Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.

Objective To investigate the application value of procalcitonin(PCT),neutrophil-to-lym-phocyte ratio(NLR)and C-reactive protein to albumin ratio(CAR)in the short-term prognosis of the pa-tients with severe community acquired pneumonia(SCAP).Methods A total of 225 patients with communi-ty-acquired pneumonia(CAP)treated in this hospital from July 2021 to December 2022 were selected as the study subjects and divided into the SCAP group and non-SCAP group.Then the patients with SCAP were di-vided into the survival group and death group according to their survival state in 28 d.The general data and re-lated laboratory indexes were collected.NLR and CAR were calculated.The binary logistic regression was a-dopted to analyze the risk factors of death on 28 d for the SCAP patients.The receiver operating characteristic(ROC)curve was drawn and the area under the curve(AUC)was calculated to evaluate the predictive value of relevant indicators.Results The age,levels of PCT,NLR,CAR,WBC and NEU,and the proportion of cor-onary heart disease in the SCAP group were higher than those in the non-SCAP group,while the levels of LYM and ALB were lower than those in the non-SCAP group,and the differences were statistically significant(P＜0.05).The age,levels of PCT,NLR,CAR,WBC and NEU,and the proportion of COPD in the death group were higher than those in the survival group,while the levels of LYM and ALB were lower than those in the survival group,and the differences were statistically significant(P＜0.05).The binary logistic regres-sion analysis showed that the age(OR=1.069,95％CI:1.020-1.120),chronic obstructive pulmonary dis-ease(OR=5.633,95％CI:2.019-15.712),PCT(OR=1.045,95％CI:1.002-1.090)and CAR(OR=2.170,95％CI:1.616-2.915)were the independent influencing factor for the death on 28 d in the patients with SCAP.The ROC curve analysis indicated that AUC,sensitivity and specificity of PCT,NLR and CAR combined detection were superior to those of detection alone,having good predictive value.Conclusion PCT,NLR and CAR have a certain predictive value for death within 28 d in the patients with SCAP.The combined detection has better predictive efficiency.

Objective To investigates the diagnostic value of infrared thermography-based skin temper-ature monitoring for lower extremity arterial disease(LEAD)in patients with diabetic foot.Methods A total of 160 patients with diabetic foot admitted to the hospital from March 2023 to December 2024 were selected as the research subjects and divided into the LEAD group(n=120)and the non-lesion group(n=40)based on the diagnostic results of color Doppler ultrasound.Spearman analysis was used to evaluate the correlation be-tween the relative temperature of diabetic foot ulcer(DFU)wounds measured by infrared thermography and the diameter and blood flow of lower limb arteries.Stepwise logistic regression analysis was performed to i-dentify the influencing factors of LEAD and subgroup analysis was conducted based on the presence or absence of infection.Receiver operating characteristic(ROC)curve analysis was used to assess the diagnostic efficacy of DFU wound relative temperature for LEAD and lower limb arterial atherosclerotic plaques,lumen stenosis,and lumen occlusion.Results There were statistically significant differences between the two groups in DFU wound temperature,skin temperature at the same site on the healthy side,DFU wound relative temperature,ankle brachial index(ABI),C-reactive protein(CRP),uric acid,and the peak velocity(PSV)and pulsatility index(PI)levels of the femoral artery,popliteal artery,and dorsalis pedis artery,as well as the proportions of lower limb arterial atherosclerotic plaques and lumen stenosis(P＜0.05).Spearman analysis showed that the relative temperature of DFU wounds was negatively correlated with PSV of the femoral artery,popliteal arter-y,and dorsalis pedis artery,and positively correlated with PI(P＜0.05).Univariate logistic regression analy-sis indicated that ABI,DFU wound relative temperature,uric acid,and the PSV and PI of the femoral artery,popliteal artery,and dorsalis pedis artery were influencing factors for LEAD(P＜O.05).Multivariate logistic regression analysis revealed that DFU wound relative temperature and uric acid were influencing factors for LEAD in diabetic foot(P＜0.05).Subgroup analysis showed that DFU wound relative temperature was an in-fluencing factor for LEAD in diabetic foot(P＜0.05),and there was no interaction between diabetic foot in-fection and the relationship between DFU wound relative temperature and LEAD in diabetic foot(P＞0.05).The area under the curve(AUC)for predicting LEAD using DFU wound relative temperature was 0.923,with the cut-off temperature being 5.4 ℃.The AUCs for predicting lower limb arterial atherosclerotic plaques,lumen stenosis,and lumen occlusion were 0.720,0.657,and 0.554,respectively,with the cut-off temperatures being 5.6,6.3,and 4.6 ℃,respectively.Conclusion DFU wound surface relative temperature of infrared thermog-raphy can effectively diagnose LEAD in diabetic foot.

OBJECTIVE To study the regulation effects and mechanism of liquiritin （LIQ） on immune function in gastric cancer-bearing mice based on the Janus kinase 2 （JAK2）/signal transducer and activator of transcription 3 （STAT3） pathway. METHODS Gastric cancer cells MFC were injected subcutaneously to establish gastric cancer-bearing model of mice. The model mice were divided into model group， LIQ low-dose group （LIQ-L group， 20 mg/kg）， LIQ high-dose group （LIQ-H group， 40 mg/kg）， and high-dose LIQ+JAK2 activator coumermycin A1 group （LIQ-H+coumermycin A1 group， 40 mg/kg LIQ+1 mg/kg coumermycin A1）， with 12 mice in each group. Another 12 mice without modeling were set as normal group. Mice in each group were given the corresponding drug or normal saline by intragastric administration/intraperitoneal injection， once a day， for consecutive 14 days. After the last administration， the volume and mass of gastric cancer tumor and organ index were measured. The percentages of CD4+ and CD8+T lymphocytes were detected in peripheral blood. The histopathological morphology of gastric cancer tumor tissues was observed， and the expression levels of JAK2/STAT3 signaling pathway-related proteins and interleukin-6 （IL-6） protein in gastric cancer tumor tissues were detected. RESULTS Compared with the normal group， the thymus index， spleen index， and the percentage of CD8 T lymphocyte in the peripheral blood of mice were obviouslyincreased in model group （P＜0.05）， while the percentage of CD4+T lymphocyte in the peripheral blood were decreased （P＜0.05）. Compared with model group， the above indexes in LIQ-L group and LIQ-H group were significantly reversed （P＜0.05）， while the volume and mass of gastric cancer tumor， the phosphorylation levels of JAK2 and STAT3 protein and the expression level of IL-6 protein were significantly decreased in tumor tissue （P＜0.05）， and the effect of LIQ was in a dose-dependent manner （P＜0.05）； the tumor cells showed varying degrees of loose arrangement， vacuolization， and uneven distribution. JAK2 activator coumermycin A1 weakened the improvement effect of LIQ on the immune function of gastric cancer-bearing mice and its inhibitory effect on gastric cancer tumors （P＜0.05）. CONCLUSIONS LIQ can improve the immune function of gastric cancer-bearing mice by inhibiting the activation of JAK2/STAT3 signaling pathway， thus playing an anti-tumor role.

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1-/-mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1-/-mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1-/-mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1-/-mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1-/-mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1-/-mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.