With the main pathological features of glomerulosclerosis and interstitial fibrosis， renal fibrosis is a key pathological process causing chronic kidney disease to progress to end-stage disease. As a cellular autophagic process， mitochondrial autophagy plays a crucial role in maintaining mitochondrial mass and functional stability. Mitochondrial dysfunction is considered to be one of the key factors driving the progression of fibrosis. Phosphatase and tension protein homologue （PTEN） induce various signalling pathways such as putative kinase 1/parkin， Nip3-like protein X/Bcl-2 interacting protein 3， and FUN14 structural domain-containing protein 1 to activate mitochondrial autophagy to participate in the regulation of fibrogenic factors， amelioration of oxidative stress， and inhibition of inflammatory response and apoptosis， which in turn effectively slows down the progression of renal fibrosis. Studies have shown that traditional Chinese medicine monomers and compound preparations， including phenolics， terpenoids， ketones， and alkaloids， can regulate mitochondrial autophagy-related signalling pathways and achieve significant clinical efficacy in intervening in the progression of renal fibrosis for the treatment of chronic kidney disease. This paper summarized the mechanism of mitochondrial autophagy and the research progress of traditional Chinese medicine intervention in renal fibrosis to provide new ideas for the study of the mechanism of traditional Chinese medicine in treating renal fibrosis.

With the main pathological features of glomerulosclerosis and interstitial fibrosis， renal fibrosis is a key pathological process causing chronic kidney disease to progress to end-stage disease. As a cellular autophagic process， mitochondrial autophagy plays a crucial role in maintaining mitochondrial mass and functional stability. Mitochondrial dysfunction is considered to be one of the key factors driving the progression of fibrosis. Phosphatase and tension protein homologue （PTEN） induce various signalling pathways such as putative kinase 1/parkin， Nip3-like protein X/Bcl-2 interacting protein 3， and FUN14 structural domain-containing protein 1 to activate mitochondrial autophagy to participate in the regulation of fibrogenic factors， amelioration of oxidative stress， and inhibition of inflammatory response and apoptosis， which in turn effectively slows down the progression of renal fibrosis. Studies have shown that traditional Chinese medicine monomers and compound preparations， including phenolics， terpenoids， ketones， and alkaloids， can regulate mitochondrial autophagy-related signalling pathways and achieve significant clinical efficacy in intervening in the progression of renal fibrosis for the treatment of chronic kidney disease. This paper summarized the mechanism of mitochondrial autophagy and the research progress of traditional Chinese medicine intervention in renal fibrosis to provide new ideas for the study of the mechanism of traditional Chinese medicine in treating renal fibrosis.

BACKGROUND: Double-stranded RNA-specific adenosine deaminase 1 (ADAR1) binds to double-stranded RNA and catalyzes the deamination of adenosine (A) to inosine (I). The functional mechanism of ADAR1 in non-small cell lung cancer (NSCLC) remains incompletely understood. This study aimed to investigate the prognostic significance of ADAR1 in NSCLC and to elucidate its potential role in regulating tumor cell proliferation and migration. METHODS: Data from The Cancer Genome Atlas (TCGA) and cBioPortal were analyzed to assess the correlation between high ADAR1 expression and clinicopathological features as well as prognosis in lung cancer. We performed Western blot (WB), cell proliferation assays, Transwell invasion/migration assays, and nude mouse xenograft modeling to examine the phenotypic changes and molecular mechanisms induced by ADAR1 knockdown. Furthermore, the ADAR1 p150 overexpression model was utilized to validate the proposed mechanism. RESULTS: ADAR1 expression was significantly elevated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared with adjacent non-tumor tissues (LUAD: P=3.70×10-15, LUSC: P=0.016). High ADAR1 expression was associated with poor prognosis (LUAD: P=2.03×10-2, LUSC: P=2.81×10-2) and distant metastasis (P=0.003). Gene Set Enrichment Analysis (GSEA) indicated that elevated ADAR1 was associated with mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activation, matrix metalloproteinase-9 (MMP-9) expression, and cell adhesion. ADAR1 and MMP-9 levels showed a strongly positive correlation (P=6.45×10-34) in 10 lung cancer cell lines, highest in H1581. Knockdown of ADAR1 in H1581 cells induced a rounded cellular morphology with reduced pseudopodia. Concomitantly, it suppressed cell proliferation, invasion, migration, and in vivo tumorigenesis. It also suppressed ERK phosphorylation and downregulated cellular Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog (c-FOS), MMP-9, N-cadherin, and Vimentin. Conversely, ADAR1 p150 overexpression in PC9 cells enhanced ERK phosphorylation and increased c-FOS and MMP-9 expression. CONCLUSIONS High ADAR1 expression is closely associated with poor prognosis and distant metastasis in NSCLC patients. Mechanistically, ADAR1 may promote proliferation, invasion, migration, and tumorigenesis in lung cancer cells via the ERK/c-FOS/MMP-9 axis.
Humans ; Lung Neoplasms/physiopathology* ; Adenosine Deaminase/genetics* ; Matrix Metalloproteinase 9/genetics* ; Cell Proliferation ; Carcinoma, Non-Small-Cell Lung/physiopathology* ; Cell Movement ; Animals ; Mice ; RNA-Binding Proteins/genetics* ; Female ; Male ; Cell Line, Tumor ; Proto-Oncogene Proteins c-fos/genetics* ; Middle Aged ; MAP Kinase Signaling System ; Gene Expression Regulation, Neoplastic ; Mice, Nude ; Extracellular Signal-Regulated MAP Kinases/genetics*

Abstract Alzheimer′s disease(AD) is a common neurodegenerative disease. It has been found that AD is related to various pathogenic factors such as genetics, cardiovascular and cerebrovascular disease, and excessive phosphorylation of tau protein. However, no definitive conclusions on its pathogenesis have been reached. In this paper, the research progress on the pathogenesis of AD inC.elegansmodel and the therapeutic effects of traditional Chinese medicine extracts on AD are reviewed, providing a basis for further research on the alleviating effects of Chinese medicine extracts on AD.

Objective:To evaluate the effect of autologous hematopoietic stem cell transplantation (ASCT) on the treatment of relapsed/refractory multiple myeloma (RRMM) with chimeric antigen receptor T cell (CAR-T) therapy.Methods:A retrospective cohort study. The clinical data of 168 patients with RRMM who underwent CAR-T therapy at the Department of Hematology, Xuzhou Medical University Hospital from 3 January 2020 to 13 September 2022 were analyzed. Patients were classified into a transplantation group (TG; n=47) and non-transplantation group (NTG; n=121) based on whether or not they had undergone ASCT previously. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the levels of CD3, CD4, CD8, CD19, CD56 and natural killer (NK) cells before CAR-T infusion were analyzed by χ2 test, Kaplan-Meier method and independent sample t-test. Results:Among 168 patients with RRMM, 98 (58.3%) were male. The median age of onset was 57 (range 30-70) years. After CAR-T therapy, the ORR of patients was 89.3% (92/103) in the NTG and 72.9% (27/73) in the TG. The ORR of the NTG was better than that of the TG ( χ2=5.71, P=0.017). After 1 year of CAR-T therapy, the ORR of the NTG was 78.1% (75/96), and that of the TG was 59.4% (19/32). The ORR of the NTG was better than that of the TG ( χ2=4.32, P=0.038). The median OS and PFS in the NTG were significantly longer than those in the TG (OS, 30 vs. 20 months; PFS, 26 vs. 12 months; both P<0.05). The CD4 level before CAR-T infusion in the TG was significantly lower than that in the NTG (25.65±13.56 vs. 32.64±17.21; t=-2.15, P=0.034), and there were no significant differences in the counts of CD3, CD8, CD19, CD56, and NK cells between the TG and NTG (all P>0.05). Conclusion:Among patients suffering from RRMM who received CAR-T therapy, patients who did not receive ASCT had significantly better outcomes than those who had received ASCT previously, which may have been related to the CD4 level before receiving CAR-T therapy.

Objective To examine the possible factors affecting the attainment of target serum trough concentration of vancomycin in premature newborns for optimization of clinical dosing regimens.Methods The vancomycin trough concentration data were collected retrospectively from preterm newborns who received intravenous infusion of vancomycin from December 2016 to March 2021.According to the Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin:2020 Update by the Division of Therapeutic Drug Monitoring,Chinese Pharmacological Society,the patients were assigned to failure(＜5 mg/L)or success(5-15 mg/L)in target attainment,or beyond target group(＞15 mg/L)base on vancomycin trough concentration.Statistical software SPSS was used to analyze differences in clinical characteristics between different groups,and profile various factors that may affect attainment of target serum trough concentration of vancomycin.Results The median(interquartile range)trough concentration of vancomycin was 12.50(7.95-18.05)mg/L in 82 preterm newborns.The target trough concentration of vancomycin was attained in 47 preterm newborns(57.32％),and the corresponding trough concentration of vancomycin was 10.90(7.80-13.30)mg/L.The trough concentration of vancomycin was beyond target in 27 preterm newborns(32.93％).The corresponding median trough concentration of vancomycin was 21.80(18.00-23.80)mg/L.Serum trough concentration of vancomycin failed to achieve the target in only 8 preterm newborns(9.75％).The corresponding median trough concentration was 4.10(2.48-4.60)mg/L.Univariate analysis showed that there were statistically significant differences(P＜0.05)in postmenstrual age and current weight between the patients succeeded in attaining target trough concentration and those who failed to attain the target.Baseline serum creatinine and dosing interval showed statistically significant differences(P＜0.01)between the newborns who attained the target concentration and those with higher trough concentration beyond the target.Multivariate regression analysis showed that baseline serum creatinine(OR=1.063,95％CI 1.024-1.102,P=0.001,cutoff:62 pmol/L)and dosing interval(OR=6.693,95％CI 1.604-27.920,P=0.009)were independent risk factors for excessively high vancomycin trough concentrations.Conclusions The dosing regimens as recommended in the current package insert only enable the attainment of target serum trough concentration of vancomycin in half of the premature newborns.The dosing regimen of vancomycin should be optimized by taking postmenstrual age,current weight,baseline serum creatinine and dosing interval into account.Therapeutic drug monitoring is necessary to ensure safety and effectiveness.

BACKGROUND: The switch/sucrose nonfermentable chromatin-remodeling (SWI/SNF) complex is a pivotal chromatin remodeling complex, and the genomic alterations (GAs) of the SWI/SNF complex are observed in several cancer types, correlating with multiple biological features of tumor cells. However, their role in liver metastasis of non-small cell lung cancer (NSCLC) remains unclear. Our study aims to investigate the role and potential mechanisms underlying NSCLC liver metastasis induced by the GAs of SWI/SNF complex. METHODS: The GAs of SWI/SNF complex in NSCLC cell lines (H1299, H23 and H460) were identified by whole-exome sequencing (WES). ARID1A knockout H1299 cell was constructed with the CRISPR/Cas9 technology. The mouse model of liver metastasis from NSCLC was established to simulate lung cancer liver metastasis and observe the metastasis rate under different gene mutation conditions. RNA sequencing and Western blot were conducted for differential gene expression analysis. Immunohistochemistry (IHC) analysis was used to assess protein expression levels of SWI/SNF-regulated target molecules in mouse liver metastases. RESULTS: WES analysis revealed intracellular gene mutations. The animal experiments demonstrated a correlation between the GAs of SWI/SNF complex and a higher liver metastasis rate in immunodeficient mice. Transcriptome sequencing and Western blot analysis showed upregulated expression of ALDH1A1 and APOBEC3B in SWI/SNF-mut cells, particularly in ARID1A-deficient H460 and H1299 sgARID1A cells. IHC staining of mouse liver metastases further demonstrated elevated expression of ALDH1A1 in the H460 and H1299 sgARID1A group. CONCLUSIONS This study underscores the critical role of the GAs of SWI/SNF complex, such as ARID1A and SMARCA4, in promoting liver metastasis of lung cancer cells. The GAs of SWI/SNF complex may promote liver-specific metastasis by upregulating ALDH1A1 and APOBEC3B expression, providing novel insights into the molecular mechanisms underlying lung cancer liver metastasis.
Animals ; Mice ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Liver Neoplasms/genetics*

Objective:To explore the expression of long-chain noncoding RNA (lncRNA) and myocardial infarction-associated transcription (MIAT) in Leukocyte differentiation antigen (CD)4+T cells in peripheral blood of gastric cancer patients and its value of clinical application.Methods:Peripheral blood CD4+T cells were collected from 124 patients with gastric cancer, 90 benign gastric diseases patients and 80 healthy controls enrolled in Taizhou People′s Hospital from January 2019 to April 2021. The expression levels of MIAT and N6-methyladenosine(m6A) binding to MIAT promoter in CD4+T cells were detected by real-time fluorescent quantitative polymerase chain reaction (qPCR) and Chromatin immunoprecipitation (ChIP)-qPCR, respectively. Spearman test was used to analyze the correlation between MIAT and clinicopathological features, as well as between MIAT and regulatory T cell levels. The receivor operating characteristic curve (ROC) of the subjects was used to evaluate the MIAT expression level in the auxiliary diagnostic value of gastric cancer.Results:The relative expression levels of MIAT in the gastric cancer patients, the benign gastric diseases patients, and the healthy controls were 2.849 (2.131, 4.062), 1.511 (0.916, 1.855) and 0.963 (0.729, 1.432), respectively. The difference among the three groups was statistically significant ( H=158.25, P<0.001). The relative expression level of MIAT in the gastric cancer patients was significantly higher than the levels in the benign gastric diseases patients and healthy controls. The difference was statistically significant ( Z=100.63, 145.14, P<0.001). The binding activity of m6A to MIAT promoter in patients with early stage (stage Ⅰ and Ⅱ) and end stage (stage Ⅲ and Ⅳ) gastric cancer was 8.590±1.483 and 4.274±0.425, respectively. The difference was statistically significant ( t=6.255, P=0.002). Furthermore, the binding activity of m6A to MIAT promoter in the gastric cancer patients was significantly lower than that in patients with benign gastric diseases (17.267±3.106) and healthy controls (27.637±3.945) ( t=-7.331,-12.832, P<0.001). The relative expression of MIAT in CD4+T cells in peripheral blood of the gastric cancer patients had no significant difference in age(χ2=0.000, P=1.000), gender(χ2=0.000, P=1.000), CEA (χ2=0.648, P=0.421) and CA199(χ2=1.554, P=0.213), but had significant difference with tumor size expression(χ2=9.443, P<0.01), TNM stage(χ2=23.571, P=0.002) and lymph node metastasis (χ2=45.248, P<0.01). In addition, there was a significant positive correlation between the relative expression of MIAT in CD4+T cells and Treg level ( r2=0.76, P<0.001). The diagnostic efficacies of MIAT in CD4+T cells, CEA and CA199 in the gastric cancer patients were analyzed by ROC curve. When compared with patients with benign gastric diseases, the areas under the curve were 0.879, 0.635 and 0.611, respectively. When compared with healthy patients, the areas under the curve were 0.953, 0.784 and 0.598, respectively. Conclusions:The level of MIAT in CD4+T cells in peripheral blood of patients with gastric cancer is significantly higher than the levels in patients with benign gastric diseases and the healthy controls, which may be related with the decreased activity of m6A binding to the promoter of MIAT. The level of MIAT in CD4+T cells may be a relevant biomarker for the diagnosis and prognosis of gastric cancer.

ObjectiveTo explore the mechanism of Gancao Fuzitang （GCFZ）in inhibiting the bone destruction of collagen-induced arthritis （CIA） model in mice. MethodThirty male DBa/1J mice were randomly divided into normal group， CIA group， low-dose GCFZ group （GCFZ-L， 2.4 g·kg^-1）， high-dose GCFZ group （GCFZ-H， 4.8 g·kg^-1）， and methotrexate group （MTX， 1 mg·kg^-1）， with six mice in each group. The CIA model was induced by secondary immunization method. The arthritis index of mice in each group was observed and recorded， and the histopathological changes in ankle joint were observed by hematoxylin-eosin （HE） staining. The damage to ankle cartilage was detected by safranin O-fast green staining. Micro-CT scanning was used to detect the bone destruction of ankle joint， and the expression of nuclear factor-κB p65 （NF-κB p65）， p-NF-κB p65， inhibitory-κB kinase α/β （IKKα/β）， and p-IKKα/β was observed by immunohistochemical staining. ResultCompared with the normal group， the CIA group showed manifest joint swelling and increased arthritis index score （P<0.01）. Compared with the CIA group， the groups with drug intervention could inhibit joint swelling and reduce arthritis index score （P<0.05， P<0.01）. As revealed by HE staining and safranine O-green staining， compared with the CIA group， the groups with drug intervention could inhibit synovial invasion and reduce the destruction of articular cartilage. Micro-CT scanning analysis showed that compared with the CIA group， the GCFZ-H group and the MTX group showed reduced bone destruction scores （P<0.01）. The immunohistochemical results showed that compared with the normal group， the CIA group showed increased optical density values of NF-κB p65， p-NF-κB p65， IKKα/β， and p-IKKα/β（P<0.01）. Compared with the CIA group， the GCFZ-H group and the MTX group showed reduced optical density values of NF-κB p65， p-NF-κB p65， IKKα/β， and p-IKKα/β（P<0.05，P<0.01）. In the GCFZ-L group， only the NF-κB p65 optical density value decreased（P<0.01）. ConclusionGCFZ may inhibit bone destruction in CIA mice by regulating the NF-κB signaling pathway.

Hand, foot and mouth disease (HFMD) is an acute infectious disease induced by enterovirus. More than 30 pathogenic viruses for hand, foot and mouth disease have been discovered, of which enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16) are the most common. Enterovirus 71 (EV-A71) is also the main cause of severe hand, foot and mouth disease. In recent years, it has been discovered that Coxsackievirus A6 (CV-A6) infection has broken out in many regions of the world, and the pathogenicity rate is increasing, which indicatesthat it may rise to become a new major pathogenic agent of hand, foot and mouth disease. Hand, foot and mouth disease has become a global public health problem. Therefore, research on the pathogenic mechanism of multiple enteroviruses that induce hand, foot and mouth disease and analysis of its epidemiology will become the top priority of prevention, control and treatment of the disease.