A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

AIM: The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. MATERIALS AND METHODS: This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. RESULTS: Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. CONCLUSIONS: At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

First report on establishment and characterization of the extrahepatic cholangiocarcinoma sarcoma cell line CBC2T-2.

BACKGROUND: Extrahepatic cholangiocarcinoma sarcoma is extremely rare in clinical practice. These cells consist of both epithelial and mesenchymal cells. Patient-derived cell lines that maintain tumor characteristics are valuable tools for studying the molecular mechanisms associated with carcinosarcoma. However, cholangiocarcinoma sarcoma cell lines are not available in cell banks. AIM: To establish and characterize a new extrahepatic cholangiocarcinoma sarcoma cell line, namely CBC2T-2. METHODS: We conducted a short tandem repeat (STR) test to confirm the identity of the CBC2T-2 cell line. Furthermore, we assessed the migratory and invasive properties of the cells and performed clonogenicity assay to evaluate the ability of individual cells to form colonies. The tumorigenic potential of CBC2T-2 cells was tested in vivo using non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. The cells were injected subcutaneously and tumor formation was observed. In addition, immunohistochemical analysis was carried out to examine the expression of epithelial marker CK19 and mesenchymal marker vimentin in both CBC2T-2 cells and xenografts. The CBC2T-2 cell line was used to screen the potential therapeutic effects of various clinical agents in patients with cholangiocarcinoma sarcoma. Lastly, whole-exome sequencing was performed to identify genetic alterations and screen for somatic mutations in the CBC2T-2 cell line. RESULTS: The STR test showed that there was no cross-contamination and the results were identical to those of the original tissue. The cells showed round or oval-shaped epithelioid cells and mesenchymal cells with spindle-shaped or elongated morphology. The cells exhibited a high proliferation ratio with a doubling time of 47.11 h. This cell line has migratory, invasive, and clonogenic abilities. The chromosomes in the CBC2T-2 cells were polyploidy, with numbers ranging from 69 to 79. The subcutaneous tumorigenic assay confirmed the in vivo tumorigenic ability of CBC2T-2 cells in NOD/SCID mice. CBC2T-2 cells and xenografts were positive for both the epithelial marker, CK19, and the mesenchymal marker, vimentin. These results suggest that CBC2T-2 cells may have both epithelial and mesenchymal characteristics. The cells were also used to screen clinical agents in patients with cholangiocarcinoma sarcoma, and a combination of paclitaxel and gemcitabine was found to be the most effective treatment option. CONCLUSION: We established the first human cholangiocarcinoma sarcoma cell line, CBC2T-2, with stable biogenetic traits. This cell line, as a research model, has a high clinical value and would facilitate the understanding of the pathogenesis of cholangiocarcinoma sarcoma.

Lanatoside C decelerates proliferation and induces apoptosis through inhibition of STAT3 and ROS-mediated mitochondrial membrane potential transformation in cholangiocarcinoma.

Introduction: The incidence of cholangiocarcinoma (CCA) has increased worldwide in recent years. Given the poor prognosis associated with the current management approach of CCA, new therapeutic agents are warranted to improve the prognosis of this patient population. Methods: In this study, we extracted five cardiac glycosides (CGs) from natural plants: digoxin, lanatoside A, lanatoside C, lanatoside B, and gitoxin. Follow-up experiments were performed to assess the effect of these five extracts on cholangiocarcinoma cells and compounds with the best efficacy were selected. Lanatoside C (Lan C) was selected as the most potent natural extract for subsequent experiments. We explored the potential mechanism underlying the anticancer activity of Lan C on cholangiocarcinoma cells by flow cytometry, western blot, immunofluorescence, transcriptomics sequencing, network pharmacology and in vivo experiments. Results: We found that Lan C time-dependently inhibited the growth and induced apoptosis of HuCCT-1 and TFK-1 cholangiocarcinoma cells. Besides Lan C increased the reactive oxygen species (ROS) content in cholangiocarcinoma cells, decreased the mitochondrial membrane potential (MMP) and resulted in apoptosis. Besides, Lan C downregulated the protein expression of STAT3, leading to decreased expression of Bcl-2 and Bcl-xl, increased expression of Bax, activation of caspase-3, and initiation of apoptosis. N-acetyl-L-cysteine (NAC) pretreatment reversed the effect of Lan C. In vivo, we found that Lan C inhibited the growth of cholangiocarcinoma xenografts without toxic effects on normal cells. Tumor immunohistochemistry showed that nude mice transplanted with human cholangiocarcinoma cells treated with Lan C exhibited decreased STAT3 expression and increased caspase-9 and caspase-3 expression in tumors, consistent with the in vitro results. Conclusion: In summary, our results substantiates that cardiac glycosides have strong anti-CCA effects. Interestingly the biological activity of Lan C provides a new anticancer candidate for the treatment of cholangiocarcinoma.

Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as add-on to metformin in patients with type 2 diabetes in SUSTAIN China: A 30-week, double-blind, phase 3a, randomized trial.

AIM: To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, versus once-daily sitagliptin as add-on to metformin in patients with type 2 diabetes (T2D) in a multiregional clinical trial. MATERIALS AND METHODS: In the 30-week, randomized, double-blind, double-dummy, active comparator SUSTAIN China trial, 868 adults with T2D inadequately controlled on metformin (HbA1c 7.0%-10.5%) were randomized to receive once-weekly semaglutide 0.5 mg (n = 288), semaglutide 1.0 mg (n = 290) or once-daily sitagliptin 100 mg (n = 290). The primary and confirmatory secondary endpoints were change from baseline to week 30 in HbA1c and body weight, respectively. RESULTS: The trial enrolled ~70% (605/868) of the patients in China, and the remaining patients from four other countries, including the Republic of Korea. Both doses of semaglutide were superior to sitagliptin in reducing HbA1c and body weight after 30 weeks of treatment. The odds of achieving target HbA1c of less than 7.0% (53 mmol/mol), weight loss of 5% or higher, or 10% or higher, and the composite endpoint of HbA1c less than 7.0% (53 mmol/mol) without severe or blood glucose-confirmed symptomatic hypoglycaemia no weight gain, were all significantly higher with both semaglutide doses compared with sitagliptin. The safety profile for semaglutide was consistent with the known class effects of GLP-1 receptor agonists (RAs). Consistent efficacy and safety findings were seen in the Chinese subpopulation. CONCLUSIONS: Once-weekly semaglutide was superior to sitagliptin in improving glycaemic control and reducing body weight in patients with T2D inadequately controlled on metformin. The safety and tolerability profiles were consistent with those of semaglutide and other GLP-1 RAs. Semaglutide is an effective once-weekly treatment option for the Chinese population.

Characterization of the plastome of Camellia pingguoensis (Theaceae), an endangered and endemic yellow camellia species in China.

Camellia pingguoensis D. Fang is a shrub which is found on limestone of karst forests in Guangxi, China. In this study, we characterized the whole plastid genome of C. pingguoensis using Illumina paired-end sequencing reads. The plastome is 156,621 bp in length, containing two copies of inverted repeat (IR) regions (26,046 bp), a large-single copy (LSC) region (86,289 bp), and a small-single copy (SSC) region (18,240 bp). A total of 114 unique genes in the genome has 80 protein-coding genes, 30 tRNA genes, and 4 rRNA genes. The phylogenetic result indicates C. pingguoensis is closely related to C. nitidissima C. W. Chi.

Left ventricular diastolic dysfunction -- early cardiac impairment in patients with polymyositis/dermatomyositis: a tissue Doppler imaging study.

OBJECTIVE: To investigate early cardiac involvement in patients with polymyositis/dermatomyositis (PM/DM), and to evaluate the risk factors for early cardiac impairment. METHODS: The study population included 46 patients with PM/DM who did not have overt cardiovascular manifestations and 21 age- and sex-matched healthy controls. Traditional echocardiography and tissue Doppler imaging (TDI) were used to evaluate cardiac function in both groups. Clinical characteristics were recorded. Multivariate logistics regression analysis was applied to investigate risk factors for early cardiac impairment in patients with PM/DM. RESULTS: No significant difference was found between patients and controls by traditional echocardiography. However, compared to controls, PM/DM patients had a significantly lower ratio of early diastolic mitral annulus velocity to late diastolic mitral annulus velocity (Em/Am; 1.23 ± 0.52, 1.79 ± 0.37, respectively; t = -4.485, p < 0.001) and a higher ratio of peak early diastolic transmitral flow velocity to Em (E/Em; 8.26 ± 2.57, 6.76 ± 1.17; t = 3.287, p < 0.05) as found by TDI measurements. There was no significant difference between the TDI variables of patients with PM and DM. The multivariate regression analysis showed that female sex (OR 11.044, 95% CI 1.066-114.357, p = 0.044), late onset (OR 1.157, 95% CI 1.047-1.278, p = 0.004), and duration of disease (OR 1.060, 95% CI 1.008-1.115, p = 0.023) were risk factors for abnormal left ventricular filling pressures. CONCLUSION: TDI is useful for detecting early cardiac impairment in patients with PM/DM. Left ventricular diastolic dysfunction is an early feature of cardiac involvement. Female sex, late onset, and long course of disease are 3 independent risk factors for predicting left ventricular diastolic dysfunction in patients with PM/DM.

Changes of peripheral blood lymphocyte subsets in patients with polymyositis and dermatomyositis / 中华风湿病学杂志

ObjectiveTo investigate the clinical significance of peripheral blood lymphocyte subsets in patients with idiopathic inflammatory myopathy (ⅡM).MethodsPeripheral blood lymphocyte subsets was determined by flow cytometry in 89 patients with polymyositis(PM ) or dermatomyositis ( DM ).The association between clinical features and peripheral blood lymphocyte subsets was analyzed by F test,t test and x2 test.ResultsPatients with active DM showed significant decreases in counts of CD3+ cell,CD3+CD4+ cell and CD3+CD8+ cell[(8±4),(5.4±2.8) and (2.6±1.6) ×108/L respectively],compared with those in inactive DM [(16±6), (10.4±5.6) and (5.6±3.8) ×108/L respectively] and healthy controls [(14±4), (8.3±2.8) and (4.6±1.7) ×108/Lrespectively](F=12.901,8.257,7.084; P＜0.05).Logistic regression analysis indicated that myositis disease activity could influence the counts of peripheral blood CD3+ cell,CD3+CD4+ cell and CD3+ CD8+ cell (b=0.211,0.344,0.289; P＜0.05 ).ILD in ⅡM could influence the counts of CD3+ cell and the ratio of CD3+CD4+cell (b=0.928,1.974; P＜0.05 ).Logistic regression analysis indicated that the count of CD3+CD8+ cell was risk factor for death,and the relative risk was 0.989(b=-0.011 ; P＜0.05).ConclusionPeripheral blood lymphocyte subsets may be regarded as useful laboratory parameters for monitoring RA disease activity.Decreased CD8+ T cell may predict a poor outcome of patients with IIM.

The expression of the type Ⅰ interferon system in muscle and lung of autoimmune myositis rat model / 中华内科杂志

ObjectiveTo investigate the expression levels of the type Ⅰ IFN system in muscle and lung of experimental autoimmune myositis (EAM) model and to evaluate whether the type Ⅰ IFN system associates with the pathogenesis of the EAM model in rats.MethodsThe EAM model was established to determine creatine kinase (CK) in blood serum.The pathology of muscle and lung tissue was examined by hematoxylin-eosin staining.The concentration of type Ⅰ IFN system mRNA in muscle and lung tissue was detected by real-time PCR.ResultsThe concentration of CK in model group [(209.17 ±91.95) IU/L]was significantly higher than that of two control groups(P ＜0.05).The scores of muscle and lung in EAM model were significantly higher than that of control groups (all P ＜ 0.05).The expression levels of the type Ⅰ IFN system in muscle of EAM model were significantly higher than that of control groups(all P ＜0.05).The expression levels of the type Ⅰ IFN system in muscle with EAM model were positively correlated with CK and the scores of muscle (all P ＜ 0.05).The expression levels of IFNα, IFNβ, IFNαR1, signal transducer and activator of transcription 1 (STAT1), myxovirus resistance protein 1 (MX1) in lung of EAM model were significantly higher than those of control groups(P ＜ 0.05), but not seen in INF-induced protein with tetratricopetide repeats 1 (IFIT1) and IFN-stimulated gene 15 (ISG15).The expression levels of IFNα, IFNβ, IFNαR1, STAT1 and MX1 in lung with EAM model were positively correlated with the scores of lung pathology (all P ＜ 0.05).ConclusionThe type Ⅰ IFN system probably played a crucial role in the pathogenesis and the pathology of muscle and lung of EAM modeL

Effect of saikosaponin-d on rat's glomerular mesangial cell proliferation and extracellular matrix hyperplasia in vitro / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To investigate the effects of saikosaponin-d (SSd) on glomerular mesangial cells (MCs) proliferation and hyperplastic extracellular matrix (ECM) induced by lipopolysaccharide (LPS) to provide experimental proof for its use in prevention and treatment of glomerulosclerosis.</p><p><b>METHODS</b>Rat's MCs were cultivated and identified. The cultured MCs were stimulated by LPS and incubated with different concentrations of SSd. Cell proliferation was determined by MTT assay, LDH assay and flow cytometry, respectively. Type IV collagen (Col IV), fibronectin (FN) and transforming growth factor beta1 (TGF-beta1) in the conditioned medium were measured by ELISA. The expressions of cyclin-dependent kinase 4 (CDK4), c-Jun and c-Fos were detected by immunohistochemistry.</p><p><b>RESULTS</b>After treated by SSd, MC proliferation was inhibited, cells in G0/G1 phase increased, and apoptosis induced. Moreover, secretion of Col IV, FN and TGF-beta1 and the expressions of CDK4, c-Jun and c-Fos in MC were inhibited.</p><p><b>CONCLUSION</b>The inhibitory action of SSd on glomerulosclerosis was realized through inhibiting the expressions of CDK4, c-J un and c-Fos.</p>

Pharmacokinetics of rebamipide in the patients with peptic ulcer / 中国临床药理学与治疗学

0.05).Cmax of domestic and imported rebamipide tablet were (0.56?0.24) and (0.59?0.29)mg?L-1, with that tmax were (1.75?0.92) and (1.98?1.05)h,t1/2(?) were (1.86?1.38) and (1.93?1.45)h,AUC0～∞ were (2.48?1.06) and (2.62?1.35)mg?h?L-1. Conclusion The pharmacokinetics of the two products are similar.