A green environmental protection and enhanced leaching process was proposed to recover all elements from spent lithium iron phosphate(LiFePO_(4)) lithium batteries.In order to reduce the influence of Al impurity in th...A green environmental protection and enhanced leaching process was proposed to recover all elements from spent lithium iron phosphate(LiFePO_(4)) lithium batteries.In order to reduce the influence of Al impurity in the recovery process,NaOH was used to remove impurity.After impurity removal,the spent LiFePO_(4) cathode material was used as raw material under the H_(2)SO_(4) system,and the pressure oxidation leaching process was adopted to achieve the preferential leaching of lithium.The E-pH diagram of the Fe-P-Al-H_(2)O system can determine the stable region of each element in the recovery process of spent LiFePO_(4)Li-batteries.Under the optimal conditions(500 r·min^(-1),15 h,363.15 K,0.4 MPa,the liquid-solid ratio was 4:1 ml·g^(-1)and the acid-material ratio was 0.29),the leaching rate of Li was 99.24%,Fe,Al,and Ti were 0.10%,2.07%,and 0.03%,respectively.The Fe and P were precipitated and recovered as FePO_(4)·2H_(2)O.The kinetic analysis shows that the process of high-pressure acid leaching of spent LiFePO_(4) materials depends on the surface chemical reaction.Through the life cycle assessment(LCA)of the spent LiFePO_(4) whole recovery process,eight midpoint impact categories were selected to assess the impact of recovery process.The results can provide basic environmental information on production process for recycling industry.展开更多
BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there ar...BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.展开更多
BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 fin...BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.展开更多
AIM To assess daclatasvir plus asunaprevir(d UAL) in treatment-na?ve patients from China's Mainland, Russia and South Korea with hepatitis C virus(HCV) genotype 1 b infection. METHODS Patients were randomly assign...AIM To assess daclatasvir plus asunaprevir(d UAL) in treatment-na?ve patients from China's Mainland, Russia and South Korea with hepatitis C virus(HCV) genotype 1 b infection. METHODS Patients were randomly assigned(3:1) to receive 24 wk of treatment with d UAL(daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period(immediate treatment arm) or following 12 wk of matching placebo(placebodeferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12(SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin(70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in d UAL-treated patients compared with placebo patients during the first 12 wk(doubleblind phase), and during 24 wk of d UAL in both arms combined.RESULTS In total, 207 patients were randomly assigned to immediate(n = 155) or placebo-deferred(n = 52) treatment. Most patients were Asian(86%), female(59%) and aged < 65 years(90%). Among them, 13% had cirrhosis, 32% had IL28 B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/m L. Among patients in the immediate treatment arm, SVR12 was achieved by 92%(95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate(70%). SVR12 was largely unaffected by cirrhosis(89%), age ≥ 65 years(92%), male sex(90%), baseline HCV RNA ≥ 6 million(89%) or IL28 B non-CC genotypes(96%), although SVR12 was higher among patients without(96%) than among those with(53%) baseline NS5 A resistanceassociated polymorphisms(at L31 or Y93 H). during the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving d UAL. during 24 wk of d UAL therapy(combined arms), the most common adverse events(≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities(alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued d UAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths.CONCLUSION d UAL was well-tolerated during this phase 3 study, and SVR12 with d UAL treatment(92%) exceeded thehistorical SVR rate for peg-interferon plus ribavirin of 70%.展开更多
BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants signif...BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants significantly improve the predictive sensitivity of TIL,more than 50%of cases of this toxicity cannot be predicted by this mutation.The potential use of the 6-thioguanine nucleotide(6TGN)level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139C,thiopurine S methyltransferase,and 6TGN concentrations were measured.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 red blood cells(RBC),which was not different from that of patients without TIL(P=0.071).Then,we compared the 6TGN levels based on NUDT15 R139C.For CC(n=342)and CT(n=65)genotypes,the median 6TGN level in patients with TIL was significantly higher than that in patients without(474.8 vs 306.0 pmol/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes.Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.展开更多
Objective:The role of intestine-derived factors in promoting liver regeneration after partial hepatectomy(PHx)are not entirely known,but bile acids(BAs)and fibroblast growth factor 15(Fgf15)that are highly expressed i...Objective:The role of intestine-derived factors in promoting liver regeneration after partial hepatectomy(PHx)are not entirely known,but bile acids(BAs)and fibroblast growth factor 15(Fgf15)that are highly expressed in the mouse ileum could promote hepatocyte proliferation.Fgf15 strongly suppresses the synthesis of BAs,and emerging evidence indicates that Fgf15 is important for liver regeneration.展开更多
Overview Drug-induced liver injury(DILI)due to acetaminophen overdose and idiosyncratic drug reactions usually occurs 5–90 days after exposure to the causative drug.Ninety percent of DILI cases are acute.As one of th...Overview Drug-induced liver injury(DILI)due to acetaminophen overdose and idiosyncratic drug reactions usually occurs 5–90 days after exposure to the causative drug.Ninety percent of DILI cases are acute.As one of the most common non-infectious liver diseases,DILI represents a growing challenge for clinicians.According to data from WHO[1],DILI is the fifth leading cause of liver disease mortality.In China,DILI accounts for 1%–5%of hospitalized patients with liver diseases,10%of patients展开更多
AIM To explore hepatitis C virus(HCV) adaptive mutations or combinations thereof responsible for enhanced viral production and investigate the underlying mechanisms.METHODS A series of plasmids with adaptive mutations...AIM To explore hepatitis C virus(HCV) adaptive mutations or combinations thereof responsible for enhanced viral production and investigate the underlying mechanisms.METHODS A series of plasmids with adaptive mutations were constructed. After the plasmids were transfected into Huh7.5 cells, we determined the infectious HCV particle titers by NS5 A immunofluorescence assays, and detected HCV RNA replication by real-time PCR and protein expression by Western blot. Then we carried out immunoblotting of supernatants and celllysates with anti-NS3 to analyze the virus release level. In addition, co-localization of lipid droplets(LDs) with NS5 A was measured using confocal laser scanning microscopy. The ratio between the p56 and p58 phosphoforms of NS5 A was analyzed further.RESULTS The plasmids named JFH1-m E2, JFH1-mp7, JFH1-m NS4 B, JFH1-m NS5 A, JFH1-m E2/NS5 A, JFH1-mp7/NS5 A, JFH1-m NS4 B/NS5 A, JFH1-m E2/p7/NS5 A, and m JFH1 were constructed successfully. This study generated infectious HCV particles with a robust titer of 1.61 × 106 focus-forming units(FFUs)/m L. All of the six adaptive mutations increased the HCV particle production at varying levels. The NS5 A(C2274 R, I2340 T, and V2440 L) and p7(H781 Y) were critical adaptive mutations. The effect of NS5 A(C2274 R, I2340 T, and V2440 L), p7(H781 Y), and NS4 B(N1931 S) on infectious HCV titers was investigated by measuring the HCV RNA replication, protein expression, and virion release. However, the six adaptive mutations were not required for the LD localization of NS5 A proteins or the phosphorylation of NS5 A.CONCLUSION In this study, we generated infectious HCV particles with a robust titer of 1.61 × 106 FFUs/m L, and found that the viral replication and release levels could be enhanced by some of the adaptive mutations.展开更多
BACKGROUND Liver fibrosis and hepatocellular carcinoma(HCC)are common adverse consequences of chronic liver injury.The interaction of various risk factors may cause them to happen.Identification of specific biomarkers...BACKGROUND Liver fibrosis and hepatocellular carcinoma(HCC)are common adverse consequences of chronic liver injury.The interaction of various risk factors may cause them to happen.Identification of specific biomarkers is of great significance for understanding the occurrence,development mechanisms,and determining the novel tools for diagnosis and treatment of both liver fibrosis and HCC.AIM To identify liver fibrosis-related core genes,we analyzed the differential expression pattern of core genes in liver fibrosis and HCC.METHODS Gene expression profiles of three datasets,GSE14323,GSE36411,and GSE89377,obtained from the Gene Expression Omnibus(GEO)database,were analyzed,and differentially expressed genes(DEGs)between patients with liver cirrhosis and healthy controls were identified by screening via R software packages and online tool for Venn diagrams.The WebGestalt online tool was used to identify DEGs enriched in biological processes,molecular functions,cellular components,and Kyoto Encyclopedia of Genes and Genomes pathways.The protein–protein interactions of DEGs were visualized using Cytoscape with STRING.Next,the expression pattern of core genes was analyzed using Western blot and immunohistochemistry in a carbon tetrachloride(CCl_(4))-induced liver cirrhosis mouse model and in patient liver samples.Finally,Kaplan-Meier curves were constructed using the Kaplan-Meier plotter online server.RESULTS Forty-five DEGs(43 upregulated and 2 downregulated genes)associated with liver cirrhosis were identified from three GEO datasets.Ten hub genes were identified,which were upregulated in liver cirrhosis.Western blot and immunohistochemical analyses of the three core genes,decorin(DCN),dermatopontin(DPT),and SRY-box transcription factor 9(SOX9),revealed that they were highly expressed in the CCl4-induced liver cirrhosis mouse model.The expression levels of DCN and SOX 9 were positively correlated with the degree of fibrosis,and SOX 9 level in HCC patients was significantly higher than that in fibrosis patients.However,high expression of DPT was observed only in patients with liver fibrosis,and its expression in HCC was low.The gene expression profiling interactive analysis server(GEPIA)showed that SOX9 was significantly upregulated whereas DCN and DPT were significantly downregulated in patients with HCC.In addition,the Kaplan-Meier curves showed that HCC patients with higher SOX9 expression had significantly lower 5-year survival rate,while patients with higher expression of DCN or DPT had significantly higher 5-year survival rates.CONCLUSION The expression levels of DCN,DPT,and SOX9 were positively correlated with the degree of liver fibrosis but showed different correlations with the 5-year survival rates of HCC patients.展开更多
Congenital coronary sinus(CS)fistula is a rare form of cardiac abnormality.The fistula forms an abnormal communication between the cardiac chambers and the coronary arteries.The most common form of fistula arises from...Congenital coronary sinus(CS)fistula is a rare form of cardiac abnormality.The fistula forms an abnormal communication between the cardiac chambers and the coronary arteries.The most common form of fistula arises from the right coronary arteries while the left ventricular and CS fistula is rare.Coronary slow-flow phenomenon(CSFP)is defined as a delayed opacification of distal vessels without any epicardial disease.[1]展开更多
Background: Recent studies reported that patients with coronavirus disease-2019(COVID-19) might have liver injury. However, few data on the combined analysis and change patterns of alanine aminotransferase(ALT), aspar...Background: Recent studies reported that patients with coronavirus disease-2019(COVID-19) might have liver injury. However, few data on the combined analysis and change patterns of alanine aminotransferase(ALT), aspartate aminotransferase(AST) and total bilirubin(TBil) have been shown.Methods: This is a single-center retrospective study. A total of 105 adult patients hospitalized for confirmed COVID-19 in Beijing Ditan Hospital between January 12, and March 17, 2020 were included, and divided into mild group(n=79) and severe group(n=26). We compared liver functional test results between the two groups. Category of ALT change during the disease course was also examined.Results: 56.2%(59/105) of the patients had unnormal ALT, AST, or total TBil throughout the course of the disease, but in 91.4%(96/105) cases the level of ALT, AST or TBil ≤3 fold of the upper limit of normal reference range(ULN). The overall distribution of ALT, AST, and TBil were all significantly difference between mild and severe group(P<0.05). The percentage of the patients with elevated both ALT and AST was 12.7%(10/79) in mild cases vs. 46.2%(12/26) in severe cases(P=0.001). 34.6%(9/26) severe group patients started to have abnormal ALT after admission, and 73.3%(77/105) of all patients had normal ALT before discharge.Conclusions: Elevated liver function index is very common in patients with COVID-19 infection, and the level were less than 3×ULN, but most are reversible. The abnormality of 2 or more indexes is low in the patients with COVID-19, but it is more likely to occur in the severe group.展开更多
Objective:Network pharmacology method was adopted in this study to screen the target of Zhitong Rushen Decoction of the treatment to Functional Anorectal Pain(FAP)and explore its mechanism of treatment.Methods:Chemica...Objective:Network pharmacology method was adopted in this study to screen the target of Zhitong Rushen Decoction of the treatment to Functional Anorectal Pain(FAP)and explore its mechanism of treatment.Methods:Chemical components and selected targets related to the ten traditional Chinese medicine(TCM)herbs were searched through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).Through GeneCards database,OMIM database,disease targets of FAP were searched.R language was used to screen the common targets between drugs and disease,and then the interaction network diagram of the targets was constructed by String.Cytoscape3.7.0 was applied to construct the active ingredients-targets interacted network.GO enrichment analysis and KEGG enrichment analysis of targets were based on R language.Results:Four main chemical components including quercetin,wogonin,fisetin and kaempferol were screened,and four key targets including ESR1、NOS2、PGR and CHRM3 were identified.In GO enrichment analysis,66 molecular function entries,1040 biological process entries,26 cell component entries were obtained.KEGG pathway enrichment analysis showed that zhitong rushen decoction played a therapeutic role in functional anorectal pain by regulating AGE-RAGE signaling pathway in diabetic complications,Bladder cancer,Estrogen signaling pathway,HIF-1 signaling pathway.Conclusion:Zhitong rushen decoction for the treatment of functional anorectal pain may be related to its multi-component effect on multiple targets and multiple signaling pathways,providing theoretical basis for further study of active ingredients and mechanism of action.展开更多
Hepatic encephalopathy(HE)is a complex,neuropsychiatric abnormality that occurs as a consequence of metabolic disorders in patients with hepatic insufficiency.The pathogenesis is complex with a strong prognosticator o...Hepatic encephalopathy(HE)is a complex,neuropsychiatric abnormality that occurs as a consequence of metabolic disorders in patients with hepatic insufficiency.The pathogenesis is complex with a strong prognosticator of death.To standardize the clinical management of HE,relevant new data were reviewed and assessed by Chinese Committee of Experts on Hepatic Encephalopathy in China and was discussed and debated extensively.Then the consensus on the management of HE was developed.The final recommendations are based on the data available at the time of production of the document and may be updated with pertinent scientific developments at a later time.All the discussion was organized by the editorial board of Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition),Chinese Journal of Liver Diseases(Electronic Edition)and Infection International(Electronic Edition).The evidence gradings in the consensus are listed in Table1.展开更多
Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology.3’-Phosphoadenosine 5’-phosphosulfate(PAPS)synthase 2(PAPSS2)is the primary enzyme to generate the un...Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology.3’-Phosphoadenosine 5’-phosphosulfate(PAPS)synthase 2(PAPSS2)is the primary enzyme to generate the universal sulfonate donor PAPS.The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli(APC)mutation-promoted colonic carcinogenesis has not been reported.Here,we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages,and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer.Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout(Apc^(Δgut-Het)Papss2^(Δgut))mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^(Δgut-Het)mice.Apc^(Δgut-Het)Papss2^(Δgutmice) were more sensitive to gut tumorigenesis,which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor(FXR)-transducin-like enhancer of split 3(TLE3)gene regulatory axis.Chondroitin sulfate supplementation in Apc^(Δgut-Het)Papss2^(Δgutmice) alleviated intestinal tumorigenesis.In summary,we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling.Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.展开更多
Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gas...Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.展开更多
The protein kinase B(Akt)pathway can regulate the growth,proliferation,and metabolism of tumor cells and stem cells through the activation of multiple downstream target genes,thus affecting the development and treatme...The protein kinase B(Akt)pathway can regulate the growth,proliferation,and metabolism of tumor cells and stem cells through the activation of multiple downstream target genes,thus affecting the development and treatment of a range of diseases.thioesterase superfamily member 4(THEM4),a member of the thioesterase superfamily,is one of the Akt kinase-binding proteins.Some studies on the mechanism of cancers and other diseases have shown that THEM4 binds to Akt to regulate its phosphorylation.Initially,THEM4 was considered an endogenous inhibitor of Akt,which can inhibit the phosphorylation of Akt in diseases such as lung cancer,pancreatic cancer,and liver cancer,but subsequently,THEM4 was shown to promote the proliferation of tumor cells by positively regulating Akt activity in breast cancer and nasopharyngeal carcinoma,which contradicts previous findings.Considering these two distinct views,this review summarizes the important roles of THEM4 in the Akt pathway,focusing on THEM4 as an Akt-binding protein and its regulatory relationship with Akt phosphorylation in various diseases,especially cancer.This work provides a better understanding of the roles of THEM4 combined with Akt in the treatment of diseases.展开更多
The widespread applications of lithium-ion batteries(LIBs)generate tons of spent LIBs.Therefore,recycling LIBs is of paramount importance in protecting the environment and saving the resources.Current commercialized L...The widespread applications of lithium-ion batteries(LIBs)generate tons of spent LIBs.Therefore,recycling LIBs is of paramount importance in protecting the environment and saving the resources.Current commercialized LIBs mostly adopt layered oxides such as LiCoO_(2)(LCO)or LiNi_(x)Co_(y)Mn_(1-x-y)O_(2)(NMC)as the cathode materials.Converting the intercalation-type spent oxides into conversion-type cathodes(such as metal fluorides(MFs))offers a valid recycling strategy and provides substantially improved energy densities for LIBs.Herein,two typical Co-based cathodes,LCO and LiNi_(0.6)Co_(0.2)Mn_(0.2)O_(2)(NMC622),in spent LIBs were successfully converted to CoF_(2) and(Ni_(x)Co_(y)Mn_(z))F_(2) cathodes by a reduction and fluorination technique.The as converted CoF_(2) and(Ni_(x)Co_(y)Mn_(z))F_(2) delivered cell energy densities of 650 and 700 Wh/kg,respectively.Advanced atomic-level electron microscopy revealed that the used LCO and NMC622 were converted to highly phase pure Co metal and Ni_(0.6)Co_(0.2)Mn_(0.2) alloys in the used graphite-assisted reduction roasting,simultaneously producing the important product of Li_(2)CO_(3) using only environment friendly solvent.Our study provided a versatile strategy to convert the intercalation-type Co-based cathode in the spent LIBs into conversion-type MFs cathodes,which offers a new avenue to recycle the spent LIBs and substantially increase the energy densities of next generation LIBs.展开更多
Dear Editor,The characteristics and importance of the whitefly Bemisia tabaci as an economic pest seem to continually get more and more attention.Among the whiteflies B.tabaci including,at least 11 genetic groups and ...Dear Editor,The characteristics and importance of the whitefly Bemisia tabaci as an economic pest seem to continually get more and more attention.Among the whiteflies B.tabaci including,at least 11 genetic groups and 36 morphologically indistinguishable cryptic species,invasive MEAMl(Middle East-Asia Minor 1,"B"type)and MED(the Mediterranean,"Q"type)are the 2 most destructive cryptic species of the B.展开更多
Bisphenol A(BPA),one of the most commonly used plastic organic monomers,is widely used in manufacturing food packaging and containers.However,the gradual emissions of BPA from manufacturing plastic products bring grea...Bisphenol A(BPA),one of the most commonly used plastic organic monomers,is widely used in manufacturing food packaging and containers.However,the gradual emissions of BPA from manufacturing plastic products bring great potential in human health threats,which urgently need to develop a simple and rapid method for detecting BPA.Cetyltrimethylammonium bromide(CTAB),a typical surfactant,is used to enhance the electrochemical detection of trace endocrine disruptors due to the fact that it can effectively enrich and absorb hydrophobic phenolic compounds through the hydrophobicity of its long-chain alkanes.Based on these,the present study reports a ternary composite of Au on zinc oxide/reduced graphene oxide nanosheets(Au/ZnO/rGO)as electrochemical sensor for detecting BP A.With the addition of CTAB,the analytic performances toward BP A detection are significantly improved 3.8 times compared with those without CTAB.The pH,accumulation potential and time are optimized.Moreover,the electrochemical activity of CTAB/Au/ZnO/rGO sensor is also evaluated by cyclic voltammetry(CV),electrochemical impedance spectroscopy(EIS),differential pulse voltammetry(DPV)and scan rate.The sensor displays two linear range from 10to 1340 nmol·L^(-1)and 1340 to 10,000 nmol·L^(-1),and a low detection limit of 4.95 nmol·L^(-1).Lastly,the sensor also exhibits good reproducibility,selectivity and potential practical application for BPA detection in real samples.展开更多
基金supported by the National Natural Science Foundation of China(51834008,52022109,52274307,and 21804319)National Key Research and Development Program of China(2021YFC2901100)+1 种基金Science Foundation of China University of Petroleum,Beijing(2462022QZDX008,2462021QNX2010,2462020YXZZ019 and 2462020YXZZ016)State Key Laboratory of Heavy Oil Processing(HON-KFKT2022-10).
文摘A green environmental protection and enhanced leaching process was proposed to recover all elements from spent lithium iron phosphate(LiFePO_(4)) lithium batteries.In order to reduce the influence of Al impurity in the recovery process,NaOH was used to remove impurity.After impurity removal,the spent LiFePO_(4) cathode material was used as raw material under the H_(2)SO_(4) system,and the pressure oxidation leaching process was adopted to achieve the preferential leaching of lithium.The E-pH diagram of the Fe-P-Al-H_(2)O system can determine the stable region of each element in the recovery process of spent LiFePO_(4)Li-batteries.Under the optimal conditions(500 r·min^(-1),15 h,363.15 K,0.4 MPa,the liquid-solid ratio was 4:1 ml·g^(-1)and the acid-material ratio was 0.29),the leaching rate of Li was 99.24%,Fe,Al,and Ti were 0.10%,2.07%,and 0.03%,respectively.The Fe and P were precipitated and recovered as FePO_(4)·2H_(2)O.The kinetic analysis shows that the process of high-pressure acid leaching of spent LiFePO_(4) materials depends on the surface chemical reaction.Through the life cycle assessment(LCA)of the spent LiFePO_(4) whole recovery process,eight midpoint impact categories were selected to assess the impact of recovery process.The results can provide basic environmental information on production process for recycling industry.
基金Supported by the National Natural Science Foundation of China,No.82020108031,No.81973398,and No.82104290Guangdong Provincial Key Laboratory of Construction Foundation,No.2020B1212060034Guangdong Basic and Applied Basic Research Foundation,No.2022A1515012549 and No.2023A1515012667.
文摘BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.
基金Supported by the Special Research Project for Capital Health Development,No.2022-2-2174the Beijing Municipal Science and Technology Commission,No.Z191100007619037.
文摘BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.
文摘AIM To assess daclatasvir plus asunaprevir(d UAL) in treatment-na?ve patients from China's Mainland, Russia and South Korea with hepatitis C virus(HCV) genotype 1 b infection. METHODS Patients were randomly assigned(3:1) to receive 24 wk of treatment with d UAL(daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period(immediate treatment arm) or following 12 wk of matching placebo(placebodeferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12(SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin(70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in d UAL-treated patients compared with placebo patients during the first 12 wk(doubleblind phase), and during 24 wk of d UAL in both arms combined.RESULTS In total, 207 patients were randomly assigned to immediate(n = 155) or placebo-deferred(n = 52) treatment. Most patients were Asian(86%), female(59%) and aged < 65 years(90%). Among them, 13% had cirrhosis, 32% had IL28 B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/m L. Among patients in the immediate treatment arm, SVR12 was achieved by 92%(95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate(70%). SVR12 was largely unaffected by cirrhosis(89%), age ≥ 65 years(92%), male sex(90%), baseline HCV RNA ≥ 6 million(89%) or IL28 B non-CC genotypes(96%), although SVR12 was higher among patients without(96%) than among those with(53%) baseline NS5 A resistanceassociated polymorphisms(at L31 or Y93 H). during the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving d UAL. during 24 wk of d UAL therapy(combined arms), the most common adverse events(≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities(alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued d UAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths.CONCLUSION d UAL was well-tolerated during this phase 3 study, and SVR12 with d UAL treatment(92%) exceeded thehistorical SVR rate for peg-interferon plus ribavirin of 70%.
基金Supported by the National Natural Science Foundation of China,No.81573507,No.81473283,No.81173131,and No.81320108027Guangdong Provincial Key Laboratory Construction Foundation,No.2017B030314030+1 种基金The National Key Research and Development Program,No.2016YFC0905003the 111 Project,No.B16047
文摘BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants significantly improve the predictive sensitivity of TIL,more than 50%of cases of this toxicity cannot be predicted by this mutation.The potential use of the 6-thioguanine nucleotide(6TGN)level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139C,thiopurine S methyltransferase,and 6TGN concentrations were measured.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 red blood cells(RBC),which was not different from that of patients without TIL(P=0.071).Then,we compared the 6TGN levels based on NUDT15 R139C.For CC(n=342)and CT(n=65)genotypes,the median 6TGN level in patients with TIL was significantly higher than that in patients without(474.8 vs 306.0 pmol/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes.Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.
文摘Objective:The role of intestine-derived factors in promoting liver regeneration after partial hepatectomy(PHx)are not entirely known,but bile acids(BAs)and fibroblast growth factor 15(Fgf15)that are highly expressed in the mouse ileum could promote hepatocyte proliferation.Fgf15 strongly suppresses the synthesis of BAs,and emerging evidence indicates that Fgf15 is important for liver regeneration.
文摘Overview Drug-induced liver injury(DILI)due to acetaminophen overdose and idiosyncratic drug reactions usually occurs 5–90 days after exposure to the causative drug.Ninety percent of DILI cases are acute.As one of the most common non-infectious liver diseases,DILI represents a growing challenge for clinicians.According to data from WHO[1],DILI is the fifth leading cause of liver disease mortality.In China,DILI accounts for 1%–5%of hospitalized patients with liver diseases,10%of patients
基金Beijing Natural Science Foundation,No.7161006Beijing Municipal Administration of Hospitals’ Youth Program,No.QML20161801 and No.QML20171801
文摘AIM To explore hepatitis C virus(HCV) adaptive mutations or combinations thereof responsible for enhanced viral production and investigate the underlying mechanisms.METHODS A series of plasmids with adaptive mutations were constructed. After the plasmids were transfected into Huh7.5 cells, we determined the infectious HCV particle titers by NS5 A immunofluorescence assays, and detected HCV RNA replication by real-time PCR and protein expression by Western blot. Then we carried out immunoblotting of supernatants and celllysates with anti-NS3 to analyze the virus release level. In addition, co-localization of lipid droplets(LDs) with NS5 A was measured using confocal laser scanning microscopy. The ratio between the p56 and p58 phosphoforms of NS5 A was analyzed further.RESULTS The plasmids named JFH1-m E2, JFH1-mp7, JFH1-m NS4 B, JFH1-m NS5 A, JFH1-m E2/NS5 A, JFH1-mp7/NS5 A, JFH1-m NS4 B/NS5 A, JFH1-m E2/p7/NS5 A, and m JFH1 were constructed successfully. This study generated infectious HCV particles with a robust titer of 1.61 × 106 focus-forming units(FFUs)/m L. All of the six adaptive mutations increased the HCV particle production at varying levels. The NS5 A(C2274 R, I2340 T, and V2440 L) and p7(H781 Y) were critical adaptive mutations. The effect of NS5 A(C2274 R, I2340 T, and V2440 L), p7(H781 Y), and NS4 B(N1931 S) on infectious HCV titers was investigated by measuring the HCV RNA replication, protein expression, and virion release. However, the six adaptive mutations were not required for the LD localization of NS5 A proteins or the phosphorylation of NS5 A.CONCLUSION In this study, we generated infectious HCV particles with a robust titer of 1.61 × 106 FFUs/m L, and found that the viral replication and release levels could be enhanced by some of the adaptive mutations.
基金Supported by the Beijing Natural Science Foundation,No.7222097Beijing Hospitals Authority the Digestive Medical Coordinated Development Center,No.XXZ0401+1 种基金National Natural Science Foundation of China,No.82000555 and No.81900547Beijing Municipal Science and Technology Commission,No.D171100003117005.
文摘BACKGROUND Liver fibrosis and hepatocellular carcinoma(HCC)are common adverse consequences of chronic liver injury.The interaction of various risk factors may cause them to happen.Identification of specific biomarkers is of great significance for understanding the occurrence,development mechanisms,and determining the novel tools for diagnosis and treatment of both liver fibrosis and HCC.AIM To identify liver fibrosis-related core genes,we analyzed the differential expression pattern of core genes in liver fibrosis and HCC.METHODS Gene expression profiles of three datasets,GSE14323,GSE36411,and GSE89377,obtained from the Gene Expression Omnibus(GEO)database,were analyzed,and differentially expressed genes(DEGs)between patients with liver cirrhosis and healthy controls were identified by screening via R software packages and online tool for Venn diagrams.The WebGestalt online tool was used to identify DEGs enriched in biological processes,molecular functions,cellular components,and Kyoto Encyclopedia of Genes and Genomes pathways.The protein–protein interactions of DEGs were visualized using Cytoscape with STRING.Next,the expression pattern of core genes was analyzed using Western blot and immunohistochemistry in a carbon tetrachloride(CCl_(4))-induced liver cirrhosis mouse model and in patient liver samples.Finally,Kaplan-Meier curves were constructed using the Kaplan-Meier plotter online server.RESULTS Forty-five DEGs(43 upregulated and 2 downregulated genes)associated with liver cirrhosis were identified from three GEO datasets.Ten hub genes were identified,which were upregulated in liver cirrhosis.Western blot and immunohistochemical analyses of the three core genes,decorin(DCN),dermatopontin(DPT),and SRY-box transcription factor 9(SOX9),revealed that they were highly expressed in the CCl4-induced liver cirrhosis mouse model.The expression levels of DCN and SOX 9 were positively correlated with the degree of fibrosis,and SOX 9 level in HCC patients was significantly higher than that in fibrosis patients.However,high expression of DPT was observed only in patients with liver fibrosis,and its expression in HCC was low.The gene expression profiling interactive analysis server(GEPIA)showed that SOX9 was significantly upregulated whereas DCN and DPT were significantly downregulated in patients with HCC.In addition,the Kaplan-Meier curves showed that HCC patients with higher SOX9 expression had significantly lower 5-year survival rate,while patients with higher expression of DCN or DPT had significantly higher 5-year survival rates.CONCLUSION The expression levels of DCN,DPT,and SOX9 were positively correlated with the degree of liver fibrosis but showed different correlations with the 5-year survival rates of HCC patients.
文摘Congenital coronary sinus(CS)fistula is a rare form of cardiac abnormality.The fistula forms an abnormal communication between the cardiac chambers and the coronary arteries.The most common form of fistula arises from the right coronary arteries while the left ventricular and CS fistula is rare.Coronary slow-flow phenomenon(CSFP)is defined as a delayed opacification of distal vessels without any epicardial disease.[1]
基金supported by Scientific Research Projects of Beijing Ditan HospitalCapital Medical University+1 种基金Projects from Beijing Municipal Science and Technology Commission (D171100003117005)Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXZ0402)。
文摘Background: Recent studies reported that patients with coronavirus disease-2019(COVID-19) might have liver injury. However, few data on the combined analysis and change patterns of alanine aminotransferase(ALT), aspartate aminotransferase(AST) and total bilirubin(TBil) have been shown.Methods: This is a single-center retrospective study. A total of 105 adult patients hospitalized for confirmed COVID-19 in Beijing Ditan Hospital between January 12, and March 17, 2020 were included, and divided into mild group(n=79) and severe group(n=26). We compared liver functional test results between the two groups. Category of ALT change during the disease course was also examined.Results: 56.2%(59/105) of the patients had unnormal ALT, AST, or total TBil throughout the course of the disease, but in 91.4%(96/105) cases the level of ALT, AST or TBil ≤3 fold of the upper limit of normal reference range(ULN). The overall distribution of ALT, AST, and TBil were all significantly difference between mild and severe group(P<0.05). The percentage of the patients with elevated both ALT and AST was 12.7%(10/79) in mild cases vs. 46.2%(12/26) in severe cases(P=0.001). 34.6%(9/26) severe group patients started to have abnormal ALT after admission, and 73.3%(77/105) of all patients had normal ALT before discharge.Conclusions: Elevated liver function index is very common in patients with COVID-19 infection, and the level were less than 3×ULN, but most are reversible. The abnormality of 2 or more indexes is low in the patients with COVID-19, but it is more likely to occur in the severe group.
基金The 13th Five-Year plan for Nanjing famous traditional Chinese medicine studio construction project(No.ZXP-2019-NJ)Nanjing medical science and technology development project(No.YKK18137)
文摘Objective:Network pharmacology method was adopted in this study to screen the target of Zhitong Rushen Decoction of the treatment to Functional Anorectal Pain(FAP)and explore its mechanism of treatment.Methods:Chemical components and selected targets related to the ten traditional Chinese medicine(TCM)herbs were searched through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP).Through GeneCards database,OMIM database,disease targets of FAP were searched.R language was used to screen the common targets between drugs and disease,and then the interaction network diagram of the targets was constructed by String.Cytoscape3.7.0 was applied to construct the active ingredients-targets interacted network.GO enrichment analysis and KEGG enrichment analysis of targets were based on R language.Results:Four main chemical components including quercetin,wogonin,fisetin and kaempferol were screened,and four key targets including ESR1、NOS2、PGR and CHRM3 were identified.In GO enrichment analysis,66 molecular function entries,1040 biological process entries,26 cell component entries were obtained.KEGG pathway enrichment analysis showed that zhitong rushen decoction played a therapeutic role in functional anorectal pain by regulating AGE-RAGE signaling pathway in diabetic complications,Bladder cancer,Estrogen signaling pathway,HIF-1 signaling pathway.Conclusion:Zhitong rushen decoction for the treatment of functional anorectal pain may be related to its multi-component effect on multiple targets and multiple signaling pathways,providing theoretical basis for further study of active ingredients and mechanism of action.
文摘Hepatic encephalopathy(HE)is a complex,neuropsychiatric abnormality that occurs as a consequence of metabolic disorders in patients with hepatic insufficiency.The pathogenesis is complex with a strong prognosticator of death.To standardize the clinical management of HE,relevant new data were reviewed and assessed by Chinese Committee of Experts on Hepatic Encephalopathy in China and was discussed and debated extensively.Then the consensus on the management of HE was developed.The final recommendations are based on the data available at the time of production of the document and may be updated with pertinent scientific developments at a later time.All the discussion was organized by the editorial board of Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition),Chinese Journal of Liver Diseases(Electronic Edition)and Infection International(Electronic Edition).The evidence gradings in the consensus are listed in Table1.
基金supported by NIH grants DK117370,DK135538,and ES030429(to Wen Xie,US)a Pilot&Feasibility grant(to Pengfei Xu,US)from the Pittsburgh Liver Research Center funded by NIH grant P30DK120531NIH shared instrumentation grant:Olympus FV3000 Confocal Microscope SIG:NIH S10OD030254-01A1。
文摘Sulfation is a crucial and prevalent conjugation reaction involved in cellular processes and mammalian physiology.3’-Phosphoadenosine 5’-phosphosulfate(PAPS)synthase 2(PAPSS2)is the primary enzyme to generate the universal sulfonate donor PAPS.The involvement of PAPSS2-mediated sulfation in adenomatous polyposis coli(APC)mutation-promoted colonic carcinogenesis has not been reported.Here,we showed that the expression of PAPSS2 was decreased in human colon tumors along with cancer stages,and the lower expression of PAPSS2 was correlated with poor prognosis in advanced colon cancer.Gut epithelial-specific heterozygous Apc deficient and Papss2-knockout(Apc^(Δgut-Het)Papss2^(Δgut))mice were created,and the phenotypes were compared to the spontaneous intestinal tumorigenesis of Apc^(Δgut-Het)mice.Apc^(Δgut-Het)Papss2^(Δgutmice) were more sensitive to gut tumorigenesis,which was mechanistically accounted for by the activation of Wnt/β-catenin signaling pathway due to the suppression of chondroitin sulfation and inhibition of the farnesoid X receptor(FXR)-transducin-like enhancer of split 3(TLE3)gene regulatory axis.Chondroitin sulfate supplementation in Apc^(Δgut-Het)Papss2^(Δgutmice) alleviated intestinal tumorigenesis.In summary,we have uncovered the protective role of PAPSS2-mediated chondroitin sulfation and bile acids-FXR-TLE3 activation in the prevention of gut carcinogenesis via the antagonization of Wnt/β-catenin signaling.Chondroitin sulfate may be explored as a therapeutic agent for Papss2 deficiency-associated colonic carcinogenesis.
基金This work was supported by the Beijing Municipal Natural Science Foundation Grant 7212148(to Mengxi Jiang,China)the National Natural Science Foundation of China Grant 82000807(to Mengxi Jiang,China)the Beijing Municipal Education Commission Grant KM202110025023(to Mengxi Jiang,China).
文摘Drug repurposing offers an efficient approach to therapeutic development.In this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal ulcers.We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in mice.Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism.Mechanistically,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent manner.Our results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor signaling.In summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.
基金supported by the National Natural Science Foundation of China(Nos.82071399 and 81773179)the Key Research and Development Program of Hunan Province(No.2022SK2055)the Natural Science Foundation of Hunan Province(No.2023JJ30733),China.
文摘The protein kinase B(Akt)pathway can regulate the growth,proliferation,and metabolism of tumor cells and stem cells through the activation of multiple downstream target genes,thus affecting the development and treatment of a range of diseases.thioesterase superfamily member 4(THEM4),a member of the thioesterase superfamily,is one of the Akt kinase-binding proteins.Some studies on the mechanism of cancers and other diseases have shown that THEM4 binds to Akt to regulate its phosphorylation.Initially,THEM4 was considered an endogenous inhibitor of Akt,which can inhibit the phosphorylation of Akt in diseases such as lung cancer,pancreatic cancer,and liver cancer,but subsequently,THEM4 was shown to promote the proliferation of tumor cells by positively regulating Akt activity in breast cancer and nasopharyngeal carcinoma,which contradicts previous findings.Considering these two distinct views,this review summarizes the important roles of THEM4 in the Akt pathway,focusing on THEM4 as an Akt-binding protein and its regulatory relationship with Akt phosphorylation in various diseases,especially cancer.This work provides a better understanding of the roles of THEM4 combined with Akt in the treatment of diseases.
基金supported by the National Natural Science Foundation of China(Nos.U20A20336,21935009,52002346,52022088,51971245,22205191)the Science and Technology Innovation Program of Hunan Province(No.2021RC3109)+1 种基金the Natural Science Foundation of Hunan Province,China(No.2022JJ40446)Natural Science Foundation of Hebei Province(Nos.B2020203037,B2018203297).
文摘The widespread applications of lithium-ion batteries(LIBs)generate tons of spent LIBs.Therefore,recycling LIBs is of paramount importance in protecting the environment and saving the resources.Current commercialized LIBs mostly adopt layered oxides such as LiCoO_(2)(LCO)or LiNi_(x)Co_(y)Mn_(1-x-y)O_(2)(NMC)as the cathode materials.Converting the intercalation-type spent oxides into conversion-type cathodes(such as metal fluorides(MFs))offers a valid recycling strategy and provides substantially improved energy densities for LIBs.Herein,two typical Co-based cathodes,LCO and LiNi_(0.6)Co_(0.2)Mn_(0.2)O_(2)(NMC622),in spent LIBs were successfully converted to CoF_(2) and(Ni_(x)Co_(y)Mn_(z))F_(2) cathodes by a reduction and fluorination technique.The as converted CoF_(2) and(Ni_(x)Co_(y)Mn_(z))F_(2) delivered cell energy densities of 650 and 700 Wh/kg,respectively.Advanced atomic-level electron microscopy revealed that the used LCO and NMC622 were converted to highly phase pure Co metal and Ni_(0.6)Co_(0.2)Mn_(0.2) alloys in the used graphite-assisted reduction roasting,simultaneously producing the important product of Li_(2)CO_(3) using only environment friendly solvent.Our study provided a versatile strategy to convert the intercalation-type Co-based cathode in the spent LIBs into conversion-type MFs cathodes,which offers a new avenue to recycle the spent LIBs and substantially increase the energy densities of next generation LIBs.
基金The authors would like to thank Dr.Zhangjun Fei(Boyce Thompson Institute,USA)for computational support and comments on an earlier draft.This research was supported by the National Key R&D Program of China(2022YFD1400800)National Natural Science Foundation of China(32272534 and 32161143020)+5 种基金the Hainan Major Science and Technology Project(ZDKJ2021007)the Beijing Key Laboratory for Pest Control and Sustainable Cultivation of Vegetables and the Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciences(CAAS-ASTIP-IVFCAAS)The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.Data Availability Statement This Whole Genome Shotgun project(Bemisia tabaci MED,Asial,Asialll,AsialI6,and AsialI7)has been deposited at DDBJ/ENA/GenBank under accession VMOE00000000,VMEI00000000,VMEH00000000,VMEG00000000,and VLTD00000000,respectively.Raw sequences including Illumina,PacBio,Hi-C,and RNA-seq reads have been deposited in the NCBI SRA)under accessions SRR11649531-SRR11649533(MED)SRR11692174-SRR11692176(Asial),SRR11613039-SRR11613041(AsiaII1)SRR11609251-SRR11609253(Asiall6)SRR11609258-SRR11609260(Asial7).The genome and predicted gene sequences of all available whitefly genomes are also available via the Whitefly Genome Database(WF-DB,http:/82.157.25.63/whitefly/homepage.php).
文摘Dear Editor,The characteristics and importance of the whitefly Bemisia tabaci as an economic pest seem to continually get more and more attention.Among the whiteflies B.tabaci including,at least 11 genetic groups and 36 morphologically indistinguishable cryptic species,invasive MEAMl(Middle East-Asia Minor 1,"B"type)and MED(the Mediterranean,"Q"type)are the 2 most destructive cryptic species of the B.
基金financially supported by the Fundamental Research Funds for the Central UniversitiesGuangdong Basic and Applied Basic Research Foundation(No.2020B1515020038)Funding by Science and Technology Projects in Guangzhou(No.202201020083)。
文摘Bisphenol A(BPA),one of the most commonly used plastic organic monomers,is widely used in manufacturing food packaging and containers.However,the gradual emissions of BPA from manufacturing plastic products bring great potential in human health threats,which urgently need to develop a simple and rapid method for detecting BPA.Cetyltrimethylammonium bromide(CTAB),a typical surfactant,is used to enhance the electrochemical detection of trace endocrine disruptors due to the fact that it can effectively enrich and absorb hydrophobic phenolic compounds through the hydrophobicity of its long-chain alkanes.Based on these,the present study reports a ternary composite of Au on zinc oxide/reduced graphene oxide nanosheets(Au/ZnO/rGO)as electrochemical sensor for detecting BP A.With the addition of CTAB,the analytic performances toward BP A detection are significantly improved 3.8 times compared with those without CTAB.The pH,accumulation potential and time are optimized.Moreover,the electrochemical activity of CTAB/Au/ZnO/rGO sensor is also evaluated by cyclic voltammetry(CV),electrochemical impedance spectroscopy(EIS),differential pulse voltammetry(DPV)and scan rate.The sensor displays two linear range from 10to 1340 nmol·L^(-1)and 1340 to 10,000 nmol·L^(-1),and a low detection limit of 4.95 nmol·L^(-1).Lastly,the sensor also exhibits good reproducibility,selectivity and potential practical application for BPA detection in real samples.