Progresses on genetic susceptibility of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a broad clinical spectrum of coronavirus disease 2019 (COVID-19). Genetic factors might influence susceptibility to the SARS-CoV-2 infection or disease severity. Genome-wide association studies (GWASs) have identified multiple susceptible genes related to COVID-19 phenotypes, providing the scientific basis for the COVID-19 prevention and treatment. In this review, we summarize the recent progresses of COVID-19 susceptible genes, including the GWASs on multiple phenotypes of COVID-19, GWASs of COVID-19 in multiple ethnic populations, GWASs of COVID-19 based on multiple types of genetic variations, and the fine-mapping of the regions surrounding the susceptible genes.

[Total alkaloids of Coptidis Rhizoma combined with exercise inhibits tumor growth of orthotopically transplanted 4T1 breast cancer mice by blocking cell cycle G_1/S transformation].

Breast cancer is one of the leading causes for cancer-related death among women worldwide. Coptidis Rhizoma has antibacterial,anti-inflammatory,anti-tumor and other pharmacological activities,but whether exercise could synergistically promote the role of RC in the treatment of breast cancer has not been reported. In this experiment,the effects and mechanism of total alkaloids of Coptidis Rhizoma combined with exercise on the tumor growth of orthotopically transplanted 4 T1 breast cancer were systemically studied in mice. Balb/C mice transplanted with 4 T1 cells in situ were used as models. The total alkaloids of RC(145 mg·kg-1·d-1) alone or in combination with exercise(10 m·min-1,30 min/time,5 times/week) were given for 28 days,and then the changes in body weight and tumor volume,tumor weight,interleukin-1ß(IL-1ß),serum estradiol(E2) content,and expression levels of estrogen receptor α(ERα),cell cycle related proteins CDK4,CDK6,cyclin D1,CDK2,and cyclin E in tumor tissues. The results showed that total alkaloids of Coptidis Rhizoma could significantly inhibit the growth of 4 T1 breast cancer in mice(P< 0. 01),and exercise significantly promoted the anti-tumor activity of total alkaloids of Coptidis Rhizoma(P<0. 01),and reduced E2 and IL-1ß levels in mice. Western blot and flow cytometry showed that the total alkaloids of Coptidis Rhizoma combined with exercise could down-regulate the protein expression levels of ERα,CDK4,CDK6,cyclin D1,CDK2 and cyclin E in cancer cells,block the transformation of G1/S in 4 T1 cell cycle,and inhibit DNA synthesis in breast cancer cells. The total alkaloids of Coptidis Rhizoma combined with exercise showed synergistic effect in inhibition of tumor growth in mice with orthotopically transplanted 4 T1 breast cancer.

[Research advances on medical genetics in China in 2015].

Steady progress has been achieved in the medical genetics in China in 2015, as numerous original researches were published in the world's leading journals. Chinese scientists have made significant contributions to various fields of medical genetics, such as pathogenicity of rare diseases, predisposition of common diseases, somatic mutations of cancer, new technologies and methods, disease-related microRNAs (miRNAs), disease-related long non-coding RNAs (lncRNAs), disease-related competing endogenous RNAs (ceRNAs), disease-related RNA splicing and molecular evolution. In these fields, Chinese scientists have gradually formed the tendency, from common variants to rare variants, from single omic analyses to multipleomics integration analyses, from genetic discovery to functional confirmation, from basic research to clinical application. Meanwhile, the findings of Chinese scientists have been drawn great attentions of international peers. This review aims to provide an overall picture of the front in Chinese medical genetics, and highlights the important findings and their research strategy.

UPLC-MS metabolomics method provides valuable insights into the effect and underlying mechanisms of Rhizoma Drynariae protecting osteoporosis.

Osteoporosis (OP) is a metabolic bone disease in which that volume of bone tissue per unit volume decrease, which is a common disease disturbing the elderly or postmenopausal women. Rhizoma Drynariae (RD) is a kind of herb widely used in thousands of years of clinical practice in China to tonify kidney and prevent osteoporosis, with reliable curative effect. However, the mechanism of its anti-osteoporosis action is still unclear. This study is dedicated to exploration the therapeutic effect of RD on retinoic acid solution-induced OP model rats based on high-throughput metabolomics technology platform, and reveal its influence on metabolomics level, so as to find effective potential biomarkers and therapeutic targets for diagnosing OP. OP model was established by intragastric administration of retinoic acid solution for 21 days, and then the treatment group was treated by intragastric administration of RD solution for 60 days. Blood samples of all groups were collected and analyzed based on UPLC-MS metabolomics and combined with EZinfo 3.0 data analysis, 32 potential biomarkers were identified, including 22 in ESI+ and 10 in ESI-, these biomarkers are related to 9 metabolic pathways. After treatment with RD solution, 21 biomarkers were obviously regulated, these mainly affected linoleic acid metabolic, glycerophospholipid metabolism and arachidonic acid metabolism pathway. The results show that RD can reduce the risk of OP disease, which may be related to the metabolic pathway mentioned above, and provides the foundation for the administer prophylaxis and treatment of OP with natural products.

Comparative metabolomics unveils molecular changes and metabolic networks of syringin against hepatitis B mice by untargeted mass spectrometry.

Untargeted metabolomics technology was used to discover the metabolic pathways and biomarkers for revealing the potential biological mechanism of syringin on hepatitis B virus. Serum samples were analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based comparative metabolomics coupled with pattern recognition methods and network pathway. In addition, the histopathology, HBV DNA detection of liver tissue, and biochemical indicators of liver function change were also explored for investigating the antiviral effect of syringin. In comparison to the model group, the metabolic profiles of the turbulence in transgenic mice tended to recover to the same as the control group after syringin therapy. A total of 33 potential biomarkers were determined to explore the metabolic disorders in the hepatitis B animal model, of which 25 were regulated by syringin, and 8 metabolic pathways, such as phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, glyoxylate and dicarboxylate metabolism, were involved. Syringin markedly reduced the liver pathology change, inhibited HBV DNA replication, and improved liver function. Amino acid metabolism is a potential target for the treatment of hepatitis B. The hepatoprotective effect of syringin may contribute to ameliorating oxidative stress and preventing protein and DNA replication. Comparative metabolomics is a promising tool for discovering metabolic pathways and biomarkers of the hepatitis B animal model as targets to reveal the effects and mechanism of syringin, which benefits the development of natural products and advances the treatment of diseases.

[Effects of butyl benzyl phthalate on neurobehavioral development of rats].

OBJECTIVE: To study the effects of butyl benzyl phthalate on neurobehavioral development of rats. METHODS: Levels of 0 (control), 0.05%, 0.25%, and 0.75% butyl benzyl phthalate (BBP) was given in the diet from 4 weeks of age of female F0 generation to 6 weeks of age of F1 generation in Wistar rats, including the period of the female F0 generation's mating, gestation and lactation and the F1 generation's growth and development. Selected parameters of neurobehavioral development were observed in F1 generation. RESULTS: (1)For the male F(1) generation, surface righting at postnatal (PND) 4 th day was significantly delayed in the low-dose group (P < 0.05) (scoring: 56 vs 61), cliff avoidance at PND 7 was significantly depressed in the high-dose group (P < 0.05) (scoring: 41), air righting at PND 14 was significantly depressed in all treatment groups (P < 0.05). In open field test, low- and high-dose groups moved more than control group (P < 0.05). In Morris water maze test, the escape latency was significantly delayed in the low-dose group at the 5th day of the 5 days' place navigation task (P < 0.05). (2) For the female F1 generation, there were no differences among groups in any parameter in the experiment (P > 0.05). CONCLUSION: BBP may affect the neurobehavioral development only in male rats in the F1 generation.

Metabolomic estimation of the diagnosis of hepatocellular carcinoma based on ultrahigh performance liquid chromatography coupled with time-of-flight mass spectrometry.

Metabolomics has been shown to be an effective tool for biomarker screening and pathway characterization and disease diagnosis. Metabolic characteristics of hepatocellular carcinoma (HCC) may enable the discovery of novel biomarkers for its diagnosis. In this work, metabolomics was used to investigate metabolic alterations of HCC patients. Plasma samples from HCC patients and age-matched healthy controls were investigated using high resolution ultrahigh performance liquid chromatography-mass spectrometry and metabolic differences were analyzed using pattern recognition methods. 23 distinguishable metabolites were identified. The altered metabolic pathways were associated with arginine and proline metabolism, glycine, serine and threonine metabolism, steroid hormone biosynthesis, starch and sucrose metabolism, etc. To demonstrate the utility of plasma biomarkers for the diagnosis of HCC, five metabolites comprising deoxycholic acid 3-glucuronide, 6-hydroxymelatonin glucuronide, 4-methoxycinnamic acid, 11b-hydroxyprogesterone and 4-hydroxyretinoic acid were selected as candidate biomarkers. These metabolites that contributed to the combined model could significantly increase the diagnostic performance of HCC. It has proved to be a powerful tool in the discovery of new biomarkers for disease detection and suggest that panels of metabolites may be valuable to translate our findings to clinically useful diagnostic tests.

Protective effect of Coptisine from Rhizoma Coptidis on LPS/D-GalN-induced acute liver failure in mice through up-regulating expression of miR-122.

Coptisine (COP), one of the main active ingredients of Rhizoma Coptidis, reportedly has anti-inflammatory, anti-colon cancer properties, but it remains elusive whether COP owns hepatoprotective activity. Mice were pretreated with COP for 7d prior to lipopolysaccharide/d-galactosamine (LPS/D-GalN) administration to detect the hepatic protective effects of COP. The mechanism was explored in using HepG2 cells with low level of miR-122 and LO2 cells with high level of miR-122, combining with miR-122 agomir transfection by means of detecting the expression of miR-122 and proteins, clinical index and apoptosis. COP ameliorated the LPS/D-GalN-induced liver failure by lowering serum levels of ALT and AST, raising hepatic GSH and SOD levels, and maintaining the morphology of hepatocytes, along with an increase in miR-122 expression in mice. The results in vitro indicated that, after miR-122 mimic administration, the alone treatment of COP and the co-treatment of COP and LPS transfection obviously promoted the apoptosis of HepG2, which was increased by 152.67% and 113.97% compared with NC (P < 0.05 vs NC). LPS significantly induced the apoptosis of L02 cells, but COP treatment attenuated that of L02 cells. Further analysis showed that COP increased the miR-122 level and the expression of Bax, cleaved-casp3 and decreased Bcl-2, Bcl-xL in LPS-treated HepG2 cells. COP increased the miR-122 level but decreased the expression of TLR4, Bcl-2, Bcl-xL in LPS-treated L02 cells. COP attenuated LPS/D-GalN-induced ALF by up-regulating the level of miR-122, synergistically promoting apoptosis, and suggesting COP which showed a potential protective effect on ALF.

Coptisine from Rhizoma coptidis exerts an anti-cancer effect on hepatocellular carcinoma by up-regulating miR-122.

With increasing incidence and mortality, hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. In this study, microRNA-122 (miR-122) mimics and relevant control oligonucleotides were transfected into HepG2 cells in vitro, followed by coptisine (COP) and sorafenib treatments. Cell proliferation, migration, and apoptosis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay, wound-healing assay, Hoechst 33258 staining and flow cytometry, respectively. Histopathology and miR-122 were analyzed by haemotoxylin and eosin (H&E) staining and real-time RT-PCR, respectively; whereas, the relevant protein expressions were detected by western blot. In vivo, COP enhanced the expression of miR-122 by 160% compared to control in male BALB/c nude mice; COP not only protected the liver morphology but also showed a significant anti-cancer effect. Further, there was no remarkable difference between the tumor weights in the COP and sorafenib groups, but there was a striking difference to the tumor control group (p < 0.05). Hence, COP inhibited the proliferation, migration and promoted apoptosis of HCC cells; moreover, it inhibited the tumor growth in nude mice by up-regulating the expression of miR-122.

[Protective effect of melatonin on oxidative damage by deltamethrin in rat brain].

OBJECTIVE: To study the potential protective effect of melatonin on the oxidative damage induced by deltamethrin in cerebral cortex, hippocampus and cerebellum of rats. METHODS: 35 male wistar rats were randomly divided into five groups(seven rats per group): olive oil control, deltamethrin-treated (12.5 mg/kg), melatonin(25.0 mg/kg) and deltamethrin plus melatonin (25.0 mg/kg , 2.5 mg/kg respectively) group. Levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione (GSH) in cerebral cortex, hippocampus and cerebellum were determined after 5 days of DM treatments. RESULTS: MDA content in cerebral cortex, hippocampus and cerebellum tissue of the DM-treated rats were significantly higher than those in control group, and compared with DM-treated group, MDA content in those tissue of MT + DM-treated group have significantly decreased after 5 days of DM exposure (P < 0.05). Activities of GSH-Px in DM-treated group were significantly lower than those in control group, and those in the MT + DM group were significantly higher than DM group(P < 0.05). CONCLUSION: DM can induce the oxidative damage in rat brain and melatonin has protective effects on deltamethrin-induced oxidative damage in hippocampus, cerebral cortex and cerebellum of rats.

Synthesis of novel 4'-acylamino modified 21E-benzylidene steroidal derivatives and their cytotoxic activities.

A series of 4'-acylamino modified Δ1,4-pregnadien-21E-benzylidene-3,20-dione derivatives (6a-v) was synthesized from the commercially available progesterone (1). These title compounds were evaluated for their toxicity against brine shrimp (Artemia salina) and cytotoxic activities against two human cancer cell lines (HeLa and MCF-7). The results revealed that compound 6f exhibited promising in vitro cytotoxic activity to the two cancer cell lines and the nature of acylamino functional group in the benzylidene moiety had a significant influence on cytotoxicity.

[Toxicity and oxidative stress on rats by hexachlorobenzene].

OBJECTIVE: To study the toxicity on rats by hexachlorobenzene (HCB), and to explore the role of oxidative stress in the mechanism of HCB intoxication. METHODS: SD female rats were fed on a powdered diet containing 0.25 per thousand or 2.00 per thousand HCB for 14 days. The content of malondialdehyde (MDA) and the activity of total-superoxide dismutase (T-SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in cerebral cortex, hippocampus, liver tissue and serum were determined. Eleven biochemical indicators including alkaline phosphatase (ALP) were surveyed. RESULTS: (1) MDA levels in cerebral cortex, hippocampus, liver and serum of the high dosage group rats and that in hippocampus and serum of the low dosage group were significantly higher than that of the control group. (2) The activity of T-SOD was increased in cerebral cortex and hippocampus of the rats in both groups (P < 0.01), but decreased in the serum of the high dosage group (P < 0.01). (3) The activity of CAT was also increased in the hippocampus of rats in the high dosage group. (4) In cerebral cortex and hippocampus of the rats in the high dosage group and in the hippocampus of the rats in the low dosage group, the activity of GSH-PX was significantly higher compared with the control group. However, in liver of both dosage groups, the activity of GSH-PX was decreased (P < 0.01). (5) The activity of serum alkaline phosphatase of both dosage groups was also decreased, but the contents of both serum albumin and total cholesterol were significantly higher than those of the control group (P < 0.01). CONCLUSION: HCB can induce enhanced lipid peroxidation on SD rats, and the oxidative stress plays an important role in the mechanism of neurotoxicity and hepatotoxicity.

Prognostic Significance of Dickkopf-1 in Gastric Cancer Survival: A Meta-Analysis.

AIMS: The prognostic role of dickkopf-1 (DKK1) in gastric cancer (GC) remains poorly characterized. We performed a meta-analysis to evaluate correlations between DKK1 overexpression and the prognosis of patients with GC. MATERIALS AND METHODS: We included five published studies to assess the relationship between DKK1 and the clinicopathological characteristics and overall survival of GC patients. Literature searches, article selection, data collection, and statistical analysis were performed using RevMan 5.3 software. RESULTS: Our analyses revealed that DKK1 overexpression was significantly associated with vascular invasion (odds ratio [OR] = 2.43, 95% confidence interval [CI] = [1.21, 4.89], p = 0.01, random effect), lymphatic invasion (OR = 2.61, 95% CI = [1.30, 5.24], p = 0.007, random effect), and distant metastasis (OR = 2.99, 95% CI = [1.95, 4.59], p < 0.00001, fixed effect). Moreover, we also found that DKK1 overexpression was significantly associated with poor overall survival in GC patients (risk ratio = 2.67, 95% CI = [2.24, 3.48], p < 0.00001, fixed effect). CONCLUSION: This meta-analysis demonstrated that DKK1 may be a useful prognostic marker for GC.

Reduction of preanalytical errors in laboratory by establishment and application of training system.

OBJECTIVES: Errors in preanalytical phase occupied for almost half of total errors in clinical laboratory, and the causes are related to medical staff's quality awareness and behaviors. In order to reduce the preanalytical errors in our hospital, we established and applied a training system to improve the situation. METHODS: The disqualified sample types and major causes of errors in the preanalytical phase were investigated in clinical laboratory department from September 2008 to August 2009. In the following year, we established and applied a training system to affect the quality awareness and behaviors of medical staff. Questionnaire investigation was analyzed to illustrate the changes of respondents' quality awareness and behavior, and the preanalytical errors were reanalyzed according to different departments to evaluate the effects of the intervention measures. RESULTS: The total disqualification rate in the preanalytical phase obtained from September 2008 to August 2009 was 1.36%, and the major types of disqualified samples were coagulation of anticoagulant sample, sample inadequacy, sample container error, sample information error, and sample type error. After application of established training system, respondents' quality awareness on preanalytical samples changed dominantly, and respondents' own behavior and behavior to others also changed notably. The total disqualification rate in preanalytical phase dropped to 0.94%, among 33 clinical departments, the preanalytical errors in 25 departments decreased to various degrees, and 10 departments had overall decreasing amplitude over 50%. CONCLUSIONS: The overall effect of the application of established training system is very good, and the disqualification rate of the major departments decrease to various degrees.