Background/Aims: Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regulates cell proliferation and malignant transformation in nonalcoholic steatoheaptitis-associated hepatocellular carcinoma (NASH-HCC). However, its participation in cholestatic fibrosis has not been explored yet. Methods: Serial sections of liver tissue of PBC patients were stained with immunofluorescence. Hepatic fibrosis was induced by bile duct ligation (BDL) in wild-type (WT), global JCAD knockout mice (JCAD-KO) and HSC-specific JCAD knockout mice (HSC-JCAD-KO), and evaluated by histopathology and biochemical tests. In situ-activated HSCs isolated from BDL mice were used to determine effects of JCAD on HSC activation. Results: In consistence with staining of liver sections from PBC patients, immunofluorescent staining revealed that JCAD expression was identified in smooth muscle α-actin (α-SMA)-positive fibroblast-like cells and was significantly up-regulated in WT mice with BDL. JCAD deficiency remarkably ameliorated BDL-induced hepatic injury and fibrosis, as documented by liver hydroxyproline content, when compared to WT mice with BDL. Histopathologically, collagen deposition was dramatically reduced in both JCAD-KO and HSC-JCAD-KO mice compared to WT mice, as visualized by Trichrome staining and semi-quantitative scores. Moreover, JCAD deprivation significantly attenuated in situ HSC activation and reduced expression of fibrotic genes after BDL. Conclusions JCAD deficiency effectively suppressed hepatic fibrosis induced by BDL in mice, and the underlying mechanisms are largely through suppressed Hippo-YAP signaling activity in HSCs.

Objective: The purpose of this study was to assess the safety and efficacy of a second allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reduced-intensity conditioning (RIC) in patients with hematological malignancies who had relapsed after the first allo-HSCT. Methods: Between April 2018 and June 2021, 44 patients with hematological malignancies (B-ALL 23, T-ALL/T-LBL 4, AML15, and MDS 2) were enrolled and retrospectively examined. Unrelated donors (n=12) or haploidentical donors (n=32) were used. Donors were replaced in all patients for the second allo-HSCT. Hematological and immunological germline predisposition genes and hematopoietic and immune function tests were used to select the best-related donor. Total body irradiation (TBI) /fludarabine (FLU) -based (n=38), busulfan (BU) /FLU-based (n=4), total marrow irradiation (TMI) /FLU-based (n=1), and BU/cladribine-based (n=1) were the RIC regimens used. For graft versus host disease (GVHD) prevention, cyclosporine, mycophenolate mofetil, short-term methotrexate, and ATG were used. Eighteen (40.9%) of 44 patients with gene variations for which targeted medications are available underwent post-transplant maintenance therapy. Results: The median age was 25 years old (range: 7-55). The median interval between the first and second HSCT was 19.5 months (range: 6-77). Before the second allo-HSCT, 33 (75%) of the patients were in complete remission (CR), whereas 11 (25%) were not. All patients had long-term engraftment. The grade Ⅱ-Ⅳ GVHD and severe acute GVHD rates were 20.5% and 9.1%, respectively. Chronic GVHD was found in 20.5% of limited patterns and 22.7% of severe patterns. CMV and EBV reactivation rates were 29.5% and 6.8%, respectively. Hemorrhage cystitis occurred in 15.9% of cases, grade Ⅰ or Ⅱ. The 1-yr disease-free survival (DFS), overall survival (OS), and cumulative recurrence incidence (RI) rates of all patients were 72.5% (95% CI, 54.5%-84.3%), 80.6% (95% CI, 63.4%-90.3%), and 25.1% (95% CI, 13.7%-43.2%), respectively, with a median follow-up of 14 (2-39) months. There were eight deaths (seven relapses and one infection). The rate of non-relapse mortality (NRM) was only 2.3%. The CR patients' 1-yr RI rate was significantly lower than the NR patients (16.8% vs 48.1%, P=0.026). The DFS rate in CR patients was greater than in NR patients, although there was no statistical difference (79.9% vs 51.9%, P=0.072). Univariate analysis revealed that CR before the second allo-HSCT was an important prognostic factor. Conclusion: With our RIC regimens, donor change, and post-transplant maintenance therapy, the second allo-HSCT in relapsed hematological malignancies after the first allo-HSCT is a safe and effective treatment with high OS and DFS and low NRM and relapse rate. The most important factor influencing the prognosis of the second allo-HSCT is the patient's illness condition before the transplant.
Humans ; Adult ; Retrospective Studies ; Neoplasm Recurrence, Local ; Hematologic Neoplasms/therapy* ; Busulfan/therapeutic use* ; Graft vs Host Disease/prevention & control* ; Chronic Disease ; Unrelated Donors ; Hematopoietic Stem Cell Transplantation ; Transplantation, Homologous ; Transplantation Conditioning

Inflammation, abnormal cholesterol metabolism, and macrophage infiltration are involved in the destruction of the extracellular matrix of the nucleus pulposus (NP), culminating in intervertebral disc degeneration (IDD). Whether nimbolide (Nim), a natural extract, can alleviate IDD is unclear. In this study, we demonstrated that Nim promotes cholesterol efflux and inhibits the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways by activating sirtuin 1 (SIRT1) in nucleus pulposus cells (NPCs) during inflammation. Thus, Nim balanced matrix anabolism and catabolism of NPCs. However, the inhibition of SIRT1 significantly attenuated the effects of Nim. We also found that Nim promoted the expression of SIRT1 in RAW 264.7, which enhanced the proportion of M2 macrophages by facilitating cholesterol homeostasis reprogramming and impeded M1-like macrophages polarization by blocking the activation of inflammatory signaling. Based on these results, Nim can improve the microenvironment and facilitate matrix metabolism equilibrium in NPCs. Furthermore, in vivo treatment with Nim delayed IDD progression by boosting SIRT1 expression, modulating macrophage polarization and preserving the extracellular matrix. In conclusion, Nim may represent a novel therapeutic strategy for treating IDD.

Objective:To analyze and evaluate the impact of balance training on patients with chronic obstructive pulmonary disease (COPD).Methods:The randomized controlled trials of balance training in COPD patients in PubMed, Embase, Web of science, the Cochrane Library, CNKI, Wanfang, VIP, and Chinese Biomedical Literature Database were searched. The retrieval time was from the establishment of the database to November 20, 2022. A Meta-analysis was conducted using RevMan5.3 on balance ability, exercise ability, quality of life, and balance confidence in patients with COPD.Results:A total of 432 patients were included in 7 studies. The results of the Meta-analysis showed that compared with other training, balanced training could improve the balance ability of patients [Timed Up and Go Test: mean difference ( MD)=-2.19, 95% CI (-2.86, -1.52); P<0.001, Berg Balance Scale: MD=4.02, 95% CI (0.78, 7.27); P=0.020, the Balance Evaluation Systems Test: MD=7.83, 95% CI (0.13, 15.52); P=0.050], exercise ability [Six-Minute Walk Test: standard mean difference ( SMD)=0.21, 95% CI (0.01, 0.40); P=0.040] and quality of life [COPD Assessment Test and St. George′s Respiratory Questionnaire: SMD=-0.54, 95% CI (-1.08, -0.01); P=0.050], but balance training did not effectively enhance patients′ activity balance confidence [Activities-Specific Balance Confidence Scale: MD=9.34, 95% CI (-0.98, 19.66); P=0.080]. Conclusion:Balance training can improve the balance ability, exercise ability, and quality of life of patients with COPD, but the impact on patients′ activity balance confidence needs to be further verified.

OBJECTIVE: To assess the association of gene expression with development potential of early embryos derived from patients with polycystic ovary syndrome (PCOS). METHODS: Three pairs of infertile patients with respectively matched age, body mass index, ovarian reserve and treatment with gonadotrophin-releasing hormone (GnRH) antagonists were selected. Patients with fewer embryos were assigned as the case group (n = 3), whilst the remainders were assigned as the control group (n = 3). Ovarian granulosa cells from patients were collected for the extraction of total RNA and subjected to RNA sequencing. The results were subjected to differential gene expression and functional enrichment analyses. RESULTS: Compared with the control group, 76 genes were up-regulated and 110 genes were down-regulated in the case group. The level of estradiol (E₂) was significantly higher in the control group on the trigger day with the injection of human chorionic gonadotrophin (HCG). Compared with the control group, the KRT7 gene was most significantly up-regulated, whilst the CCNYL2 gene was most significantly down-regulated in the case group. Gene ontology (GO) entries enrichment has found those associated with chromosome segregation, cell cycle regulation, and fatty acid metabolism to be significantly enriched. The genes participating in the regulation of cell assembly, differentiation, negative regulation of cell cycle, negative regulation of development, extracellular regulated protein kinases (ERK), ERK1 and ERK2 signaling pathways to be significantly down-regulated. KEGG enrichment analysis of cell signaling pathways revealed that steroid hormone biosynthesis-related genes were enriched. CONCLUSION Among patients treated with GnRH antagonists, the significant difference in the number of oocytes fertilized in vitro and the number of available embryos are associated with the difference in the expression of genes of ovarian granulosa cells.
Female ; Humans ; Pregnancy ; Embryonic Development ; Gene Expression ; Gonadotropin-Releasing Hormone/antagonists & inhibitors* ; Granulosa Cells ; Polycystic Ovary Syndrome/genetics*

Objective: To summarize the single center experience of transcatheter aortic valve replacement (TAVR) with a simplified operative protocol. Methods: Consecutive patients who underwent transfemoral TAVR (TF-TAVR) from July 2020 to December 2020 in Fuwai Hospital were retrospectively analyzed. We compared the baseline characteristic, procedure information, 30-day follow-up outcomes of the patients who underwent TF-TAVR without the simplified operative protocol (routine group) or with the simplified operative protocol (simplified protocol group). Results: 93 patients were collected, 42 patients belonging to routine group, 51 patients belonging to simplified protocol group. In simplified protocol group, there were 51 patients planned to use ultrasound-guided femoral access puncture, procedure was successful in all 51 patients (100%). There were 49 patients planned to use the radial artery as the secondary access, procedure was successful in 45 patients (92%). There were 48 patients planned to use the strategy of avoidance of urinary catheter, this strategy was achieved in 35 patients (73%). There were 12 patients planned to use the left ventricular guidewire to pace, procedure was successful in 11 patients (92%). There were no differences in baseline characteristics, major clinical endpoints and 30-day follow-up outcomes between the two groups. Meanwhile, the procedure time ((62.5±17.9)min vs. (78.3±16.7)min, P<0.001), operation room time ((133.7±25.1)min vs. (159.2±42.6)min, P<0.001), X-ray exposure time ((17.2±6.5)min vs. (20.2±7.7)min, P=0.027) were significantly shorten in simplified protocol group compared with the routine group. Conclusion: Our study results indicate that the simplified operative protocol of TF-TAVR is as effective and safe as the routine operative protocol, meanwhile using the simplified operative protocol can significantly increase the operative efficiency of TF-TAVR.
Aortic Valve ; Aortic Valve Stenosis/surgery* ; Femoral Artery/surgery* ; Humans ; Retrospective Studies ; Risk Factors ; Time Factors ; Transcatheter Aortic Valve Replacement/methods* ; Treatment Outcome

Osteoporotic vertebral compression fracture (OVCF) can lead to lower back pain and may be even accompanied by scoliosis, neurological dysfunction and other complications, which will affect the daily activities and life quality of patients. Vertebral augmentation is an effective treatment method for OVCF, but it cannot correct unbalance of bone metabolism or improve the osteoporotic status, causing complications like lower back pain, limited spinal activities and vertebral refracture. The post-operative systematic and standardized rehabilitation treatments can improve curative effect and therapeutic efficacy of anti-osteoporosis, reduce risk of vertebral refracture, increase patient compliance and improve quality of life. Since there still lack relevant clinical treatment guidelines for postoperative rehabilitation treatments following vertebral augmentation for OVCF, the current treatments are varied with uneven therapeutic effect. In order to standardize the postoperative rehabilitation treatment, the Spine Trauma Group of the Orthopedic Branch of Chinese Medical Doctor Association organized relevant experts to refer to relevant literature and develop the "Guideline for postoperative rehabilitation treatment following vertebral augmentation for osteoporotic vertebral compression fracture (2022 version)" based on the clinical guidelines published by the American Academy of Orthopedic Surgeons (AAOS) as well as on the principles of scientificity, practicality and advancement. The guideline provided evidence-based recommendations on 10 important issues related to postoperative rehabilitation treatments of OVCF.

Chronic psychological stress can promote vascular diseases, such as hypertension and atherosclerosis. This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification (AMC). Rat arterial calcification model was established by nicotine gavage in combination with vitamin D₃ (VitD₃) intramuscular injection, and rat model of chronic psychological stress was induced by humid environment. Aortic calcification in rats was evaluated by using Alizarin red staining, aortic calcium content detection, and alkaline phosphatase (ALP) activity assay. The expression levels of the related proteins, including vascular smooth muscle cells (VSMCs) contractile phenotype marker SM22α, osteoblast-like phenotype marker RUNX2, and endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP), were determined by Western blot. The results showed that chronic psychological stress alone induced AMC in rats, further aggravated AMC induced by nicotine in combination with VitD₃, promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation, and significantly increased the plasma cortisol levels. The 11β-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats. Conversely, the glucocorticoid receptor agonist dexamethasone induced AMC, promoted AMC induced by nicotine combined with VitD₃, and further activated aortic ERS. The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate. These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis, which may provide new strategies and targets for the prevention and control of AMC.
Rats ; Animals ; Glucocorticoids/metabolism* ; Rats, Sprague-Dawley ; Nicotine/metabolism* ; Hydrocortisone/metabolism* ; Muscle, Smooth, Vascular ; Dexamethasone/metabolism* ; Vascular Calcification/metabolism* ; Myocytes, Smooth Muscle/metabolism* ; Cells, Cultured

Gut microbiota is a bridge between the metabolism and health state of the host,which plays a very important role in maintaining homeostasis. Natural polysaccharides,widely existed in nature,are a kind of biological macromolecules with prebiotics effects,which can improve a degree of physiological status by selectively changing the gut microbiota structure and function,enhancing the content of short chain fatty acids(SCFAs)and decreasing the level of inflammatory cytokines. In addition,the majority of polysaccharides can be degraded by gut microbiota to enhance their bioavailability and to promote the health state of the host. In this paper we discuss the interaction among polysaccharides and gut microbiotanatural,degradation mechanism and review gut microbiota as a target in the treatment of metabolic diseases,so as to provide future prospects of natural polysaccharides as " prebiotics " functional factors in the field of biological medicine and health products.

Aim To investigate the effect of terpinene 4-alcohol(T4O)on the malignant behavior of colorectal cancer cell RKO and HCT116 and the underlying mechanism. Methods RKO and HCT116 cells were treated with 0, 1, 2, 4 μmol·L-1 T4O and 4 μmol·L-1 5-Fu, respectively. The proliferation, clonal formation, apoptosis, cell cycle, migration and invasion of RKO and HCT116 cells were detected by CCK-8, colony formation, flow cytometry, wound healing and Transwell assay; the expressions of E-Cadherin, N-Cadherin, p21, CyclinB1 and cleaved-Caspase7 in each group of cells were detected by Western blot. Based on pharmacophore, the target of T4O was analyzed and then the effects of T4O on the expression and degradation rate of NR3C1 were explored. NR3C1 knockdown cells were constructed, and the effects of NR3C1 knockdown on the proliferating and migrating inhibition induced by T4O were detected by wound healing and CCK-8 assay. Results T4O significantly inhibited the proliferation, colony formation, migration and invasion of RKO and HCT116 cells, as well as induced apoptosis and G1 phase arrest(P all <0. 05). The effect of T4O was better than that induced by 5-Fu with the same dose. T4O obviously reduced N-Cadherin and Cyclin B1 expression, and elevated the E-Cadherin, p21 and cleaved-Caspase7 expression(P all <0. 05). A total of 10 targets of T4O were discovered, among which NR3C1 had the highest binding score. After T4O treatment, NR3C1 level in cells increased obviously, and the degradation rate decreased markedly(P<0.05). NRC3C1 knockdown significantly relieved the inhibitory effects of T4O on cell prolfieration and migration(P<0.05). Conclusion T4O can inhibit the malignant behavior of colorectal cancer cells RKO and HCT116 by maintaining the stability of NR3C1 protein.