Objective To observe the effects of Bushen Huoxue Prescription on the pathway related to necroptosis of nucleus pulposus cells in a model rabbit of intervertebral disc degeneration;To explore its mechanisms in delaying intervertebral disc degeneration.Methods A intervertebral disc degeneration rabbit model was established using the spinal instability method.Totally 40 model rabbits were randomly divided into model group,ibuprofen group and Bushen Huoxue Prescription low-,medium-and high-dosage groups.Additionally,a normal control group and a sham-operation group were set up,with 8 rabbits in each group.Each treatment groups received the corresponding drugs via gavage for two consecutive weeks.HE staining was used to observe morphology of nucleus pulposus tissue,transmission electron microscopy was used to observe ultrastructure in nucleus pulposus cells,immunohistochemical staining was used to assess the expressions of Aggrecan and Collagen Ⅱ in nucleus pulposus tissue,Western blot was used to detect the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein in nucleus pulposus tissue.Results Compared with the sham-operation group,the model group showed a significant decrease in nucleus pulposus cells,disordered cell arrangement,reduced extracellular matrix,interrupted cell membrane continuity under transmission electron microscopy,organelle swelling,nuclear membrane disruption,partial chromatin loss,and positive expression of Aggrecan and Collagen Ⅱ in nucleus pulposus tissue decreased(P<0.01),while the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein significantly increased(P<0.01).Compared with the model group,the treatment groups showed an increased number of nucleus pulposus cells with orderly arrangement and more extracellular matrix,the ultrastructural damage of the cell membrane,organelle and nucleus in nucleus pulposus cells was partially restored under transmission electron microscopy,the positive expressions of Aggrecan and Collagen Ⅱ significantly increased in Bushen Huoxue Prescription medium-and high-dosage groups and the ibuprofen group(P<0.05,P<0.01),while the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein significantly decreased(P<0.05,P<0.01).Conclusion Bushen Huoxue Prescription may delay intervertebral disc degeneration of the model rabbit by inhibiting the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein in nucleus pulposus cells,and promoting the generation of extracellular matrix components Aggrecan and Collagen Ⅱ.

Objective To observe the effects of Bushen Huoxue Prescription on pressure-induced necroptosis in human nucleus pulposus cells and the expressions of RIPK1/RIPK3/MLKL pathway;To explore its potential mechanism in delaying intervertebral disc degeneration.Methods Human primary nucleus pulposus cells were cultured in vitro,and a model of nucleus pulposus cell degeneration was established using continuous load pressure method.After modeling,the nucleus pulposus cells were divided into model group,Bushen Huoxue Prescription group and inhibitor group,blank serum,Bushen Huoxue Prescription containing serum and necroptotic apoptosis inhibitor(Nec-1)intervention were administered,respectively.Normal group nucleus pulposus cells were cultured routinely.AO/EB fluorescence dual staining method was used for detecting cell apoptosis,flow cytometry was used to detect the necroptosis rate of nucleus pulposus cells,Western blot was used to detect the protein expressions of p-receptor interacting protein kinase(RIPK)1,p-RIPK3 and p-mixed lineage kinase domain like protein(MLKL),RT-qPCR was used to detect the mRNA expressions of RIPK1,RIPK3 and MLKL.Results Compared with the normal group,the model group showed more red fluorescence under AO/EB staining of nucleus pulposus cells,which were round and condensed,the necroptosis rate of nucleus pulposus cells increased(P<0.05),the protein expressions of p-RIPK1,p-RIPK3 and p-MLKL increased(P<0.05,P<0.01),while there was no significant difference in RIPK1 mRNA expression(P>0.05),and RIPK3 and MLKL mRNA expression increased(P<0.01).Compared with the model group,Bushen Huoxue Prescription group and the inhibitor group had less red condensed chromatin in the nucleus pulposus cells,Bushen Huoxue Prescription group had a lower rate of necroptosis(P<0.05),while the inhibitor group showed a decreasing trend in necroptosis rate(P>0.05),the protein expressions of p-RIPK1,p-RIPK3 and p-MLKL decreased in Bushen Huoxue Prescription group and the inhibitor group(P<0.05,P<0.01),while there was no significant difference in RIPK1 mRNA expression(P>0.05),and RIPK3 and MLKL mRNA expressions decreased(P<0.01).Conclusion Bushen Huoxue Prescription can alleviate pressure-induced damage to nucleus pulposus cells and inhibit necroptosis,thereby slowing the progression of intervertebral disc degeneration.Its mechanism may be related to the RIPK1/RIPK3/MLKL pathway mediated necroptosis.

Objective: To investigate the association between edentulism and the risk of social isolation in middle-aged and elderly populations, provide empirical evidence for formulating social isolation prevention and intervention policies targeting edentulous middle-aged and elderly populations. Methods: Data were derived from the baseline survey (2011) and three follow-ups (2013, 2015, 2018) of the China Health and Retirement Longitudinal Study (CHARLS). Participants were enrolled in the follow-up from the baseline. Those identified as socially isolated in any of the follow-up surveys conducted in 2013, 2015, or 2018 were considered to have reached the endpoint; otherwise, the follow-up was continued until the end of the 2018 survey; 9 870 individuals were ultimately included. Subjects were grouped by edentulism status. Chi-square test and multivariate Cox regression analysis were performed using Stata 17.0. Results: During a median follow-up of 6.54 years, 1 800 cases of social isolation occurred, with an incidence rate of 18.23%（17.47%~18.99%）. Multivariate Cox regression showed that edentulism was associated with an increased risk of social isolation (HR=1.21, 95% CI: 1.03-1.42) after adjusting for confounders. Subgroup analysis revealed population heterogeneity. Sensitivity analyses confirmed the stability of the results. Conclusion Edentulism is associated with an increased risk of social isolation in middle-aged and elderly adults.

Objective To observe the effects of Bushen Huoxue Prescription on the pathway related to necroptosis of nucleus pulposus cells in a model rabbit of intervertebral disc degeneration;To explore its mechanisms in delaying intervertebral disc degeneration.Methods A intervertebral disc degeneration rabbit model was established using the spinal instability method.Totally 40 model rabbits were randomly divided into model group,ibuprofen group and Bushen Huoxue Prescription low-,medium-and high-dosage groups.Additionally,a normal control group and a sham-operation group were set up,with 8 rabbits in each group.Each treatment groups received the corresponding drugs via gavage for two consecutive weeks.HE staining was used to observe morphology of nucleus pulposus tissue,transmission electron microscopy was used to observe ultrastructure in nucleus pulposus cells,immunohistochemical staining was used to assess the expressions of Aggrecan and Collagen Ⅱ in nucleus pulposus tissue,Western blot was used to detect the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein in nucleus pulposus tissue.Results Compared with the sham-operation group,the model group showed a significant decrease in nucleus pulposus cells,disordered cell arrangement,reduced extracellular matrix,interrupted cell membrane continuity under transmission electron microscopy,organelle swelling,nuclear membrane disruption,partial chromatin loss,and positive expression of Aggrecan and Collagen Ⅱ in nucleus pulposus tissue decreased(P<0.01),while the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein significantly increased(P<0.01).Compared with the model group,the treatment groups showed an increased number of nucleus pulposus cells with orderly arrangement and more extracellular matrix,the ultrastructural damage of the cell membrane,organelle and nucleus in nucleus pulposus cells was partially restored under transmission electron microscopy,the positive expressions of Aggrecan and Collagen Ⅱ significantly increased in Bushen Huoxue Prescription medium-and high-dosage groups and the ibuprofen group(P<0.05,P<0.01),while the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein significantly decreased(P<0.05,P<0.01).Conclusion Bushen Huoxue Prescription may delay intervertebral disc degeneration of the model rabbit by inhibiting the expressions of p-RIPK1,p-RIPK3 and p-MLKL protein in nucleus pulposus cells,and promoting the generation of extracellular matrix components Aggrecan and Collagen Ⅱ.

Objective To observe the effects of Bushen Huoxue Prescription on pressure-induced necroptosis in human nucleus pulposus cells and the expressions of RIPK1/RIPK3/MLKL pathway;To explore its potential mechanism in delaying intervertebral disc degeneration.Methods Human primary nucleus pulposus cells were cultured in vitro,and a model of nucleus pulposus cell degeneration was established using continuous load pressure method.After modeling,the nucleus pulposus cells were divided into model group,Bushen Huoxue Prescription group and inhibitor group,blank serum,Bushen Huoxue Prescription containing serum and necroptotic apoptosis inhibitor(Nec-1)intervention were administered,respectively.Normal group nucleus pulposus cells were cultured routinely.AO/EB fluorescence dual staining method was used for detecting cell apoptosis,flow cytometry was used to detect the necroptosis rate of nucleus pulposus cells,Western blot was used to detect the protein expressions of p-receptor interacting protein kinase(RIPK)1,p-RIPK3 and p-mixed lineage kinase domain like protein(MLKL),RT-qPCR was used to detect the mRNA expressions of RIPK1,RIPK3 and MLKL.Results Compared with the normal group,the model group showed more red fluorescence under AO/EB staining of nucleus pulposus cells,which were round and condensed,the necroptosis rate of nucleus pulposus cells increased(P<0.05),the protein expressions of p-RIPK1,p-RIPK3 and p-MLKL increased(P<0.05,P<0.01),while there was no significant difference in RIPK1 mRNA expression(P>0.05),and RIPK3 and MLKL mRNA expression increased(P<0.01).Compared with the model group,Bushen Huoxue Prescription group and the inhibitor group had less red condensed chromatin in the nucleus pulposus cells,Bushen Huoxue Prescription group had a lower rate of necroptosis(P<0.05),while the inhibitor group showed a decreasing trend in necroptosis rate(P>0.05),the protein expressions of p-RIPK1,p-RIPK3 and p-MLKL decreased in Bushen Huoxue Prescription group and the inhibitor group(P<0.05,P<0.01),while there was no significant difference in RIPK1 mRNA expression(P>0.05),and RIPK3 and MLKL mRNA expressions decreased(P<0.01).Conclusion Bushen Huoxue Prescription can alleviate pressure-induced damage to nucleus pulposus cells and inhibit necroptosis,thereby slowing the progression of intervertebral disc degeneration.Its mechanism may be related to the RIPK1/RIPK3/MLKL pathway mediated necroptosis.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase and its rearrangements occur in non-small cell lung cancer (NSCLC), resulting in signal dysregulation in kinase domain. As a new generation of potent ALK tyrosine kinase inhibitors (TKIs), Brigatinib was approved in China in March 2022 as a treatment for locally advanced or metastatic NSCLC patients with ALK rearrangement positive. Brigatinib significantly improved the survival, cranial efficacy and quality of life compared to Crizotinib in clinical trials. Brigatinib is generally well tolerated. Brigatinib has been one of the preferred treatments and an addition of options in ALK-rearranged NSCLC. Pulmonary toxicity is one of the adverse effects observed during the treatment of TKIs and deserves the intense attention of clinicians, despite of its low incidence rate. Pulmonary toxicity reported during the treatment of Brigatinib has shown distinct clinical presentations, such as early-onset (median time to onset, 2 days) and rapid tolerance and reversibility of symptoms. In view of this, the concept of early-onset pulmonary events (EOPEs) was proposed and established during the submission for regulatory review and approval. We focused on clinical characteristics, potential mechanism of etiology, and management strategies of EOPEs to provide clinicians evidence for better clinical decision support.
.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/genetics* ; Quality of Life ; Receptor Protein-Tyrosine Kinases ; Protein Kinase Inhibitors/adverse effects*

Nonalcoholic fatty liver disease (NAFLD) includes a series of diseases affected by various complex factors. Mitochondrial dysfunction often occurs in NAFLD and may lead to the progression of hepatitis and liver fibrosis. This article reviews the important role of mitochondrial oxidative stress, respiration, energy metabolism, quality control, and mitochondrial DNA in NAFLD and summarizes the current status of mitochondria-targeted therapy for NAFLD, hoping to provide a new direction for the research and clinical treatment of NAFLD.

microRNAs (miRNAs) are low-molecular-weight non-coding RNAs that regulate various physiological and pathological functions through the regulation of gene expression at the post-transcriptional level. More and more evidence has shown that microRNA-27a (miRNA-27a) plays a role in the development and pathogenesis of liver diseases. By reviewing and updating related studies, this article introduces the research advances in the role of miRNA-27a in various liver diseases including fatty liver disease, hepatitis, hepatic fibrosis, and liver cancer and analyzes the role of miRNA-27a in liver regeneration and its potential as a biomarker, so as to provide a reference for future studies and more possibilities for new treatment ideas for chronic hepatic diseases.

Objective To investigate the mechanism of occurrence and development of zinc-alpha-2-glycoprotein (AZGP1) in the activated hepatic stellate cells (HSCs) and liver fibrosis.Methods The activated human hepatic stellate cell line LX2 was induced by the stimulation of transforming growth factor-β1 to construct carbon tetrachloride liver fibrosis mice model.The situation expression of AZGP1 in liver cells and tissues were observed.Plasmid transfection method was used to detect the activation,proliferation,apoptotic functions and changes in related factors of LX2 cells,respectively,after the overexpression and inhibition of AZGP1expression.Univariate analysis of variance was used for multiple group comparison.Results The results of immunofluorescence staining showed that AZGP1 protein was decreased and α-smooth muscle actin was increased in the activated LX2 cells,and the two were negatively correlated.AZGP1 gene and protein were significantly under-expressed in activated LX2 cells and liver tissues of mice with carbon tetrachloride liver fibrosis.Collagen I,matrix metalloproteinase-2,and α-smooth muscle actin genes and proteins were significantly down-regulated in LX2 cells after over-expression of AZGP 1.Cell fluorescence showed that AZGP 1-overexpressing cells were activated and α-smooth muscle actin protein was reduced.In addition,the proliferative activity and G1/S-specific cyclin D1 protein of LX2 cells were significantly reduced after overexpression of AZGP1,while cell cycle experiments showed that the proportion of cells overexpressing AZGP1 was significantly increased in the G0/G1 phase,and the proportion of S phase was significantly reduced.AZGP1 had no significant effect on the apoptosis of LX2 cells.Conclusion AZGP1 can reverse liver fibrosis by inhibiting the activation and proliferation of hepatic stellate cells,and thereby overexpression of AZGP1 is expected to become a new target for liver fibrosis treatment.

Objective To study the surgical treatment of hepatic hemangiomas and the timing of surgery.Methods A retrospective study was conducted on 908 patients with giant hemangiomas who underwent surgery between December 1997 and December 2017.The clinical data,surgical indications,surgical outcomes,lesion size,and the effect of TAE were compared.Results The diameter (mean + /-S.D.)of the resected hepatic cavernous hemangiomas was (11.1 ± 6.2) cm (the longest diameter was 60 cm).585 patients (64.4％) underwent enucleation of hepatic hemangiomas and 323 patients (35.6％) underwent anatomical hepatectomy.Six patients died perioperatively (mortality rate 0.7％).The incidence of severe complication (Clavien-Dindo grade 3 ～ 5) was 3.8％.The incidence of severe postoperative complication for enucleation (2.7％) was significantly less than anatomic liver resection (5.6％,P ＜0.05).When the lesion was more than 20 cm,the complication and mortality rates were significantly higher than those less than 20 cm (P ＜ 0.05).The complication and mortality rates in patients who underwent TAE before surgery were significantly higher than those without TAE (P ＜ 0.05).Conclusions Surgical enucleation of hemangiomas was superior to anatomical hepatectomy.With increase in tumor size,the risk of surgery increased.Surgical treatment was safe and effective for giant hepatic hemangiomas.For giant hepatic hemangiomas with significant increase in size,prompt surgical treatment is recommended.