Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Objectives To explore the causal relationship between asthma-related pneumonia and heart failure(HF)by using two-sample Mendelian randomization(MR)analysis.Methods The causal relationship between asthma-related pneumonia and HF were systematically evaluated through two-sample MR analysis based on publicly available Genome-Wide Association Study data.Inverse variance weighted(IVW),MR-Egger,weighted median,weighted mode,and simple mode methods were used.Different models were used to analyze sensitivity.Testing approaches were conducted to assess the robustness of the results.Results IVW analysis results showed that there was a causal relationship between asthma-related pneumonia and HF risk(OR=1.113,95％CI:1.027-1.206,P=0.009).HF was not found to have a causal effect on asthma-related pneumonia risk based on IVW analysis(OR=1.018,95％CI:0.780-1.328,P=0.893).The variance used in all MR analyses showed no heterogeneity or horizontal pleiotropy.The leave-one-out analysis revealed that no single nucleotide polymorphism disproportionately influenced the results,further confirming the credibility of the bidirectional MR findings.Conclusion This study established a causal relationship between asthma-related pneumonia and HF risk.No clear causal relationship between HF and asthma-related pneumonia risk was found.

Objectives To explore the causal relationship between asthma-related pneumonia and heart failure(HF)by using two-sample Mendelian randomization(MR)analysis.Methods The causal relationship between asthma-related pneumonia and HF were systematically evaluated through two-sample MR analysis based on publicly available Genome-Wide Association Study data.Inverse variance weighted(IVW),MR-Egger,weighted median,weighted mode,and simple mode methods were used.Different models were used to analyze sensitivity.Testing approaches were conducted to assess the robustness of the results.Results IVW analysis results showed that there was a causal relationship between asthma-related pneumonia and HF risk(OR=1.113,95％CI:1.027-1.206,P=0.009).HF was not found to have a causal effect on asthma-related pneumonia risk based on IVW analysis(OR=1.018,95％CI:0.780-1.328,P=0.893).The variance used in all MR analyses showed no heterogeneity or horizontal pleiotropy.The leave-one-out analysis revealed that no single nucleotide polymorphism disproportionately influenced the results,further confirming the credibility of the bidirectional MR findings.Conclusion This study established a causal relationship between asthma-related pneumonia and HF risk.No clear causal relationship between HF and asthma-related pneumonia risk was found.

Objective To observe the effect of hyperbaric oxygen therapy (HBOT) on the improvement of executive function of the patients with traumatic brain injury (TBI) by using resting state functional magnetic resonance (rs-fMRI).Methods Fifty patients with executive disorder after traumatic brain injury were randomly divided into the HBO group (n =25) and the control group (n =25).The patients of the control group received routine treatment and executive function rehabilitation training,while the patients of the HBO group were supplemented with HBOT in addition to the treatment received by the control group.The applied HBO pressure was 2.0 MPa,one session a day with a duration of 105 minutes,five days a week,for a total of 20 sessions.Both before and after treatment,all the subjects received executive function assessment and rs-fMRI examination by using the drawing of clock test,the Chinese version Stroop color word test and the Wechsler adult intelligence scale similarity subtest.In the study,we closely observed the effects of HBOT on the intensity of metabolic activities in the brain,changes in neuron cell synchronization and coordination in TBI patients through the approach of rs-fMRI technique combined with ReHo and ALFF analysis methods.At the same time,the correlation between imaging data and neuropsychological assessment results was also analyzed in the study.Results (1) After intervention,Stroop-A time-consumption and Stroop-C time-consumption,correct reading scores,as well as interference scores of the HBO group were all significantly better than those of the control group,and statistical significance could be found when comparisons were made between the 2 groups (P ＜ 0.05).(2) Following intervention with different methods,obvious differences in the ALFF value of superior parietal lobe in the common brain regions of the TBI patients in the 2 groups could be seen,with statistical significance (P ＜ 0.05).Correlation analysis revealed that there was a positive correlation between the superior parietal lobe and interference time in the HBO group (P ＜ 0.05).(3) There was also a positive correlation between correct readings of Stroop-A in the middle frontal gyrus of the HBO group (P ＜ 0.05).Conclusion Executive function rehabilitation training,HBO therapy combined with executive function rehabilitation training could improve the executive function of TBI patients to various degrees.HBO therapy combined with executive function rehabilitation training was more beneficial to further improvement of executive function in patients with TBI.The improvement of executive function in TBI patients by HBO therapy might be achieved through the regulation of spontaneous activity and regional homogeneity of neurons in the middle frontal gyms,and superior parietal lobe.

Objective To observe the effect of hyperbaric oxygen therapy (HBOT) on the improvement of executive function of the patients with traumatic brain injury (TBI) by using resting state functional magnetic resonance (rs-fMRI).Methods Fifty patients with executive disorder after traumatic brain injury were randomly divided into the HBO group (n =25) and the control group (n =25).The patients of the control group received routine treatment and executive function rehabilitation training,while the patients of the HBO group were supplemented with HBOT in addition to the treatment received by the control group.The applied HBO pressure was 2.0 MPa,one session a day with a duration of 105 minutes,five days a week,for a total of 20 sessions.Both before and after treatment,all the subjects received executive function assessment and rs-fMRI examination by using the drawing of clock test,the Chinese version Stroop color word test and the Wechsler adult intelligence scale similarity subtest.In the study,we closely observed the effects of HBOT on the intensity of metabolic activities in the brain,changes in neuron cell synchronization and coordination in TBI patients through the approach of rs-fMRI technique combined with ReHo and ALFF analysis methods.At the same time,the correlation between imaging data and neuropsychological assessment results was also analyzed in the study.Results (1) After intervention,Stroop-A time-consumption and Stroop-C time-consumption,correct reading scores,as well as interference scores of the HBO group were all significantly better than those of the control group,and statistical significance could be found when comparisons were made between the 2 groups (P ＜ 0.05).(2) Following intervention with different methods,obvious differences in the ALFF value of superior parietal lobe in the common brain regions of the TBI patients in the 2 groups could be seen,with statistical significance (P ＜ 0.05).Correlation analysis revealed that there was a positive correlation between the superior parietal lobe and interference time in the HBO group (P ＜ 0.05).(3) There was also a positive correlation between correct readings of Stroop-A in the middle frontal gyrus of the HBO group (P ＜ 0.05).Conclusion Executive function rehabilitation training,HBO therapy combined with executive function rehabilitation training could improve the executive function of TBI patients to various degrees.HBO therapy combined with executive function rehabilitation training was more beneficial to further improvement of executive function in patients with TBI.The improvement of executive function in TBI patients by HBO therapy might be achieved through the regulation of spontaneous activity and regional homogeneity of neurons in the middle frontal gyms,and superior parietal lobe.