BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities ...BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities is coagulopathies,including thrombosis and disseminated intravascular coagulation.Because of this,the administration of low molecular weight heparin is required for patients that need to be hospitalized.In addition,Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome,Ebola,Acute Respiratory Syndrome,and other diseases,showing satisfactory results on recovery.Besides,there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19.AIM To investigate in silico the interaction between Remdesivir and clotting factors,pursuing a possibility of using it as medicine.METHODS In this in silico study,the 3D structures of angiotensin-converting enzyme 2(ACE2),Factor I(fibrinogen),Factor II(prothrombin),Factor III(thromboplastin),Factor V(proaccelerin),Factor VII(proconvertin),Factor VIII(antihemophilic factor A),Factor IX(antihemophilic factor B),Factor X(Stuart-Prower factor),and Factor XI(precursor of thromboplastin(these structures are technically called receptors)were selected from the Protein Data Bank.The structures of the antivirals Remdesivir and Osetalmivir(these structures are called ligands)were selected from the PubChem database,while the structure of Atazanavir was selected from the ZINC database.The software AutoDock Tools(ADT)was used to prepare the receptors for molecular docking.Ions,peptides,water molecules,and other ones were removed from each ligand,and then,hydrogen atoms were added to the structures.The grid box was delimited and calculated using the same software ADT.A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors,and still the software Marvin sketch®(ChemAxon®)was used to forecast the protonation state.To perform molecular docking,ADT and Vina software was connected.Using PyMol®software and Discovery studio®software from BIOVIA,it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands.Ligand tortions,atoms that participated in the interactions,and the type,strength,and duration of the interactions were also analyzed using those software.RESULTS Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of-8.8 kcal/moL,forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2.Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor.Similar to that,Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor.While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor,and Factor VII connected with the drug by four hydrogen bonds,which involved three atoms of the drug and three residues of amino acids of the factor.The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor,plus one electrostatic bond and three hydrophobic interactions.Factor X and Remdesivir had an affinity energy of-9.6 kcal/moL,and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor.The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms.CONCLUSION Because of the in silico significant affinity,Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.展开更多
Background Inflammation and coagulation are two intimately cross-linked defense mechanisms of most, if not all organisms to injuries. During cardiopulmonary bypass （CPB）, these two processes are activated and intera...Background Inflammation and coagulation are two intimately cross-linked defense mechanisms of most, if not all organisms to injuries. During cardiopulmonary bypass （CPB）, these two processes are activated and interact with each other through several common pathways, which may result in subsequent organ dysfunction. In the present study, we hypothesized that the addition of nitric oxide, prostaglandin E1 （PGE1）, and aprotinin to the systemic circulation, hereby referred to as blood hibernation, would attenuate the inflammation and coagulation induced by CPB. Methods Thirty adult mongrel dogs were equally divided into five groups, anesthetized and placed on hypothermic CPB （32℃）. Each group received respectively the following treatments： （1） inhalation of 40 ppm nitric oxide; （2） intravenous infusion of 20 ng.kgl.min1 of PGE1; （3） 80 000 kallikrein inhibitor units （KIU）/kg of aprotinin; （4） the combination of all three agents （blood hibernation group）; and （5） no treatment （control group） during CPB. Activation of leukocyte, platelet, endothelial cell, and formation of thrombin were assessed after CPB. Results As compared with the other four groups, leukocyte counts were higher, while plasma elastase, interleukin-8, CD11b mRNA expression, myeloperoxidase activities and lung tissue leukocyte counts were lower in the blood hibernation group （P 〈0.05 versus other four groups after CPB）. Plasma prothrombin fragment （PTF）1＋2, and platelet activation factors were lower, while platelet counts were higher in the blood hibernation group （P 〈0.05 versus other four groups at 6 and 12 hours after CPB）. Electron microscopy showed endothelial pseudopods protrusion, with cell adherence in all four groups except the blood hibernation group where endothelial cells remained intact. Conclusion Blood hibernation, effected by the addition of nitric oxide, PGE1 and aprotinin to the circulating blood during extra-corporeal circulation, was observed to attenuate the inflammation and coagulation induced by cardiopulmonary bypass, most likely by inhibiting the important common intermediates between the two cross-linked processes.展开更多
Contamination by dexamethasone(DEX)in aquatic environments is expected to rise significantly as it is used in the treatment of inflammation,allergies,and autoimmune disorders,especially COVID-19.However,the underlying...Contamination by dexamethasone(DEX)in aquatic environments is expected to rise significantly as it is used in the treatment of inflammation,allergies,and autoimmune disorders,especially COVID-19.However,the underlying effects and mechanisms of DEX in leading to metabolic or infectious diseases have remained largely unexplored in teleosts.Here,we used zebrafish(Danio rerio)as a model to study the effects of DEX exposure on metabolic and infectious diseases.We found that DEX-induced hepatobiliary syndrome significantly increased susceptibility to type Ⅱ grass carp reovirus(GCRV-Ⅱ),which causes severe hemorrhagic disease in aquaculture.Comparative transcriptomic analysis demonstrated the shared and disease-specific immunometabolic responses among zebrafish larvae with hepatobiliary syndrome and/or GCRV-Ⅱ infection.Moreover,compared with those of wild-type zebrafish,zebrafish larvae with DEX-induced hepatobiliary syndrome and/or GCRV-Ⅱ infection presented increased expression of inflammatory markers(il1b),coagulation markers(fibrinogens and antithrombin Ⅲ),and genes involved in autophagy,including hsp90aa.In vivo inhibition of autophagy via 3-MA and Hsp90 activity via geldanamycin markedly suppressed hepatic lipid deposition and reactive oxygen species accumulation caused by hepatobiliary syndrome and/or GCRV-Ⅱ infection,thus significantly reducing the severity of disease and level of mortality induced by DEX and/or GCRV-Ⅱ infection.In conclusion,our findings establish that the inhibition of autophagy and Hsp90 activity are promising therapeutic targets for DEX-induced hepatobiliary syndrome,GCRV-Ⅱ infection,and DEX-induced hepatobiliary syndrome complicated with GCRV-Ⅱ infection.展开更多
Idiopathic pulmonary fibrosis(IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure.Recently, phosphatidyli...Idiopathic pulmonary fibrosis(IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure.Recently, phosphatidylinositol 3-kinase(PI3 K)/protein kinase B(PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3 K/AKT in fibrotic processes is increasingly prominent, with PI3 K/AKT inhibitors currently under clinical evaluation in IPF. Therefore,PI3 K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3 K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3 K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.展开更多
Pancreatic cancer is a devastating malignant disease with 5-year survival rate less than 8%.The impenetrable desmoplastic stroma of pancreatic tissue and serious side-effects of existing drugs hinder the effective tre...Pancreatic cancer is a devastating malignant disease with 5-year survival rate less than 8%.The impenetrable desmoplastic stroma of pancreatic tissue and serious side-effects of existing drugs hinder the effective treatment for pancreatic carcinoma.Thus,it is imperative to exploit much more safe and efficient methods to prolong the survival of pancreatic cancer patients.In this study,we explored a superior anti-pancreatic cancer strategy based on gadofullerene nanoparticles(GFNPs)using an orthotopic human pancreatic carcinoma(PANC-1)tumor model.It was demonstrated that GFNPs could efficiently suppress orthotopic pancreatic cancer in a dose manner,and significantly extend the survival rate of tumor-bearing mice.Of note,the proteomic profiling of tumor tissues revealed that GFNPs ameliorated the coagulation cascade dysfunction and downregulated the thrombin expression in pancreatic tumor tissues.The regulation of abnormal thrombin by GFNPs was validated in vitro and in vivo.More importantly,GFNPs suppressed orthotopic pancreatic cancer with negligible adverse effects,superior to the widely recognized clinical antipancreatic cancer drug,gemcitabine.Together,this study provides a promising therapeutic for intractable pancreatic cancer as well as a potential to alleviate the cancer-associated thromboembolic diseases.展开更多
文摘BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities is coagulopathies,including thrombosis and disseminated intravascular coagulation.Because of this,the administration of low molecular weight heparin is required for patients that need to be hospitalized.In addition,Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome,Ebola,Acute Respiratory Syndrome,and other diseases,showing satisfactory results on recovery.Besides,there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19.AIM To investigate in silico the interaction between Remdesivir and clotting factors,pursuing a possibility of using it as medicine.METHODS In this in silico study,the 3D structures of angiotensin-converting enzyme 2(ACE2),Factor I(fibrinogen),Factor II(prothrombin),Factor III(thromboplastin),Factor V(proaccelerin),Factor VII(proconvertin),Factor VIII(antihemophilic factor A),Factor IX(antihemophilic factor B),Factor X(Stuart-Prower factor),and Factor XI(precursor of thromboplastin(these structures are technically called receptors)were selected from the Protein Data Bank.The structures of the antivirals Remdesivir and Osetalmivir(these structures are called ligands)were selected from the PubChem database,while the structure of Atazanavir was selected from the ZINC database.The software AutoDock Tools(ADT)was used to prepare the receptors for molecular docking.Ions,peptides,water molecules,and other ones were removed from each ligand,and then,hydrogen atoms were added to the structures.The grid box was delimited and calculated using the same software ADT.A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors,and still the software Marvin sketch®(ChemAxon®)was used to forecast the protonation state.To perform molecular docking,ADT and Vina software was connected.Using PyMol®software and Discovery studio®software from BIOVIA,it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands.Ligand tortions,atoms that participated in the interactions,and the type,strength,and duration of the interactions were also analyzed using those software.RESULTS Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of-8.8 kcal/moL,forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2.Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor.Similar to that,Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor.While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor,and Factor VII connected with the drug by four hydrogen bonds,which involved three atoms of the drug and three residues of amino acids of the factor.The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor,plus one electrostatic bond and three hydrophobic interactions.Factor X and Remdesivir had an affinity energy of-9.6 kcal/moL,and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor.The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms.CONCLUSION Because of the in silico significant affinity,Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 30772153 and 30872455）.
文摘Background Inflammation and coagulation are two intimately cross-linked defense mechanisms of most, if not all organisms to injuries. During cardiopulmonary bypass （CPB）, these two processes are activated and interact with each other through several common pathways, which may result in subsequent organ dysfunction. In the present study, we hypothesized that the addition of nitric oxide, prostaglandin E1 （PGE1）, and aprotinin to the systemic circulation, hereby referred to as blood hibernation, would attenuate the inflammation and coagulation induced by CPB. Methods Thirty adult mongrel dogs were equally divided into five groups, anesthetized and placed on hypothermic CPB （32℃）. Each group received respectively the following treatments： （1） inhalation of 40 ppm nitric oxide; （2） intravenous infusion of 20 ng.kgl.min1 of PGE1; （3） 80 000 kallikrein inhibitor units （KIU）/kg of aprotinin; （4） the combination of all three agents （blood hibernation group）; and （5） no treatment （control group） during CPB. Activation of leukocyte, platelet, endothelial cell, and formation of thrombin were assessed after CPB. Results As compared with the other four groups, leukocyte counts were higher, while plasma elastase, interleukin-8, CD11b mRNA expression, myeloperoxidase activities and lung tissue leukocyte counts were lower in the blood hibernation group （P 〈0.05 versus other four groups after CPB）. Plasma prothrombin fragment （PTF）1＋2, and platelet activation factors were lower, while platelet counts were higher in the blood hibernation group （P 〈0.05 versus other four groups at 6 and 12 hours after CPB）. Electron microscopy showed endothelial pseudopods protrusion, with cell adherence in all four groups except the blood hibernation group where endothelial cells remained intact. Conclusion Blood hibernation, effected by the addition of nitric oxide, PGE1 and aprotinin to the circulating blood during extra-corporeal circulation, was observed to attenuate the inflammation and coagulation induced by cardiopulmonary bypass, most likely by inhibiting the important common intermediates between the two cross-linked processes.
基金supported by the National Natural Science Foundation of China(U22A20535)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0730100)the National Key Research and Development Program(2023YFD2401603).
文摘Contamination by dexamethasone(DEX)in aquatic environments is expected to rise significantly as it is used in the treatment of inflammation,allergies,and autoimmune disorders,especially COVID-19.However,the underlying effects and mechanisms of DEX in leading to metabolic or infectious diseases have remained largely unexplored in teleosts.Here,we used zebrafish(Danio rerio)as a model to study the effects of DEX exposure on metabolic and infectious diseases.We found that DEX-induced hepatobiliary syndrome significantly increased susceptibility to type Ⅱ grass carp reovirus(GCRV-Ⅱ),which causes severe hemorrhagic disease in aquaculture.Comparative transcriptomic analysis demonstrated the shared and disease-specific immunometabolic responses among zebrafish larvae with hepatobiliary syndrome and/or GCRV-Ⅱ infection.Moreover,compared with those of wild-type zebrafish,zebrafish larvae with DEX-induced hepatobiliary syndrome and/or GCRV-Ⅱ infection presented increased expression of inflammatory markers(il1b),coagulation markers(fibrinogens and antithrombin Ⅲ),and genes involved in autophagy,including hsp90aa.In vivo inhibition of autophagy via 3-MA and Hsp90 activity via geldanamycin markedly suppressed hepatic lipid deposition and reactive oxygen species accumulation caused by hepatobiliary syndrome and/or GCRV-Ⅱ infection,thus significantly reducing the severity of disease and level of mortality induced by DEX and/or GCRV-Ⅱ infection.In conclusion,our findings establish that the inhibition of autophagy and Hsp90 activity are promising therapeutic targets for DEX-induced hepatobiliary syndrome,GCRV-Ⅱ infection,and DEX-induced hepatobiliary syndrome complicated with GCRV-Ⅱ infection.
基金supported by the National Natural Science Foundation of China(No.82003873)the Postdoctoral Science Foundation of China(No.2020M681899)the Zhejiang Provincial Natural Science Foundation of China(No.LR21H310001)。
文摘Idiopathic pulmonary fibrosis(IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure.Recently, phosphatidylinositol 3-kinase(PI3 K)/protein kinase B(PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3 K/AKT in fibrotic processes is increasingly prominent, with PI3 K/AKT inhibitors currently under clinical evaluation in IPF. Therefore,PI3 K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3 K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3 K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.
基金supported by the National Major Scientific Instruments and Equipments Development Project(ZDYZ2015-2)the Key Research Program of the Chinese Academy of Sciences(QYZDJSSW-SLH025)the National Natural Science Foundation of China(51902313)。
文摘Pancreatic cancer is a devastating malignant disease with 5-year survival rate less than 8%.The impenetrable desmoplastic stroma of pancreatic tissue and serious side-effects of existing drugs hinder the effective treatment for pancreatic carcinoma.Thus,it is imperative to exploit much more safe and efficient methods to prolong the survival of pancreatic cancer patients.In this study,we explored a superior anti-pancreatic cancer strategy based on gadofullerene nanoparticles(GFNPs)using an orthotopic human pancreatic carcinoma(PANC-1)tumor model.It was demonstrated that GFNPs could efficiently suppress orthotopic pancreatic cancer in a dose manner,and significantly extend the survival rate of tumor-bearing mice.Of note,the proteomic profiling of tumor tissues revealed that GFNPs ameliorated the coagulation cascade dysfunction and downregulated the thrombin expression in pancreatic tumor tissues.The regulation of abnormal thrombin by GFNPs was validated in vitro and in vivo.More importantly,GFNPs suppressed orthotopic pancreatic cancer with negligible adverse effects,superior to the widely recognized clinical antipancreatic cancer drug,gemcitabine.Together,this study provides a promising therapeutic for intractable pancreatic cancer as well as a potential to alleviate the cancer-associated thromboembolic diseases.
