Transcriptomic Features of systemic lupus erythematosus Patients in Flare and Changes during Acute In-Hospital Treatment.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with varying symptoms and multi-organ damage. Relapse-remission cycles often persist for many patients for years with the current treatment. Improved understanding of molecular changes caused by SLE flare and intensive treatment may result in more targeted therapies. METHODS: RNA-sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 65 SLE patients in flare, collected both before (SLE1) and after (SLE2) in-hospital treatment, along with 15 healthy controls (HC). Differentially expressed genes (DEGs) were identified among the three groups. Enriched functions and key molecular signatures of the DEGs were analyzed and scored to elucidate the transcriptomic changes during treatment. RESULTS: Few upregulated genes in SLE1 vs HC were affected by treatment (SLE2 vs SLE1), mostly functional in interferon signalling (IFN), plasmablasts, and neutrophils. IFN and plasmablast signatures were repressed, but the neutrophil signature remained unchanged or enhanced by treatment. The IFN and neutrophil scores together stratified the SLE samples. IFN scores correlated well with leukopenia, while neutrophil scores reflected relative cell compositions but not cell counts. CONCLUSIONS: In-hospital treatment significantly relieved SLE symptoms with expression changes of a small subset of genes. Notably, IFN signature changes matched SLE flare and improvement, while enhanced neutrophil signature upon treatment suggested the involvement of low-density granulocytes (LDG) in disease development.

Serum triglyceride glucose index is a valuable predictor for visceral obesity in patients with type 2 diabetes: a cross-sectional study.

BACKGROUND: Since the triglyceride glucose (TyG) index can reflect insulin resistance, it has been proven to be an efficient predictor of glycolipid-metabolism-related diseases. Therefore, this study aimed to investigate the predictive value of the TyG index for visceral obesity (VO) and body fat distribution in patients with type 2 diabetes mellitus (T2DM). METHODS: Abdominal adipose tissue characteristics in patients with T2DM, including visceral adipose area (VAA), subcutaneous adipose area (SAA), VAA-to-SAA ratio (VSR), visceral adipose density (VAD), and subcutaneous adipose density (SAD), were obtained through analyses of computed tomography images at the lumbar 2/3 level. VO was diagnosed according to the VAA (> 142 cm2 for males and > 115 cm2 for females). Logistic regression was performed to identify independent factors of VO, and receiver operating characteristic (ROC) curves were used to compare the diagnostic performance according to the area under the ROC curve (AUC). RESULTS: A total of 976 patients were included in this study. VO patients showed significantly higher TyG values than non-VO patients in males (9.74 vs. 8.88) and females (9.59 vs. 9.01). The TyG index showed significant positive correlations with VAA, SAA, and VSR and negative correlations with VAD and SAD. The TyG index was an independent factor for VO in both males (odds ratio [OR] = 2.997) and females (OR = 2.233). The TyG index ranked second to body mass index (BMI) for predicting VO in male (AUC = 0.770) and female patients (AUC = 0.720). Patients with higher BMI and TyG index values showed a significantly higher risk of VO than the other patients. TyG-BMI, the combination index of TyG and BMI, showed significantly higher predictive power than BMI for VO in male patients (AUC = 0.879 and 0.835, respectively) but showed no significance when compared with BMI in female patients (AUC = 0.865 and 0.835, respectively). CONCLUSIONS: . TyG is a comprehensive indicator of adipose volume, density, and distribution in patients with T2DM and is a valuable predictor for VO in combination with anthropometric indices, such as BMI.

A phase III randomized, double-blind, placebo-controlled trial of the denosumab biosimilar QL1206 in postmenopausal Chinese women with osteoporosis and high fracture risk.

The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk.

Association between dietary inflammatory index score and muscle mass and strength in older adults: a study from National Health and Nutrition Examination Survey (NHANES) 1999-2002.

PURPOSE: Chronic low-grade systemic inflammation affects muscle protein metabolism. The dietary inflammatory index (DII®) is a tool designed to assess the inflammatory potential of the diet. The available data on the association between DII and sarcopenia are limited. We aimed to investigate the association of the DII with components of sarcopenia in individuals over 50 years of age. METHODS: This cross-sectional study used the National Health and Nutrition Examination Survey (NHANES) 1999-2002 dataset. Body composition was measured, and isokinetic strength of the knee extensors (peak force) was evaluated. Low muscle mass and strength were defined using sex-specific thresholds. Energy-adjusted DII (E-DII™) scores were calculated using 24-h dietary recall data. Regression models were fit to evaluate the association between E-DII scores and low muscle mass and low muscle strength, alone and combined. RESULTS: Mean age of study participants was 62.1 ± 9.5 years, and 138 participants (7.4%) belonged to the combination group of low muscle mass and low muscle strength. In multivariable-adjusted regression models, higher E-DII score was associated with lower appendicular skeletal muscle index (ASMI) (ß = - 0.03, P  < 0.001, P trend <0.001), and lower peak force (ß = -2.15, P  = 0.04, P trend = 0.01) and higher likelihood for these components combined (OR = 1.12, 95% CI 1.01-1.25, P = 0.03). CONCLUSION: Higher E-DII score is associated with lower muscle mass and muscle strength, and increased likelihood for the combination of low muscle mass and low muscle strength in older adults. This has important implications for healthy aging.

[A multiplex PCR-based sensitive and specific method for detecting Y chromosome material in patients with Turner syndrome].

OBJECTIVE: To develop a multiplex PCR method for a rapid detection of Y chromosome-specific sequences in patients with Turner syndrome. METHODS: Nine genes were selected from various regions of the Y chromosome for designing the primers, which included SRY, TBL1Y, TSPY on the short arm of the Y chromosome, DDX3Y, HSFY1, RPS4Y2 and CDY1 on the long arm of Y chromosome and SHOX in the short arm and SPRY3 in the long arm of the pseudoautosomal region (PAR) of X and Y chromosomes. A multiplex PCR method for the nine genes in Y chromosome was established and optimized. The sensitivity was tested by using different amounts of genomic DNA. A total of 36 patients with Turner syndrome and a patient with male dwarfism with karyotype of 46, X, +mar were examined by the multiplex PCR method for the existence of materials from the Y chromosome. RESULTS: The optimization results of the multiplex PCR reaction system (50 µL) showed that when the final concentration of upstream and downstream of each pair of primers was 0.1 µM, the multiplex PCR reaction of the 9 pairs of primers clearly amplified the target with the expected band size, and there was no non-specific amplification. The bands were clearly visible when the amount of genomic DNA in the multiple PCR reaction system was as low as 1 ng. By using the method, we have examined the 36 patients with Turner syndrome. One patient with Turner syndrome with karyotype of 45,X[40]/47XYY[21] amplified specific seven genes on Y chromosome, 35 patients with Turner syndrome amplified only two target genes SHOX and SPRY3, but not the other seven specific genes on the Y chromosome, which was in keeping with the clinical manifestations of such patients. CONCLUSION: This study established a multiplex PCR reaction system with nine genes, which can quickly and accurately screen Y chromosome materials in patients with Turner syndrome. It has the advantages of low cost, simple operation, high specificity and rapid turn-around time, and can be used to detect Turner syndrome patients with Y chromosome material in time. The method has provided a diagnostic basis for preventive gonad resection to prevent malignant gonadal tumors.

Genome-wide association study on Northern Chinese identifies KLF2, DOT1L and STAB2 associated with systemic lupus erythematosus.

OBJECTIVES: To identify novel genetic loci associated with systemic lupus erythematosus (SLE) and to evaluate potential genetic differences between ethnic Chinese and European populations in SLE susceptibility. METHODS: A new genome-wide association study (GWAS) was conducted from Jining, North China, on 1506 individuals (512 SLE cases and 994 matched healthy controls). The association results were meta-analysed with existing data on Chinese populations from Hong Kong, Guangzhou and Central China, as well as GWAS results from four cohorts of European ancestry. A total of 26 774 individuals (9310 SLE cases and 17 464 controls) were included in this study. RESULTS: Meta-analysis on four Chinese cohorts identifies KLF2 as a novel locus associated with SLE [rs2362475; odds ratio (OR) = 0.85, P=2.00E-09]. KLF2 is likely an Asian-specific locus as no evidence of association was detected in the four European cohorts (OR = 0.98, P =0.58), with evidence of heterogeneity (P=0.0019) between the two ancestral groups. Meta-analyses of results from both Chinese and Europeans identify STAB2 (rs10082873; OR= 0.89, P=4.08E-08) and DOT1L (rs4807205; OR= 1.12, P=8.17E-09) as trans-ancestral association loci, surpassing the genome-wide significance. CONCLUSIONS: We identified three loci associated with SLE, with KLF2 a likely Chinese-specific locus, highlighting the importance of studying diverse populations in SLE genetics. We hypothesize that DOT1L and KLF2 are plausible SLE treatment targets, with inhibitors of DOT1L and inducers of KLF2 already available clinically.

Off-label use of letrozole in Chinese short pubertal boys: Effectiveness, safety, and exposure-response analysis.

AIMS: Recently, letrozole has been used off-label to treat short pubertal boys. The experience on letrozole effectiveness and safety has been obtained primarily from Caucasian children. A simple extrapolation of the data to Chinese paediatric populations is questionable because of the substantial ethnic differences between the two populations. Therefore, the present study aimed to determine the effectiveness and safety of letrozole use in Chinese short pubertal boys as well as to establish an exposure-response relationship. METHODS: Forty-one Chinese boys were included in the study. Patients were given letrozole tablets (2.5 mg) once daily in combination with growth hormone, and follow-up visits were made after 1, 3, 6 and 12 months of treatment. Plasma samples were taken from clinical examinations and analysed using high performance liquid chromatography with fluorescence detection. RESULTS: After 1 year of treatment, 35 (88%) boys showed increased predicted adult heights. However, possible adverse drug reactions were seen in nine boys (22%). Predicted adult heights increased significantly from 168.4 ± 3.7 to 173.0 ± 4.2 cm, while oestrogen levels dropped from 33.2 ± 7.4 to 21.6 ± 7.3 pg/mL. Increments in predicted adult height were significantly correlated with trough letrozole concentrations (r = 0.39, P = .01). CONCLUSION: Letrozole treatment in Chinese pubertal populations should be further optimized, and more personalized therapies should be developed.

Association between serum uric acid and triglycerides in Chinese children and adolescents with short stature.

BACKGROUND: Elevated triglyceride (TG) levels are a biomarker for cardiovascular disease (CVD) risk. The correlation between serum uric acid (SUA) and TG concentrations in adults or obese children is well established. However, studies on SUA and TG in children with short stature are limited. AIM: To determine the relationship between SUA and TG levels in short children and adolescents. METHOD: This was a cross-sectional evaluation of a cohort of 1095 patients with short stature (720 males and 375 females). The related clinical characteristics, including anthropometric and biochemical parameters, were determined. RESULTS: Smooth curve fitting, adjusted for potential confounders was performed, which indicated the existence of a non-linear relationship between these measures. Piecewise multivariate linear analysis revealed a significant positive relationship between SUA and TG at SUA concentrations over 7 mg/dL (ß = 0.13, 95% CI: 0.05-0.22, P = 0.002) but no significant correlation at lower SUA levels (ß = 0.01, 95% CI: 0.01-0.04, P = 0.799). Furthermore, a stratified analysis was performed to appraise changes in this relationship for different sexes and standard deviation levels of body mass index (BMI). The non-linear relationship remained consistent in males and females with BMI standard deviation scores (BMI SDS) ≥ 0, with inflection points of 6.71 mg/dL and 3.93 mg/dL, respectively. Within these two groups, SUA and TG levels showed a positive association when SUA levels were higher than the inflection point (ß = 0.21, 95% CI: 0.11-0.31, P < 0.001 for males and ß = 0.1, 95% CI: 0.03-0.17, P = 0.005 for females). However, a specific relationship was not observed at lower SUA levels. No significant relationships were found between SUA and TG levels in males and females with BMI SDS < 0. CONCLUSION: The present study identified the non-linear association of SUA and TG levels with short children and adolescents. This relationship was based on BMI status. This finding suggests that health status should be considered for short stature children with high SUA levels, especially in children with a high BMI standard deviation score.

Relationship between hemoglobin and insulin-like growth factor-1 in children and adolescents with idiopathic short stature.

BACKGROUND: The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis is critical for the regulation of children's growth and development. Serum IGF-1 concentrations are usually low in individuals with idiopathic short stature (ISS) despite normal endogenous GH levels, and the associated underlying factors are unknown. This study aimed to explore the relationship between IGF-1 and hemoglobin (Hb) in children with ISS. METHODS: A cross-sectional analysis was performed including 178 children and adolescents with ISS who were enrolled from March 2013 to February 2019. The related clinical and biochemical parameters were evaluated for each patient. Univariate analysis, smooth curve fitting and multivariate piecewise linear regression were performed. RESULT: The mean levels of IGF-1 standard deviation scores (SDS) and Hb were - 0.99 (- 1.60 - -0.09) and 131.81 ± 9.36 g/L, respectively. Univariate analysis displayed a significant positive association between Hb and IGF-1 SDS (P < 0.001). After adjusting for potential confounding factors, the positive relationship between Hb and IGF-1 SDS remained (P = 0.001). Furthermore, there was an inflection point for Hb in the curve. In a multivariate piecewise linear regression model, IGF-1 SDS was significantly positively associated with Hb when Hb concentrations were lower than 145 g/L (B 0.05; 95% CI 0.02, 0.07; P < 0.001). However, IGF-1 SDS decreased with increasing Hb levels when Hb concentrations were greater than 145 g/L (B -0.15; 95% CI -0.23, - 0.06; P = 0.001). CONCLUSION: This study demonstrated that Hb is associated with IGF-1 in Chinese children and adolescents with ISS. The levels of IGF-1 increased with the elevation of Hb, but when the concentration of Hb exceeded a certain range, with the increase of Hb, IGF-1 decreased instead.

LPS-enhanced IGF-IIR pathway to induce H9c2 cardiomyoblast cell hypertrophy was attenuated by Carthamus tinctorius extract via IGF-IR activation.

The use of herbs as alternative cardiovascular disease treatment has attracted a great deal of attention owing to their lower toxicity. Whether Carthamus tinctorius extract prevent cardiomyoblast cell hypertrophy remains unclear. The present study was performed to investigate the effect of C tinctorius extract (CTF) on rat cardiomyoblast cell H9c2 and the possible molecular mechanisms. H9c2 cells were treated with lipopolysaccharide (LPS; 2 µg/mL) for 12 hours, subsequently treated with CTF (1-25 µg/mL) The incubation continued for another 24 hours, and the cells were analyzed with actin staining assay, western blot analysis, and siRNA transfection assays. In the present study, the increased cell size induced by LPS was significantly decreased by pretreating at a concentration of 1-25 µg/mL CTF. It was found that CTF could inhibit cardiac hypertrophy induced by LPS and decrease hypertrophic proteins calcineurin, p-GATA-4, GATA-4, atrial natriuretic peptide, and B-type natriuretic peptide levels in H9c2 cells. Additionally, LPS-induced insulin-like growth factor-II receptor (IGF-IIR) hypertrophy pathway was downregulated by CTF. Moreover, IGF-IR siRNA or inhibitors both reversed the CTF effects, confirming that CTF activates IGF-1R to prevent LPS-induced H9c2 cardiomyoblast cell hypertrophy. The current findings indicate that CTF activates IGF-IR to inhibit IGF-IIR signaling pathway which resulted in reducing H9c2 cardiomyoblast cell hypertrophy induced by LPS.

Low-density lipoprotein cholesterol levels are associated with insulin-like growth factor-1 in short-stature children and adolescents: a cross-sectional study.

BACKGROUND: Elevated low-density lipoprotein cholesterol (LDL-C) levels in childhood have recently been found to be the strongest predictive risk factor for coronary artery disease in adulthood. There is an increased level of LDL-C in children and adolescents with short stature. However, the underlying factors associated with increased LDL-C levels in children and adolescents with short stature are unknown. In addition, the insulin-like growth factor 1 (IGF-1) level in the short-stature population is usually below the normal reference range. The aim of this study was to investigate the relationship between IGF-1 standard deviation score (IGF-1 SDS) and LDL-C level in children and adolescents with short stature. METHODS: A cross-sectional study was conducted in a single centre of China, 557 short-stature children and adolescents whose height SDS was lower than - 2 SD after adjustment for age and gender were included. The related clinical and laboratory examinations, including anthropometric parameters, lipid profiles, IGF-1 levels and the levels of other cofactors, were assessed in all participants. RESULTS: The univariate analysis results showed a significant negative correlation between IGF-1 SDS and LDL-C levels (P = 0.006). Furthermore, a nonlinear relationship was observed between IGF-1 SDS and LDL-C by smooth curve fitting after adjusting for possible confounders. A multivariate piecewise linear regression model revealed a significant negative correlation between IGF-1 SDS and LDL-C when the IGF-1 level was greater than - 2 SDS (ß - 0.07, 95% CI -0.12, - 0.02; P = 0.006). However, we did not observe a significant relationship between IGF-1 SDS and LDL-C when the IGF-1 level was lower than - 2 SDS (ß 0.08, 95% CI -0.02, 0.17; P = 0.119). CONCLUSION: This study demonstrated a nonlinear relationship between IGF-1 and LDL-C independent of other potential confounding factors, suggesting that circulating IGF-1 may contribute to the regulation of LDL-C levels, thus meriting further investigation.

Taiwanin C elicits apoptosis in arecoline and 4-nitroquinoline-1-oxide-induced oral squamous cell carcinoma cells and hinders proliferation via epidermal growth factor receptor/PI3K suppression.

Oral Squamous Cell Carcinoma (OSSC) is a major life-threatening disease with high incidence in the Southeast Asian countries. Chronic exposure to arecoline causes genetic changes in the epithelial cells of the oral mucosa, induces proliferation through activation of the EGF receptor and promotes downstream COX-2 expression. Taiwanin C, a podophyllotoxin derived from Taiwania cryptomerioides Hayata is known to inhibit COX activity and to hinder PGE2 production in macrophages. In this study a tumor cell line T28 and a non-tumor cell line N28 derived from mice OSCC models were used to study the effect of Taiwanin C on PGE2 associated COX-2 expression and cell cycle regulators. Taiwanin C activated p21 protein expression, down-regulated cell cycle regulatory proteins, elevated apoptosis and down-regulated p-PI3K/p-Akt survival mechanism in T28 oral cancer cells. Our results therefore emphasize the therapeutic potential of Taiwanin C against arecoline-induced oral cancer.

Carthamus tinctorius L. extract activates insulin-like growth factor-I receptor signaling to inhibit FAS-death receptor pathway and suppress lipopolysaccharides-induced H9c2 cardiomyoblast cell apoptosis.

Carthamus tinctorius L. (Compositae) is used in Chinese medicine to treat heart disease and inflammation. In our previous study, we found that C. tinctorius L. inhibited lipopolysaccharides (LPS)-induced tumor necrosis factor-alpha (TNF-α) activation, JNK expression, and apoptosis in H9c2 cardiomyoblast cells. The present study was performed to investigate the protective effect of C. tinctorius extract (CTF) on LPS-challenged H9c2 myocardioblast cell and to explore the possible underlying mechanism. Cell viability assay showed that LPS treatment decreased the cell viability of H9c2 cell, whereas CTF treatment reversed LPS cytotoxicity in a dose-dependent manner, especially in the LPS + CTF 25 (µg/mL) group. LPS treatment-induced apoptosis was determined by transferase-mediated dUTP nick end labeling assay, and by Western blot. LPS-induced apoptotic bodies were decreased following CTF treatment. Expression of TNF-α, FAS-L, FAS, FADD, caspase-8, BID, and t-BID was significantly increased in LPS-treated H9c2 cells. In contrast, it was significantly suppressed by the administration of CTF extract. In addition, CTF treatment activates antiapoptotic proteins, Bcl-2 and p-Bad, and downregulates Bax, cytochrome-c, caspase-9, caspase-3, and apoptosis-inducing factor expression. Furthermore, CTF exerted cytoprotective effects by activating insulin-like growth factor-I (IGF-I) signaling pathway leading to downregulation of the apoptotic proteins involved in FAS death receptor pathway. In addition, AG1024 and IGF-I receptor (IGF-IR) inhibitor and siRNA silencing reverses the effect of CTF implying that CTF functions through the IGF-IR pathway to inhibit LPS-induced H9c2 apoptosis. These results suggest that treatment with CTF extract prevented the LPS-induced apoptotic response through IGF-I pathway.

TCR Vß Usage of Peripheral Blood and Liver Infiltrating Lymphocytes in Patients with Chronic Hepatitis B.

INTRODUCTION: Chronic hepatitis B (CHB) is still a public health problem and its mechanism remains unclear. In this study, we detect the skewness of T cell receptor beta chain variable gene (TCR Vß) in peripheral blood lymphocytes (PBL) and the liver infiltrating lymphocytes (LIL) of patients with CHB; and hope to provide information for further research on the pathogenic mechanism of CHB. MATERIAL AND METHODS: Fifteen patients with CHB, ten healthy volunteers and three patients with liver cysts were recruited as the subjects. The usage of TCR Vß of PBL and LIL were measured and compared; the associations of the TCR Vß usage of PBL with some hematological indices, including human leukocyte antigen (HLA) alleles, percents of CD4+ and CD8+ T cells, sera levels of HBV-DNA and IFN-γ, were analyzed. RESULTS: In PBL, Vß12 and Vß13.1 were the highest predominant usage genes which usage frequencies were all 46.7%; Vß23 was the key limited usage gene (40.0%). In LIL, the mainly predominant and limited usage gene was Vß13.1 (73.3%) and Vß23 (46.7%), respectively. About half of the patients with CHB with HLA-DR9 or HLA-DR12 showed the predominant usage of Vß5.2 or Vß13.2. In patients with CHB, the percentage of CD4+ T cells was 33.41 ± 5.39 %, that of CD8+ T cells was 28.67 ± 6.77 %; the concentration of IFN-γ was 182.52 ± 44.16 pg/mL. Compared to the healthy controls, there were significant differences for these data (P < 0.05). Neither ALT nor HBV-DNA was relative to the usage of TCR Vß. CONCLUSIONS: PBL and LIL share the common sknewness of TCR Vß genes, which probably relates to some hematological indices. However, the roles of such similarities and associations in the development of CHB need further study.

Even mildly elevated TSH is associated with an atherogenic lipid profile in postmenopausal women with subclinical hypothyroidism.

Postmenopausal women, a population with increased risk of atherosclerosis, also have an appreciable risk of subclinical hypothyroidism (SCH). The current study sought an association between serum thyrotropin (TSH), the biomarker of SCH and atherosclerosis lipid profile changes. A total of 45 postmenopausal women with SCH and 27 healthy women matched by age and body mass index were enrolled in this observational study. Serum lipid profiles and thyroid function were assessed. Compared with healthy controls, the serum levels of TC, TG, LDL-c and oxidized LDL (oxLDL) in SCH were increased by ~22.8%, 29.6%, 30.5% and 23.2%, respectively. TSH was positively correlated with TC, LDL-c and oxLDL in all of the study subjects after adjusting for age and BMI. In particular, the positive correlation remained significant after adjusting for serum FT3 and FT4. When further stratified by TSH levels, both the subgroup of mildly elevated TSH (4.78-9.99 mU/L) and overtly elevated TSH (>10.00 mU/L) exhibited significantly higher serum levels of TC, TG, LDL-c and oxLDL compared to the normal TSH subgroup. Path analysis revealed that the total effects of TSH on TC (total effectsTC,TSH = 0.4323) included a significant direct effect (direct effectTC,TSH = 0.4932) and an indirect effect via an intermediary variable (FT3, FT4). Furthermore, TC exhibited a direct effect on LDL-c, as did LDL-c on oxLDL. In conclusion, even with a mild elevation of serum TSH, SCH is associated with atherogenic lipid profiles in postmenopausal women independent of thyroid hormones.

[Treatment of type 2 diabetic peripheral neuropathy patients of qi-yin deficiency complicated phlegm-dampness blocking collaterals syndrome by internal application of qigui mixture and external application of qigui huoxue lotion: a clinical study].

OBJECTIVE: To evaluate the efficacy of internal application of Qigui Mixture (QM) and external application of Qigui Huoxue Lotion (QHL) in treating type 2 diabetic peripheral neuropathy (DNP) patients of qi-yin deficiency complicated phlegm-dampness blocking collaterals syndrome (QYD-PDBCS), and to primarily discuss its mechanism. METHODS: Totally 62 DPN patients of QYD-PDBCS were randomly assigned to the treatment group (31 cases) and the control group (31 cases). All patients received routine comprehensive therapy. Patients in the control group took Mecobalamine Tablet, 500 microg each time, 3 times per day. Patients in the treatment group additionally took QM, 200 mL per day, twice daily. Besides, they had foot bath in QHL 10 - 15 min every evening for 3 months. The efficacy was assessed by Chinese medical symptom integrals and Toronto clinical scoring system (TCSS) before treatment, 2 and 3 months after treatment. The nerve conduction velocity was determined; the serum levels of total antioxidant capacity (T- AOC), malondialdehyde (MDA), and superoxide dismutase (SOD) were detected 2 and 3 months after treatment. RESULTS: The total effective rates of Chinese medical symptom integrals and TCSS score were obviously higher in the treatment group than in the control group (P < 0.05). The nerve conduction velocity was significantly improved in the treatment group, when compared with before treatment (P < 0.01). There was statistical difference in the nerve conduction velocity difference of right median nerve motor branch, bilateral tibial nerve motor branches, bilateral common peroneal nerve motor branches, bilateral ulnar nerve sensory branches, and left tibial nerve sensory branch (P < 0.05). Compared with before treatment, serum levels of T-AOC and SOD significantly increased, and the level of MDA decreased significantly in the treatment group after 2 and 3 months of treatment (P < 0.01). But only the SOD level increased significantly in the control group (P < 0.01). There was no statistical difference in increased T-AOC level between the two groups after 2 months of treatment (P > 0.05), but there was statistical difference in increased SOD level and decreased MDA level (P < 0.05). There was statistical difference in increased T-AOC and SOD levels and decreased MDA level between the two groups after 3 months of treatment (P < 0.05). No adverse reaction occurred during the therapeutic course. CONCLUSIONS: The internal application of QM and external application of QHL combined with Mecobalamine in treating DPN was safe and effective, with more significant efficacy than using Mecobalamine alone. Its mechanism might be associated with resistance to oxidative stress.

Effects of metformin on the glucose regulation, lipid levels and gut microbiota in high-fat diet with streptozotocin induced type 2 diabetes mellitus rats.

OBJECTIVE: Metformin, an anti-diabetic drug, regulates blood glucose by affecting gut microbiotas. However, the potential mechanism underlying this effect remains unclear. This study aimed to evaluate the effect of metformin on glucose regulation, lipid levels, and the gut microbiota in rats with type 2 diabetes mellitus induced by a high-fat diet with streptozotocin. RESEARCH DESIGN METHODS: Thirty Wistar rats was using in this experiment. T2DM rats were administered 300 mg/kg metformin for 8 weeks. The glucose regulation, lipid levels, organ coefficients, and gut microbiotawere measured by 16S rDNA. RESULT: The metformin-gavaged rats exhibited significant improvements in blood glucose and serum lipid levels, accompanied by alterations in short-chain fatty acid levels and the intestinal microbiota (p < 0.05). In the diabetic rats, metformin potentially increased specific probiotics, thus improving the hypoglycaemic effects of the oral anti-diabetic drug. Further, damage to the liver and kidney was effectively alleviated in the metformin-gavaged rats. CONCLUSION: This study's findings demonstrate that metformin exerts a positive anti-diabetic effect in HFD- and STZ-induced T2DM rats. These findings potentially provide a basis for the recommended use of metformin as a reliable oral drug for T2DM owing to its positive effect on the intestinal microbiota.

Letrozole combined with rhGH treatment increases the adult height of short pubertal boys.

OBJECTIVES: This study was performed to investigate the effectiveness of the combination of letrozole and recombinant human growth hormone (rhGH) to improve the predicted adult height (PAH) and final adult height (FAH) of Chinese short pubertal boys. METHODS: In total, 171 Chinese short pubertal boys were recruited for this study. 96 of them received letrozole (2.5 mg/d) combined with rhGH (33.3-66.6 µg/kg.d), and the others received rhGH alone. Follow-up visits were conducted at 1, 3, 6, 9, and 12 months or regularly after the first treatment. During each visit, plasma samples were collected for clinical tests and biomedical analyses, all of which were performed according to standard protocols. This study was registered at www.chictr.org.cn under ID number ChiCTR1900026142. RESULTS: After receiving treatment for at least 3 months, 68 boys (91 %) in the rhGH therapy group and 90 (94 %) in the letrozole combined with rhGH (letrozole+rhGH) therapy group achieved an increase in PAH, with the latter treatment leading to a more effective slowing of bone age (BA) advancement. Moreover, the increased PAH showed a significant positive correlation with treatment time in both groups, and letrozole+rhGH increased the PAH to a greater degree than rhGH alone (p=0.0023). And letrozole+rhGH not only slowed the increase in BA more efficiently than rhGH therapy alone (p=0.0025), but also achieved a higher FAH (p=0.0078). CONCLUSIONS: Letrozole combined with rhGH treatment is a promising therapy to increase the PAH and FAH of Chinese short pubertal boys.

Bone marrow stromal cell antigen 2: Tumor biology, signaling pathway and therapeutic targeting (Review).

Bone marrow stromal cell antigen 2 (BST2) is a type II transmembrane protein that serves critical roles in antiretroviral defense in the innate immune response. In addition, it has been suggested that BST2 is highly expressed in various types of human cancer and high BST2 expression is related to different clinicopathological parameters in cancer. The molecular mechanism underlying BST2 as a potential tumor biomarker in human solid tumors has been reported on; however, to the best of our knowledge, there has been no review published on the molecular mechanism of BST2 in human solid tumors. The present review focuses on human BST2 expression, structure and functions; the molecular mechanisms of BST2 in breast cancer, hepatocellular carcinoma, gastrointestinal tumor and other solid tumors; the therapeutic potential of BST2; and the possibility of BST2 as a potential marker. BST2 is involved in cell membrane integrity and lipid raft formation, which can activate epidermal growth factor receptor signaling pathways, providing a potential mechanistic link between BST2 and tumorigenesis. Notably, BST2 may be considered a universal tumor biomarker and a potential therapeutical target.

Functional investigation of a novel ANKRD11 frameshift variant identified in a Chinese family with KBG syndrome.

KBG syndrome is a rare autosomal dominant condition characterized by multisystem developmental disorder, primarily caused by loss-of-function variants in ankyrin repeat domain-containing protein 11 (ANKRD11). Approximately 80 % of ANKRD11 variants associated with KBG syndrome, are frameshift and nonsense variants. Current insight into the pathogenesis of KBG syndrome resulting from ANKRD11 truncating variants remains limited. Here, we presented two members from a non-consanguineous Chinese pedigree both exhibiting characteristics fitting the KBG syndrome-associated phenotypic spectrum. Whole-exome sequencing identified a novel heterozygous frameshift variant in ANKRD11 (NM_013275.6, c.2280_2281delGT, p.Y761Qfs*20) in the proband. Sanger sequencing confirmed that the variant was inherited from her mother and co-segregated with KBG syndrome phenotype. In vitro functional assays revealed that the frameshift variant escaped nonsense-mediated mRNA decay, and resulting in a truncated protein with significantly increased expression levels compared to full-length ANKRD11. Immunofluorescence results demonstrated that truncated protein was predominantly expressed in the nucleus of HEK293 cells, while wild-type ANKRD11 was equally distributed in both the nucleus and cytoplasm. Moreover, the truncated protein significantly reduced CDKN1A/P21-promoter luciferase activity in comparison to wild-type ANKRD11 protein, as well as a remarkably decrease in the endogenous CDKN1A/P21 mRNA level in HEK293 cells. These findings suggest a loss of transcriptional activation function and potentially a dominant-negative mechanism. Overall, our study expands the mutational spectrum of ANKRD11 gene and provides new insights into the pathogenic mechanism of KBG syndrome caused by ANKRD11 truncating variants.