Programmed cell death-1(PD-1)/programmed cell death ligand-1(PD-L1)blocking therapy has become a major pillar of cancer immunotherapy.Compared with antibodies targeting,small-molecule checkpoint inhibitors which have ...Programmed cell death-1(PD-1)/programmed cell death ligand-1(PD-L1)blocking therapy has become a major pillar of cancer immunotherapy.Compared with antibodies targeting,small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed.Here we identified berberine(BBR),a proven anti-inflammation drug,as a negative regulator of PDL1 from a set of traditional Chinese medicine(TCM)chemical monomers.BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells.In addition,BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumorinfiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells(MDSCs)and regulatory T-cells(Tregs).BBR triggered PD-L1 degradation through ubiquitin(Ub)/proteasome-dependent pathway.Remarkably,BBR selectively bound to the glutamic acid76 of constitutive photomorphogenic-9 signalosome 5(CSN5)and inhibited PD-1/PD-L1 axis through its deubiquitination activity,resulting in ubiquitination and degradation of PD-L1.Our data reveals a previously unrecognized antitumor mechanism of BBR,suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.展开更多
Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2A...Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.展开更多
Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast ...Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre- existing T-cell function to modulate antitumor immunity. in this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-IIPD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural informationwill benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.展开更多
In underground rock engineering,water-bearing faults may be subjected to dynamic loading,resulting in the coupling of hydraulic and dynamic hazards.Understanding the interaction mechanism between the stress waves indu...In underground rock engineering,water-bearing faults may be subjected to dynamic loading,resulting in the coupling of hydraulic and dynamic hazards.Understanding the interaction mechanism between the stress waves induced by dynamic loadings and liquid-filled rock joints is therefore crucial.In this study,an auxiliary device for simulating the liquid-filled layer was developed to analyze the dynamic response characteristics of liquid-filled rock joints in laboratory.Granite and polymethyl methacrylate(PMMA)specimens were chosen for testing,and high-amplitude shock waves induced by a split Hopkinson pressure bar(SHPB)were used to produce dynamic loadings.Impact loading tests were conducted on liquid-filled rock joints with different joint inclinations.The energy propagation coefficient and peak liquid pressure were proposed to investigate the energy propagation and attenuation of waves propagating across the joints,as well as the dynamic response characteristics of the liquid in the liquid-filled rock joints.For the inclination angle range considered herein,the experimental results showed that the energy propagation coefficient gently diminished with increasing joint inclination,and smaller coefficient values were obtained for granite specimens compared with PMMA specimens.The peak liquid pressure exhibited a gradually decreasing trend with increasing joint inclination,and the peak pressure for granite specimens was slightly higher than that for PMMA specimens.Overall,this paper may provide a considerably better method for studying liquid-filled rock joints at the laboratory scale,and serves as a guide for interpreting the underlying mechanisms for interactions between stress waves and liquid-filled rock joints.展开更多
The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular an...The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.展开更多
The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity.Here,we show that carrimycin,a new macrolide antibiotic in the...The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity.Here,we show that carrimycin,a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials,decreases the efficiency of programmed–1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion.Carrimycin binds directly to the coronaviral frameshift-stimulatory element(FSE)RNA pseudoknot,interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes.Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses.Because the FSE mechanism is essential in all coronaviruses,carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA.This finding may open a new direction in antiviral drug discovery for coronavirus variants.展开更多
Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network...Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network-based deep learning model,employing different training sets of 13,638 molecules for pre-training and fine-tuning,was aided in predicting and exploring novel molecules against H.pylori.A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H.pylori strains with minimum inhibitory concentrations(MICs)of 0.25-0.5μg/mL.Pharmacokinetic studies demonstrated an ideal gastric retention of 8,with the stomach concentration significantly higher than its MIC at 24 h post dose.Oral administration of 8 and omeprazole(OPZ)showed a comparable gastric bacterial reduction(2.2-log reduction)to the triple-therapy,namely OPZ+amoxicillin(AMX)+clarithromycin(CLA)without obvious disturbance on the intestinal flora.A combination of OPZ,AMX,CLA,and 8 could further decrease the bacteria load(2.8-log reduction).More importantly,the mono-therapy of 8 exhibited comparable eradication to both triple-therapy(OPZ+AMX+CLA)and quadrupletherapy(OPZ+AMX+CLA+bismuth citrate)groups.SecA and BamD,playing a major role in outer membrane protein(OMP)transport and assembling,were identified and verified as the direct targets of 8 by employing the chemoproteomics technique.n summary,by targeting the relatively conserved OMPs transport and assembling system,8 has the potential to be developed as a novel anti-H.pylori candidate,especially for the eradication of drug-resistant strains.展开更多
Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalab...Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability.Of them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against HCoV-OC43.Furthermore,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane fusion.Accordingly,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).展开更多
A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against c...A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant(MDR)Gram-negative strains,with a highly druglike nature.The checkerboard assay reveals its significant synergistic effect withβ-lactamase inhibitor avibactam,and the MIC values against MDR enterobacteria were reduced up to 4—512folds.X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and Cβ-lactamases.Accordingly,preclinical studies of 33a alone and 33a-avibactam combination as potential innovative candidates are actively going on,in the treatment ofβ-lactamase-producing MDR Gram-negative bacterial infections.展开更多
Landslides are one of the most common geological hazards worldwide,especially in Sichuan Province(Southwest China).The current study's main,purposes are to explore the potential applications of convolutional neura...Landslides are one of the most common geological hazards worldwide,especially in Sichuan Province(Southwest China).The current study's main,purposes are to explore the potential applications of convolutional neural networks(CNN)hybrid ensemble metaheuristic optimization algorithms,namely beluga whale optimization(BWO)and coati optimization algorithm(COA),for landslide susceptibility mapping in Sichuan Province(China).For this aim,fourteen landslide conditioning factors were compiled in a spatial database.The effectiveness of the conditioning factors in the development of the landslide predictive model was quantified using the linear support vector machine model.The receiver operating characteristic(ROC)curve(AUC),the root mean square error,and six statistical indices were used to test and compare the three resultant models.For the training dataset,the AUC values of the CNN-COA,CNN-BWO and CNN models were 0.946,0.937 and 0.855,respectively.In terms of the validation dataset,the CNN-COA model exhibited a higher AUC value of 0.919,while the AUC values of the CNN-BWO and CNN models were 0.906 and 0.805,respectively.The results indicate that the CNN-COA model,followed by the CNN-BWO model,and the CNN model,offers the best overall performance for landslide susceptibility analysis.展开更多
Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 30-substituents at the 11–side chain were synthesized and evaluated for their anticancer activity from soph...Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 30-substituents at the 11–side chain were synthesized and evaluated for their anticancer activity from sophoridine(1), a natural antitumor medicine. Among them, the sophoridinic ketones 5a–b, alkenes 7a–b and sophoridinic amines 14a–b displayed reasonable antiproliferative activity with IC50 values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin(AMD)-susceptible and resistant MCF-7 breast carcinoma cells,indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1. Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.展开更多
The investigation of the in situ stress distribution has always been a key condition for engineering design of deep tunnels and analysis of surrounding rock stability.In this paper,a comprehensive judgment method coup...The investigation of the in situ stress distribution has always been a key condition for engineering design of deep tunnels and analysis of surrounding rock stability.In this paper,a comprehensive judgment method coupled with pressure/tension(P/T)axis mechanism and geological structure is proposed to invert the in situ stress in the Duoxiongla tunnel in Tibet.In the process of TBM tunnel excavation,3887 groups of microseismic events were collected by means of microseismic monitoring technology.By studying the temporal and spatial distribution of 3887 groups of microseismic events,42 groups of microseismic data were selected for in situ stress inversion.Then the focal mechanisms of 42 groups of microseisms were inverted.Combined with the analysis of the previous geological survey,the inversion results of the in situ stress were analyzed.According to the focal mechanism of the tunnel area,the linear in situ stress inversion method was used to invert the in situ stress in the source area.Finally,according to the PTGS(pressure/tension axis mechanism and geological structure)comprehensive judgment method proposed in this paper,the in situ stress of the tunnel microseismic region was determined.The results show that there are mainly three groups of fissures and joint surfaces in the tunnel area,and the in situ stress is dominated by the horizontrun tectonic stress;the main driving force of the rupture surface in the excavation process of Duoxiongla tunnel is the horizontal tectonic stress;the distribution of the maximum and minimum principal stress obtained by the inversion is consistent with the distribution of the P/T axis;combined with the linear in situ stress inversion method and the comprehensive judgment of PTGS,the azimuth and dip angles of the three principal stresses are finally determined as N90.71°E,4.06°,N5.35°W,3.06°,and N8.10W,85.32°,respectively.The study verifies the feasibility of microseismic inversion of in situ stress.展开更多
Chronic hepatitis C virus(HCV)infection has become a major public health burden worldwide.Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro.The...Chronic hepatitis C virus(HCV)infection has become a major public health burden worldwide.Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro.The structure-activity analysis revealed that(i)sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold;(ii)the introduction of an electron-withdrawing group on the phenyl ring in 12-N-benzenesulfonylΔβγsophocarpinic acids was beneficial for the antiviral activity against HCV.Among them,compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9,respectively.Therefore,both were selected as antiviral candidates for further investigation.展开更多
Tuberculosis(TB)is a disease which kills two million people every year and infects over one-third of the world's population.Eighteen new 8-substituted berberine derivatives were synthesized and evaluated for their...Tuberculosis(TB)is a disease which kills two million people every year and infects over one-third of the world's population.Eighteen new 8-substituted berberine derivatives were synthesized and evaluated for their anti-mycobacterial activities against M ycobacterium tuberculosis(M.tuberculosis)strain H_(37)Rv.Among these compounds,compound 6i was the most effective antitubercular agent with an MIC of 1.0μg/mL.Most importantly,compound 6i also exhibited a potent effect against clinically isolated rifampicin-and isoniazid-resistant M.tuberculosis strains,suggesting a different mode of action from the current drugs.Therefore,it shows potential for the development of new anti-TB agents.展开更多
Tuberculosis is a serious threat to public health throughout the world.A series of new l3-n-nonylprotoberberine derivatives was designed,synthesized and evaluated for anti-mycobacterial activity against Mycobacterium ...Tuberculosis is a serious threat to public health throughout the world.A series of new l3-n-nonylprotoberberine derivatives was designed,synthesized and evaluated for anti-mycobacterial activity against Mycobacterium tuberculosis strain H_(37)Rv.Several compounds(2,11a-c,11g,13d,15c)exhibited excellent anti-tubercular activity with an MIC below 1.0μg/mL.Notably,compound 13d showed potential antibacterial effect against both drug-susceptible and multidrug-resistant(MDR)M.tuberculosis with MIC ranges of 0.0625-1.0μg/mL.These results suggest a mode of action different from that of the current anti-mycobacterial drugs rifampicin and isoniazid.Hence,compound 13d is an attractive lead compound for the development of new antitubercular agents.展开更多
Ultrasound(US)is a biofavorable mechanical wave that has shown practical significance in biomedical fields.Due to the cavitation effect,sonoluminescence,sonoporation,pyrolysis,and other biophysical and chemical effect...Ultrasound(US)is a biofavorable mechanical wave that has shown practical significance in biomedical fields.Due to the cavitation effect,sonoluminescence,sonoporation,pyrolysis,and other biophysical and chemical effects,a wide range of matters have been elucidated to be responsive to the stimulus of US.This review addresses and discusses current developments in US-responsive matters,including US-breakable intermolecular conjugations,US-catalytic sonosensitizers,fluorocarbon compounds,microbubbles,and US-propelled micro-and nanorobots.Meanwhile,the interactions between US and advanced matters create various biochemical products and enhanced mechanical effects,leading to the exploration of potential biomedical applications,from US-facilitated biosensing and diagnostic imaging to US-induced therapeutic applications and clinical translations.Finally,the current challenges are summarized and future perspectives on US-responsive matters in biomedical applications and clinical translations are proposed.展开更多
基金supported by grants from National Natural Science Foundation of China(81973366,81773782 and 81903695)CAMS Innovation Fund for Medical Sciences(2016-12M-1-011,China)+2 种基金Open Project of State Key Laboratory of Bioactive Substance and Function of Natural Medicines(GTZK201908,China)National Mega-project for Innovative Drugs(2019ZX09721-001,China)Chinese Pharmaceutical Association-Yiling Pharmaceutical Innovation Fund for Biomedicine(GL-1-B04-20180366,China)
文摘Programmed cell death-1(PD-1)/programmed cell death ligand-1(PD-L1)blocking therapy has become a major pillar of cancer immunotherapy.Compared with antibodies targeting,small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed.Here we identified berberine(BBR),a proven anti-inflammation drug,as a negative regulator of PDL1 from a set of traditional Chinese medicine(TCM)chemical monomers.BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells.In addition,BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumorinfiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells(MDSCs)and regulatory T-cells(Tregs).BBR triggered PD-L1 degradation through ubiquitin(Ub)/proteasome-dependent pathway.Remarkably,BBR selectively bound to the glutamic acid76 of constitutive photomorphogenic-9 signalosome 5(CSN5)and inhibited PD-1/PD-L1 axis through its deubiquitination activity,resulting in ubiquitination and degradation of PD-L1.Our data reveals a previously unrecognized antitumor mechanism of BBR,suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.
基金the CAMS initiative for innovative medicine(2022-I2M-2-002,China)National Natural Science Foundation of China(32141003)。
文摘Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.
基金This work was supported by the National Basic Research Program （973 Program） （Nos. 2013CB531502 and 2014CB542503）, the National Natural Science Foundation of China （Grant Nos. 31390432 and 31500722）, Grand S＆T project of China Health and Family Planning Commission （2013ZX10004608-002 and 2016ZX10004201-009）, the Strategic Priority Research Program of the Chinese Academy of Sciences （CAS XDB08020100）. GFG is supported partly as a leading principal investigator of the NSFC Innovative Research Group （81321063）.
文摘Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre- existing T-cell function to modulate antitumor immunity. in this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-IIPD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural informationwill benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.
基金financially supported by the National Key Research and Development Plan of China(Grant No.2018YFC1504902)the National Natural Science Foundation of China(Grant No.52079068)the State Key Laboratory of Hydroscience and Engineering,China(Grant No.2021-KY-04)。
文摘In underground rock engineering,water-bearing faults may be subjected to dynamic loading,resulting in the coupling of hydraulic and dynamic hazards.Understanding the interaction mechanism between the stress waves induced by dynamic loadings and liquid-filled rock joints is therefore crucial.In this study,an auxiliary device for simulating the liquid-filled layer was developed to analyze the dynamic response characteristics of liquid-filled rock joints in laboratory.Granite and polymethyl methacrylate(PMMA)specimens were chosen for testing,and high-amplitude shock waves induced by a split Hopkinson pressure bar(SHPB)were used to produce dynamic loadings.Impact loading tests were conducted on liquid-filled rock joints with different joint inclinations.The energy propagation coefficient and peak liquid pressure were proposed to investigate the energy propagation and attenuation of waves propagating across the joints,as well as the dynamic response characteristics of the liquid in the liquid-filled rock joints.For the inclination angle range considered herein,the experimental results showed that the energy propagation coefficient gently diminished with increasing joint inclination,and smaller coefficient values were obtained for granite specimens compared with PMMA specimens.The peak liquid pressure exhibited a gradually decreasing trend with increasing joint inclination,and the peak pressure for granite specimens was slightly higher than that for PMMA specimens.Overall,this paper may provide a considerably better method for studying liquid-filled rock joints at the laboratory scale,and serves as a guide for interpreting the underlying mechanisms for interactions between stress waves and liquid-filled rock joints.
基金supported by the National Natural Science Foundation of China,Nos.82271327 (to ZW),82072535 (to ZW),81873768 (to ZW),and 82001253 (to TL)。
文摘The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.
基金supported by grants from the National Natural Science Foundation,China(82151525)the National key research and development program,China(2022YFC0869000)the CAMS Innovation Fund for Medical Sciences(2022-I2M-JB-013,2021-I2M-1-028 and 2022-I2M-2-002,China).
文摘The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity.Here,we show that carrimycin,a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials,decreases the efficiency of programmed–1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion.Carrimycin binds directly to the coronaviral frameshift-stimulatory element(FSE)RNA pseudoknot,interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes.Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses.Because the FSE mechanism is essential in all coronaviruses,carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA.This finding may open a new direction in antiviral drug discovery for coronavirus variants.
基金This research project was supported by grants from National Natural Science Foundationof China(32141003,82330110,61976050,61972384,and 82003575)CAMS Initiative for Innovative Medicine(2021-1-12M-030).
文摘Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network-based deep learning model,employing different training sets of 13,638 molecules for pre-training and fine-tuning,was aided in predicting and exploring novel molecules against H.pylori.A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H.pylori strains with minimum inhibitory concentrations(MICs)of 0.25-0.5μg/mL.Pharmacokinetic studies demonstrated an ideal gastric retention of 8,with the stomach concentration significantly higher than its MIC at 24 h post dose.Oral administration of 8 and omeprazole(OPZ)showed a comparable gastric bacterial reduction(2.2-log reduction)to the triple-therapy,namely OPZ+amoxicillin(AMX)+clarithromycin(CLA)without obvious disturbance on the intestinal flora.A combination of OPZ,AMX,CLA,and 8 could further decrease the bacteria load(2.8-log reduction).More importantly,the mono-therapy of 8 exhibited comparable eradication to both triple-therapy(OPZ+AMX+CLA)and quadrupletherapy(OPZ+AMX+CLA+bismuth citrate)groups.SecA and BamD,playing a major role in outer membrane protein(OMP)transport and assembling,were identified and verified as the direct targets of 8 by employing the chemoproteomics technique.n summary,by targeting the relatively conserved OMPs transport and assembling system,8 has the potential to be developed as a novel anti-H.pylori candidate,especially for the eradication of drug-resistant strains.
基金supported by the National Natural Science Foundation of China(No.81974494)CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-070).
文摘Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability.Of them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against HCoV-OC43.Furthermore,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane fusion.Accordingly,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).
基金supported by CAMS Innovation Fund for Medical Sciences(2021-12M-1-070)National Natural Science Foundation of China(32141003)。
文摘A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant(MDR)Gram-negative strains,with a highly druglike nature.The checkerboard assay reveals its significant synergistic effect withβ-lactamase inhibitor avibactam,and the MIC values against MDR enterobacteria were reduced up to 4—512folds.X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and Cβ-lactamases.Accordingly,preclinical studies of 33a alone and 33a-avibactam combination as potential innovative candidates are actively going on,in the treatment ofβ-lactamase-producing MDR Gram-negative bacterial infections.
基金supported by China Postdoctoral Science Foundation:[grant number 2020M680583]National Natural Science Foundation of China[grant number 52208359]+1 种基金National Natural Science Foundation of China:[grant number 52109125]National Postdoctoral Program for Innovative Talents:[grant number BX20200191].
文摘Landslides are one of the most common geological hazards worldwide,especially in Sichuan Province(Southwest China).The current study's main,purposes are to explore the potential applications of convolutional neural networks(CNN)hybrid ensemble metaheuristic optimization algorithms,namely beluga whale optimization(BWO)and coati optimization algorithm(COA),for landslide susceptibility mapping in Sichuan Province(China).For this aim,fourteen landslide conditioning factors were compiled in a spatial database.The effectiveness of the conditioning factors in the development of the landslide predictive model was quantified using the linear support vector machine model.The receiver operating characteristic(ROC)curve(AUC),the root mean square error,and six statistical indices were used to test and compare the three resultant models.For the training dataset,the AUC values of the CNN-COA,CNN-BWO and CNN models were 0.946,0.937 and 0.855,respectively.In terms of the validation dataset,the CNN-COA model exhibited a higher AUC value of 0.919,while the AUC values of the CNN-BWO and CNN models were 0.906 and 0.805,respectively.The results indicate that the CNN-COA model,followed by the CNN-BWO model,and the CNN model,offers the best overall performance for landslide susceptibility analysis.
基金supported by the National Natural Science Foundation of China(No.81473248)Tianjin Medical University General Hospital Funding(ZYYFY2015030)
文摘Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 30-substituents at the 11–side chain were synthesized and evaluated for their anticancer activity from sophoridine(1), a natural antitumor medicine. Among them, the sophoridinic ketones 5a–b, alkenes 7a–b and sophoridinic amines 14a–b displayed reasonable antiproliferative activity with IC50 values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin(AMD)-susceptible and resistant MCF-7 breast carcinoma cells,indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1. Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.
基金National Postdoctoral Program for Innovative Talent of China,Grant/Award Number:BX20200191National Natural Science Foundation of China,Grant/Award Number:52079068The State Key Laboratory of Hydroscience and Hydraulic Engineering,Grant/Award Number:2021-KY-04。
文摘The investigation of the in situ stress distribution has always been a key condition for engineering design of deep tunnels and analysis of surrounding rock stability.In this paper,a comprehensive judgment method coupled with pressure/tension(P/T)axis mechanism and geological structure is proposed to invert the in situ stress in the Duoxiongla tunnel in Tibet.In the process of TBM tunnel excavation,3887 groups of microseismic events were collected by means of microseismic monitoring technology.By studying the temporal and spatial distribution of 3887 groups of microseismic events,42 groups of microseismic data were selected for in situ stress inversion.Then the focal mechanisms of 42 groups of microseisms were inverted.Combined with the analysis of the previous geological survey,the inversion results of the in situ stress were analyzed.According to the focal mechanism of the tunnel area,the linear in situ stress inversion method was used to invert the in situ stress in the source area.Finally,according to the PTGS(pressure/tension axis mechanism and geological structure)comprehensive judgment method proposed in this paper,the in situ stress of the tunnel microseismic region was determined.The results show that there are mainly three groups of fissures and joint surfaces in the tunnel area,and the in situ stress is dominated by the horizontrun tectonic stress;the main driving force of the rupture surface in the excavation process of Duoxiongla tunnel is the horizontal tectonic stress;the distribution of the maximum and minimum principal stress obtained by the inversion is consistent with the distribution of the P/T axis;combined with the linear in situ stress inversion method and the comprehensive judgment of PTGS,the azimuth and dip angles of the three principal stresses are finally determined as N90.71°E,4.06°,N5.35°W,3.06°,and N8.10W,85.32°,respectively.The study verifies the feasibility of microseismic inversion of in situ stress.
基金This work was supported by the National Natural Science Fund for Young Scientists(No.81302645)Beijing National Natural Science Fund(No.7121009).
文摘Chronic hepatitis C virus(HCV)infection has become a major public health burden worldwide.Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro.The structure-activity analysis revealed that(i)sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold;(ii)the introduction of an electron-withdrawing group on the phenyl ring in 12-N-benzenesulfonylΔβγsophocarpinic acids was beneficial for the antiviral activity against HCV.Among them,compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9,respectively.Therefore,both were selected as antiviral candidates for further investigation.
基金This work was supported by the National Natural Science Foundation for Young Scientists(81102312)the National S&T Major Special Projecton Major New Drug Innovation(2012ZX09301002-001-017).
文摘Tuberculosis(TB)is a disease which kills two million people every year and infects over one-third of the world's population.Eighteen new 8-substituted berberine derivatives were synthesized and evaluated for their anti-mycobacterial activities against M ycobacterium tuberculosis(M.tuberculosis)strain H_(37)Rv.Among these compounds,compound 6i was the most effective antitubercular agent with an MIC of 1.0μg/mL.Most importantly,compound 6i also exhibited a potent effect against clinically isolated rifampicin-and isoniazid-resistant M.tuberculosis strains,suggesting a different mode of action from the current drugs.Therefore,it shows potential for the development of new anti-TB agents.
基金This work was supported by the National Natural Science Fund for Young Scientists(81102312)the National S&T Major Special Projecton Major New Drug Innovation(2012ZX09301002-001).
文摘Tuberculosis is a serious threat to public health throughout the world.A series of new l3-n-nonylprotoberberine derivatives was designed,synthesized and evaluated for anti-mycobacterial activity against Mycobacterium tuberculosis strain H_(37)Rv.Several compounds(2,11a-c,11g,13d,15c)exhibited excellent anti-tubercular activity with an MIC below 1.0μg/mL.Notably,compound 13d showed potential antibacterial effect against both drug-susceptible and multidrug-resistant(MDR)M.tuberculosis with MIC ranges of 0.0625-1.0μg/mL.These results suggest a mode of action different from that of the current anti-mycobacterial drugs rifampicin and isoniazid.Hence,compound 13d is an attractive lead compound for the development of new antitubercular agents.
基金supported by the National Key Research and Development Program of China(2020YFA0908200)the National Natural Science Foundation of China(T2225003,52073060 and 61927805)+2 种基金the NanjingMedical Science and Technique Development Foundation(ZKX21019)the Guangdong Basic and Applied Basic Research Foundation(2021B1515120054)the Shenzhen Fundamental Research Program(JCYJ20190813152616459 and JCYJ20210324133214038).
文摘Ultrasound(US)is a biofavorable mechanical wave that has shown practical significance in biomedical fields.Due to the cavitation effect,sonoluminescence,sonoporation,pyrolysis,and other biophysical and chemical effects,a wide range of matters have been elucidated to be responsive to the stimulus of US.This review addresses and discusses current developments in US-responsive matters,including US-breakable intermolecular conjugations,US-catalytic sonosensitizers,fluorocarbon compounds,microbubbles,and US-propelled micro-and nanorobots.Meanwhile,the interactions between US and advanced matters create various biochemical products and enhanced mechanical effects,leading to the exploration of potential biomedical applications,from US-facilitated biosensing and diagnostic imaging to US-induced therapeutic applications and clinical translations.Finally,the current challenges are summarized and future perspectives on US-responsive matters in biomedical applications and clinical translations are proposed.
