing pathways in diabetes patients. Ameliorating lipid control in elderly diabetes patients, especially female patients, will benefit both vitamin D and bone metabolism.

Ethnic disparities in prevalence of chronic non-communicable diseases and its multimorbidity among older adults in rural southwest China.

BACKGROUND: As the population ages, chronic non-communicable diseases (NCDs) multimorbidity has emerged as a major public health issue globally. This study examines ethnic disparities in prevalence of NCDs and its multimorbidity among rural southwest Chinese older adults. METHODS: A cross-sectional survey was conducted in rural southwest population aged ≥ 60 years consisting of 5,642 consenting participants of Han and three ethnic minority groups (Dai, Ha Ni, and Bai). Information about participants' demographic characteristics and lifestyle behaviors was obtained using a standard questionnaire. Anthropometric measurements including height, weight, and waist circumference, fasting blood sugar and blood pressure measurement, as well as post-bronchodilator spirometry test were recorded for each participant. RESULTS: The age-standardized prevalence of five common chronic NCDs- hypertension, diabetes, coronary heart disease (CHD), stroke, chronic obstructive pulmonary disease (COPD) - and its multimorbidity was 72.8%, 15.9%, 4.0%, 10.0%, 9.8%, and 27.6%, respectively. Bai participants had both the highest overall and sex-specific prevalence rates of hypertension, diabetes, stroke, and COPD, whereas Han participants had the highest rates of CHD (P < 0.01). The results of multivariate logistic regression analysis indicated that female and older participants had a higher probability of chronic NCDs multimorbidity than their counterparts (P < 0.01). Bai ethnic minority participants were more likely to have NCDs multimorbidity while Ha Ni and Dai ethnic minority participants were less likely to have NCD multimorbidity relative to the Han participants (P < 0.05). Older adults with a higher level of education and family history of chronic NCDs, and who were also current smokers, current drinkers, obese, centrally obese, and physically inactive had a greater probability of developing chronic NCDs multimorbidity (P < 0.01). CONCLUSIONS: Ethnicity and individual demographic and lifestyle factors significantly impact prevalence of chronic NCDs multimorbidity. Future chronic NCDs prevention and control strategies must be tailored to address ethnicity, and culturally tailored lifestyle interventions may reduce the prevalence of chronic NCDs multimorbidity in rural southwest China.

Method for quantitative extraction of copper hydroxide nanoparticles from farmland soil.

With the development of nanotechnology, nano-pesticides have been developed and show better application effects than traditional pesticides, which have a good development prospect. Copper hydroxide nanoparticles (Cu(OH)2 NPs) are one of the specific fungicides. However, there is still no reliable method to evaluate their environmental processes, which is essential for the broad application of new pesticides. Since soil is a vital link between pesticides and crops, this study took linear and slightly soluble Cu(OH)2 NPs as the research object and established a method to quantitatively extract Cu(OH)2 NPs from the soil. Five essential parameters in the extraction process were optimized first, and then the extraction effect of this optimal method was further tested under different nanoparticles and soil conditions. The optimal extraction method was determined, including (i) Dispersant: 0.2 % carboxymethyl cellulose (CMC) with a molecular weight of 250,000; (ii) Mixing conditions of soil and dispersant: water bath shaking for 30 min, water bath ultrasonication for 10 min (energy of the ultrasonication = 6 kJ/ml); (iii) Phase separation conditions: settlement for 60 min; (iv) Solid-to-liquid ratio: 1:20; (v) 1 extraction cycle. After optimization, 81.5 % of the supernatant was Cu(OH)2 NPs, and 2.6 % was dissolved copper ions (Cu2+). This method showed good applicability to different concentrations of Cu(OH)2 NPs and different farmland soils. It also showed significant differences in the extraction rates of copper oxide nanoparticles (CuO NPs), Cu2+, and other copper sources. The addition of a small amount of silica was confirmed to improve the extraction rate of Cu(OH)2 NPs. The establishment of this method lays the foundation for the quantitative analysis of nano-pesticides and other non-spherical and slightly soluble nanoparticles.

Inflammation markers and the risk of hypertension in people living with HIV.

Background: The incidence of hypertension is high in people living with HIV (PLWH). High-sensitivity C-reactive protein (hsCRP), systemic inflammation response index (SIRI), and neutrophil-to-monocyte ratio (NMR) are considered economic and convenient parameters that reflect the levels of inflammation in patients. Our aim was to explore whether indirect inflammation markers are associated with hypertension in PLWH. Methods: This was a case-control study. The case group (hypertension) comprised PLWH with hypertension, and the control group (non-hypertension) comprised sex- and age-(± 3 years)-matched PLWH without hypertension. Demographic parameters, hsCRP, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune- inflammation index (SII), SIRI, lymphocyte-to-monocyte ratio (LMR), platelet-to-neutrophil ratio (PNR), platelet-to-monocyte ratio (PMR), NMR, time to HIV diagnosis, antiretroviral therapy (ART) duration, recent CD4+ and CD8+ cell counts, recent CD4+/CD8+ ratio, recent HIV viral load (HIV-RNA),and recent ART regimen were obtained from the patients' electronic medical records. A t-test or Wilcoxon rank-sum test was performed to compare differences between the two groups, and conditional logistic regression was used to analyze the risk factors of hypertension. Correlations between inflammation markers and CD4+ cell counts, CD8+ cell counts, and CD4+/CD8+ ratio were analyzed using Spearman's correlation. Results: In the hypertension group, body mass index (BMI), hsCRP, NLR, SII, SIRI, NMR, time to HIV diagnosis, ART duration, CD4+ and CD8+ cell counts, and CD4+/CD8+ ratio, the ratio of HIV-RNA < 100 copies/mL were all higher than those in the non-hypertension group, while the PNR was lower than that in the non-hypertension group. ART duration, CD4+ cell counts, HIV-RNA < 100 copies/mL, hsCRP, SIRI, and NMR were positively associated with hypertensive risk in PLWH. CD8+ cell counts and CD4+/CD8+ ratio was negatively associated with hypertensive risk in PLWH. SIRI was negatively correlated with CD4+ cell counts and CD8+ cell counts, but positively correlated with CD4+/CD8+ ratio. Conclusions: We identified positive associations between inflammation markers hsCRP, SIRI, NMR and hypertensive risk in PLWH. Alleviating inflammation may help control or delay the occurrence of hypertension in PLWH.

Diabetes Mellitus Type 2 Patients with Abdominal Obesity Are Prone to Osteodysfunction: A Cross-Sectional Study.

Introduction: The interaction between diabetes, obesity, and bone metabolism was drawing increasing public attention. However, the osteometabolic changes in diabetes mellitus type 2 (T2DM) patients with abdominal obesity have not been fully revealed. This study is aimed at investigating the association between abdominal obesity indices and bone turnover markers among T2DM participants. Methods: 4351 subjects were involved in the METAL study. Abdominal obesity indices included neck, waist, and hip circumference, visceral adiposity index (VAI), lipid accumulation product (LAP), waist-to-hip ratio (WHR), and Chinese visceral adiposity index (CVAI). They were applied to elucidate the nexus between ß-C-terminal telopeptide (ß-CTX), osteocalcin (OC), and intact N-terminal propeptide of type I collagen (P1NP). Results: Abdominal obesity indices were strongly negatively associated with ß-CTX and OC. Among males, five indices were negatively correlated with ß-CTX (BMI, WC, LAP, WHR, and CVAI) and OC (BMI, NC, WC, WHR, and CVAI). There were no significant associations with P1NP. Among females, all eight indices were negatively associated with ß-CTX. Seven indices were negatively related to OC (BMI, NC, WC, HC, LAP, WHR, and CVAI). The VAI was negatively correlated with P1NP. Conclusions: The present study demonstrated that in T2DM, abdominal obesity had an obviously negative correlation with bone metabolism. Abdominal obesity indices were significantly negatively associated with skeletal destruction (ß-CTX) and formation (OC). In routine clinical practice, these easily obtained indices could be used as a preliminary screening method and relevant factors for osteodysfunction incidence risk at no additional cost and may be of particular value for postmenopausal women in T2DM populations.

Mechanism of Ginseng-Rhodiola rosea in treatment of myocardial ischemia-reperfusion injury based on network pharmacology and molecular docking / 中国药理学通报

Aim To investigate the sites and mechanisms of action of Ginseng-Rhodiola rosea in the treat ment of myocardial ischemia-reperfusion injury ( MI-RI) via using network pharmacology approach, molecu¬lar docking techniques and experimental studies. Methods The active ingredients and targets of Gin¬seng-Rhodiola rosea were screened through the TCMSP database and literature supplementation, and the GEN-EC ARDS ,DISGENET and DRUGBANK databases were searched to obtain the targets of MIRI. Functional pro¬tein interaction networks (PPIs) and the STRING database were used to screen out core targets. The DAVID database was also selected for gene ontology functional analysis ( GO) and KEGG signaling pathway enrich¬ment analysis. Lastly, the preliminary validation was performed with the help of molecular docking techniques and experimental studies. Results Forty-three active ingredients and 348 potential targets of Ginseng-Rhodiola were obtained, and targets such as IL-6 , TNF-α and VEGFA were found to be closely related to MIRI, mainly involving TNF, PDK-Akt, HIF-1 and other signaling pathways.The molecular docking results showed that soysterol, ginsenoside rh2 and rhodioloside had good binding effects and high matching with IL-6, TNF-α,Caspase-3,VEGFA,MAPK1 and other targets, among which the best binding was between Caspase-3 and ginsenoside rh2. The results of the experimental study further showed that Ginseng-Rhodiola rosea could improve myocardial tissue necrosis after myocardial ischemia-reperfusion , reduce myocardial cell edema and vascular congestion, and decrease the expression levels of TNF-α and IL-6 in MIRI rats. Conclusions Ginseng-Rhodiola may modulate multiple targets such as IL-6,TNF-α, Caspase-3, VEGFA and MAPK1 through dousterol, ginsenoside rh2 and rhodiol glycosides to inhibit inflammatory response and oxidative stress, reduce cardiomyocyte damage and exert therapeutic effects on MIRI.

Transcriptomic Profiling Reveals Underlying Immunoregulation Mechanisms of Resistant Hypertension in Injection Drug Users.

Background: Hypertension is a common complication in injection drug users (IDU), especially a high proportion of resistant hypertension occurs among them. However, the involving mechanisms remain largely unknown. Methods: We here investigated the key signaling moieties in resistant hypertension in drug users. Analyses were performed with high-throughput transcriptomic sequencing data of peripheral blood from individuals with drug-sensitive hypertension (Ctrl-DS), IDU with resistant hypertension (IDU-DR), and IDU with sensitive hypertension (IDU-DS). Results: We showed that 17 and 1 genes in IDU-DS, 48 and 4 genes in IDU-DR were upregulated and downregulated compared Ctrl-DS, and 2 and 4 genes were upregulated and downregulated in IDU-DR compared with IDU-DS, respectively (p ≤ 0.01 and |log2(FC)| ≥ 1). Differentially expressed genes (DEGs) between Ctrl-DS and IDU-DS were mainly involved in Gene ontology terms of immunoglobulin complex and blood microparticle. DEGs between IDU-DS and IDU-DR were mainly involved in immune system process and immunoglobulin complex. DEGs between Ctrl-DS and IDU-DR were mainly involved in immunoglobulin complex, blood microparticle and cytoplasmic vesicle lumen. We identified 2 gene clusters (brown modules, MEbrown; turquoise module, MEturquoise) correlated with IDU-DR and a gene cluster (magenta module, MEmagenta) correlated with IDU-DS by weighted gene co-expression network analysis (WGCNA). Functional analysis demonstrated that pathways of focal adhesion and focalin-1-rich granule lumen were involved in the development of IDU-DR, and the cytosolic large ribosomal subunit may relate to IDU-DR. Further, immune cell infiltration analysis demonstrated that the abundance of dendritic cells (DCs), natural Treg cells (nTreg), and exhausted T cells (Tex) in IDU-DR and IDU-DS, naïve CD8+ T cells in IDU-DS was significantly different compared with that in Ctrl-DS. The abundance of cytotoxic T cells (Tc) was significantly different between IDU-DS and IDU-DR. Conclusion: Our findings indicated a potential function of immunoregulation mechanisms for resistant hypertension.

Positive association of glucagon with bone turnover markers in type 2 diabetes: A cross-sectional study.

AIMS: The osteo-metabolic changes in type 2 diabetes (T2D) patients are intricate and have not been fully revealed. It is not clear whether glucagon is entirely harmful in the pathogenesis of diabetes or a possible endocrine counter-regulation mechanism to reverse some abnormal bone metabolism. This study aimed to investigate the association between glucagon and bone turnover markers (BTMs) in T2D patients. METHODS: A total of 3984 T2D participants were involved in a cross-sectional study in Shanghai, China. Serum glucagon was measured to elucidate its associations with intact N-terminal propeptide of type I collagen (P1NP), osteocalcin (OC), and ß-C-terminal telopeptide (ß-CTX). Glucagon was detected with a radioimmunoassay. Propeptide of type I collagen, OC, and ß-CTX were detected using chemiluminescence. The diagnosis of T2D was based on American Diabetes Association criteria. RESULTS: The concentration of glucagon was positively correlated with two BTMs [OC-ß: 0.034, 95% CI: 0.004, 0.051, p = 0.024; CTX-ß: 0.035, 95% CI: 0.004, 0.062, p = 0.024]. The result of P1NP was [P1NP-regression coefficient (ß): 0.027, 95% CI: -0.003, 0.049, p = 0.083]. In the glucagon tertiles, P for trend of the BTMs is [P1NP: 0.031; OC: 0.038; CTX: 0.020], respectively. CONCLUSIONS: Glucagon had a positive effect on bone metabolism. The concentrations of the three BTMs increased as glucagon concentrations rose. This implied that glucagon might speed up skeletal remodelling, accelerate osteogenesis, and promote the formation of mature bone tissue. At the same time, the osteoclastic process was also accelerated, providing raw materials for osteogenesis to preserve the dynamic balance. In view of the successful use of single-molecule as well as dual/triple agonists, it would be feasible to develop a preparation that would reduce osteoporosis in diabetic patients.

Sludge reduction and microbial community evolution of activated sludge induced by metabolic uncoupler o-chlorophenol in long-term anaerobic-oxic process.

Excess sludge management is a restrictive factor for the development of municipal wastewater treatment plants. The addition of metabolic uncouplers has been proven to be effective in sludge reduction. However, the long-term effect of metabolic uncoupler o-chlorophenol (oCP) on the biological wastewater treatment system operated in anaerobic-oxic mode is still unclear. To this end, two parallel reactors operated in anaerobic-oxic mode with and without 10 mg/L of oCP addition were investigated for 91 days. The results showed that 56.1 ± 2.3% of sludge reduction was achieved in the oCP-added system, and the nitrogen and phosphorus removal ability were negatively affected. Dosing oCP stimulated the formation of microbial products and increased the DNA concentration, but resulted in a decrease in the electronic transport activity of activated sludge. Microbial community analysis further demonstrated that a significant reduction of bacterial richness and diversity occurred after oCP dosing. However, after stopping oCP addition, the pollutant removal ability of activated sludge was gradually increased, but the sludge yield, as well as species richness and diversity, did not recover to the previous level. This study will provide insightful guidance on the long-term application of metabolic uncouplers in the activated sludge system.

FSH may mediate the association between HbA1c and bone turnover markers in postmenopausal women with type 2 diabetes.

INTRODUCTION: Recent studies in postmenopausal women have found associations of follicle-stimulating hormone (FSH) levels with both glucose metabolism and bone turnover. The objective of the study was to investigate whether FSH may contribute to suppressed bone turnover markers (BTMs) in postmenopausal women with type 2 diabetes (T2D). MATERIALS AND METHODS: 888 postmenopausal women with T2D, 352 nondiabetes (prediabetes plus normoglycemia) were included from the METAL study. HbA1c, sex hormones, 25-hydroxy vitamin D (25(OH)D), serum procollagen type I N-terminal propeptide (P1NP), and ß-C-terminal telopeptide (ß-CTX) were measured. RESULTS: P1NP and ß-CTX decreased in postmenopausal T2D women compared with nondiabetes controls (both p < 0.001). The major factors responsible for the changes in P1NP were HbA1c (ß = - 0.050, p < 0.001), 25(OH)D (ß = - 0.003, p = 0.006), FSH (ß = 0.001, p = 0.044) and metformin (ß = - 0.109, p < 0.001), for ß-CTX were HbA1c (ß = - 0.049, p < 0.001), body mass index (BMI) (ß = - 0.011, p = 0.005), 25(OH)D (ß = - 0.003, p = 0.003), FSH (ß = 0.002, p = 0.022) and metformin (ß = - 0.091, p = 0.001) in postmenopausal T2D women based on multivariate regression analysis. With the increase in HbA1c, FSH decreased significantly (p for trend < 0.001). Mediation analysis demonstrated that FSH partly mediated the suppression of LnP1NP and Lnß-CTX by HbA1c (ß = - 0.009 and - 0.010, respectively), and Lnß-CTX by BMI (ß = - 0.015) when multiple confounders were considered (all p < 0.05). CONCLUSION: HbA1c was the crucial determinant contributing to the suppression of BTMs. FSH might play a novel mediation role in BTM suppression due to HbA1c or BMI.

Adult versus paediatric undifferentiated embryonal sarcoma of the liver: a SEER database analysis.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare liver tumour that occurs mainly in children. Herein, we aimed to identify any differences in clinical characteristics and survival between adult and paediatric patients with UESL. METHODS: From 1975 to 2015 in the Surveillance, Epidemiology and End Results (SEER) database, patients diagnosed with UESL were identified and divided into paediatric (<18 years) and adult (≥18 years) groups. We then compared the clinical characteristics, management, and overall survival (OS) of adults and children diagnosed with UESL. RESULTS: We analysed 113 patients with UESL (81 children and 32 adults). UESL was significantly more common in adult male than paediatric male patients (71.9% vs. 48.2%; P = 0.022). When compared to adult patients, paediatric patients were more likely to receive chemotherapy (93.8% vs. 65.6%; P < 0.001). Adults had a significantly worse OS than paediatric patients (5-year OS, 30.0% vs. 81.2%; P < 0.001). Univariate analysis found that adult age, surgical therapy and chemotherapy were associated with OS. Multivariate analysis revealed that adult age, SEER summary stage and surgical therapy were independent prognostic factors for OS. CONCLUSIONS: UESL had a male predominance among adult patients. Moreover, the prognosis of adult patients with UESL was significantly worse than that of paediatric patients. Surgery and chemotherapy should be considered in the treatment of patients with UESL.

Dynamic transcriptome landscape of Paragonimus proliferus developmental stages in the rat lungs.

Paragonimus proliferus, a lung fluke of the genus Paragonimus, was first reported in Yunnan province, China. P. proliferus can infect Sprague-Dawley (SD) rats and cause lung damage, but there is still no direct evidence of human infection. Until now, there has been a lack of studies on P. proliferus parasitism and development in mammalian lung tissue. The aim of this study was to perform transcriptomic profiling of P. proliferus at different developmental stages. SD rats were infected with P. proliferus metacercariae obtained from crabs; worms isolated from the lungs at different time points as well as metacercariae were subjected to whole transcriptome sequencing. Overall, 34,403 transcripts with the total length of 33,223,828 bp, average length of 965 bp, and N50 of 1833 bp were assembled. Comparative analysis indicated that P. proliferus, similar to other Paragonimus spp., expressed genes related to catabolism, whereas P. proliferus-specific transcripts were related to the maintenance of cellular redox homeostasis, sensitivity to bacteria, and immune response. Transcriptional dynamics analysis revealed that genes involved in the regulation of catabolism and apoptosis had stable expression over the P. proliferus life cycle, whereas those involved in development and immune response showed time-dependent changes. High expression of genes associated with immune response corresponded to that of genes regulating the sensitivity to bacteria and immune protection. We constructed a P. proliferus developmental model, including the development of the body, suckers, blood cells, reproductive and tracheal systems, lymph, skin, cartilage, and other tissues and organs, and an immune response model, which mainly involved T cells and macrophages. Our study provides a foundation for further research into the molecular biology and infection mechanism of P. proliferus.

Association of Insulin Resistance and ß-cell Function With Bone Turnover Biomarkers in Dysglycemia Patients.

Background: The interrelation between glucose and bone metabolism is complex and has not been fully revealed. This study aimed to investigate the association between insulin resistance, ß-cell function and bone turnover biomarker levels among participants with abnormal glycometabolism. Methods: A total of 5277 subjects were involved through a cross-sectional study (METAL study, http://www.chictr.org.cn, ChiCTR1800017573) in Shanghai, China. Homeostasis model assessment of insulin resistance (HOMA-IR) and ß-cell dysfunction (HOMA-%ß) were applied to elucidate the nexus between ß-C-terminal telopeptide (ß-CTX), intact N-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC). ß-CTX, OC and P1NP were detected by chemiluminescence. Results: HOMA-IR was negatively associated with ß-CTX, P1NP and OC (regression coefficient (ß) -0.044 (-0.053, -0.035), Q4vsQ1; ß -7.340 (-9.130, -5.550), Q4vsQ1 and ß -2.885 (-3.357, -2.412), Q4vsQ1, respectively, all P for trend <0.001). HOMA-%ß was positively associated with ß-CTX, P1NP and OC (ß 0.022 (0.014, 0.031), Q4vsQ1; ß 6.951 (5.300, 8.602), Q4vsQ1 and ß 1.361 (0.921, 1.800), Q4vsQ1, respectively, all P for trend <0.001). Conclusions: Our results support that lower bone turnover biomarker (ß-CTX, P1NP and OC) levels were associated with a combination of higher prevalence of insulin resistance and worse ß-cell function among dysglycemia patients. It is feasible to detect bone turnover in diabetes or hyperglycemia patients to predict the risk of osteoporosis and fracture, relieve patients' pain and reduce the expenses of long-term cure.

Exosomal NNMT from peritoneum lavage fluid promotes peritoneal metastasis in gastric cancer.

Peritoneal metastasis (PM) is the major cause of recurrence in patients with gastric cancer (GC) and is associated with poor prognosis. The oncogenic role of Nicotinamide N-methyltransferase (NNMT) in GC has been reported, but the role of secreted NNMT that is transported by exosomes remains unknown. In this study, exosomes were isolated from GC patients with or without PM and from GC cell line, including GC-114, GC-026, MKN45, and SNU-16 cells. The contents of NNMT were significantly enhanced in exosomes isolated from GC patients with PM compared with those from GC patients without PM. Furthermore, the levels of NNMT were significantly enhanced in exosomes from GC cell lines relative to those from normal human gastric epithelial cell line GES-1 cells. These data indicate that NNMT may be involved in intercellular communication for peritoneal dissemination. Moreover, colocalization of GC-derived exosomal NNMT was found in human peritoneal mesothelial cell line HMrSV5 cells. Additionally, relative to GES-1 exosomes, SNU-16 exosomes significantly activated TGF-ß/smad2 signaling in HMrSV5 cells. However, when NNMT was silenced, the activation of TGF-ß/smad2 by SNU-16 exosomes was abolished in HMrSV5 cells. We propose that NNMT-containing exosomes derived from GC cells could promote peritoneal metastasis via TGF-ß/smad2 signaling.

Physalin B ameliorates nonalcoholic steatohepatitis by stimulating autophagy and NRF2 activation mediated improvement in oxidative stress.

Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Physalin B (PB), a withanolide isolated from Physalis species (Solanaceae), exhibits a broad spectrum of biological activities, however, the potential role of PB in NASH has not been evaluated. The present study investigated the protective effects of PB against NASH and further elucidated the mechanisms of PB in hepatic autophagy and oxidative stress in vitro and in vivo. We conducted a series of experiments using methionine-choline deficient (MCD) diet induced NASH mice and cultured L02 cells. Serum markers of liver injury, morphology, and the histology of liver tissues were investigated. Western blot assays and quantitative real-time PCR were used to investigate the hepatoprotective effect of PB. PB significantly ameliorated hepatic injury, including hepatic index, transaminase activities, histology, and inflammation in MCD-induced mice. Moreover, PB markedly increased the expression of P62 and the ratio of LC3Ⅱ/Ⅰ in vitro and in vivo. Furthermore, PB promoted the interaction between endogenous KEAP1 and P62, reduced the interaction between KEAP1 and NRF2, activated the nuclear translocation of NRF2 and NRF2 target gene expression, and ultimately attenuated oxidative stress. In addition, knockdown of P62 blocked PB-mediated activation of NRF2 in L02 cells. These results clearly indicated that PB ameliorated NASH by stimulating autophagy and P62-KEAP1-NRF2 antioxidative signaling, suggesting that PB is expected to become a novel therapeutic drug for NASH.

Pathogenesis of NASH and Promising Natural Products.

Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. The mechanism of the diaease progression, which is lacking effective therapy, remains obsure. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary. Currently, an increasing number of studies have focused on natural constituents from medicinal plants which have been emerged as a new hope for NASH. This review summarized the pathogenesis of NASH, animal models commonly used, and the promising targets for therapeutics. We also reviewed the natural constituents as potential NASH therapeutic agents.

New triterpenes from Cimicifuga yunnanensis down-regulating the mRNA expression of CD147, MMP-2, and MMP-9.

Eleven new 9,19-cycloartane triterpenes (1-9, 11-12) and one undescribed lanostane-type aglycone (10) were identified from the aerial parts of Cimicifuga yunnanensis. The new structures were elucidated by analysis of spectroscopic data. Compounds 3-5, 7-9, and 11, without obvious cytotoxicity at 50 µM, were evaluated for inhibiting the mRNA expressions of atherosclerosis-related factors of CD147 (extracellular matrix metalloproteinase inducer, EMMPRIN), matrix metalloproteinase 2 (MMP-2) and MMP-9 in phorbol-12-myristate-13-acetate (PMA) induced Human monocytic THP-1 cells by using a quantitative real-time PCR method (q-PCR). Among them, aglycones 7 and 8 showed potent activities, whereas all tested glycosides were inactive. Compounds 7 and 8 suppressed the mRNA expression of CD147 in a dose-dependent manner, with an IC50 value of 3.38 ± 0.27 µM and 8.25 ± 0.33 µM, respectively. Besides, 7 dose-related down-regulated the mRNA expression of MMP-2, and MMP-9, having an IC50 value of 6.32 ± 0.31 µM and 11.57 ± 0.23 µM, respectively. Meanwhile, 8 at 10 µM reduced the mRNA expression of MMP-2 and MMP-9 by 35% and 25%, respectively. Significantly, the migration ability of the induced THP-1 cells was potently and dose-dependently inhibited by 7, with an IC50 value of 5.87 ± 0.27 µM.