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Objective:To explore the protective effect of AGK2, a selective inhibitor of sirtuin 2 (SIRT2), on the mitochondria of L02 hepatocytes induced by thioacetamide (TAA) and its related mechanism.Methods:Human-derived hepatocyte line L02 cells were cultured in vitro. Different concentrations of SIRT2 inhibitor AGK2 were used as intervention drugs. Cell counting kit-8 (CCK8) was used to detect the effects of different concentrations of AGK2 on the activity of L02 cells, and the appropriate concentration was selected as the AGK2 intervention group. The normal group was not given any drug intervention. The model group was given 90 mmol/L TAA for modeling. Low, medium and high dose AGK2 groups were added with 1, 2 and 4 μmol/L AGK2, respectively 2 h before modeling. CCK8 was used to detect cell activity in each group. Morphological changes of cells were observed under inverted light microscope. The relative protein expression levels of isocitrate dehydrogenase (IDH1), malate dehydrogenase (MDH1), SIRT2 and fission protein 1 homologue (FIS1) were detected by Western blot. The expression of SIRT2 in cells of each group was observed by confocal laser scanning microscope. The mitochondrial membrane potential of cells in each group was observed under a fluorescence microscope. Results:When AGK2 concentration was 1, 2 and 4 μmol/L, the survival rate of cells were 98.05%, 95.76% and 91.65%, respectively, with no statistical significance compared with normal group (all P>0.05). When AGK2 concentration was 8, 16, 32, 64, 128 μmol/L, the cell survival rate was significantly decreased compared with normal group (all P<0.05). Compared with the model group, the L02 cells in low, medium and high AGK2 groups had better activity and adherence, and the floating cells were significantly reduced. The higher the concentration of AGK2, the better the cell activity and adherence, and the less floating cells. Compared with the model group, the red fluorescence of L02 cells in AGK2 group was enhanced, while the green fluorescence was weakened. The higher the AGK2 concentration was, the stronger the red fluorescence was, and the weaker the green fluorescence was. Compared with the model group, the fluorescence of SIRT2 in L02 cells of low, medium and high AGK2 groups was weakened, and the higher the concentration of AGK2, the weaker the fluorescence of SIRT2. The protein expressions of IDH1 and MDH1 in L02 cells of low, medium and high AGK2 groups were significantly higher than those of model group (all P<0.05), and were positively correlated with the concentration of AGK2 ( r=0.818, P<0.05; r=0.960, P<0.05); the protein expressions of SIRT2 and FIS1 were significantly lower than those of the model group (all P<0.05), and were negatively correlated with the concentration of AGK2 ( r=-0.992, P<0.05; r=-0.998, P<0.05). Conclusions:AGK2 can reduce the mitochondrial membrane potential stimulated by TAA in L02 cells, increase the protein expression of IDH1 and MDH1, and inhibit the protein expression of SIRT2 and FIS1 in L02 cells in a dose-dependent manner.
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Novel coronavirus Omicron variant infection can cause severe illness and even death in certain populations. Omicron variant infection may lead to systemic inflammatory response, coagulation disorder, multi-organ dysfunction and other pathophysiological changes, which are different from other Novel coronavirus variants to a certain extent, so therapeutic strategies should not be the same. The National Medical Center for Major Public Health Events invited experts in fields of infectious diseases, respiratory medicine, intensive care, pediatrics and fever clinic to develop this quick guideline based on the current best evidence and extensive clinical practices. This quick guideline aims to standardize the diagnosis and treatment of novel coronavirus Omicron infection, and to improve the disease management abilities of clinicians.
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The liver is the main place for metabolism in human body, and when severe liver injury is induced by various factors, there will be disorders in the functions of synthesis, metabolism, and biological conversion. This article summarizes the features of the metabolism of nutrients such as glucose, amino acids, and lipids in the presence of liver failure, as well as the assessment of malnutrition and clinical interventions. For patients with liver failure, it is of great importance to identify and correct malnutrition in a timely manner, so as to improve energy metabolism and inflammation and increase survival rate.
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Liver failure is a familiar severe disease, with no good clinical early diagnostic indicators and treatment methods. Studies have shown that non-encoding RNA (ncRNA) characterized by microRNA (miRNA) and long non-coding RNA (lncRNA) can be used not only as an early diagnostic indicator of liver failure, but also play a key regulatory role in an inflammatory response to liver failure, hepatocyte death and hepatocyte regeneration. Simultaneously, the epigenetic regulation of ncRNA also participates in the initiation and progression of liver failure. This article reviews the relationship between miRNA, lncRNA, and liver failure to find new targets for the diagnosis and treatment of liver failure.
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Objective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.
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Objective@#To investigate the protective effect of ACY1215 (Rocilinostat), a histone deacetylase inhibitor, against brain edema in mice with acute liver failure.@*Methods@#Lipopolysaccharide combined with D-galactosamine was used to establish a mouse model of acute liver failure, and ACY1215 was used for intervention. The effect of ACY1215 on histopathological changes of the liver was observed after 24 hours, as well as the changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood ammonia, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), brain water content, blood-brain barrier structure, NF-κB-p65, histone, acetylated histone, and TNF-α mRNA in brain tissue.@*Results@#The mice with acute liver failure had marked pathological damage in liver tissue, as well as significant increases in the levels of ALT, AST, blood ammonia, TNF-α, and IFN-γ (t≥5.367, all P < 0.05). ACY1215 significantly improved the pathological damage in liver tissue and reduced the serum levels of ALT, AST, blood ammonia, TNF-α, and IFN-γ (t≤-3.515, all P < 0.05). ACY1215 also significantly reduced the expression of NF-κB-p65 (t = -5.871, P = 0.004) and the mRNA expression of TNF-α (t = -11.913, P < 0.01) in brain tissue and brain water content (t = -2.355, P < 0.01). According to the results of electron microscopy, the model group had an abnormal blood-brain barrier structure, and the ACY1215 group had slighter damage than the model group. Compared with the normal group, the model group had significant increases in the acetylation level of histone H3 and H4 in brain tissue (t≥3.009, both P < 0.05), while ACY1215 further upregulated the acetylation levels of histone H3 and H4 (t≥6.682, both P < 0.05).@*Conclusion@#ACY1215 exerts a protective effect against brain edema in mice with acute liver failure, possibly by regulating histone acetylation and inhibiting inflammation.
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Objective@#To observe the therapeutic efficacy of alanyl glutamine injection on patients with gastrointestinal function obstacle caused by severe phorate poisoning.@*Methods@#A total of 80 eligible patients with gastrointestinal function obstacle caused by severe phorate poisoning were randomly divided into the control group (n=40) and treatment group (n=40) . The control group was treated with the conventional therapy, which included forbidden diet, atropine, pralidoxime iodide, anti-inflammatory, albumin infusion, ω-3 fish oil fat emulsion, protection of organs function, blood perfusion, and Fat Emulsion, Amino Acids (17) and Glucose Injection. The treatment group was treated with alanyl glutamine injection plus the conventional therapy. To observe the time of recovering to normal of gastrointestinal function between the two groups, compared the AChE activity and changes of prealbumin, albumin and total protein of the two groups respectively. Furthermore, the total atropine dosage, the total pralidoxime iodide dosage and ICU stay time between the two groups were also compared.@*Results@#The gastrointestinal function recovery time of patients in the treatment group was less than the control group, the difference was statistically significant (P<0.05) . From the third day of treatment, the serum cholinesterase activity of the treatment group was higher than the control group, the difference was statistically significant (P<0.05) . On the 5th day and 10th day of the treatment, the prealbumin, albumin and total protein of the treatment group were significantly higher than these indexes of the control group in the same period, the difference were statistically significant (P<0.05) . The total atropine dosage, the total pralidoxime iodide dosage and ICU stay time in the treatment group were lower than the control group, the difference were statistically significant (P<0.05) .@*Conclusion@#Alanyl glutamine injection has a great therapeutic effect for gastrointestinal function obstacle patients caused by severe phorate poisoning.
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Antiviral therapy is the most important thing in the treatment of chronic hepatitis B (CHB). Pegylated interferon (PEG-IFN) has both antiviral and immunomodulatory effects, and after drug withdrawal, 30%-40% of patients can achieve HBeAg seroconversion and sustained virologic response. Many studies have shown that HBsAg quantification can be used as an index to predict the anti-HBV effect of PEG-IFN and sustained immune control after drug withdrawal. This article reviews the relationship between HBsAg levels before, during, and after PEG-IFN therapy and antiviral effect to clarify the significance of HBsAg quantification in the PEG-IFN treatment of CHB and to guide the regimen of antiviral therapy.
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Objective To investigate the effect of MS-275, an histone deacetylase ( HDAC ) inhibitor, on acute liver failure ( ALF ) induced by D-galactosamine and lipopolysaccharide in mice. Methods Thirty specific pathogen free (SPF) C57BL/6 male mice were randomly and equally divided into control, ALF model and MS-275 groups. ALF model was induced by D-galactosamine ( D-Gal ) and lipopolysaccharide (LPS), and the mice in MS-275 group received MS-275 (1 mg/kg) at 2 h before the induction of ALF.Serum and liver samples of mice were obtained at 24 h after ALF induction.The serum levels of ALT, AST, TBil and tumor necrosis factor-alpha ( TNF-α) , interferon γ( IFNγ) , interleukin ( IL )-1β, high mobility group box 1 ( HMGB1 ) were tested by biochemical methods or ELISA kit, respectively.The expression of HDAC1, HDAC3, acetylation of histone H3, H4, P65, acetylation and phosphorylation of P65 in liver were detected by Western blotting.The changes of histology in liver was detected by HE staining, and the translocation of P65 in liver was detected by immunohistochemistry. Comparison of variables among the groups was performed using t test.Results MS-275 inhibited the infiltration of inflammatory cells and improved the pathological changes of liver tissue.Compared with ALF group, serum ALT, AST, TBil levels were decreased in MS-275 group ( t =-22.215, -11.914 and-12.160, all P<0.05), but still higher than those in the control group (t=14.852, 11.692 and 8.333, all P<0.05); serum TNF-α, IFNγ, IL-1β, HMGB1 levels were also significantly decreased in MS-275 group (t=-7.926, -3.427, -2.475 and -5.920, all P<0.05), but TNF-αand IFNγwere still higher than those in the control group (t=5.541 and 5.514, all P<0.05).Compared with control group, the expression of class I HDAC in liver tissue was significantly decreased in MS-275 group ( t=-3.676 and-10.576, P<0.05), while the expressions of acetylation of histone H3, H4 and P65 were significantly increased (t=3.976, 5.559 and 4.588, all P<0.05).MS-275 inhibited the translocation of P65 from cytoplasm to the nucleus.Conclusion MS-275 can protect liver from acute failure in mice through enhancing the acetylation levels of non-histones.
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Objective To investigate changes of regulatory T (Treg) cell proportion and activity in patients with decompensated hepatitis B-related cirrhosis complicated with bacterial infections.Methods Thirty patients with decompensated hepatitis B-related cirrhosis complicated with bacterial infections,20patients with decompensated hepatitis B-related cirrhosis without bacterial infection and 10 healthy controls were recruited in the study from Renmin Hospital of Wuhan University during January 2009 and December 2011.Peripheral blood mononuclear cells (PBMCs) were obtained from blood samples via density gradient centrifugation.The proportion of CD4+ CD25+ CD127low Treg cells in CD4+ cells was detected by flow cytometry.The immune activity of Treg cells isolated from PBMCs was observed by a suppression assay of allogeneic mixed lymphocyte response (MLR).Results Patients with decompensated hepatitis B-related cirrhosis complicated with bacterial infections had significantly lower percentage of Treg cells in CD4 + T cells of PBMCs than the patients with decompensated hepatitis B-related cirrhosis without bacterial infections [(4.07±1.18)％ vs.(9.74 ±3.00)％,t =9.35,P＜0.01].The suppression ability to homologous PBMCs proliferation of Treg cells isolated from patients with decompensated hepatitis B-related cirrhosis complicated with bacterial infections was significantly weakened as demonstrated in MLR assay [ cpm =(22.79 ± 4.94) × 103],which had a statistical difference compared with both the patients with decompensated hepatitis B-related cirrhosis without bacterial infection and the healthy controls [ cpm =(6.43±1.19) × 103 and (5.96 ± 1.25) × 103 respectively; t =16.09 and 16.51,P＜ 0.01].Conclusion There is a decrease of both quantity and activity of Treg cell in the patients with decompensated hepatitis B-related cirrhosis complicated with bacterial infections.
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Objective To evaluate the effects of adenovirus-thediated PTEN gene transfer on growth and invasion of H22 cells in vitro. Methods H22 cells were tnmsfected with Ad-PTEN and Ad-PTENG-129R it vitro, The mRNA expressions of PTEN were detected with RT-PCR. Cell viability was determined by MTT assay. Invasion of H22 in vitro was observed using Boyden chamber. Results Gene and protein expressions of PTEN were shown to be up-regulated when H22 was transfected with Ad-PTEN. MTT assay showed that the group transfected with Ad-PTEN had much lower cell viability than other groups (P<0.05) . The number of 1422 invasion cells in the group of Ad-PTEN was (15.64±3.27) %, which was lower than the number in other groups (P<0.05). Conclusion These results imply that the number of H22 invasion cells was significantly decreased after infected with Ad-PTEN in vitro.
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Objective To investigate the expression of signal transduction molecule STAT-1 in patients with chronic hepatitis B (CHB) who received interferon-alpha (IFNα) treatment with different responses. Methods A total of 13 CHB patients received IFNα treatment, among who 5 demonstrated complete viral response ( Group A) and 8 showed no response ( Group B). All patients underwent liver biopsy before and after the therapy. STAT-1 mRNA of liver tissue was semi-quantified by RT-PCR and levels of STAT-1 protein were detected by Western-blot. Results Absorbance values (A) of STAT-1 mRNA in group A and B were (1. 18±0.06) and (0.21±0.04) respectively (t =35.27, P<0. 01). The levels of STAT-1 protein of liver tissue in group A were also significantly higher than those in group B. Conclusion IFNα resistance may be closely related to the down-regulation of STAT-1.
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Objective To study the sequence variation in the env V3-V4 human immunodeficiency virus (HIV)-1 predominant subtype B strains in Hubei Province and to understand the epidemic characteristics and mutations of HIV-1. Methods Epidemiologic survey was done in the HIV-1 carriers in Hubei area. HIV-1 env V3-V4 regions were amplified by nested-polymerase chain reaction (nPCR). The sequences were determined and then phylogenetic analysis was performed. The difference of gene distance were checked by chi square test and the variation of gene distance were descriptively analyzed. Results Four HIV-1 strains or circulating recombinant forms (CRF) were identified in Hubei Province subtype B', B'/C, CRF01_AE and C were 82.69%, 7.69%, 7.69% and 1.92% ,respectively. B' strains were closely related with B. CN. RL 42 from Yunnan Province and B. CN. 02. 02HN from Province Henan, the gene distances were 7.08 ± 2.19 and 7.88 ± 2.28, respectively. Genetic divergence of env of B' strains showed that subtype B' has existed in Hubei area for about 10 years. Amino acid sequence analysis of section env showed V4 was more variable than C3, V3. The top four peptides of V3 loop were GPGR (46.5%), GPGK (30.2%), GPGQ (13.6%) and GQGR (9.3%). Predictions for the potential use of co-receptors on the basis of the critical amino acids within V3 loop disclosed that 16.28% were CCR5-using (R5/NSI), 13.95% were CXCR4-using (X4/SI) while the co-receptor usage of the vast majority (69.77%) could not be predicted. The analysis of glycosylation sites showed that there were 9 sites in env V3-V4 regions of HIV-1 strains in Hubei area and there were deletions in 8 of them, Conclusions Subtype B' is still the main epidemic subtype in Hubei Province and high homologous to the strains from Yunan and Henan Province.
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Objective To explore the quality of life (QOL) for the patients with chronic hepatitis B (CHB). And the intervention effect of anti-viral therapy on QOL in patients with CHB was investigated. Methods A cross-sectional study based on 212 patients with CHB was carried out in the department of infectious diseases, Renmin Hospital of Wuhan University, using SF-36 questionnaire, special hepatitis questionnaire and medical coping modes questionnaire (MCMQ) during 2003 to 2004. Results Compared with healthy controls, patients with CHB had lower QOL on all scales of the SF-36(P0.05). The reduction in QOL was directly associated with age, the scores of special hepatitis questionnaire, confrontation and resignation in MCMQ (P
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Object To investigate the therapeutic effects and mechanism of traditional Chinese compound decoction of Radix Curcumae (RC), Rhizoma Sparganii (RS), and Rhizoma Zedoariae (RZ) (DRRR) on liver fibrosis in rats induced by carbon tetrachloride (CCl 4). Methods Fifty Wistar rats were randomly divided into four groups: group A was healthy control (n=8), group B was model rats of liver fibrosis induced by CCl 4 (n=14), group C and D were treated with DRRR after the liver fibrosis in rats induced by CCl 4 four weeks later (n=14). B, C, and D groups were injected subcutaneously with CCl 4; C and D groups were administrated with DRRR 0.6 and 1.2 g/100 g, once per day. After administration of DRRR four weeks all rats were sacrificed, their blood and liver were harvested for further examination. The effect of DRRR was explored by the expressions and sites of transforming growth factor-beta 1 (TGF-? 1), Smad3 and Smad7 in liver tissues by immunohistochemical staining. The liver function, serum hyaluronic acid (HA), and liver histopathology were also examined by biochemsitry, RIA, HE, and Van Gieson stainings respectively. Results To compare with model group, in rats that received DRRR, the expressions of TGF-? 1 and Smad3 were significantly decreased, while the expression of Smad7 was obviously increased in the livers (P
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Objective To investigate the effect and its mechanism of “JinSanE” on liver fibrosis induced by carbon tetrachloride (CCl4) in rats. Methods Thirty-six Wistar rats were divided into three groups: healthy controls, CCl4 induced cirrhotic rats, and CCl4 induced cirrhotic rats treated with “JinSanE”, which was begun at the fourth week after exposure to CCl4. “JinSanE” was given once a day. Rats were killed after the administration of “JinSanE” for 4 weeks. The anti-fibrosis effect was determined by the expressions of connective tissue growth factor (CTGF) and transforming growth factor-? 1 (TGF-? 1) in liver tissue. The CTGF and TGF-? 1 mRNA expressions were detected by RT-PCR, CTGF and TGF-? 1 were assessed after immunohistochemistry staining. The serum level of hyaluronic acid (HA) was determined by RIA, and the liver histopathology was observed with light and electronic microscopy. Results Compared with the CCl4 induced cirrhotic rats, the expressions of TGF-? 1 and CTGF were decreased in the liver of the rats which were given “JinSanE” (P