Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide.Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase（RT）inhibitors,a...Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide.Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase（RT）inhibitors,a new template bearing N-phenylbenzenesulfonamide（PBSA） structure was designed to enhance the interactions with HIV-1 RT.In this manuscript,a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity.The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC_（50） values ranging of 0.105-14.531 μmol/L.In particular,compound 13 f not only has high anti-HIV-1 activity（0.108 μmol/L）,but also possesses low toxicity with a Tl value of 1816.6.Furthermore,the major interactions of the inhibitor 13 f with HIV-1 RT were also investigated using the molecular modelling.Our discovered structure-activity relationships（SARs） of these analogues may serve as an important clue for further optimizations.展开更多
The discovery of antibiotics marked a golden age in the revolution of human medicine. However,decades later, bacterial infections remain a global healthcare threat, and a return to the pre-antibiotic era seems inevita...The discovery of antibiotics marked a golden age in the revolution of human medicine. However,decades later, bacterial infections remain a global healthcare threat, and a return to the pre-antibiotic era seems inevitable if stringent measures are not adopted to curb the rapid emergence and spread of multidrug resistance and the indiscriminate use of antibiotics. In hospital settings, multidrug resistant(MDR) pathogens, including carbapenem-resistant Pseudomonas aeruginosa, vancomycin-resistant enterococci(VRE), methicillin-resistant Staphylococcus aureus(MRSA), and extendedspectrum β-lactamases(ESBL) bearing Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae are amongst the most problematic due to the paucity of treatment options,increased hospital stay, and exorbitant medical costs. Antimicrobial peptides(AMPs) provide an excellent potential strategy for combating these threats. Compared to empirical antibiotics, they show low tendency to select for resistance, rapid killing action, broad-spectrum activity, and extraordinary clinical efficacy against several MDR strains. Therefore, this review highlights multidrug resistance among nosocomial bacterial pathogens and its implications and reiterates the importance of AMPs as next-generation antibiotics for combating MDR superbugs.展开更多
Weight loss and cachexia are common problems in colorectal cancer patients;thus,parenteral and enteral nutrition support play important roles in cancer care.However,the impact of nonessential amino acid components of ...Weight loss and cachexia are common problems in colorectal cancer patients;thus,parenteral and enteral nutrition support play important roles in cancer care.However,the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied.In this study,we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival(P<0.001)than those who did not.Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice,predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis,resulting in mTORCl activation.mTORCl inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation.In addition,cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione.We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin.These findings indicate that cyst(e)ine;as part of supplemental nutrition,plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.展开更多
Dear Editor,Glucose-6-phosphate dehydrogenase(G6PD)is the rate-limiting enzyme in the oxidative pentose phosphate pathway(oxPPP)that can generate cytosolic NADPH(Fig.1a)for biosynthesis and oxidative defence.Here,we r...Dear Editor,Glucose-6-phosphate dehydrogenase(G6PD)is the rate-limiting enzyme in the oxidative pentose phosphate pathway(oxPPP)that can generate cytosolic NADPH(Fig.1a)for biosynthesis and oxidative defence.Here,we reveal a previously unidentified function of G6PD.It,even the natural G6PD deficiency-associated mutant without the activity to maintain the normal oxPPP,can antagonize the stresses by supporting the reductive glutamine metabolism and AMPK activation,independently of the NADPH generation by the oxPPP.展开更多
The authors would like to correct Fig.2g.An annotation error was introduced in the preparation of this figure for publication.The authors declare that this correction does not change the results or conclusions of this...The authors would like to correct Fig.2g.An annotation error was introduced in the preparation of this figure for publication.The authors declare that this correction does not change the results or conclusions of this paper.The authors sincerely apologize for having this error in the article,and apologize for any inconvenience caused.展开更多
基金supported by the National Natural Science Fundation of China(No.30772647)the special major science and technology project of"Creation of Major New Drugs"(No.2009ZX09102-033)
基金supported in part by grants from the National Natural Science Foundation of China(No.81402788)the Ph.D. Start-up Fund of Natural Science Foundation of Liaoning Province, China(No.20141115)
文摘Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide.Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase（RT）inhibitors,a new template bearing N-phenylbenzenesulfonamide（PBSA） structure was designed to enhance the interactions with HIV-1 RT.In this manuscript,a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity.The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC_（50） values ranging of 0.105-14.531 μmol/L.In particular,compound 13 f not only has high anti-HIV-1 activity（0.108 μmol/L）,but also possesses low toxicity with a Tl value of 1816.6.Furthermore,the major interactions of the inhibitor 13 f with HIV-1 RT were also investigated using the molecular modelling.Our discovered structure-activity relationships（SARs） of these analogues may serve as an important clue for further optimizations.
基金supported by the National Natural Science Foundation of China(21761142002 and 31801975)Chinese Academy of Sciences(XDB31000000,SAJC201606,KFZD-SW-219-2,KFJ-BRP-008,and KGFZD-135-17-011)Yunnan Province Grant(2015HA023)
文摘The discovery of antibiotics marked a golden age in the revolution of human medicine. However,decades later, bacterial infections remain a global healthcare threat, and a return to the pre-antibiotic era seems inevitable if stringent measures are not adopted to curb the rapid emergence and spread of multidrug resistance and the indiscriminate use of antibiotics. In hospital settings, multidrug resistant(MDR) pathogens, including carbapenem-resistant Pseudomonas aeruginosa, vancomycin-resistant enterococci(VRE), methicillin-resistant Staphylococcus aureus(MRSA), and extendedspectrum β-lactamases(ESBL) bearing Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae are amongst the most problematic due to the paucity of treatment options,increased hospital stay, and exorbitant medical costs. Antimicrobial peptides(AMPs) provide an excellent potential strategy for combating these threats. Compared to empirical antibiotics, they show low tendency to select for resistance, rapid killing action, broad-spectrum activity, and extraordinary clinical efficacy against several MDR strains. Therefore, this review highlights multidrug resistance among nosocomial bacterial pathogens and its implications and reiterates the importance of AMPs as next-generation antibiotics for combating MDR superbugs.
基金supported by National Key Research and Development Program of China[2020YFA0112300 and 2018YFC2000400 to C.C.]the National Natural Science Foundation of China[82072622,81860488,and 81560432 to Y.R.,81830087 and 31771516 to C.C.,81772847 to L.R.,81672639 to Z.Z.,and 81872414 and 81802671 to J.D.]+1 种基金Yunnan Leading Medical Talents Program[L-201610]to Y.R.,Yunnan Fundamental Research Projects[2019FB112]Yunnan excellent young scientist foundation(2020)to J.D.,and Project of Innovative Research Team of Yunnan Province[2018HC004 and 2019HC005].S.-C.J.Y.
文摘Weight loss and cachexia are common problems in colorectal cancer patients;thus,parenteral and enteral nutrition support play important roles in cancer care.However,the impact of nonessential amino acid components of nutritional intake on cancer progression has not been fully studied.In this study,we discovered that gastrointestinal cancer patients who received cysteine as part of the parenteral nutrition had shorter overall survival(P<0.001)than those who did not.Cystine indeed robustly promotes colon cancer cell growth in vitro and in immunodeficient mice,predominately by inhibiting SESN2 transcription via the GCN2-ATF4 axis,resulting in mTORCl activation.mTORCl inhibitors Rapamycin and Everolimus block cystine-induced cancer cell proliferation.In addition,cystine confers resistance to oxaliplatin and irinotecan chemotherapy by quenching chemotherapy-induced reactive oxygen species via synthesizing glutathione.We demonstrated that dietary deprivation of cystine suppressed colon cancer xenograft growth without weight loss in mice and boosted the antitumor effect of oxaliplatin.These findings indicate that cyst(e)ine;as part of supplemental nutrition,plays an important role in colorectal cancer and manipulation of cyst(e)ine content in nutritional formulations may optimize colorectal cancer patient survival.
基金supporled in part by grants from the National Nature Science Foundation of China(81972567 and 81672762 to B.L.,81830087,U1602221 and 31771516 to C.C.81802671 and 81872414 to DJ.)Grant CIT&TCD20190333 from the Support Projectof High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan,Tianjin Natural Science Foundation(No.18JCONJC79600)+1 种基金Project oflnnovative Research Team of Yunnan Province(2019HCO05)Yunnan Funda-mentall Pesearch Projects(12019FB112 and 202001A070018 to DJ).
文摘Dear Editor,Glucose-6-phosphate dehydrogenase(G6PD)is the rate-limiting enzyme in the oxidative pentose phosphate pathway(oxPPP)that can generate cytosolic NADPH(Fig.1a)for biosynthesis and oxidative defence.Here,we reveal a previously unidentified function of G6PD.It,even the natural G6PD deficiency-associated mutant without the activity to maintain the normal oxPPP,can antagonize the stresses by supporting the reductive glutamine metabolism and AMPK activation,independently of the NADPH generation by the oxPPP.
文摘The authors would like to correct Fig.2g.An annotation error was introduced in the preparation of this figure for publication.The authors declare that this correction does not change the results or conclusions of this paper.The authors sincerely apologize for having this error in the article,and apologize for any inconvenience caused.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29050301,XDB32030200,and XDA16020900)the National Key R&D Program of China(2017YFB0405404)+6 种基金the National Science and Technology Major Project(2018ZX09201017-001-001)Yunnan Key Research and Development Program(202003AD150009)the National Natural Science Foundation of China(31671038,31971373,8170347081803492)China Postdoctoral Science Foundation(2019M660065)Innovation Program of Science and Research from the Dalian Institute of Chemical PhysicsChinese Academy of Sciences(DICP I201934)。
