Intrahepatic cholangiocarcinoma is a malignant tumor with an extremely poor prognosis， and its pathogenesis is complex and remains unclear. In recent years， more and more studies have focused on the role of bile-gut axis in the development and progression of intrahepatic cholangiocarcinoma. Bile-gut axis refers to the complex interaction between bile and gut microbiota， including bile salt metabolism， dynamic changes of microbiota， inflammatory response， and immune system regulation. This article elaborates on the potential mechanisms of bile-gut axis in intrahepatic cholangiocarcinoma， especially gut microbiota dysbiosis， abnormal bile salt metabolism， chronic inflammatory response， and immune system interaction， this article aims to provide new perspectives and possible therapeutic targets for future research and promote the early diagnosis and effective treatment of intrahepatic cholangiocarcinoma.

Objective:To establish a predictive model for myocardial contusion (MC) in patients with rib fractures and evaluate its clinical application value.Methods:A retrospective case-control study was conducted to analyze the clinical data of 370 patients with rib fractures admitted to the Affiliated Jiangsu Shengze Hospital of Nanjing Medical University from January 2017 to December 2019, including 257 males and 113 females, aged 18-95 years [(56.5±14.0)years]. All the patients underwent electrocardiogram examination and myocardial biomarker test within 24 hours on admission, of whom 159 were diagnosed with MC, and 211 with non-MC (NMC). The 370 patients were divided into a training set of 264 patients (106 with MC, 158 with NMC) and a validation set of 106 patients (53 with MC, 53 with NMC) at a ratio of 7∶3 through the completely randomized method. In the training set, the MC group and NMC group were compared in terms of their demographic characteristics, vital signs on admission, types of rib fractures, number of rib fractures, locations of rib fractures, associated thoracic injuries, trauma scores, and laboratory indices. Variables of positive correlation with MC in patients with rib fractures were screened by Spearman correlation analysis, followed by univariate binary Logistic regression analysis for these variables to determine the risk factors for MC in patients with rib fractures. LASSO regression analysis and multivariate Logistic regression analysis were applied to identify the independent risk factors for MC in patients with rib fractures, and the regression equation was constructed. A nomogram prediction model was plotted based on the regression equation with R software. The receiver operating characteristic (ROC) curve was plotted to evaluate the model′s discriminability. Hosmer-Lemeshow (H-L) goodness-of-fit test and calibration curves of 1000 repeated samplings by the Bootstrap method were used to evaluate the calibration of the model. The decision curve analysis (DCA) and clinical impact curve analysis (CIC) were plotted to evaluate its clinical efficacy. A risk scoring was performed according to the assigned β coefficient of independent risk factors. Accordingly, the 370 selected patients with rib fractures were divided into low-risk subgroup of 202 patients, moderate-risk subgroup of 108 patients, high-risk subgroup of 50 patients, and extremely high-risk subgroup of 10 patients. The incidence of MC and in-hospital mortality were compared among different subgroups so as to further verify the clinical application value of the predictive model.Results:In the training set, there were significant differences between the MC group and NMC group in bilateral rib fractures, flail chest, number of rib fractures, upper chest proximal sternum segment, upper chest anterolateral segment, upper chest proximal spinal segment, middle chest anterolateral segment, middle chest proximal spinal segment, lower chest anterolateral segment, pneumothorax, mediastinal emphysema, hemothorax, sternal fractures, chest abbreviated injury scale (c-AIS), injury severity score (ISS), new injury severity score (NISS), white blood cell counts, hemoglobin, hematocrit, total cholesterol, low density lipoprotein, albumin, aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen ( P<0.05 or 0.01). Spearman correlation analysis showed that the bilateral rib fractures, flail chest, number of rib fractures, upper chest proximal sternum segment, upper chest anterolateral segment, upper chest proximal spinal segment, middle chest anterolateral segment, middle chest proximal spinal segment, lower chest anterolateral segment, pneumothorax, hemothorax, sternal fractures, c-AIS, ISS, NISS, white blood cell count, aspartate aminotransferase and blood urea nitrogen were positively correlated with MC ( P<0.05 or 0.01). Univariate binary Logistic regression analysis verified that the above variables with positive correlation were significantly correlated with MC in patients with rib fractures ( P<0.05 or 0.01). The 4 predictor variables screened by LASSO regression analysis were the upper chest anterolateral segment, middle chest proximal spinal segment, pneumothorax, and sternal fractures. Multivariate Logistic regression analysis confirmed that the aforementioned 4 predictor variables were independent risk factors for MC in patients with rib fractures ( P<0.05 or 0.01). The regression equation of the training set was established based on the above independent risk factors: P=e x/(1+e x), with the x=1.57×"upper chest anterolateral segment"+0.73×"middle chest proximal spinal segment"+1.36×"pneumothorax"+2.16×"sternal fractures"-1.10. In the predictive model for MC in patients with rib fractures established based on the equation, the area under the ROC curve (AUC) was 0.77 (95% CI 0.72, 0.83) and 0.77 (95% CI 0.71, 0.82) in the training set and validation set. The H-L goodness-of-fit test showed χ2=2.77, P=0.429 in the training set, and χ2=1.33, P=0.515 in the validation set, indicating that there was no significant difference between the predicted probability and the actual probability of the model ( P>0.05). The calibration curves showed that the bias-corrected curves of the training set and validation set were in good consistency with the actual curves and were both close to the ideal curves. The DCA of the training set and the validation set showed that within the threshold probability range of 0.2-0.8, the predictive model could obtain good net clinical benefits. The CIC of the training set and the validation set indicated that when the threshold probability was >0.4, the population identified as high-risk MC patients by the predictive model highly matched the actual MC patients. Risk scoring of subgroups found that the incidence of MC and in-hospital mortality among the patients with rib fractures were 80.0% and 6.0% in the high-risk subgroup and 90.0% and 20.0% in the extremely high-risk subgroup, significantly higher than those in the low-risk subgroup (24.8%, 1.0%) and the moderate-risk subgroup (55.6%, 1.9%) ( P<0.05). Conclusions:The predictive model for MC in patients with rib fractures constructed based on the upper chest anterolateral segment, middle chest proximal spinal segment, pneumothorax, and sternal fractures has good predictive efficacy and clinical application value.

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.
Animals ; Humans ; Mice ; Rats ; Bone Remodeling/physiology* ; Caspase 1 ; Periodontal Ligament ; Pyroptosis ; Tooth Movement Techniques

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.

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.