Taxifolin (TAX) is a natural compound known for its liver protection effect, but the mechanism remains unknown. Phosphorylated proteomics analyses discovered that the phosphorylation level of NDRG1 at T328 was a key event of TAX-improved liver fibrosis. We established models with NDRG1 knockout (KO) in vivo and in vitro, demonstrating that NDRG1 KO attenuated the development of hepatocyte injury, and combining NDRG1 KO and TAX administration did not result in a reduction in protection against liver injury. Cellular thermal shift assay and surface plasma resonance analysis showed that TAX directly binds to NDRG1 rather than its upstream kinase, subsequently demonstrating that TAX regulated phosphorylation of NDRG1 at T328 through binding to its C289 site. NDRG1 T328A (phosphorylated mutation) and T328E (mimic phosphorylation) in vivo and in vitro confirmed that pNDRG1_T328 exacerbates hepatocyte injury along with DNA damage, inflammatory response, and apoptosis, thereby contributing to hepatic stellate cells (HSCs) activation. In contrast, TAX can inhibit the above pathological abnormalities and block hepatocyte injury-triggered HSCs activation and fibrosis. Overall, TAX is a potent liver protection drug primarily targeting NDRG1 and inhibiting pNDRG1_T328 in hepatocytes.

Cornus officinalis,a medicinal and edible plant known for its liver-nourishing properties,has shown promise in inhibiting the activation of hepatic stellate cells(HSCs),crucial indicators of hepatic fibrosis,especially when processed by high pressure wine steaming(HPWS).Herein,this study aims to investigate the regulatory effects of cornus officinalis,both in its raw and HPWS forms,on inflammation and apoptosis in liver fibrosis and their underlying mechanisms.In vivo liver fibrosis models were established by subcutaneous injection of CCl4,while in vitro HSCs were exposed to transforming growth factor-β(TGF-β).These findings demonstrated that cornus officinalis with HPWS conspicuously ameliorated his-topathological injury,reduced the release of proinflammatory factors,and decreased collagen deposition in CCl4-induced rats compared to its raw form.Utilizing ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer(UHPLC-QTOF-MS)combined with network analysis,we identified that the pharmacological effects of the changed components of cornus officinalis before and after HPWS,primarily centered on the adenosine phosphate(AMP)-activated protein kinase(AMPK)pathway.Of note,cornus officinalis activated AMPK and sirtuin 3(SIRT3),promoting the apoptosis of activated HSCs through the caspase cascade by regulating caspase3,caspase6 and caspase9.small interfering RNA(siRNA)experiments showed that cornus officinalis could regulate AMPK activity and its mediated-apoptosis through SIRT3.In conclusion,cornus officinalis exhibited the ability to reduce inflammation and apoptosis,with the SIRT3-AMPK signaling pathway identified as a potential mecha-nism underlying the synergistic effect of cornus officinalis with HPWS on anti-liver fibrosis.

Renal fibrosis is a devastating consequence of progressive chronic kidney disease,representing a major public health challenge worldwide.The underlying mechanisms in the pathogenesis of renal fibrosis remain unclear,and effective treatments are still lacking.Renal tubular epithelial cells(RTECs)maintain kidney function,and their dysfunction has emerged as a critical contributor to renal fibrosis.Cellular quality control comprises several components,including telomere homeostasis,ubiquitin-proteasome system(UPS),autophagy,mitochondrial homeostasis(mitophagy and mitochondrial metabolism),endoplasmic reticulum(ER,unfolded protein response),and lysosomes.Failures in the cellular quality control of RTECs,including DNA,protein,and organelle damage,exert profibrotic functions by leading to senescence,defective autophagy,ER stress,mitochondrial and lysosomal dysfunction,apoptosis,fibro-blast activation,and immune cell recruitment.In this review,we summarize recent advances in un-derstanding the role of quality control components and intercellular crosstalk networks in RTECs,within the context of renal fibrosis.

Objectives: To evaluate the feasibility and preliminary clinical results of transcatheter pulmonary valve replacement (TPVR) with the domestically-produced balloon-expandable Prizvalve system. Methods: This is a prospective single-center observational study. Patients with postoperative right ventricular outflow tract (RVOT) dysfunction, who were admitted to West China Hospital of Sichuan University from September 2021 to March 2023 and deemed anatomically suitable for TPVR with balloon-expandable valve, were included. Clinical, imaging, procedural and follow-up data were analyzed. The immediate procedural results were evaluated by clinical implant success rate, which is defined as successful valve implantation with echocardiography-assessed pulmonary regurgitationResults: A total of 5 patients were included, with 4 males, aged 14 to 37 years. The initial diagnosis included Tetralogy of Fallot (2 cases), truncus arteriosus (1 case), pulmonary atresia (1 case) and subaortic stenosis (1 case, prior Ross procedure). Four patients underwent RVOT reconstruction with homograft or artificial conduit, and one patient was treated with trans-annular patch technique. The indications of TPVR included RVOT obstruction and regurgitation (3 cases), isolated obstruction (1 case), and isolated regurgitation (1 case). Of the 4 patients with varying severity of ROVT obstruction, the average preprocedural peak jet velocity of RVOT was 3.5 m/s, and the average peak pressure gradient was 50.0 mmHg. Except for one patient, who had previously been implanted with a covered Cheatham-Platinum (CP) stent due to severe stenosis of the main pulmonary artery, other patients underwent pre-stenting with a covered CP stent before TPVR. Clinical implant success was achieved in all of the 5 patients, and there was no serious periprocedural complications. The average trans-pulmonary peak jet velocity and peak pressure gradient derived from postprocedural echocardiography was 2.3 m/s and 21.2 mmHg, respectively. All patients experienced significant symptom relief after the procedure. All patients completed 3-month follow-up, and 4 completed 6-month follow-up. There was no case of infectious endocarditis during follow-up. All patients were graded as NYHA functional class one at the latest follow-up. Conclusions: TPVR using the domestically-produced balloon-expandable Prizvalve system is safe and feasible for the treatment of patients with post-surgical RVOT dysfunction and suitable landing-zone anatomy. The safety, effectiveness, and long-term valve durability of the Prizvalve system deserve further research.
Male ; Humans ; Pulmonary Valve/surgery* ; Heart Valve Prosthesis/adverse effects* ; Heart Valve Prosthesis Implantation ; Constriction, Pathologic/surgery* ; Prospective Studies ; Ventricular Outflow Obstruction/surgery* ; Treatment Outcome ; Cardiac Catheterization/methods* ; Transcatheter Aortic Valve Replacement

Objective: To provide survival evidence of anthracycline-free neoadjuvant chemotherapy for patients with stages Ⅱ-Ⅲ human epidermal growth factor receptor-2 (HER-2) positive and hormone receptor (HR) negative breast cancer. Methods: The prospective cohort study was conducted at the Department of Medical Oncology of Cancer Hospital, Chinese Academy of Medical Sciences. Patients with HER-2 positive and HR negative breast cancer in stages Ⅱ-Ⅲ were enrolled to receive neoadjuvant therapy (NAT) of dose-dense paclitaxel (175 mg/m(2)) plus carboplatin (AUC=4.0) biweekly for 6 cycles in combination with trastuzumab (PCbH), and matched patients who received standard adjuvant therapy of physicians' choice were recruited for survival and safety comparison. Results: From July 2013 to November 2019, 166 patients were included (neoadjuvant 51, adjuvant 115). Compared with those who received adjuvant therapy, patients receiving NAT were younger (<35 years: 19.6% vs 5.2%, P=0.014), had larger tumors (T3: 62.7% vs 7.8%, P<0.001) and more advanced diseases (stage ⅡA: 2.0% vs 41.7%, P<0.001). Patients in the neoadjuvant group all received surgery, and 96 (83.5%) in the adjuvant group received anthracycline-and-taxane-containing regimens. A total of 98 patients (49 pairs) were matched, and the covariates between the two groups were acceptably balanced. Within a median follow-up of 46.5 (range, 14-87) months, the 4-year recurrence-free survival (RFS) rate among patients who received NAT was 73.3% (95% CI: 59.0%-87.6%), versus 80.6% (95% CI: 67.9%-93.3%) among those in the adjuvant group without statistical difference (P=0.418). A similar result was observed for the 4-year overall survival (OS) [neoadjuvant versus adjuvant: 91.5% (95% CI: 81.7%-100.0%) vs 97.8% (95% CI: 93.5%-100.0%), P=0.314]. Compared with standard adjuvant therapy, PCbH was related to less neutropenia and better cardiac safety. Conclusions: These results support the consideration of anthracycline-free neoadjuvant chemotherapy combined with anti-HER-2 therapy for patients with stages Ⅱ-Ⅲ HER-2-positive and HR-negative breast cancer. Optimized regimens with both efficacy and safety are needed and to be further investigated.
Female ; Humans ; Anthracyclines/therapeutic use* ; Antibiotics, Antineoplastic/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Carboplatin/therapeutic use* ; Chemotherapy, Adjuvant ; Hormones/therapeutic use* ; Neoadjuvant Therapy ; Paclitaxel/therapeutic use* ; Prospective Studies ; Receptor, ErbB-2/metabolism* ; Trastuzumab/therapeutic use* ; Triple Negative Breast Neoplasms/drug therapy*

Objectives: To evaluate the feasibility and preliminary clinical results of transcatheter pulmonary valve replacement (TPVR) with the domestically-produced balloon-expandable Prizvalve system. Methods: This is a prospective single-center observational study. Patients with postoperative right ventricular outflow tract (RVOT) dysfunction, who were admitted to West China Hospital of Sichuan University from September 2021 to March 2023 and deemed anatomically suitable for TPVR with balloon-expandable valve, were included. Clinical, imaging, procedural and follow-up data were analyzed. The immediate procedural results were evaluated by clinical implant success rate, which is defined as successful valve implantation with echocardiography-assessed pulmonary regurgitationResults: A total of 5 patients were included, with 4 males, aged 14 to 37 years. The initial diagnosis included Tetralogy of Fallot (2 cases), truncus arteriosus (1 case), pulmonary atresia (1 case) and subaortic stenosis (1 case, prior Ross procedure). Four patients underwent RVOT reconstruction with homograft or artificial conduit, and one patient was treated with trans-annular patch technique. The indications of TPVR included RVOT obstruction and regurgitation (3 cases), isolated obstruction (1 case), and isolated regurgitation (1 case). Of the 4 patients with varying severity of ROVT obstruction, the average preprocedural peak jet velocity of RVOT was 3.5 m/s, and the average peak pressure gradient was 50.0 mmHg. Except for one patient, who had previously been implanted with a covered Cheatham-Platinum (CP) stent due to severe stenosis of the main pulmonary artery, other patients underwent pre-stenting with a covered CP stent before TPVR. Clinical implant success was achieved in all of the 5 patients, and there was no serious periprocedural complications. The average trans-pulmonary peak jet velocity and peak pressure gradient derived from postprocedural echocardiography was 2.3 m/s and 21.2 mmHg, respectively. All patients experienced significant symptom relief after the procedure. All patients completed 3-month follow-up, and 4 completed 6-month follow-up. There was no case of infectious endocarditis during follow-up. All patients were graded as NYHA functional class one at the latest follow-up. Conclusions: TPVR using the domestically-produced balloon-expandable Prizvalve system is safe and feasible for the treatment of patients with post-surgical RVOT dysfunction and suitable landing-zone anatomy. The safety, effectiveness, and long-term valve durability of the Prizvalve system deserve further research.
Male ; Humans ; Pulmonary Valve/surgery* ; Heart Valve Prosthesis/adverse effects* ; Heart Valve Prosthesis Implantation ; Constriction, Pathologic/surgery* ; Prospective Studies ; Ventricular Outflow Obstruction/surgery* ; Treatment Outcome ; Cardiac Catheterization/methods* ; Transcatheter Aortic Valve Replacement

Objective: To provide survival evidence of anthracycline-free neoadjuvant chemotherapy for patients with stages Ⅱ-Ⅲ human epidermal growth factor receptor-2 (HER-2) positive and hormone receptor (HR) negative breast cancer. Methods: The prospective cohort study was conducted at the Department of Medical Oncology of Cancer Hospital, Chinese Academy of Medical Sciences. Patients with HER-2 positive and HR negative breast cancer in stages Ⅱ-Ⅲ were enrolled to receive neoadjuvant therapy (NAT) of dose-dense paclitaxel (175 mg/m(2)) plus carboplatin (AUC=4.0) biweekly for 6 cycles in combination with trastuzumab (PCbH), and matched patients who received standard adjuvant therapy of physicians' choice were recruited for survival and safety comparison. Results: From July 2013 to November 2019, 166 patients were included (neoadjuvant 51, adjuvant 115). Compared with those who received adjuvant therapy, patients receiving NAT were younger (<35 years: 19.6% vs 5.2%, P=0.014), had larger tumors (T3: 62.7% vs 7.8%, P<0.001) and more advanced diseases (stage ⅡA: 2.0% vs 41.7%, P<0.001). Patients in the neoadjuvant group all received surgery, and 96 (83.5%) in the adjuvant group received anthracycline-and-taxane-containing regimens. A total of 98 patients (49 pairs) were matched, and the covariates between the two groups were acceptably balanced. Within a median follow-up of 46.5 (range, 14-87) months, the 4-year recurrence-free survival (RFS) rate among patients who received NAT was 73.3% (95% CI: 59.0%-87.6%), versus 80.6% (95% CI: 67.9%-93.3%) among those in the adjuvant group without statistical difference (P=0.418). A similar result was observed for the 4-year overall survival (OS) [neoadjuvant versus adjuvant: 91.5% (95% CI: 81.7%-100.0%) vs 97.8% (95% CI: 93.5%-100.0%), P=0.314]. Compared with standard adjuvant therapy, PCbH was related to less neutropenia and better cardiac safety. Conclusions: These results support the consideration of anthracycline-free neoadjuvant chemotherapy combined with anti-HER-2 therapy for patients with stages Ⅱ-Ⅲ HER-2-positive and HR-negative breast cancer. Optimized regimens with both efficacy and safety are needed and to be further investigated.
Female ; Humans ; Anthracyclines/therapeutic use* ; Antibiotics, Antineoplastic/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Carboplatin/therapeutic use* ; Chemotherapy, Adjuvant ; Hormones/therapeutic use* ; Neoadjuvant Therapy ; Paclitaxel/therapeutic use* ; Prospective Studies ; Receptor, ErbB-2/metabolism* ; Trastuzumab/therapeutic use* ; Triple Negative Breast Neoplasms/drug therapy*

OBJECTIVE: To explore the early clinical efficacy of primary total hip arthroplasty(THA) with Corail standard stems (KS type) and high offset stems (KHO type), by analyzing the postoperative radiographic parameters of different offset of femoral components with Corail stem which has a neck-shaft angle of 135 ° in unilateral primary THA, by comparing the measurement results on both sides and analyzing the reconstruction of the postoperative femoral offset and the hip joint function recovery. METHODS: A retrospective analysis was made of 186 patients with unilateral hip joint lesions who underwent the first total hip arthroplasty with Johnson & Johnson Corail prostheses from January 2015 to June 2017. According to the use of femoral prostheses with different eccentricities during the operation, the patients were divided into high eccentricity group and standard eccentricity group. In the high eccentricity group, there were 52 cases of Corail high eccentricity prosthesis(KHO type), including 20 females and 32 males;aged 21 to 71 years old with an average of(50.6±13.2) years;body mass index(BMI) was (26.0±4.1) kg/m². The standard eccentricity group included 134 Corail standard femoral stem prostheses(KS type), 57 females and 77 males;aged 18 to 77 years old with an average of (47.3±14.0) years;BMI was (25.3±3.5) kg/m². The abduction arm, femoral eccentricity, acetabular eccentricity and the length difference of lower limbs were measured on the postoperatively positive X-ray film of the hip joint. Harris score and related complications were recorded before and after the operation, and the stability of the prosthesis was analyzed. RESULTS: There were significant differences in femoral eccentricity, joint eccentricity and abduction arm between the affected side and the healthy side in the high eccentricity group(P<0.05). There were significant differences in femoral eccentricity and acetabular eccentricity between the affected side and the healthy side in the standard eccentricity group(P<0.05). There were significant differences in combined eccentricity, abduction arm and length of lower limbs between two groups(P<0.05). In the high eccentricity group, the abduction arm of the affected hip joint was positively correlated with the femoral eccentricity, acetabular eccentricity and joint eccentricity(r=0.633, P<0.001;r=0.384, P=0.005;r=0.690, P<0.001). The same results were also obtained in the healthy side(r=0.688, P<0.001;r=0.574, P<0.001;r=0.765, P<0.001). In the standard eccentricity group, the abduction arm of the affected hip joint was positively correlated with the femoral eccentricity, acetabular eccentricity and combined eccentricity(r=0.734, P<0.001;r=0.418, P<0.001;r=0.749, P<0.001). The same results were also obtained in the healthy side(r=0.775, P<0.001;r=0.397, P<0.001;r=0.773, P<0.001). The difference of the length of both lower limbs was significantly correlated with the difference of bilateral joint eccentricity and bilateral abduction arm (r=0.376, P=0.006;r=-0.346, P=0.012). There was no significant correlation between the difference of the length of both lower limbs and the difference of bilateral joint eccentricity and bilateral abduction arm (r=-0.009, P=0.919;r=-0.036, P=0.682). There was no significant difference in Harris score between two groups at the last follow-up(P>0.05). At the last follow-up, Trendelenburg was negative in all patients in both groups, and the prostheses were stable. CONCLUSION Both Corail standard stem and high offset stem may be effectively reconstruct the femoral offset, reconstruct the anatomical structure and biomechanics of the hip joint, and maintain the length of lower limbs and the stability of the hip joint in the unilateral primary total hip arthroplasty. Although the offset of the femur was not reconstructed normally in some cases, the stability of the components and postoperative function were not affected.
Male ; Female ; Humans ; Young Adult ; Adult ; Middle Aged ; Aged ; Adolescent ; Arthroplasty, Replacement, Hip/methods* ; Retrospective Studies ; Hip Prosthesis ; Femur/surgery* ; Lower Extremity

Cholangiocarcinoma (CCA) is a highly invasive type of cancer with insidious onset and high mortality. Polypyrimidine tract-binding protein 1 (PTBP1) is highly over-expressed in various types of tumor tissues, which contributes to cancer progression. But the role of PTBP1 in CCA has not been explored yet. In this study, we aim to investigate the function of PTBP1 in CCA. Therefore, we used publicly available data from the cancer genome atlas (TCGA) to evaluate the dysregulation of PTBP1 in CCA. The results showed that the PTBP1 is significantly up-regulated in CCA tissues compared to the matched non-tumor tissues (P < 0. 05). We assessed the effects of PTBP1 on the growth of CCA cell lines RBE and HuH28 by performing CCK-8 and plate colony formation assays. The results showed that overexpression of PTBP1 significantly promoted the growth (P < 0. 01) of CCA cells, whereas knockdown of PTBP1 exhibited opposite effects. Transwell and Invasion assays revealed that overexpression of PTBP1 significantly promotes the migration and invasion of CCA cells (P < 0. 001), whereas knockdown of PTBP1 exhibited opposite effects (P < 0. 001). The RNA sequencing (RNA-seq) analysis in PTBP1-depleted cells showed that the up-regulated genes are significantly enriched in p53 signaling pathway, while the down-regulated genes are represented by cholesterol metabolism, Rho GTPase and TGF-β pathways. Then, the alternative splicing analysis revealed that inhibition of PTBP1 led to series of aberrant alternative splicing events, including several cancer-associated ones, such as splicing events within the TGF-β regulator TGIF1 and the p53 activity-correlated gene GNAS. These results indicate that PTBP1 promotes the progression of CCA likely by regulating the transcriptome alternative splicing to influence multiple cancer-associated signaling pathways.

Objective: To detect the difference in the incidence of small intestinal bacterial overgrowth(SIBO) in patients with liver cirrhosis and chronic hepatitis fibrosis(CHF) with the lactulose hydrogen breath test(LHBT), and to explore the relationship between SIBO and inflammatory factors and oxidative stress related indicators. Methods: LHBT was performed on 38 CHF patients, 60 cirrhosis patients and 31 healthy controls to evaluate the incidence of SIBO. The patients were further divided into SIBO-positive and negative group. Then we compared related clinical symptoms and laboratory tests between the two groups and detected lipopolysaccharide(LPS), interleukin(IL)-6, tumor necrosis factor(TNF)-α, IL-10 level, and several kinds of oxidative stress indicators such as diamine oxidase(DAO), superoxide dismutase(SOD), glutathione(GSH), catalase(CAT). Statistical analysis was conducted to analyze the correlation between the concentration of LPS, IL-6, TNF-α, DAO, SOD, GSH, CAT and LHBT summation value. Results: (1) The positive rate of SIBO in CHF group, cirrhosis group and control group was 36.84%, 60.00% and 9.68%, respectively. The difference was statistically significant(P<0.01).(2) The differences in CTP classification and ascites were statistically significant between the two subgroups with and without SIBO(P<0.05).(3) The levels of LPS, IL-6, CAT, DAO and SOD in SIBO-positive group were higher than those in negative group(P<0.05). However, the concentrations of IL-10, TNF-α and GSH were similar between the two groups.(4) The LHBT summation value was positively correlated with the concentrations of LPS, IL-6, DAO, SOD and CAT in serum(P<0.05), but had no significant correlation with TNF-α, IL-10 and GSH. Conclusion Compared with healthy controls, CHF and cirrhosis patients are more likely to develop SIBO. It is also related to the increase of inflammatory factors and oxidative stress indexes in peripheral blood. SIBO may aggravate the inflammatory response of CHF and cirrhosis patients through intestinal flora dysregulation and oxidative stress, thus aggravating the disease change.