Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop n...Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop new tools for decision-making of lung cancer.In this study,we proposed the China Protocol,a complete workflow of lung cancer tailored to the Chinese population,which is implemented by steps including early screening by evaluation of risk factors and three-dimensional thin-layer image reconstruction technique for low-dose computed tomography(Tre-LDCT),accurate diagnosis via artificial intelligence(Al)and novel biomarkers,and individualized treatment through non-invasive molecule visualization strategies.The application of this protocol has improved the early diagnosis and 5-year survival rates of lung cancer in China.The proportion of early-stage(stage I)lung cancer has increased from 46.3%to 65.6%,along with a 5-year survival rate of 90.4%.Moreover,especially for stage IA1 lung cancer,the diagnosis rate has improved from 16%to 27.9%;meanwhile,the 5-year survival rate of this group achieved 97.5%.Thus,here we defined stage IA1 lung cancer,which cohort benefits significantly from early diagnosis and treatment,as the"ultra-early stage lung cancer",aiming to provide an intuitive description for more precise management and survival improvement.In the future,we will promote our findings to multicenter remote areas through medical alliances and mobile health services with the desire to move forward the diagnosis and treatment of lung cancer.展开更多
Objectives:To investigate the risk factors in patients with drug-resistant tuberculosis(DR-TB)and clinical characteristics related to unfavorable anti-TB treatment outcomes.Methods:A total of 961 pulmonary tuberculosi...Objectives:To investigate the risk factors in patients with drug-resistant tuberculosis(DR-TB)and clinical characteristics related to unfavorable anti-TB treatment outcomes.Methods:A total of 961 pulmonary tuberculosis(TB)patients were included at West China Hospital of Sichuan University from January 2008 to November 2023.We analyzed the differences of clinical characteristics between DR-TB and drug-sensitive tuberculosis(DS-TB),and then compared these features in DR-TB patients with different outcomes.Multivariable logistic regression models were employed to quantify risk factors associated with DR-TB and adverse treatment outcomes.Results:Among 961 pulmonary TB patients,a history of anti-TB treatment[odds ratio(OR),3.289;95%confidence interval(CI),2.359–4.604]and CT-scan cavities(OR,1.512;95%CI,1.052–2.168)increased DR-TB risk.A total of 214 DR-TB patients were followed for a median of 24.5 months.Among them,116/214(54.2%)patients achieved favorable outcomes.Prior anti-TB treatment(OR,1.927;95%CI,1.033–3.640),multidrug-resistant tuberculosis(MDR-TB)(OR,2.558;95%CI,1.272–5.252),positive sputum bacteriology(OR,2.116;95%CI,1.100–4.134),and pleural effusion(OR,2.097;95%CI,1.093–4.082)were associated with unfavorable outcomes,while isoniazidresistant TB patients showed better outcomes(OR,0.401;95%CI,0.181–0.853).The clinical model for unfavorable outcome prediction of DR-TB achieved an area under the curve(AUC)of 0.754(95%CI,0.690–0.818).Conclusions:Treatment history of anti-TB not only increases the risk of the emergence of DR-TB,but also potentially leads to treatment failure during re-treatment in DR-TB patients.Drug resistance subtypes,radiological characteristics,and the results of sputum smear or culture may affect the treatment outcome of DR-TB.展开更多
Tuberculosis(TB)has one of the highest mortality rates among infectious diseases worldwide.The immune response in the host after infection is proposed to contribute significantly to the progression of TB,but the speci...Tuberculosis(TB)has one of the highest mortality rates among infectious diseases worldwide.The immune response in the host after infection is proposed to contribute significantly to the progression of TB,but the specific mechanisms involved remain to be elucidated.Single-cell RNA sequencing(scRNA-seq)provides unbiased transcriptome sequencing of large quantities of individual cells,thereby defining biological comprehension of cellular heterogeneity and dynamic transcriptome state of cell populations in the field of immunology and is therefore increasingly applied to lung disease research.Here,we first briefly introduce the concept of scRNA-seq,followed by a summarization on the application of scRNA-seq to TB.Furthermore,we underscore the potential of scRNA-seq for clinical biomarker exploration,host-directed therapy,and precision therapy research in TB and discuss the bottlenecks that need to be overcome for the broad application of scRNA-seq to TB-related research.展开更多
Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artifici...Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artificial intelligence(AI)has the capability to mine imaging features specific to different pathogens and fuse multimodal features to reach a synergistic diagnosis,enabling more precise investigation and individualized clinical management.In this study,we successfully developed a multimodal integration(MMI)pipeline to differentiate among bacterial,fungal,and viral pneumonia and pulmonary tuberculosis based on a real-world dataset of 24,107 patients.The area under the curve(AUC)of the MMI system comprising clinical text and computed tomography(CT)image scans yielded 0.910(95%confidence interval[CI]:0.904–0.916)and 0.887(95%CI:0.867–0.909)in the internal and external testing datasets respectively,which were comparable to those of experienced physicians.Furthermore,the MMI system was utilized to rapidly differentiate between viral subtypes with a mean AUC of 0.822(95%CI:0.805–0.837)and bacterial subtypes with a mean AUC of 0.803(95%CI:0.775–0.830).Here,the MMI system harbors the potential to guide tailored medication recommendations,thus mitigating the risk of antibiotic misuse.Additionally,the integration of multimodal factors in the AI-driven system also provided an evident advantage in predicting risks of developing critical illness,contributing to more informed clinical decision-making.To revolutionize medical care,embracing multimodal AI tools in pulmonary infections will pave the way to further facilitate early intervention and precise management in the foreseeable future.展开更多
In this study,we systematically investigated the interactions between Cu^(2+)and various biomolecules,including double-stranded DNA,Y-shaped DNA nanospheres,the double strand of the hybridization chain reaction(HCR),t...In this study,we systematically investigated the interactions between Cu^(2+)and various biomolecules,including double-stranded DNA,Y-shaped DNA nanospheres,the double strand of the hybridization chain reaction(HCR),the network structure of cross-linked HCR(cHCR),and small molecules(PPi and His),using Cu^(2+)as an illustrative example.Our research demonstrated that the coordination between Cu^(2+)and these biomolecules not only is suitable for modulating luminescent material signals through complexation reactions with Cu^(2+)but also enhances signal intensities in materials based on chemical reactions by increasing spatial site resistance and local concentration.Building upon these findings,we harnessed the potential for signal amplification in self-assembled DNA nanospheres and the selective complexation modulation of calcein in conjunction with the aptamer targeting mucin 1 as a recognition probe.We applied this approach to the analysis of circulating tumor cells,with the lung cancer cell line A549 serving as a representative model.展开更多
Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC a...Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.展开更多
Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role ...Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.展开更多
Comprehensive Summary,C-Glycosides are critical,naturally occurring products and medicinal candidates,and extensive efforts have been made to explore efficient approaches for creating C-glycosidic bonds.Transition-met...Comprehensive Summary,C-Glycosides are critical,naturally occurring products and medicinal candidates,and extensive efforts have been made to explore efficient approaches for creating C-glycosidic bonds.Transition-metal-catalysis,particularly nickel-catalyzed C-glycosylation reactions constitute a promising strategy.However,achieving a stereoselective synthesis ofα-andβ-C-glycosides has been a long-standing challenge.To address this problem,a variety of nickel-mediated strategies have been developed.This review highlights recent developments in the nickel-catalyzed diastereoselective C-glycosylation reactions and briefly summarizes the mechanistic understandings of these methods.展开更多
Chronic pain is often associated with cognitive decline,which could influence the quality of the patient’s life.Recent studies have suggested that Toll-like receptor 3(TLR3)is crucial for memory and learning.Nonethel...Chronic pain is often associated with cognitive decline,which could influence the quality of the patient’s life.Recent studies have suggested that Toll-like receptor 3(TLR3)is crucial for memory and learning.Nonetheless,the contribution of TLR3 to the pathogenesis of cognitive decline after chronic pain remains unclear.The level of TLR3 in hippocampal neurons increased in the chronic constriction injury(CCI)group than in the sham group in this study.Importantly,compared to the wild-type(WT)mice,TLR3 knockout(KO)mice and TLR3-specific neuronal knockdown mice both displayed improved cognitive function,reduced levels of inflammatory cytokines and neuronal apoptosis and attenuated injury to hippocampal neuroplasticity.Notably,extracellular RNAs(exRNAs),specifically double-stranded RNAs(dsRNAs),were increased in the sciatic nerve,serum,and hippocampus after CCI.The co-localization of dsRNA with TLR3 was also increased in hippocampal neurons.And the administration of poly(I:C),a dsRNA analog,elevated the levels of dsRNAs and TLR3 in the hippocampus,exacerbating hippocampus-dependent memory.In additon,the dsRNA/TLR3 inhibitor improved cognitive function after CCI.Together,our findings suggested that exRNAs,particularly dsRNAs,that were present in the condition of chronic neuropathic pain,activated TLR3,initiated downstream inflammatory and apoptotic signaling,caused damage to synaptic plasticity,and contributed to the etiology of cognitive impairment after chronic neuropathic pain.展开更多
C–H late-stage functionalization has gradually become a powerful approach for the rapid optimization of lead compounds’bioactivity.Significant advances in this field have been achieved in the past few years,mainly,t...C–H late-stage functionalization has gradually become a powerful approach for the rapid optimization of lead compounds’bioactivity.Significant advances in this field have been achieved in the past few years,mainly,the C–H functionalization system in(hetero)aryl C–H activation owing to the importance of(hetero)aryl moiety in pharmaceutical.In this review,we described the selected recent examples of how developed intermolecular C(sp^(2))–H functionalization methodologies involving diverse techniques diversify pharmaceutical molecules in the late stage.展开更多
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project of China(2024ZD0529500/2024ZD0529504,2024ZD0529500/2024ZD0529505)National Natural Science Foundation of China(82470109,92159302)+3 种基金Science and Technology Project of Sichuan(2022ZDZX0018)1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYYC23027)1.3.5 projects for Artificial Intelligence,West China Hospital,Sichuan University(ZYAI24016)1.3.5 Project of State Key Laboratory of Respiratory Health and Multimorbidity,West China Hospital,Sichuan University(RHM24208).
文摘Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop new tools for decision-making of lung cancer.In this study,we proposed the China Protocol,a complete workflow of lung cancer tailored to the Chinese population,which is implemented by steps including early screening by evaluation of risk factors and three-dimensional thin-layer image reconstruction technique for low-dose computed tomography(Tre-LDCT),accurate diagnosis via artificial intelligence(Al)and novel biomarkers,and individualized treatment through non-invasive molecule visualization strategies.The application of this protocol has improved the early diagnosis and 5-year survival rates of lung cancer in China.The proportion of early-stage(stage I)lung cancer has increased from 46.3%to 65.6%,along with a 5-year survival rate of 90.4%.Moreover,especially for stage IA1 lung cancer,the diagnosis rate has improved from 16%to 27.9%;meanwhile,the 5-year survival rate of this group achieved 97.5%.Thus,here we defined stage IA1 lung cancer,which cohort benefits significantly from early diagnosis and treatment,as the"ultra-early stage lung cancer",aiming to provide an intuitive description for more precise management and survival improvement.In the future,we will promote our findings to multicenter remote areas through medical alliances and mobile health services with the desire to move forward the diagnosis and treatment of lung cancer.
基金supported by the National Natural Science Foundation of China(grant No.82341083)the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(grant No.ZYYC23027)+1 种基金the 1·3·5 projects for Artificial Intelligence of West China Hospital,Sichuan University(grant No.ZYAI24016)the 1·3·5 Project of State Key Laboratory of Respiratory Health and Multimorbidity,West China Hospital,Sichuan University(grant No.RHM24208)。
文摘Objectives:To investigate the risk factors in patients with drug-resistant tuberculosis(DR-TB)and clinical characteristics related to unfavorable anti-TB treatment outcomes.Methods:A total of 961 pulmonary tuberculosis(TB)patients were included at West China Hospital of Sichuan University from January 2008 to November 2023.We analyzed the differences of clinical characteristics between DR-TB and drug-sensitive tuberculosis(DS-TB),and then compared these features in DR-TB patients with different outcomes.Multivariable logistic regression models were employed to quantify risk factors associated with DR-TB and adverse treatment outcomes.Results:Among 961 pulmonary TB patients,a history of anti-TB treatment[odds ratio(OR),3.289;95%confidence interval(CI),2.359–4.604]and CT-scan cavities(OR,1.512;95%CI,1.052–2.168)increased DR-TB risk.A total of 214 DR-TB patients were followed for a median of 24.5 months.Among them,116/214(54.2%)patients achieved favorable outcomes.Prior anti-TB treatment(OR,1.927;95%CI,1.033–3.640),multidrug-resistant tuberculosis(MDR-TB)(OR,2.558;95%CI,1.272–5.252),positive sputum bacteriology(OR,2.116;95%CI,1.100–4.134),and pleural effusion(OR,2.097;95%CI,1.093–4.082)were associated with unfavorable outcomes,while isoniazidresistant TB patients showed better outcomes(OR,0.401;95%CI,0.181–0.853).The clinical model for unfavorable outcome prediction of DR-TB achieved an area under the curve(AUC)of 0.754(95%CI,0.690–0.818).Conclusions:Treatment history of anti-TB not only increases the risk of the emergence of DR-TB,but also potentially leads to treatment failure during re-treatment in DR-TB patients.Drug resistance subtypes,radiological characteristics,and the results of sputum smear or culture may affect the treatment outcome of DR-TB.
基金This research was supported by the National Natural Science Foundation of China(No.82100119)Science and Technology Project of Sichuan(Nos.2022ZDZX0018 and 2023NSFSC1889)+2 种基金Science and Technology Project of Chengdu(No.2023-YF09-00007-SN)the Sichuan University from“0”to“1”Innovation Project(No.2023SCUH0051)the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(No.ZYYC23027).
文摘Tuberculosis(TB)has one of the highest mortality rates among infectious diseases worldwide.The immune response in the host after infection is proposed to contribute significantly to the progression of TB,but the specific mechanisms involved remain to be elucidated.Single-cell RNA sequencing(scRNA-seq)provides unbiased transcriptome sequencing of large quantities of individual cells,thereby defining biological comprehension of cellular heterogeneity and dynamic transcriptome state of cell populations in the field of immunology and is therefore increasingly applied to lung disease research.Here,we first briefly introduce the concept of scRNA-seq,followed by a summarization on the application of scRNA-seq to TB.Furthermore,we underscore the potential of scRNA-seq for clinical biomarker exploration,host-directed therapy,and precision therapy research in TB and discuss the bottlenecks that need to be overcome for the broad application of scRNA-seq to TB-related research.
基金supported by the National Natural Science Foundation of China(82341083,82100119)the Science and Technology Project of Sichuan(2020YFG0473,2022ZDZX0018)+3 种基金the Beijing Municipal Science and Technology Planning Project(Z211100003521009)Hong Kong Research Grants Council through General Research Fund(Grant 17207722)the Sichuan University from“0”to“1”Innovation Project(2023SCUH0051)the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYYC23027)。
文摘Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artificial intelligence(AI)has the capability to mine imaging features specific to different pathogens and fuse multimodal features to reach a synergistic diagnosis,enabling more precise investigation and individualized clinical management.In this study,we successfully developed a multimodal integration(MMI)pipeline to differentiate among bacterial,fungal,and viral pneumonia and pulmonary tuberculosis based on a real-world dataset of 24,107 patients.The area under the curve(AUC)of the MMI system comprising clinical text and computed tomography(CT)image scans yielded 0.910(95%confidence interval[CI]:0.904–0.916)and 0.887(95%CI:0.867–0.909)in the internal and external testing datasets respectively,which were comparable to those of experienced physicians.Furthermore,the MMI system was utilized to rapidly differentiate between viral subtypes with a mean AUC of 0.822(95%CI:0.805–0.837)and bacterial subtypes with a mean AUC of 0.803(95%CI:0.775–0.830).Here,the MMI system harbors the potential to guide tailored medication recommendations,thus mitigating the risk of antibiotic misuse.Additionally,the integration of multimodal factors in the AI-driven system also provided an evident advantage in predicting risks of developing critical illness,contributing to more informed clinical decision-making.To revolutionize medical care,embracing multimodal AI tools in pulmonary infections will pave the way to further facilitate early intervention and precise management in the foreseeable future.
基金supported by National Natural Science Foundation of China(82202638)the National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(Z2023YY002).
文摘In this study,we systematically investigated the interactions between Cu^(2+)and various biomolecules,including double-stranded DNA,Y-shaped DNA nanospheres,the double strand of the hybridization chain reaction(HCR),the network structure of cross-linked HCR(cHCR),and small molecules(PPi and His),using Cu^(2+)as an illustrative example.Our research demonstrated that the coordination between Cu^(2+)and these biomolecules not only is suitable for modulating luminescent material signals through complexation reactions with Cu^(2+)but also enhances signal intensities in materials based on chemical reactions by increasing spatial site resistance and local concentration.Building upon these findings,we harnessed the potential for signal amplification in self-assembled DNA nanospheres and the selective complexation modulation of calcein in conjunction with the aptamer targeting mucin 1 as a recognition probe.We applied this approach to the analysis of circulating tumor cells,with the lung cancer cell line A549 serving as a representative model.
基金This review was supported by the National Natural Science Foundation of China(82073318)Sichuan Science and Technology Program(2019YFS0003,China)the Support Program of Science&Technology Department of Sichuan Provincial(2023YFSY0046 and 2022NSFSC1365,China).
文摘Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.
基金provided by the National Natural Science Foundation of China(82073318)the Fundamental Research Funds for the Central Universities(SCU2022D025,0082604151345,China)+1 种基金Sichuan Science and Technology Program Projects(2019YFS0003,China)to Yuxi Wangprovided by the University of Tennessee College of Pharmacy Drug Discovery Center to Wei Li。
文摘Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.
基金the National Natural Science Foundation of China(21907071,21922106,and T2221004)Fok Ying Tung Education Foundation for financial support.
文摘Comprehensive Summary,C-Glycosides are critical,naturally occurring products and medicinal candidates,and extensive efforts have been made to explore efficient approaches for creating C-glycosidic bonds.Transition-metal-catalysis,particularly nickel-catalyzed C-glycosylation reactions constitute a promising strategy.However,achieving a stereoselective synthesis ofα-andβ-C-glycosides has been a long-standing challenge.To address this problem,a variety of nickel-mediated strategies have been developed.This review highlights recent developments in the nickel-catalyzed diastereoselective C-glycosylation reactions and briefly summarizes the mechanistic understandings of these methods.
基金This study received support from some sources,including the National Natural Science Foundation of China(No.82171185,No.81870858 to C.C.)the National Key R&D Program of China(No.2018YFC2001800 to T.Z.)+3 种基金the National Natural Science Foundation of China(No.81671062 to T.Z.)the Natural Science Foundation of Sichuan Province(No.2022NSFSC1322,to R.G.)the China Postdoctoral Science Foundation(No.2020M673234 to R.G.)the Postdoctoral Research Project,West China Hospital,Sichuan University(No.2020HXBH022 to R.G.).
文摘Chronic pain is often associated with cognitive decline,which could influence the quality of the patient’s life.Recent studies have suggested that Toll-like receptor 3(TLR3)is crucial for memory and learning.Nonetheless,the contribution of TLR3 to the pathogenesis of cognitive decline after chronic pain remains unclear.The level of TLR3 in hippocampal neurons increased in the chronic constriction injury(CCI)group than in the sham group in this study.Importantly,compared to the wild-type(WT)mice,TLR3 knockout(KO)mice and TLR3-specific neuronal knockdown mice both displayed improved cognitive function,reduced levels of inflammatory cytokines and neuronal apoptosis and attenuated injury to hippocampal neuroplasticity.Notably,extracellular RNAs(exRNAs),specifically double-stranded RNAs(dsRNAs),were increased in the sciatic nerve,serum,and hippocampus after CCI.The co-localization of dsRNA with TLR3 was also increased in hippocampal neurons.And the administration of poly(I:C),a dsRNA analog,elevated the levels of dsRNAs and TLR3 in the hippocampus,exacerbating hippocampus-dependent memory.In additon,the dsRNA/TLR3 inhibitor improved cognitive function after CCI.Together,our findings suggested that exRNAs,particularly dsRNAs,that were present in the condition of chronic neuropathic pain,activated TLR3,initiated downstream inflammatory and apoptotic signaling,caused damage to synaptic plasticity,and contributed to the etiology of cognitive impairment after chronic neuropathic pain.
基金the National Natural Science Foundation(Nos.21907071,22271200,and 21801178)the Sichuan Science and Technology Program(No.2020YJ0091)+2 种基金the Post-Doctor Research Project,West China Hospital,Sichuan University(No.2019HXBH008)Natural Science Foundation of Sichuan,China(Nos.2023NSFSC1716,2023NSFSC0645)the China Postdoctoral Science Foundation(No.2018M633360)for financial support.
文摘C–H late-stage functionalization has gradually become a powerful approach for the rapid optimization of lead compounds’bioactivity.Significant advances in this field have been achieved in the past few years,mainly,the C–H functionalization system in(hetero)aryl C–H activation owing to the importance of(hetero)aryl moiety in pharmaceutical.In this review,we described the selected recent examples of how developed intermolecular C(sp^(2))–H functionalization methodologies involving diverse techniques diversify pharmaceutical molecules in the late stage.
