Moxibustion preconditioning reduces inflammatory response in rats with cerebral ischemia-reperfusion injury by regulating PI3K / AKT / mTOR signaling pathway. / 艾灸预处理通过调控PI3K/AKT/mTORä¿¡å·é€šè·¯å‡è½»è„‘ç¼ºè¡€å†çŒæ³¨æŸä¼¤å¤§é¼ ç‚Žæ€§ååº”.

OBJECTIVES: To observe the effect of moxibustion preconditioning on inflammatory response in rats with cerebral ischemia reperfusion injury (CIRI), so as to explore its mechanisms underlying improving CIRI. METHODS: Seventy-five male SD rats were randomly divided into sham operation, model, moxibustion preconditioning 3 days (Moxi 1), moxibustion preconditioning 5 days (Moxi 2) and moxibustion preconditioning 7 days (Moxi 3) groups, with 15 rats in each group. Moxibustion was applied at "Baihui"(GV20), "Dazhui"(GV14) and "Zusanli"(ST36) for 20 min once a day, totally for 3, 5 or 7 days. Thirty minutes after the last moxibustion treatment, the CIRI model was established by occlusion of the middle cerebral artery. The neurological deficit score was assessed by using Longa's method. The infarct size of the brain assessed after staining with 2% triphenyltetrazolium chloride (TTC). The morphological changes of cortical neurons were observed by HE staining. The contents of inflammatory factors interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), S-100ß protein (S-100ß) and neuron-specific enolase (NSE) were detected by ELISA. The expression of phosphatidylinositol-3-kinase (PI3K), p-PI3K, protein kinase B (AKT) and mammalian target of rapamycin (mTOR) proteins in the ischemic cortex tissues were detected by immunohistochemistry and Western blot. RESULTS: Compared with the sham operation group, the neurological function score and the percentage of cerebral ischemic volume were increased (P<0.01). The contents of serum IL-1ß, TNF-α, S-100ß and NSE were significantly increased (P<0.01), while the protein expressions of PI3K, p-PI3K, AKT and mTOR in the cerebral cortex were significantly decreased (P<0.01) in the model group. Compared with the model group, the neurological function score and the percentage of cerebral ischemic volume were significantly decreased (P<0.01). The contents of serum IL-1ß, TNF-α, S-100ß and NSE were significantly decreased (P<0.01), and the expressions of PI3K, p-PI3K, AKT and mTOR proteins in the cerebral cortex were significantly increased (P<0.01) in three moxibustion groups. Compared with the Moxi 1 and Moxi 2 groups, the above indicators were significantly improved in rats of the Moxi 3 group (P<0.01, P<0.05). CONCLUSIONS: Moxibustion preconditioning can significantly improve the neurological function of rats after ischemia-reperfusion, inhibit serum inflammatory factors IL-1 ß and TNF-α, inhibit brain tissue injury markers S-100ß and NSE, which may be related to the activation of PI3K/AKT/mTOR signaling pathway. The protective effect of moxibustion preconditioning for 7 days on CIRI was better than that of 5 days and 3 days.

MiR-21 alleviates renal tubular epithelial cells injury induced by ischemia by targeting TLR4.

Renal ischemia is the initial stage of kidney damage, leading to mitochondrial metabolism disorders and cell necrosis. In this study, we aimed to investigate the biological functions and potential mechanisms of miR-21 in protecting renal tubular epithelial cells from oxidative stress and apoptosis following oxygen glucose deprivation (OGD). Following an OGD injury, miR-21 levels increased in HK-2 renal tubular epithelial cells. Overexpression of miR-21 decreased the protein expressions of cleaved caspase-3, BAX, P53, cell apoptosis and increased Bcl-2 expression in HK-2 cells with OGD injury. In vivo studies found that miR-21 agomir reduced renal tissue apoptosis, while miR-21 antagomir increased it. In addition, overexpression of miR-21 reduced levels of reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) in HK-2 cells with OGD injury. However, miR-21 inhibition exhibited the opposite effect. A dual-luciferase reporter assay demonstrated that miR-21 directly regulates Toll-like receptor 4 (TLR4) by targeting the 3'-UTR of TLR4 mRNA. Overexpression of miR-21 led to decreased TLR4 protein expression, and TLR4 knockdown was shown to greatly increase AKT activity in HK-2 cells by in vitro kinase assay. Additionally, TLR4 knockdown promoted AKT phosphorylation and hypoxia-inducible factor-1α (HIF-1α) expression, while TLR4 overexpression inhibited these processes. Furthermore, AKT activation abolished the effect of TLR4 on HIF-1α, while AKT inhibition decreased the expression of TLR4 on HIF-1α in TLR4 knockdown HK-2 cells. Further study revealed that HIF-1α inhibition abolished the protective effect of miR-21 overexpression on ROS, LDH levels and cell apoptosis in HK-2 cells after OGD injury, which is indicated by increased levels of ROS and LDH, as well as increased cell apoptosis after HIF-1α inhibition in miR-21-treated HK-2 cells. In conclusion, miR-21 defends OGD-induced HK-2 cell injury via the TLR4/AKT/HIF-1α axis.

USP10 Alleviates Palmitic Acid-induced Steatosis through Autophagy in HepG2 Cells.

Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease caused by over-nutrition. Impaired autophagy is closely related to NAFLD progression. Recently, ubiquitin-specific peptidase-10 (USP10) was reported to ameliorate hepatic steatosis, but the underlying mechanism is still unclear. In view of the potential effects of USP10 on autophagy, we investigated whether USP10 alleviated steatosis through autophagy. Methods: HepG2 cells were treated with palmitic acid (PA) to model NAFLD in vitro. Lentivirus was used to regulate USP10 level in cells. Autophagic regulators were used to autophagic progression in cells. Western blotting, real-time fluorescence quantitative polymerase chain reaction, lipid drop staining and immunofluorescent staining were performed to determine the effect of USP10 on lipid autophagy. Student's t-test and Tukey's post hoc test were used to compare the means among groups. Results: PA induced cellular steatosis with dependance on autophagy. USP10 overexpression alleviated PA-induced steatosis, restored autophagic activity, promoted autophagic flux, including synthesis and degradation of autophagosomes, and lipid-targeted autophagy. In the presence of autophagy inhibitors, the protective effectiveness of USP10 on steatosis decreased. Furthermore, the specific inhibitor to C-jun N-terminal protein kinase-1 (JNK1), DB07268, abolished USP10-induced autophagy. However, during early stage inhibition of JNK1, compensatory expression of tuberous sclerosis complex-2 (TSC2) maintained autophagy. The degree of TSC2-to-JNK1 compensation was positively associated with USP10 level. Functionally, JNK1 and TSC2 were involved in the lipid-lowering effect of USP10. Conclusions: USP10 alleviated hepatocellular steatosis in autophagy-dependent manner. JNK1/TSC2 signaling pathways were required for USP10-induced autophagy.

One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C.

BACKGROUND: Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144. AIM: To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C. METHODS: In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations. RESULTS: Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV. CONCLUSION: Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.

240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg-negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long-term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

Bioactivity-Guided Screening of Antimicrobial Secondary Metabolites from Antarctic Cultivable Fungus Acrostalagmus luteoalbus CH-6 Combined with Molecular Networking.

With the increasingly serious antimicrobial resistance, discovering novel antibiotics has grown impendency. The Antarctic abundant microbial resources, especially fungi, can produce unique bioactive compounds for adapting to the hostile environment. In this study, three Antarctic fungi, Chrysosporium sp. HSXSD-11-1, Cladosporium sp. HSXSD-12 and Acrostalagmus luteoalbus CH-6, were found to have the potential to produce antimicrobial compounds. Furthermore, the crude extracts of CH-6 displayed the strongest antimicrobial activities with 72.3-84.8% growth inhibition against C. albicans and Aeromonas salmonicida. The secondary metabolites of CH-6 were researched by bioactivity tracking combined with molecular networking and led to the isolation of two new α-pyrones, acrostalapyrones A (1) and B (2), along with one known analog (3), and three known indole diketopiperazines (4-6). The absolute configurations of 1 and 2 were identified through modified Mosher's method. Compounds 4 and 6 showed strong antimicrobial activities. Remarkably, the antibacterial activity of 6 against A. salmonicida displayed two times higher than that of the positive drug Ciprofloxacin. This is the first report to discover α-pyrones from the genus Acrostalagmus, and the significant antimicrobial activities of 4 and 6 against C. albicans and A. salmonicida. This study further demonstrates the great potential of Antarctic fungi in the development of new compounds and antibiotics.

Ubiquitin-specific peptidase 10 ameliorates hepatic steatosis in nonalcoholic steatohepatitis model by restoring autophagic activity.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a critical event in the progression of nonalcoholic fatty liver disease (NAFLD). Steatosis induces lipotoxicity, driving the transition of simple fatty liver (NAFL) to NASH. Autophagy affects NAFLD by improving steatosis. AIM: To investigate whether ubiquitin-specific peptidase (USP)10 alleviates hepatic steatosis through autophagy. METHODS: A methionine-choline-deficient diet (MCDD) and choline-deficient diet (CDD) were used to model rodent NASH and NAFL, respectively. HepG2 cells were treated with palmitic acid to model hepatocellular steatosis. A viral carrier was used to regulate the USP10 level. Real-time fluorescence quantitative polymerase chain reaction, western blotting, histology, and electron microscopy were used to detect autophagic activity and steatosis. RESULTS: In vivo, a time-dependent correlation of USP10 and autophagic activity in the liver was found during NAFLD (including NAFL and NASH) modeling. After 8 weeks of modeling, the autophagic activity of NASH was lower than that of the healthy controls and those with NAFL. USP10 could promote autophagy-related pathways and molecules and increase the synthesis of autophagosomes in NASH, improving steatosis, inflammation, and fibrosis. In vitro, autophagy inhibitors reversed the lipid-lowering effect of USP10 without decreasing the level of fatty acid ß-oxidation. CONCLUSION: USP10 ameliorated histological steatosis, inflammation, and fibrosis. USP10 alleviated hepatic steatosis in NASH in an autophagy-dependent manner.

Self-developed NF-κB inhibitor 270 protects against LPS-induced acute kidney injury and lung injury through improving inflammation.

Sepsis-induced acute kidney injury (AKI) and acute lung injury (ALI) have high morbidity and mortality, with no effective clinically available drugs. Anti-inflammation is effective strategy in the therapy of AKI and ALI. NF-κB is a target for the development of anti­inflammatory agents. The purpose of the study is to evaluate the effect of 270, self-developed NF-κB inhibitor, in LPS-induced AKI and ALI. LPS-induced macrophages were used to examine the anti-inflammation activity of 270 in vitro. Sepsis-induced AKI and ALI mice models were established by intraperitoneal injection of LPS (10 mg/kg) for 24 h. Oral administration 270 for 14 days before LPS stimulation. Plasma, kidney and lung tissues were collected and used for histopathology, biochemical assay, ELISA, RT-PCR, and western blot analyses. In vitro, we showed that 270 suppressed the inflammation response in LPS-induced RAW 264.7 macrophages and bone marrow derived macrophages. In vivo, we found that 270 ameliorated LPS-induced AKI and ALI, as evidenced by improving various pathological changes, reducing the expression of pro-inflammation genes, blocking the activation of NF-κB and JNK pathways, attenuating the elevated myeloperoxidase (MPO) activity and malondialdehyde (MDA) content, ameliorating the activated ER stress, reversing the inhibition effect on autophagy in kidney and lung tissues, and alleviating the enhanced plasma level of creatinine (Crea), blood urea nitrogen (BUN) and pro-inflammation cytokines. Our investigations provides evidence that NF-κB inhibitor 270 is a potential drug that against LPS-induced AKI and ALI in the future.

Human immune repertoire in hepatitis B virus infection.

Hepatitis B virus (HBV) infection is a public health threat that affects 257 million people worldwide and can progress to liver cirrhosis, liver failure, and hepatocellular carcinoma. The HBV antigen- induced adaptive immune response plays an important role in HBV clearance. Immune repertoire sequencing (IRS) has been used to investigate the molecular mechanisms behind the immune system, find novel ways to treat HBV infection, and evaluate the genetic responses and immune characteristics of individuals infected by HBV or immunized by HBV vaccine. This review summarizes the human immune repertoire analysis methodology, and the application of the IRS in the prediction of HBV infection progression, treatment, and vaccination.

Tenofovir disoproxil fumarate in Chinese chronic hepatitis B patients: Results of a multicenter, double-blind, double-dummy, clinical trial at 96 weeks.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is a prodrug of a nucleotide analogue. As an antiviral drug, TDF has been proposed in the first-line treatment of chronic hepatitis B (CHB). Qingzhong, a brand name of TDF, commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd., and Viread, another brand name of TDF, commercialized by GlaxoSmithKline, have both been approved by the State Food and Drug Administration, China. AIM: To investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients. METHODS: This trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857. A total of 330 Chinese CHB patients, among which 232 were hepatitis B e antigen (HBeAg)-positive, were included in this 5-year-long, multicenter, double-blinded, double-dummy, randomized-controlled, non-inferiority phase III trial. The participants were initially randomized into two groups: Group A (n = 161), in which the participants received 300 mg Qingzhong once a day for 48 wk; and Group B, in which the participants received 300 mg Viread once a day for 48 wk. Starting from week 49, all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96th week. In this study, the primary endpoint was the decrease in plasma level of hepatitis B virus (HBV) DNA at the 96th week, while the secondary endpoints were suppression of HBV replication, alanine aminotransferase (ALT) normalization, HBeAg loss, and HBeAg seroconversion rates. RESULTS: For the participants with HBeAg-positive CHB, the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B (5.77 vs 5.73 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA, HBeAg loss, and HBeAg seroconversion (71.05% vs 77.97%, 31.00% vs 27.27%, and 20.22% vs 15.79%, respectively, in Group A vs Group B; P > 0.05). For the participants with HBeAg-negative CHB, the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B (4.46 vs 4.70 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA (87.23% vs 94.12% in Group A vs Group B, respectively; P > 0.05). Finally, similar percentages of CHB patients (HBeAg-positive or HBeAg-negative) in the two groups exhibited normalization of ALT (80.14% vs 84.57% in Group A vs Group B, respectively; P > 0.05), and similar incidences of adverse events were observed (106 vs 104 in Group A vs Group B, respectively; P > 0.05). CONCLUSION: Both Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial.

Sesquiterpenoids From the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The fungal strains Pseudogymnoascus are a kind of psychrophilic pathogenic fungi that are ubiquitously distributed in Antarctica, while the studies of their secondary metabolites are infrequent. Systematic research of the metabolites of the fungus Pseudogymnoascus sp. HSX2#-11 led to the isolation of six new tremulane sesquiterpenoids pseudotremulanes A-F (1-6), combined with one known analog 11,12-epoxy-12ß-hydroxy-1-tremulen-5-one (7), and five known steroids (8-12). The absolute configurations of the new compounds (1-6) were elucidated by their ECD spectra and ECD calculations. Compounds 1-7 were proved to be isomeride structures with the same chemical formula. Compounds 1/2, 3/4, 1/4, and 2/3 were identified as four pairs of epimerides at the locations of C-3, C-3, C-9, and C-9, respectively. Compounds 8 and 9 exhibited cytotoxic activities against human breast cancer (MDA-MB-231), colorectal cancer (HCT116), and hepatoma (HepG2) cell lines. Compounds 9 and 10 also showed antibacterial activities against marine fouling bacteria Aeromonas salmonicida. This is the first time to find terpenoids and steroids in the fungal genus Pseudogymnoascus.

Nitrogenous Compounds from the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The species Pseudogymnoascus is known as a psychrophilic pathogenic fungus which is ubiquitously distributed in Antarctica. While the studies of its secondary metabolites are infrequent. Systematic research of the metabolites of the Antarctic fungus Pseudogymnoascus sp. HSX2#-11 led to the isolation of one new pyridine derivative, 4-(2-methoxycarbonyl-ethyl)-pyridine-2-carboxylic acid methyl ester (1), together with one pyrimidine, thymine (2), and eight diketopiperazines, cyclo-(dehydroAla-l-Val) (3), cyclo-(dehydroAla-l-Ile) (4), cyclo-(dehydroAla-l-Leu) (5), cyclo-(dehydroAla-l-Phe) (6), cyclo-(l-Val-l-Phe) (7), cyclo-(l-Leu-l-Phe) (8), cyclo-(l-Trp-l-Ile) (9) and cyclo-(l-Trp-l-Phe) (10). The structures of these compounds were established by extensive spectroscopic investigation, as well as by detailed comparison with literature data. This is the first report to discover pyridine, pyrimidine and diketopiperazines from the genus of Pseudogymnoascus.

New Polyketides from the Antarctic Fungus Pseudogymnoascus sp. HSX2#-11.

The species Pseudogymnoascus is known as a psychrophilic pathogenic fungus with a ubiquitous distribution in Antarctica. Meanwhile, the study of its secondary metabolites is infrequent. Systematic research of the metabolites of the fungus Pseudogymnoascus sp. HSX2#-11, guided by the method of molecular networking, led to the isolation of one novel polyketide, pseudophenone A (1), along with six known analogs (2-7). The structure of the new compound was elucidated by extensive spectroscopic investigation and single-crystal X-ray diffraction. Pseudophenone A (1) is a dimer of diphenyl ketone and diphenyl ether, and there is only one analog of 1 to the best of our knowledge. Compounds 1 and 2 exhibited antibacterial activities against a panel of strains. This is the first time to use molecular networking to study the metabolic profiles of Antarctica fungi.

Sarsasapogenin improves adipose tissue inflammation and ameliorates insulin resistance in high-fat diet-fed C57BL/6J mice.

Insulin resistance is a major cause of type 2 diabetes and metabolic syndrome. Macrophage infiltration into obese adipose tissue promotes inflammatory responses that contribute to the pathogenesis of insulin resistance. Suppression of adipose tissue inflammatory responses is postulated to increase insulin sensitivity in obese patients and animals. Sarsasapogenin (ZGY) is one of the metabolites of timosaponin AIII in the gut, which has been shown to exert anti-inflammatory action. In this study, we investigated the effects of ZGY treatment on obesity-induced insulin resistance in mice. We showed that pretreatment with ZGY (80 mg·kg-1·d-1, ig, for 18 days) significantly inhibited acute adipose tissue inflammatory responses in LPS-treated mice. In high-fat diet (HFD)-fed obese mice, oral administration of ZGY (80 mg·kg-1·d-1, for 6 weeks) ameliorated insulin resistance and alleviated inflammation in adipose tissues by reducing the infiltration of macrophages. Furthermore, we demonstrated that ZGY not only directly inhibited inflammatory responses in macrophages and adipocytes, but also interrupts the crosstalk between macrophages and adipocytes in vitro, improving adipocyte insulin resistance. The insulin-sensitizing and anti-inflammatory effects of ZGY may result from inactivation of the IKK /NF-κB and JNK inflammatory signaling pathways in adipocytes. Collectively, our findings suggest that ZGY ameliorates insulin resistance and alleviates the adipose inflammatory state in HFD mice, suggesting that ZGY may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.

A cohort study on the relationship between education level and high-risk population of stroke.

Objective: To explore the relationship between education level and high-risk population among stroke screening populations in Zunyi City, China. Methods: The cluster sampling method was adopted to collect the medical history, laboratory examinations and physical examinations for the permanent residents of Zunyi City, Guizhou Province. Taking education level as a key socioeconomic status (SES) indicator, multivariate logistic regression analysis was used to evaluate the risk factors of high-risk groups with different education levels. Results: Among the included 4149 subjects, 494 were in the high-risk group and 3655 were in the non-high-risk group. The proportion of the high-risk population with education level ≥ high secondary school (8.7%) was significantly higher than that of the low-risk population. After adjusting for age, gender, and BMI, the OR of those with education leve l ≥ high secondary school was 2.8 (95% CI 1.9-4.2), which was significantly higher than those with education level of illiterate/primary school. In the model adjusted for all confounding factors, compared with illiterate/primary school, people with education level ≥ high secondary school were more likely to be at high risk of stroke (OR 3.0, 95% CI 1.9-4.6). Conclusion: Education level ≥ high secondary school is an independent influencing factor for the high-risk population of stroke in Zunyi, which may be related to smoking and lipid metabolism abnormalities of people with high education level. Key interventions for high-risk populations with high education levels may have positive significance in reducing the incidence of stroke.

AMPK activator C24 inhibits hepatic lipogenesis and ameliorates dyslipidemia in HFHC diet-induced animal models.

Dyslipidemia is a chronic metabolic disease characterized by elevated levels of lipids in plasma. Recently, various studies demonstrate that the increased activity of adenosine 5'-monophosphate-activated protein kinase (AMPK) causes health benefits in energy regulation. Thus, great efforts have been made to develop AMPK activators as a metabolic syndrome treatment. In the present study, we investigated the effects of the AMPK activator C24 on dyslipidemia and the potential mechanisms. We showed that C24 (5-40 µM) dose-dependently increased the phosphorylation of AMPKα and acetyl-CoA carboxylase (ACC), and inhibited lipogenesis in HepG2 cells. Using compound C, an AMPK inhibitor, or hepatocytes isolated from liver tissue-specific AMPK knockout AMPKα1α2fl/fl;Alb-cre mice (AMPK LKO), we demonstrated that the lipogenesis inhibition of C24 was dependent on hepatic AMPK activation. In rabbits with high-fat and high-cholesterol diet-induced dyslipidemia, administration of C24 (20, 40, and 60 mg · kg-1· d-1, ig, for 4 weeks) dose-dependently decreased the content of TG, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) in plasma and played a role in protecting against hepatic dysfunction by decreasing lipid accumulation. A lipid-lowering effect was also observed in high-fat and high-cholesterol diet-fed hamsters. In conclusion, our results demonstrate that the small molecular AMPK activator C24 alleviates hyperlipidemia and represents a promising compound for the development of a lipid-lowering drug.

Early renal injury indicators can help evaluate renal injury in patients with chronic hepatitis B with long-term nucleos(t)ide therapy.

BACKGROUND: Patients with chronic hepatitis B (CHB) with long-term nucleos(t)ide therapy may experience renal insufficiency. Traditional renal function indicators, such as urine protein, serum urea nitrogen (BUN), and serum creatinine, are normal when early mild lesions occur. Therefore, more sensitive renal function indicators are needed. AIM: To investigate the significance of early renal injury indicators in evaluating renal injury in patients with CHB with long-term nucleos(t)ide therapy. METHODS: We collected the clinical data of 69 outpatients with CHB at Peking University First Hospital from March 2018 to January 2020 who had been treated with long-term nucleos(t)ide therapy and analyzed the results of early renal injury indicators. Continuous normal distribution data were analyzed by the t-test to determine the difference between two groups. Continuous non-normally distributed data were analyzed by the Mann-Whitney U-test between two groups. The Kruskal-Wallis H test was used to determine the differences among multiple groups. Enumeration data were analyzed by the chi-square test. The related factors of early renal injury indicators were analyzed by logistic regression analysis. RESULTS: The average treatment duration with nucleos(t)ide analogs of the 69 patients with CHB was 99.7 ± 28.7 mo. The cases of patients with elevated BUN and hypophosphatemia were 6 (8.7%) and 13 (18.8%), respectively; 31 (44.9%) patients had abnormal early renal injury indicators, including 9 patients with abnormal urine microalbumin, 7 patients with abnormal urine immunoglobulin, 6 patients with abnormal urine transferrin, and 19 patients with abnormal α1 microglobulin. There were no significant differences in the mean values of age, sex, BUN, estimated glomerular filtration rate (eGFR), serum uric acid, serum calcium, or serum phosphorus between the two groups of patients with and without early renal injury indicators. However, the mean levels of serum creatinine and urine creatinine, N-acetyl-ß-D-glucosidase enzyme, α1 microglobulin, and urine immunoglobulin in the former group of patients were significantly higher than those in the latter group of patients (P < 0.05). The incidence of early renal injury in patients with eGFR ≥ 90, 60-89, and 30-59 mL/(min·1.73 m2) was 36.4% (8/22), 47.6% (20/42), and 60% (3/5), respectively. Logistic regression analysis results showed that gamma-glutamyl transpeptidase [odds ratio (OR) = 1.05 (1.008-1.093), P = 0.020], direct bilirubin [OR = 1.548 (1.111-2.159), P = 0.010], serum creatinine [OR = 1.079 (1.022-1.139), P = 0.006], and age [OR = 0.981 (0.942-1.022), P = 0.357] were independent predictors of early renal injury. CONCLUSION: Patients with CHB treated with long-term nucleos(t)ide analog therapy had a high probability of early renal injury, and early renal injury indicators were highly sensitive and could be used to monitor early renal impairment.

[Expression and clinical significance of runt-related transcription factor 3 in children with bronchiolitis].

OBJECTIVE: To study the mRNA level of runt-related transcription factor 3 (RUNX3) in children with bronchiolitis and its clinical significance in bronchiolitis. METHODS: A total of 54 young children with bronchiolitis were enrolled as the bronchiolitis group, among whom 28 with atopic constitution were enrolled in the atopic bronchiolitis group and 26 with non-atopic constitution were enrolled in the non-atopic bronchiolitis group. A total of 48 healthy young children were enrolled as the healthy control group, among whom 24 with atopic constitution were enrolled in the atopic healthy control group and 24 with non-atopic constitution were enrolled in the non-atopic healthy control group. Quantitative real-time PCR was used to measure the mRNA level of RUNX3 in peripheral blood mononuclear cells. ELISA was used to measure the serum levels of interleukin-4 (IL-4) and interferon gamma (IFN-γ). RESULTS: The bronchiolitis group had a significantly lower mRNA level of RUNX3 than the healthy control group, and the atopic bronchiolitis group had a significantly lower mRNA level of RUNX3 than the non-atopic bronchiolitis, atopic healthy control, and non-atopic healthy control groups (P<0.05). The bronchiolitis group had a significantly higher serum level of IL-4 than the healthy control group, and the atopic bronchiolitis group had a significantly higher serum level of IL-4 than the non-atopic healthy control group (P<0.05). The bronchiolitis group had a significantly lower serum level of IFN-γ than the healthy control group, and the atopic bronchiolitis group had a significantly lower serum level of IFN-γ than the non-atopic bronchiolitis, atopic healthy control, and non-atopic healthy control groups (P<0.05). The correlation analysis showed that the mRNA level of RUNX3 was negatively correlated with the serum level of IL-4 and was positively correlated with the serum level of IFN-γ (P<0.05). CONCLUSIONS: Measurement of RUNX3 gene expression in peripheral blood mononuclear cells has a certain value in identifying children with atopic constitution at high risk of asthma among children with bronchiolitis.

Bilateral high-frequency hearing loss is associated with elevated blood pressure and increased hypertension risk in occupational noise exposed workers.

OBJECTIVE: To investigate the association of bilateral high-frequency hearing loss (BHFHL) with blood pressure and hypertension among occupational noise exposed workers. METHODS: Occupational noise exposed workers were enrolled in 2017 from the occupational diseases survey of Chengdu. BHFHL was classified as normal, mild, or high by the bilateral high-frequency tone average. Linear regression model was used to assess the effects of occupational noise exposure time and BHFHL on blood pressure. Logistic regression model was performed to estimate hypertension risk odds ratios (ORs) associated to occupational noise exposure time and BHFHL. RESULTS: Increasing years of occupational noise exposure and BHFHL were significantly associated with systolic and diastolic blood pressure increase (all P<0.001). The lineal trend was only significant in males, with adjusted ORs for hypertension gradually increasing with increasing years of occupational noise exposure (P<0.001). Furthermore, subjects having mild and high BHFHL had a higher hypertension risk of 34% and 281%, respectively (both P<0.001). Dose-response relationship between BHFHL and hypertension was found in both males and females. CONCLUSIONS: Occupational noise exposure was positively associated with blood pressure levels and hypertension risk.