Intestinal barrier damage is a prominent feature of non-alcoholic fatty liver disease （NAFLD） and serves as a critical factor driving the progression from simple fatty liver to non-alcoholic steatohepatitis （NASH）， fibrosis， and cirrhosis. The "turbid pathogenic factors entering the blood" theory integrates classical traditional Chinese medicine （TCM） principles with contemporary disease evolution trends and research findings. It posits that endogenous turbid pathogenic factors within the body infiltrate the blood vessels， leading to impure and viscous blood quality， thereby triggering various diseases. Based on this theory， this article elucidated the pathogenic mechanism of NAFLD-associated intestinal barrier damage. It argued that in NAFLD， the liver loses its dredging function， and the spleen becomes obstructed and dysfunctional. Moreover， essential nutrients fail to be properly transformed， resulting in the internal generation of turbid pathogenic factors. This subsequently initiates a series of pathological changes， namely， "infiltration of phlegm-turbidity into the blood， eroding the intestinal mucosa"， "infiltration of glucose-turbidity into the blood， macerating and eroding the intestinal mucosa"， "infiltration of heat-turbidity into the blood， scorching and eroding the intestinal mucosa"， and "infiltration of stasis-turbidity into the blood， stagnating and eroding the intestinal mucosa"， ultimately causing intestinal barrier damage. Furthermore， guided by the "turbid pathogenic factors entering the blood" theory， this article explored TCM intervention strategies： employing medicinals targeting the liver meridian to address the root cause and reduce the generation and deposition of turbid pathogenic factors in the liver， administering blood-system medicinals to clear the blood and purge turbidity， thereby intercepting the progression of the disease mechanism， and applying tonifying medicinals to bolster healthy Qi and defend against turbid invasion， allowing the damaged intestinal mucosa to gradually heal. This article presented novel theoretical and medicinal perspectives for analyzing NAFLD-associated intestinal barrier damage based on the "turbid pathogenic factors entering the blood" theory， aiming to provide new entry points and broader horizons for related research and clinical practice.

Objective:To investigate the prognosis of postoperative adjuvant therapy for hepatocellular carcinoma after conversion therapy of combined targeted therapy and immunotherapy followed by sequential hepatectomy.Methods:The retrospective cohort study was conducted. The clinicopathological data of 103 patients with initially unresectable hepatocellular carcinoma (HCC) who were admitted to 11 medical centers in China, including Mengchao Hepatobiliary Hospital of Fujian Medical University et al, from November 2019 to May 2023 were collected. There were 83 males and 20 females, aged (54±12)years. All 103 patients underwent conversion therapy of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) successfully followed by sequential hepatectomy, of which 72 patients undergoing postoperative adjuvant therapy were divided into the adjuvant therapy group, and 31 patients undergoing postoperative follow-up monitoring were divided into the follow-up monitoring group. Observation indicators: (1) follow-up and postoperative condi-tions; (2) analysis of factors influencing recurrence-free survival time of patients; (3) stratified ana-lysis. Comparison of count data between group was conducted using the chi-square test or Fisher exact probability. The R software was used to draw survival curves, and the Log-rank test was used for survival analysis. Univariate and multivariate analyses were conducted using the Cox proportional hazard model. Results:(1) Follow-up and postoperative conditions. All 103 patients were followed up for 21.0(range, 1.9?47.2)months, with the median recurrence-free survival time of 28.7 months and the 1-, 2-, 3-year recurrence-free survival rates of 68.6%, 55.6%, 41.2%. The median overall survival time of 103 patients was unreached, and the 1-, 2-, 3-year overall survival rates were 90.9%, 82.1%, 69.6%, respectively. The median recurrence-free survival time was 33.1 months in patients of the adjuvant therapy group, with the 1-, 2-year recurrence-free survival rates as 77.2%, 61.5%. The median recurrence-free survival time was 11.1 months in patients of the follow-up monitoring group, with the 1-, 2-year recurrence-free survival rates as 46.6%, 40.8%. There was a significant difference in recurrence-free survival between the two groups of patients ( χ2=5.492, P<0.05). (2) Analysis of factors influencing recurrence-free survival time of patients. Results of multivariate analy-sis showed that pathologic complete response and postoperative adjuvant therapy were independent factors influencing recurrence-free survival time of HCC patients undergoing conversion therapy of combined targeted therapy and immunotherapy followed by sequential hepatectomy ( hazard ratio=0.297, 0.492, 95% confidence interval as 0.137?0.647, 0.268?0.903, P<0.05). (3) Stratified analysis. Of the 71 patients with non-pathologic complete response, the median recurrence-free survival time of 48 patients in the adjuvant therapy group was 24.0 months, with the 1-, 2-year recurrence-free survival rates as 67.4%, 48.8%. The median recurrence-free survival time of 23 patients with non-pathological complete response in the follow-up monitoring group was 7.4 months, with the 1-, 2-year recurrence-free survival rates as 35.0%, 26.3%. There was a significant difference in recurrence-free survival between the 48 patients with non-pathologic complete response in the adjuvant therapy group and the 23 patients with non-pathologic complete response in the follow-up monitoring group ( χ2=5.241, P<0.05). Conclusion:For HCC patients with conversion therapy of TKIs and ICIs followed by sequential hepatectomy, postoperative adjuvant therapy, compared to postoperative follow-up monitoring, can prolong the recurrence-free survival time of patients, of whom cases with non-pathologic complete response can benefit from adjuvant therapy.

Objective To investigate the mechanism of Fuzheng Yangxin Prescription in improving cardiac function in rats with heart failure with reduced ejection fraction(HFrEF)through regulation of AMPK/mTOR signaling pathway.Methods An HFrEF rat model was established via left anterior descending coronary artery ligation.Rats were randomized divided into sham-operation group,model group,Fuzheng Yangxin Prescription group and Entresto group,followed by 28 days of intervention.Echocardiography was used to measure left ventricular internal dimension at end-systole(LVIDs),left ventricular internal dimension at end-diastole(LVIDd),left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),HE staining and Masson staining were used to observe myocardial morphology and fibrosis,serum contents of NT-proBNP and inflammatory factors(TNF-α,IL-1β,IL-6)were detected by ELISA,Western blot was performed to analyze p-AMPK,p-mTOR and protein expressions of autophagy markers(Beclin1,LC3,p62).Results Compared with sham-operation group,the LVIDs and LVIDd in model group significantly increased(P<0.05),while LVEF and LVFS significantly decreased(P<0.05),the structure of myocardial cells was disordered and arranged loosely,the deposition of collagen fibers in the infarct area was increased,and the contents of NT-proBNP,TNF-α,IL-1β and IL-6 in serum significantly increased(P<0.05),the protein expressions of p-AMPK,Beclin1 and LC3Ⅱ/LC3Ⅰ in myocardial tissue significantly decreased(P<0.05),while the protein expressions of p-mTOR and p62 significantly increased(P<0.05);compared with the model group,the LVIDs and LVIDd of rats in Fuzheng Yangxin Prescription group significantly decreased(P<0.05),the LVEF and LVFS were significantly increased(P<0.05),the disorder of myocardial cell arrangement and fibrosis were alleviated,the contents of NT-proBNP,TNF-α,IL-1β and IL-6 in serum significantly decreased(P<0.05),the protein expressions of p-AMPK,Beclin1 and LC3Ⅱ/LC3Ⅰ in myocardial tissue significantly increased(P<0.05),while the protein expressions of p-mTOR and p62 significantly decreased(P<0.05).Conclusion Fuzheng Yangxin Prescription may regulate autophagy by activating AMPK/mTOR pathway and improve cardiac function in HFrEF rats.

Objective:To investigate the impacts of total salvianolic acid(TSA)on macrophage polarization and mesenchymal macrophage infiltration in liver cancer bearing mice by regulating the Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor-κB(NF-κB)pathway.Methods:Mice were randomly separated into liver cancer group,TSA low concentra-tion group,TSA medium concentration group,TSA high concentration group,TSA high concentration+TLR4 inhibitor(TAK242)group and control group,with 12 mice in each group.Except for control group,mice in all other groups were injected subcutaneously into the right axilla to construct liver cancer models by intraperitoneal transmission of third-generation H22 cell suspension.After suc-cessful modeling,administration was carried out once a day for 2 weeks.Changes in tumor weight,tumor volume,spleen index and thymus index were detected.Immunofluorescence was applied to detect proportions of CD86 and CD206 positive cells in tumor tissue.ELISA was applied to detect levels of inducible nitric oxide synthase(iNOS),IL-6 and IL-10 in tumor tissues.Flow cytometry was ap-plied to detect proportion of CD11b+F4/80+in tumor tissue.Western blot was applied to detect TLR4,p-NF-κB P65 and MyD88 pro-teins in tumor tissue.The life quality and survival rate of mice were observed.Results:Compared with control group,spleen index,thymus index,proportion of CD86 positive cells in tumor tissue,levels of iNOS and IL-6,and expressions of TLR4,p-NF-κB P65 and MyD88 proteins were reduced in liver cancer group,while proportion of CD206 positive cells and level of IL-10 in tumor tissue were increased(P<0.05).Compared with liver cancer group,tumor weight and volume of mice in TSA low,medium,high concentration groups were decreased,while survival rate,spleen index,thymus index,proportion of CD86 positive cells in tumor tissue,levels of iNOS and IL-6,and expressions of TLR4,p-NF-κB P65 and MyD88 proteins were increased,proportion of CD206 positive cells,level of IL-10,and proportion of CD11b+F4/80+in tumor tissue decreased(P<0.05).TAK242 reversed the effects of high concentration TSA on macrophage polarization and myeloid macrophage infiltration in liver cancer bearing mice.Conclusion:TSA may promote M1 polari-zation of macrophages in liver cancer bearing mice and inhibit myeloid macrophage infiltration by activating the TLR4/MyD88/NF-κB pathway.

Objective:To investigate the impacts of total salvianolic acid(TSA)on macrophage polarization and mesenchymal macrophage infiltration in liver cancer bearing mice by regulating the Toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor-κB(NF-κB)pathway.Methods:Mice were randomly separated into liver cancer group,TSA low concentra-tion group,TSA medium concentration group,TSA high concentration group,TSA high concentration+TLR4 inhibitor(TAK242)group and control group,with 12 mice in each group.Except for control group,mice in all other groups were injected subcutaneously into the right axilla to construct liver cancer models by intraperitoneal transmission of third-generation H22 cell suspension.After suc-cessful modeling,administration was carried out once a day for 2 weeks.Changes in tumor weight,tumor volume,spleen index and thymus index were detected.Immunofluorescence was applied to detect proportions of CD86 and CD206 positive cells in tumor tissue.ELISA was applied to detect levels of inducible nitric oxide synthase(iNOS),IL-6 and IL-10 in tumor tissues.Flow cytometry was ap-plied to detect proportion of CD11b+F4/80+in tumor tissue.Western blot was applied to detect TLR4,p-NF-κB P65 and MyD88 pro-teins in tumor tissue.The life quality and survival rate of mice were observed.Results:Compared with control group,spleen index,thymus index,proportion of CD86 positive cells in tumor tissue,levels of iNOS and IL-6,and expressions of TLR4,p-NF-κB P65 and MyD88 proteins were reduced in liver cancer group,while proportion of CD206 positive cells and level of IL-10 in tumor tissue were increased(P<0.05).Compared with liver cancer group,tumor weight and volume of mice in TSA low,medium,high concentration groups were decreased,while survival rate,spleen index,thymus index,proportion of CD86 positive cells in tumor tissue,levels of iNOS and IL-6,and expressions of TLR4,p-NF-κB P65 and MyD88 proteins were increased,proportion of CD206 positive cells,level of IL-10,and proportion of CD11b+F4/80+in tumor tissue decreased(P<0.05).TAK242 reversed the effects of high concentration TSA on macrophage polarization and myeloid macrophage infiltration in liver cancer bearing mice.Conclusion:TSA may promote M1 polari-zation of macrophages in liver cancer bearing mice and inhibit myeloid macrophage infiltration by activating the TLR4/MyD88/NF-κB pathway.

Objective:To investigate the prognosis of postoperative adjuvant therapy for hepatocellular carcinoma after conversion therapy of combined targeted therapy and immunotherapy followed by sequential hepatectomy.Methods:The retrospective cohort study was conducted. The clinicopathological data of 103 patients with initially unresectable hepatocellular carcinoma (HCC) who were admitted to 11 medical centers in China, including Mengchao Hepatobiliary Hospital of Fujian Medical University et al, from November 2019 to May 2023 were collected. There were 83 males and 20 females, aged (54±12)years. All 103 patients underwent conversion therapy of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) successfully followed by sequential hepatectomy, of which 72 patients undergoing postoperative adjuvant therapy were divided into the adjuvant therapy group, and 31 patients undergoing postoperative follow-up monitoring were divided into the follow-up monitoring group. Observation indicators: (1) follow-up and postoperative condi-tions; (2) analysis of factors influencing recurrence-free survival time of patients; (3) stratified ana-lysis. Comparison of count data between group was conducted using the chi-square test or Fisher exact probability. The R software was used to draw survival curves, and the Log-rank test was used for survival analysis. Univariate and multivariate analyses were conducted using the Cox proportional hazard model. Results:(1) Follow-up and postoperative conditions. All 103 patients were followed up for 21.0(range, 1.9?47.2)months, with the median recurrence-free survival time of 28.7 months and the 1-, 2-, 3-year recurrence-free survival rates of 68.6%, 55.6%, 41.2%. The median overall survival time of 103 patients was unreached, and the 1-, 2-, 3-year overall survival rates were 90.9%, 82.1%, 69.6%, respectively. The median recurrence-free survival time was 33.1 months in patients of the adjuvant therapy group, with the 1-, 2-year recurrence-free survival rates as 77.2%, 61.5%. The median recurrence-free survival time was 11.1 months in patients of the follow-up monitoring group, with the 1-, 2-year recurrence-free survival rates as 46.6%, 40.8%. There was a significant difference in recurrence-free survival between the two groups of patients ( χ2=5.492, P<0.05). (2) Analysis of factors influencing recurrence-free survival time of patients. Results of multivariate analy-sis showed that pathologic complete response and postoperative adjuvant therapy were independent factors influencing recurrence-free survival time of HCC patients undergoing conversion therapy of combined targeted therapy and immunotherapy followed by sequential hepatectomy ( hazard ratio=0.297, 0.492, 95% confidence interval as 0.137?0.647, 0.268?0.903, P<0.05). (3) Stratified analysis. Of the 71 patients with non-pathologic complete response, the median recurrence-free survival time of 48 patients in the adjuvant therapy group was 24.0 months, with the 1-, 2-year recurrence-free survival rates as 67.4%, 48.8%. The median recurrence-free survival time of 23 patients with non-pathological complete response in the follow-up monitoring group was 7.4 months, with the 1-, 2-year recurrence-free survival rates as 35.0%, 26.3%. There was a significant difference in recurrence-free survival between the 48 patients with non-pathologic complete response in the adjuvant therapy group and the 23 patients with non-pathologic complete response in the follow-up monitoring group ( χ2=5.241, P<0.05). Conclusion:For HCC patients with conversion therapy of TKIs and ICIs followed by sequential hepatectomy, postoperative adjuvant therapy, compared to postoperative follow-up monitoring, can prolong the recurrence-free survival time of patients, of whom cases with non-pathologic complete response can benefit from adjuvant therapy.

BACKGROUND:Ilizarov bone transport is very effective in the treatment of open large tibial bone defects,but there are still complications,among which the difficulty of junction healing is one of the difficult points in treatment. OBJECTIVE:To investigate the effect of Ilizarov bone transport combined with antibiotic bone cement on junction healing after operation of open large tibial bone defect. METHODS:Totally 51 patients with open large tibial bone defect(bone defect>4 cm)admitted to Binzhou Medical University Hospital from August 2010 to January 2022 were selected,of which 28 received Ilizarov bone transport alone(control group)and 23 received Ilizarov bone transport combined with antibiotic bone cement treatment(trial group).External fixation time,bone healing time,bone healing index,visual analog scale score during bone removal,bone defect limb function,junction healing and complications at the final follow-up were statistically compared between the two groups. RESULTS AND CONCLUSION:(1)All the 51 patients were followed up for a mean of(22.53±5.77)months.External fixation time,bone healing time,bone healing index,postoperative infection rate,and non-healing rate of junction were less in the trial group than those in the control group(P<0.05).There was no significant difference between the two groups in visual analog scale scores at 6 months after the second surgery and in the functional excellence and good rate of limb with bone defect at the final follow-up(P>0.05).(2)These findings indicate that compared with the Ilizarov bone transport alone,Ilizarov bone transport combined with antibiotic bone cement treatment can promote the healing of open tibial fracture junction and increase the rate of bone healing.

OBJECTIVE: To prepare decellularized nerve grafts from alpha-1, 3-galactosyltransferase (GGTA1) gene-edited pigs and explore their biocompatibility for xenotransplantation. METHODS: The sciatic nerves from wild-type pigs and GGTA1 gene-edited pigs were obtained and underwent decellularization. The alpha-galactosidase (α-gal) content in the sciatic nerves of GGTA1 gene-edited pigs was detected by using IB4 fluorescence staining and ELISA method to verify the knockout status of the GGTA1 gene, and using human sciatic nerve as a control. HE staining and scanning electron microscopy observation were used to observe the structure of the nerve samples. Immunofluorescence staining and DNA content determination were used to evaluate the degree of decellularization of the nerve samples. Fourteen nude mice were taken, and subcutaneous capsules were prepared on both sides of the spine. Decellularized nerve samples of wild-type pigs ( n=7) and GGTA1 gene-edited pigs ( n=7) were randomly implanted in the subcutaneous capsules. Blood was drawn at 1, 3, 5, and 7 days after implantation to detect neutrophil counting. RESULTS: IB4 fluorescence staining and ELISA detection showed that GGTA1 gene was successfully knocked out in the nerves of GGTA1 gene-edited pigs. HE staining showed that the structure of the decellularized nerve from GGTA1 gene-edited pigs was well preserved; the nerve basement membrane tube structure was visible under scanning electron microscopy; no cell nuclei was observed, and the extracellular matrix components was retained in the nerve grafts by immunofluorescence staining; and the DNA content was significantly reduced when compared with the normal nerves ( P<0.05). In vivo experiments showed that the number of neutrophils in the two groups were similar at 1, 3, and 7 days after implantation, with no significant difference ( P>0.05); only at 5 days, the number of neutrophils was significantly lower in the GGTA1 gene-edited pigs than in the wild-type pigs ( P<0.05). CONCLUSION The decellularized nerve grafts from GGTA1 gene-edited pigs have well-preserved nerve structure, complete decellularization, retain the natural nerve basement membrane tube structure and components, and low immune response after xenotransplantation through in vitro experiments.
Animals ; Transplantation, Heterologous ; Galactosyltransferases/genetics* ; Sciatic Nerve/immunology* ; Swine ; Tissue Engineering/methods* ; Humans ; Graft Rejection/prevention & control* ; Gene Editing ; Mice ; Mice, Nude ; Heterografts/immunology* ; Animals, Genetically Modified ; Tissue Scaffolds ; Decellularized Extracellular Matrix

Objective:To explore the distribution variation of ultrasound-detected inflammatory lesions with clinical signs in patients with psoriatic arthritis (PsA).Methods:This was based on the Peking University First Hospital Psoriatic Arthritis (PKUPsA) cohort. Patients enrolled from January 2019 to June 2024 were inchuded, patients with complete data of physical examination and ultrasonographic evaluations of 62 joints in the hand and foot. The ultrasound-detected inflammatory lesions including synovitis, tenosynovitis, enthesitis, and soft tissue inflammation were compared with joint tenderness/swelling. The χ2 test was employed to analyze differences between groups. Results:A total of 7 440 joints in 120 PsA patients were included. Overall, the proportion of joints with clinical signs (tenderness or swelling) was higher than those with ultrasound-detected inflammatory lesions [9.14%(680/7 440) vs. 7.93%(590/7 440), χ2=1 245.928, P<0.001], with more tenderness joints than swelling joints [7.72%(574/7 440) vs. 6.14%(457/7 440), χ2=3 264.45, P<0.001]. Clinical signs were primarily observed in hand proximal interphalangeal (PIP), distal interphalangeal (DIP), wrist and ankle joints, mostly in DIP2 joints [19.58%(47/240)]. Ultrasound-detected inflammatory lesions were predominantly found in metatarsophalangeal (MTP), wrist, and ankle joints, mostly in MTP2 joints (18.75%, 45/240). Clinical signs were more prevalent than ultrasound-detected inflammatory lesions in hand PIP1-3, PIP5, DIP2, and DIP5 joints ( P<0.05), whereas more frequent ultrasound-detected inflammatory lesions than clinical tenderness/swelling were in MTP1-4 joints ( P<0.05). Among ultrasound-detected inflammatory lesions, synovitis in MTP2 joints (18.75%, 45/240), tenosynovitis in ankle joints (10.00%, 24/240), enthesitis in hand DIP2 joints (8.75%, 21/240), and soft tissue inflammation in MTP4 joints (2.50%, 6/240) most commonly observed. Dactylitis was more frequently observed in toes than in fingers, with the fourth toe most commonly affected(16.67%, 40/240). Ultrasound-detected inflammatory lesions were observed in 72.37%(55/240) of fingers/toes with clinical dactylitis, mainly presenting as synovitis, tenosynovitis, or combinations of these. Conclusion:PsA exhibits significant heterogeneity in the inflammatory lesions across different joints and lesion types. The discrepancies between clinical findings and ultrasonic inflammatory changes highlight the limitations of physical examination in fully capturing the pathological features of PsA. As a critical tool for PsA evaluation, ultrasonography offers distinct advantages in detecting subclinical inflammation and differentiating inflammatory from non-inflammatory lesions.

To investigate the correlation between vitamin D nutritional status and insulin resistance in pubertal adolescents.