Perspective view of allogeneic IgG tumor immunotherapy.

Allogeneic tumors are eradicated by host immunity; however, it is unknown how it is initiated until the report in Nature by Yaron Carmi et al. in 2015. Currently, we know that allogeneic tumors are eradicated by allogeneic IgG via dendritic cells. AlloIgG combined with the dendritic cell stimuli tumor necrosis factor alpha and CD40L induced tumor eradication via the reported and our proposed potential signaling pathways. AlloIgG triggers systematic immune responses targeting multiple antigens, which is proposed to overcome current immunotherapy limitations. The promising perspectives of alloIgG immunotherapy would have advanced from mouse models to clinical trials; however, there are only 6 published articles thus far. Therefore, we hope this perspective view will provide an initiative to promote future discussion.

Bioinformatics analysis reveals the potential common genes and immune characteristics between atrial fibrillation and periodontitis.

BACKGROUND AND OBJECTIVE: Atrial fibrillation (AF) and periodontitis, both classified under chronic inflammatory diseases, share common etiologies, including genetic factors and immune pathways. However, the exact mechanisms are still poorly understood. This study aimed to explore the potential common genes and immune characteristics between AF and periodontitis. METHODS: Gene expression datasets for AF and periodontitis were downloaded from the Gene Expression Omnibus (GEO) database. Differential expression analysis was used to identify common genes in the training set. Functional analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, were conducted to elucidate the underlying mechanisms. Hub genes were further screened based on expression levels, receiver operating characteristic (ROC) curves, and least absolute shrinkage and selection operator (LASSO) regression. Then, based on the expression levels and ROC values of the hub genes in the validation set, the target genes were identified. Finally, immune cell infiltration analysis was performed on the AF and periodontitis datasets in the training set using the "CIBERSORT" R package. The relationships between target genes, infiltrating immune cells, and inflammatory factors were also investigated. In addition, AF susceptibility, atrial fibrosis, inflammatory infiltration, and RGS1 protein expression in rat models of periodontitis were assessed through in vivo electrophysiology experiments, Masson's trichrome staining, hematoxylin-eosin staining, immunohistochemistry, and western blotting, respectively. RESULTS: A total of 21 common genes were identified between AF and periodontitis among the differentially expressed genes. After evaluating gene expression levels, ROC curves, and LASSO analysis, four significant genes between AF and periodontitis were identified, namely regulator of G-protein signaling 1 (RGS1), annexin A6 (ANXA6), solute carrier family 27 member 6 (SLC27A6), and ficolin 1 (FCN1). Further validation confirmed that RGS1 was the optimal shared target gene for AF and periodontitis. Immune cell infiltration analysis revealed that neutrophils and T cells play an important role in the pathogenesis of both diseases. RGS1 showed a significant positive correlation with activated memory CD4 T cells and gamma-delta T cells and a negative correlation with CD8 T cells and regulatory T cells in both training sets. Moreover, RGS1 was positively correlated with classical pro-inflammatory cytokines IL1ß and IL6. In periodontitis rat models, AF susceptibility, atrial fibrosis, and inflammatory infiltration were significantly increased, and RGS1 expression in the atrial tissue was upregulated. CONCLUSION: A common gene between AF and periodontitis, RGS1 appears central in linking the two conditions. Immune and inflammatory responses may underlie the interaction between AF and periodontitis.

FEN1 inhibitor SC13 promotes CAR-T cells infiltration into solid tumours through cGAS-STING signalling pathway.

It is well known that chimeric antigen receptor T-cell immunotherapy (CAR-T-cell immunotherapy) has excellent therapeutic effect in haematological tumours, but it still faces great challenges in solid tumours, including inefficient T-cell tumour infiltration and poor functional persistence. Flap structure-specific endonuclease 1 (FEN1), highly expressed in a variety of cancer cells, plays an important role in both DNA replication and repair. Previous studies have reported that FEN1 inhibition is an effective strategy for cancer treatment. Therefore, we hypothesized whether FEN1 inhibitors combined with CAR-T-cell immunotherapy would have a stronger killing effect on solid tumours. The results showed that low dose of FEN1 inhibitors SC13 could induce an increase of double-stranded broken DNA (dsDNA) in the cytoplasm. Cytosolic dsDNA can activate the cyclic GMP-AMP synthase-stimulator of interferon gene signalling pathway and increase the secretion of chemokines. In vivo, under the action of FEN1 inhibitor SC13, more chemokines were produced at solid tumour sites, which promoted the infiltration of CAR-T cells and improved anti-tumour immunity. These findings suggest that FEN1 inhibitors could enable CAR-T cells to overcome poor T-cell infiltration and improve the treatment of solid tumours.

Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer.

Recently, chimeric antigen receptor T cell (CAR-T) therapy has received increasing attention as an adoptive cellular immunotherapy that targets tumors. However, numerous challenges remain for the effective use of CAR-T to treat solid tumors, including ovarian cancer, which is an aggressive and metastatic cancer with a poor therapeutic response. We screened for an effective anti-MSLN single-chain Fv antibody with comparable binding activity and non-off-target properties using human phage display library. A second-generation of anti-MSLN CAR was designed and generated. We demonstrated the efficacy of our anti-MSLN CAR-T cells for ovarian cancer treatment in an in vitro experiment to kill ovarian tumor cell lines. The anti-MSLN CAR-T cells impeded MSLN-positive tumor growth concomitant with a significant increase in cytokine levels compared with the control. Then, we demonstrated the efficacy of anti-MSLN CAR-T cells in an in vivo experiment against ovarian cancer cell-derived xenografts. Furthermore, we herein report three cases with ovarian cancer who were treated with autologous anti-MSLN CAR-T cells and evaluate the safety and effectiveness of adoptive cell therapy. In this investigator-initiated clinical trials, no patients experienced cytokine release syndrome or neurological symptoms over 2 grads. Disease stabilized in two patients, with progression-free survival times of 5.8 and 4.6 months. Transient CAR expression was detected in patient blood after infusion each time. The tumor partially subsided, and the patient's condition was relieved. In conclusion, this work proves the efficacy of the anti-MSLN CAR-T treatment strategy in ovarian cancer and provides preliminary data for the development of further clinical trials.

Risk factors and prevalence of cognitive impairment in maintenance haemodialysis patients: A systematic review and meta-analysis of observational studies.

AIMS: To systematically identify the risk factors for cognitive impairment in maintenance haemodialysis patients and to assess its prevalence in included studies. DESIGN: Systematic review and meta-analysis about observational studies. DATA SOURCES: Systematic search of seven databases, including PubMed, Web of Science, Scope, Wanfang Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and Weipu Chinese Science and Technology Journal Database, from inception until October 2021. REVIEW METHODS: Observational studies reporting the risk factors for cognitive impairment in maintenance haemodialysis patients in English and Chinese language were included. Meta-analysis was performed to identify risk factors and prevalence of cognitive impairment in maintenance haemodialysis patients with STATA 15.0 software. RESULTS: Overall, 37 eligible studies encompassing 129,849 cases were included. The risk factors with statistical significance after meta-analysis were older age, female sex, fewer years of education, hypertension, diabetes, cerebrovascular accident, multiple comorbid conditions, systolic blood pressure variability, arterial stiffness and low haemoglobin and albumin level. The overall prevalence of cognitive impairment in maintenance haemodialysis patients was 49.1%. CONCLUSION: The current analysis indicated a high prevalence of cognitive impairment in maintenance haemodialysis patients. Eleven risk factors for cognitive impairment in maintenance haemodialysis patients were identified, among which more attention should be paid to modifiable factors such as cardiovascular disease risk factors and specific kidney and dialysis-related factors. IMPACT: This paper provides an updated estimate of the pooled prevalence of cognitive impairment in maintenance haemodialysis patients. Identification of risk factors associated with cognitive impairment may assist in developing targeted prevention strategies for maintenance haemodialysis patients at high risk. NO PATIENT OR PUBLIC CONTRIBUTION: This study was a systematic review completed by the authors in accordance with relevant guidelines and processes and did not include the participation of patients, service users, caregivers or the general public.

Coupling Quantum Random Walks with Long- and Short-Term Memory for High Pixel Image Encryption Schemes.

This paper proposes an encryption scheme for high pixel density images. Based on the application of the quantum random walk algorithm, the long short-term memory (LSTM) can effectively solve the problem of low efficiency of the quantum random walk algorithm in generating large-scale pseudorandom matrices, and further improve the statistical properties of the pseudorandom matrices required for encryption. The LSTM is then divided into columns and fed into the LSTM in order for training. Due to the randomness of the input matrix, the LSTM cannot be trained effectively, so the output matrix is predicted to be highly random. The LSTM prediction matrix of the same size as the key matrix is generated based on the pixel density of the image to be encrypted, which can effectively complete the encryption of the image. In the statistical performance test, the proposed encryption scheme achieves an average information entropy of 7.9992, an average number of pixels changed rate (NPCR) of 99.6231%, an average uniform average change intensity (UACI) of 33.6029%, and an average correlation of 0.0032. Finally, various noise simulation tests are also conducted to verify its robustness in real-world applications where common noise and attack interference are encountered.

TMEM98 mRNA promotes proliferation and invasion of gastric cells by directly interacting with NF90 protein.

Transmembrane protein 98 (TMEM98) is a recently discovered gene, the inhibition of which has preliminarily been demonstrated to inhibit progression of several solid cancers in vitro. However, its involvement in tumorigenesis of gastric cancer (GC) has not been reported. Here, we aimed to explore the expression of TMEM98 in GC tissues and cell lines and to determine the role of TMEM98 in GC cell proliferation and invasion. TMEM98 was significantly upregulated in GC tissues, which was associated with low survival rate of GC patients. Interestingly, GC cell proliferation and invasion were promoted by TMEM98 messenger RNA (mRNA) upregulation and inhibited by TMEM98 mRNA downregulation, but not affected by TMEM98 protein. Using RNA-binding protein immunoprecipitation assay and RNA pull-down assay, we demonstrated that TMEM98 mRNA could directly bind with and upregulate nuclear factor 90 (NF90). Similarly, NF90 protein could not only enhance the stability of TMEM98 mRNA but antagonize the suppressive effect of TMEM98-small interfering RNA on proliferation and invasion in MKN-45 cells. Moreover, RNA pull-down assay, with wild-type (WT) and binding-site-mutated biotinylated TMEM98 mRNA transcripts, demonstrated that WT TMEM98 mRNA bound with NF90 protein through an 8-nt motif at the last exon, but the motif mutation abolished the capacity of TMEM98 mRNA binding to NF90 protein. Furthermore, overexpression of the WT last exon of TMEM98 increased NF90 expression and cell proliferation/invasion expectedly, but overexpression of the mutated last exon had no obvious effect. In conclusion, TMEM98 mRNA enhanced the proliferation and invasion of GC cells by interacting with the NF90 protein.

Qiliqiangxin Attenuates Oxidative Stress-Induced Mitochondrion-Dependent Apoptosis in Cardiomyocytes via PI3K/AKT/GSK3ß Signaling Pathway.

Qiliqiangxin capsule (QLQX) is a well-known traditional Chinese medicine that exhibits cardioprotective effects in heart failure patients. However, it remains unclear whether and by which mechanism QLQX attenuates oxidative stress-induced mitochondria-dependent myocardial apoptosis. In vivo, Sprague Dawley (SD) rats received left anterior descending coronary artery ligation for 4 weeks to establish a model of heart failure after acute myocardial infarction, and then were treated with QLQX for another 4 weeks. We evaluated cardiac function, oxidative stress injury, as well as the expressions of mitochondria-dependent apoptosis and its signaling factors. The results indicated that QLQX protected cardiac function and attenuated oxidative stress-induced myocardial apoptosis. Meanwhile, QLQX elevated the Bcl-2 expression, declined the expressions of Bax, cytochrome c, apoptotic protease activating factor-1 (Apaf-1), cleaved-caspase 9 and cleaved-caspase 3, and up-regulated the ratios of phospho-AKT/AKT and phospho-glycogen synthase kinase-3ß (GSK3ß)/GSK3ß. In vitro, H9c2 cardiomyocytes were pretreated with QLQX, then exposed to H2O2 for 24 h. QLQX promoted the proliferation of H9c2 cardiomyocytes induced by H2O2 and reversed oxidative stress damage. Moreover, QLQX inhibited the apoptosis rate and the pro-apoptosis protein expressions, but improved the Bcl-2 expression as well as the ratios of phospho-AKT/AKT and phospho-GSK3ß/GSK3ß. Meanwhile, it further ameliorated mitochondrion-related apoptosis by inhibiting the mitochondrial fission, mitochondrial permeability transition pore (MPTP) opening, and mitochondrial membrane potential (MMP) decline in H9c2 cardiomyocytes induced by H2O2. In addition, all the effects of QLQX on H2O2-induced mitochondria-dependent apoptosis could be blocked by the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. We conclude that QLQX may ameliorate oxidative stress-induced mitochondria-dependent apoptosis in cardiomyocytes through PI3K/AKT/GSK3ß signaling pathway.

LncRNA MALAT1 modulates ox-LDL induced EndMT through the Wnt/ß-catenin signaling pathway.

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) plays significant roles in atherosclerosis, but the regulatory mechanisms involving lncRNAs remain to be elucidated. Here we sort to identify the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in ox-LDL-induced EndMT. METHODS: The atherosclerosis model was established by feeding ApoE-/- mice with high-fat diet, and the levels of lncRNA MALAT1 in mouse arterial tissue were detected by RT-qPCR. Cell model was established by treating human umbilical vein endothelial cells (HUVECs) with ox-LDL, and the levels of EndMT markers, such as CD31, vWF, α-SMA and Vimentin and lncRNA MALAT1 levels were detected and their correlations were analyzed. The role of MALAT1 in EndMT and its dependence on Wnt/ß-catenin signaling pathway was further detected by knocking down or overexpressing MALAT1. RESULTS: MALAT1 was upregulated in high-fat food fed ApoE-/- mice. HUVECs treated with ox-LDL showed a significant decrease in expression of CD31 and vWF, a significant increase in expression of α-SMA and vimentin, and upregulated MALAT1. An increased MALAT1 level facilitated the nuclear translocation of ß-catenin induced by ox-LDL. Inhibition of MALAT1 expression reversed nuclear translocation of ß-catenin and EndMT. Moreover, overexpression of MALAT1 enhanced the effects of ox-LDL on HUVEC EndMT and Wnt/ß-catenin signaling activation. CONCLUSIONS: Our study revealed that the pathological EndMT required the activation of the MALAT1-dependent Wnt/ß-catenin signaling pathway, which may be important for the onset of atherosclerosis. TRIAL REGISTRATION: Not applicable.

Chinese medicine Tongxinluo capsule alleviates cerebral microcirculatory disturbances in ischemic stroke by modulating vascular endothelial function and inhibiting leukocyte-endothelial cell interactions in mice: A two-photon laser scanning microscopy study.

OBJECTIVE: The aim of this study was to examine the effect of TXL, a Chinese medicine prescription, on cerebral microcirculatory disturbances after pMCAO in mice using TPLSM and further explore the underlying mechanisms. METHODS: Adlut male C57BL/6J mice were subjected to pMCAO and orally administered with TXL (3.0, 1.5 and 0.75 g/kg/d) at 1, 3, and 21 hours after pMCAO. The following parameters were examined at 6 and 24 hours after pMCAO: neurological deficits, infarct volume, BBB permeability, cerebral microvessel structure, brain microcirculation (TPLSM imaging), vasoactive factors, and adhesion molecules. RESULTS: TXL improved neurological deficits, reduced infarct volume, attenuated BBB disruption, protected cerebral microvessel structure, increased cerebral capillary flow velocity and volume flux, and inhibited leukocyte-endothelial cell interactions at 6 or 24 hours after pMCAO. The therapeutic efficacy was exerted in a dose-dependent manner. Further study revealed that TXL (high dose) regulated the expression of PGI2, TXA2, and ET-1, and suppressed ICAM-1 and P-selectin. CONCLUSIONS: TXL alleviates cerebral microcirculatory disturbances against ischemic injury by modulating endothelial function and inhibiting leukocyte-endothelial cell interactions. These effects are associated with regulating the expression of PGI2, TXA2, and ET-1, and suppressing ICAM-1 and P-selectin expression.

Genetic variants of SLC12A3 modulate serum lipid profiles in a group of Mongolian pedigree population.

BACKGROUND: The serum lipid profile, including LDL-C level, is associated with hypertension which is the major cause of cerebrovascular disease (CVD) amounting 30% of global death rate. Previous work also demonstrated important roles of genetic variants of SLC12A3 gene on human CVD, hypertension and other diseases in Mongolian population. However, the relationship between SLC12A3 gene polymorphisms on individuals' lipid profile is still unknown. METHODS: A panel of 15 SNPs of SLC12A3 gene was genotyped within a 424 Mongolians pedigree cohort. The associations between SLC12A3 polymorphisms and four lipid profiles were analyzed by family-based association test (FBAT) and confirmed with haplotype analysis. RESULTS: From both single site and haplotype analyses, the results demonstrated a close relationship between SLC12A3 polymorphisms and LDL-C level. Two SNPs, rs5803 and rs711746 showed significant associations with individuals' serum LDL-C level (z = - 2.08, P -e = 0.038; z = 2.09, P -e = 0.023, respectively), and distribution of haplotypes constructed by two SNPs also associated with participants' serum LDL-C level, significantly (Global Chi2 = 9.06 df = 3, P = 0.028). CONCLUSION: Our results demonstrated the importance of SLC12A3 polymorphisms in individuals' difference about their serum lipid profiles, thereby providing evidence that the genetic variants may contribute to CVD development via modulating person's LDL-C level and blood pressure, in certain contexts.

Polymorphisms in the SLC12A3 Gene Encoding Sodium-Chloride Cotransporter are Associated with Hypertension: A Family-Based Study in the Mongolian Population.

BACKGROUND/AIMS: Hypertension or persistent high blood pressure (BP) is a leading cause of death worldwide. Extensive evidence indicates that the thiazide-sensitive Na+-Cl- cotransporter (NCC) affects BP via regulation of renal sodium reabsorption. However, the relationship between genetic variants of the NCC-encoding SLC12A3 gene and hypertension in the Mongolian population is still ambiguous. In this study, we aimed to genotype an extended cohort of hypertensive Mongolian families for polymorphisms in the SLC12A3 locus. METHODS: Eighty-eight families with a history of hypertension, including parents, offspring, and relatives underwent clinical testing. Family-based association tests and haplotype analysis were used to evaluate the association between hypertension and polymorphisms in the SLC12A3 locus. RESULTS: We identified three single nucleotide polymorphisms (SNPs), one in the SLC12A3 coding region (p = 0.05) and two in the intron (p = 0.02 and p = 0.07), which were significantly associated with the hypertension phenotype. Haplotype-specific association tests confirmed the correlation of these SNPs with hypertension (p < 0.05). CONCLUSION: These results suggest that SNPs in the SLC12A3 gene confer susceptibility to hypertension in the Mongolian population. Further research is needed to validate the functional role of SLC12A3 polymorphisms in hypertension.

[Effect of Tongxinluo on Apoptosis of Rat Cardiac Microvascular Endothelial Cells].

OBJECTIVE: To observe the protective effects of Tongxinluo (TXL) on apoptosis of rat cardiac microvascular endothelial cells (RCMECs) resulting from homocysteine (Hcy) induced endoplasmic reticulum stress (ERS), and to determine the signaling pathway behind its protection. METHODS: Primary cultured RCMECs were isolated from neonatal rats using tissue explant method. The morphology of RCMECs was observed using inverted microscope, identified and differentiated by CD31 immunofluorescence method. Selected were well growing 2nd-4th generations of RCMECs. The optimal action time was determined by detecting the expression of glucose regulated protein 78 (GRP78) using immunofluorescence method. In the next experiment RCMECs were divided into 5 groups, i.e., the blank control group, the Hcy induced group (Hcy 10 mmol/L, 10 h), the Hcy + TXL group (Hcy 10 mmol/L + TXL 400 µg/mL), the Hcy +LY294002 group (Hcy 10 mmol/L + LY294002 5 µmol/L, LY294002 as the inhibitor of PI3K), the Hcy + LY294002 + TXL group (Hcy 10 mmol/L + LY294002 5 µmol/L + TXL 400 µg/mL). The apoptosis rate of RCMECs was detected by flow cytometry. mRNA and protein expressions of GRP78, C/ EBP homologous protein (CHOP), and cysteinyl aspartate specific proteinase-12 (caspase12) were detected by real-time reverse transcription PCR (RT-PCR) and Western blot respectively. Expression levels of phosphorylation of phosphatidylinositol 3-kinase (P-PI3K), total phosphatidylinositol 3-kinase (T- P13K) , phosphorylation of kinase B (P-Akt) , and total kinase B (T-Akt) were detected by Western blot. RESULTS: Ten hours Hcy action time was determined. Compared with the blank control group, the apoptosis rate was increased (22.77%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were increased, protein expressions of P-PI3K and P-Akt,ratios of P-PI3K/T-PI3K and P-Akt/T-Akt were decreased in the Hcy induced group (P < 0.05, P < 0.01). Compared with the Hcy induced group, the apoptosis rate was decreased (10.17%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were decreased, and expression levels of P-PI3K, P-Akt, P-PI3K/T-PI3K, and P-Akt/T-Akt were increased in the Hcy + TXL group (P < 0.05, P < 0.01). Compared with the Hcy + TXL group, the apoptosis rate was increased (17.9%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were increased, expression levels of P-PI3K and P-Akt, ratios of P-PI3K/T-PI3K and P-Akt/T-Akt were decreased in the Hcy + TXL + LY294002 group (P < 0.05, P < 0.01). CONCLUSION: TXL could inhibit the apoptosis of RCMECs resulting from Hcy-induced ERS and its mechanism might be associated with activating PI3K/Akt signaling pathway.

[Synthesis and characterization of 9-O-alkyl substituted palmatine derivatives].

For the establishment of chemical library of protoberberines provided for the bio-activity screening, the target compounds were synthesized by thermal degradation and nucleophilic substitution reactions with the bio-active alkaloid, palmatine (1), as the raw material, and their structures were identified and conformed by 1H-NMR and MS spectra. Among them, 13 compounds were new.

ECM1 and ANXA1 in urinary extracellular vesicles serve as biomarkers for breast cancer.

Objective: Although urinary extracellular vesicles (uEVs) have been extensively studied in various cancers, their involvement in breast cancer (BC) remains largely unexplored. The non-invasive nature of urine as a biofluid and its abundant protein content offer considerable potential for the early detection of breast cancer. Methods: This study analyzed the proteomic profiles of uEVs from BC patients and healthy controls (HC). The dysregulation of ECM1 and ANXA1 in the uEVs was validated in a larger cohort of 128 BC patients, 25 HC and 25 benign breast nodules (BBN) by chemiluminescence assay (CLIA). The expression levels of ECM1 and ANXA1 were also confirmed in the uEVs of MMTV-PyMT transgenic breast cancer mouse models. Results: LC-MS/MS analysis identified 571 dysregulated proteins in the uEVs of BC patients. ECM1 and ANXA1 were selected for validation in 128 BC patients, 25 HC and 25 BBN using CLIA, as their fold change showed a significant difference of more than 10 with p-value<0.05. Protein levels of ECM1 and ANXA1 in uEVs were significantly increased in BC patients. In addition, the protein levels of ECM1 and ANXA1 in the uEVs of MMTV-PyMT transgenic mice were observed to increase progressively with the progression of breast cancer. Conclusion: We developed a simple and purification-free assay platform to isolate uEVs and quantitatively detect ECM1 and ANXA1 in uEVs by WGA-coupled magnetic beads and CLIA. Our results suggest that ECM1 and ANXA1 in uEVs could potentially serve as diagnostic biomarkers for breast cancer.

Analysis of immunoinfiltration and EndoMT based on TGF-ß signaling pathway-related genes in acute myocardial infarction.

Acute myocardial infarction (AMI), a critical manifestation of coronary heart disease, presents a complex and not entirely understood etiology. This study investigates the potential role of immune infiltration and endothelial-mesenchymal transition (EndoMT) in AMI pathogenesis. We conducted an analysis of the GSE24519 and MSigDB datasets to identify differentially expressed genes associated with the TGF-ß signaling pathway (DE-TSRGs) and carried out a functional enrichment analysis. Additionally, we evaluated immune infiltration in AMI and its possible link to myocardial fibrosis. Key genes were identified using machine learning and LASSO logistic regression. The expression of MEOX1 in the ventricular muscles and endothelial cells of Sprague-Dawley rats was assessed through RT-qPCR, immunohistochemical and immunofluorescence assays, and the effect of MEOX1 overexpression on EndoMT was investigated. Our study identified five DE-TSRGs, among which MEOX1, SMURF1, and SPTBN1 exhibited the most significant associations with AMI. Notably, we detected substantial immune infiltration in AMI specimens, with a marked increase in neutrophils and macrophages. MEOX1 demonstrated consistent expression patterns in rat ventricular muscle tissue and endothelial cells, and its overexpression induced EndoMT. Our findings suggest that the TGF-ß signaling pathway may contribute to AMI progression by activating the immune response. MEOX1, linked to the TGF-ß signaling pathway, appears to facilitate myocardial fibrosis via EndoMT following AMI. These novel insights into the mechanisms of AMI pathogenesis could offer promising therapeutic targets for intervention.

Mechanism of Bazi Bushen capsule in delaying the senescence of mesenchymal stem cells based on network pharmacology and experimental validation.

Ageing is becoming an increasingly serious problem; therefore, there is an urgent need to find safe and effective anti-ageing drugs. Aims: To investigate the effects of Bazi Bushen capsule (BZBS) on the senescence of mesenchymal stem cells (MSCs) and explore its mechanism of action. Methods: Network pharmacology was used to predict the targets of BZBS in delaying senescence in MSCs. For in vitro studies, MSCs were treated with D-gal, BZBS, and NMN, and cell viability, cell senescence, stemness-related genes, and cell cycle were studied using cell counting kit-8 (CCK-8) assay, SA-ß-galactosidase (SA-ß-gal) staining, Quantitative Real-Time PCR (qPCR) and flow cytometry (FCM), respectively. Alkaline phosphatase (ALP), alizarin red, and oil red staining were used to determine the osteogenic and lipid differentiation abilities of MSCs. Finally, the expression of senescence-related genes and cyclin-related factors was detected by qPCR and western blotting. Results: Network pharmacological analysis suggested that BZBS delayed cell senescence by interfering in the cell cycle. Our in vitro studies suggested that BZBS could significantly increase cell viability (P < 0.01), decrease the quantity of ß-galactosidase+ cells (P < 0.01), downregulate p16 and p21 (P < 0.05, P < 0.01), improve adipogenic and osteogenic differentiation, and upregulate Nanog, OCT4 and SOX2 genes (P < 0.05, P < 0.01) in senescent MSCs. Moreover, BZBS significantly reduced the proportion of senescent MSCs in the G0/G1 phase (P < 0.01) and enhanced the expression of CDK4, Cyclin D1, and E2F1 (P < 0.05, P < 0.01, respectively). Upon treatment with HY-50767A, a CDK4 inhibitor, the upregulation of E2F1 was no longer observed in the BZBS group. Conclusions: BZBS can protect MSCs against D-gal-induced senescence, which may be associated with cell cycle regulation via the Cyclin D1/CDK4/E2F1 signalling pathway.

Advances in the Mechanism of Luteolin against Hepatocellular Carcinoma Based on Bioinformatics and Network Pharmacology.

As one of the most common malignant tumors, hepatocellular carcinoma (HCC) has a rising incidence rate and also seriously endangers human life and health. According to research reports, hepatitis B, hepatitis C, intake of aflatoxin in the diet, and the effects of alcohol and other chemicals can induce an increase in the incidence of liver cancer. However, in the current clinical treatment of HCC, most of the drugs are chemical drugs, which have relatively large side effects and are prone to drug resistance. Therefore, the development of natural compounds to treat HCC has become a new treatment strategy. Several studies have shown that flavonoids have shown outstanding effects and exhibit strong tumor growth inhibitory effects in vivo experimental studies. Luteolin, as a natural flavonoid, has anti-tumor, anti-inflammatory, anti-viral, anti-oxidation, immune regulation, and other pharmacological effects. The anti-cancer mechanism of luteolin mainly directly acts on tumor cells to inhibit their growth, induce cell apoptosis, reduce tumor tissue angiogenesis, regulate long non-coding RNA, affect immunogenic cell death, and regulate autophagy. As well as improving the curative effect of radiotherapy and chemotherapy and chemoprevention. In this study, we evaluated the function of luteolin in regulating cancer cell proliferation, migration, and invasion will summarize and analyze luteolin and its mechanism of regulating HCC to improve the role of luteolin in the clinical prevention and treatment of HCC.

Incidence and risk factors of falls in patients undergoing hemodialysis: A multicenter survey in northern China.

INTRODUCTION: Patients undergoing hemodialysis (HD) are at a higher risk of falls than healthy individuals. Further knowledge regarding the risk of falls could lead to better risk prevention strategies. We designed a multicenter, prospective cohort study according to the strengthening of the reporting of observational studies in epidemiology (STROBE) guidelines to investigate the incidence and risk factors of falls in patients undergoing hemodialysis in Northern China. METHODS: Patients undergoing hemodialysis in six hemodialysis units were recruited from January 2019 to January 2020. Data on demographics and disease conditions were collected at baseline. Data on other variables, the incidence of falls, and related conditions were collected every 3 months during a 1-year follow-up. The Generalized Estimating Equation model was used to evaluate factors associated with falls. FINDINGS: This study included 472 patients. The incidence of falls was 0.31 per patient year. In patients aged 45-64 years (p = 0.01; odds ratio [OR]: 14.801; 95% confidence interval [CI]: 1.897-115.453) and ≥ 65 years (p = 0.007; OR: 16.562; 95% CI: 2.118-129.521), anemia (p = 0.015; OR: 2.122; 95% CI: 1.154-3.902) and moderately (p = 0.003; OR: 5.439; 95% CI: 1.791-16.516) and severely abnormal timed up and go test (TUGT) levels (p = 0.001; OR: 7.032; 95% CI: 2.226-22.216) were identified as independent risk factors of falls. DISCUSSION: Falls are prevalent among patients undergoing in-center hemodialysis. Advanced age, anemia, and moderately and severely abnormal TUGT levels may be risk factors of falls.