Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

ObjectiveBased on functional near-infrared spectroscopy (fNIRS), we investigated the brain activity characteristics of gross motor tasks in children with autism spectrum disorder (ASD) and motor dysfunctions (MDs) to provide a theoretical basis for further understanding the mechanism of MDs in children with ASD and designing targeted intervention programs from a central perspective. MethodsAccording to the inclusion and exclusion criteria, 48 children with ASD accompanied by MDs were recruited into the ASD group and 40 children with typically developing (TD) into the TD group. The fNIRS device was used to collect the information of blood oxygen changes in the cortical motor-related brain regions during single-handed bag throwing and tiptoe walking, and the differences in brain activation and functional connectivity between the two groups of children were analyzed from the perspective of brain activation and functional connectivity. ResultsCompared to the TD group, in the object manipulative motor task (one-handed bag throwing), the ASD group showed significantly reduced activation in both left sensorimotor cortex (SMC) and right secondary visual cortex (V2) (P<0.05), whereas the right pre-motor and supplementary motor cortex (PMC&SMA) had significantly higher activation (P<0.01) and showed bilateral brain region activity; in terms of brain functional integration, there was a significant decrease in the strength of brain functional connectivity (P<0.05) and was mainly associated with dorsolateral prefrontal cortex (DLPFC) and V2. In the body stability motor task (tiptoe walking), the ASD group had significantly higher activation in motor-related brain regions such as the DLPFC, SMC, and PMC&SMA (P<0.05) and showed bilateral brain region activity; in terms of brain functional integration, the ASD group had lower strength of brain functional connectivity (P<0.05) and was mainly associated with PMC&SMA and V2. ConclusionChildren with ASD exhibit abnormal brain functional activity characteristics specific to different gross motor tasks in object manipulative and body stability, reflecting insufficient or excessive compensatory activation of local brain regions and impaired cross-regions integration, which may be a potential reason for the poorer gross motor performance of children with ASD, and meanwhile provides data support for further unraveling the mechanisms underlying the occurrence of MDs in the context of ASD and designing targeted intervention programs from a central perspective.

This study aims to explore whether Naoxintong Capsules improve multiple cerebral infarctions and myocardial injury via promoting angiogenesis, thereby exerting a simultaneous treatment effect on both the brain and heart. Male SD rats were randomly divided into six groups: sham-operated group, model group, high-dose, medium-dose, and low-dose groups of Naoxintong Capsules(440, 220, and 110 mg·kg~(-1)), and nimodipine group(10.8 mg·kg~(-1)). Rat models of multiple cerebral infarctions were established by injecting autologous thrombus, and samples were collected and tested seven days after modeling. Evaluations included multiple cerebral infarction model assessments, neurological function scores, grip strength tests, and rotarod tests, so as to evaluate neuromotor functions. Morphological structures of brain and heart tissue were observed using hematoxylin-eosin(HE) staining, Nissl staining, and Masson staining. Network pharmacology was employed to screen the mechanisms of Naoxintong Capsules in improving multiple cerebral infarctions and myocardial injury. Neuronal and myocardial cell ultrastructures were observed using transmission electron microscopy. Apoptosis rate in brain neuronal cells was detected by TdT-mediated dUTP nick end labeling(TUNEL) staining, and reactive oxygen species(ROS) levels in myocardial cells were measured. Immunofluorescence was used to detect the expression of platelet endothelial cell adhesion molecule-1(CD31), antigen identified by monoclonal antibody Ki67(Ki67), hematopoietic progenitor cell antigen CD34(CD34), and hypoxia inducible factor-1α(HIF-1α) in brain and myocardial tissue. Western blot, and real-time quantitative polymerase chain reaction(RT-qPCR) were used to detect the expression of HIF-1α, vascular endothelial growth factor(VEGF), vascular endothelial growth factor receptor 2(VEGFR2), sarcoma(Src), basic fibroblast growth factor(bFGF), angiopoietin-1(Ang-1), and TEK receptor tyrosine kinase(Tie-2). Compared with the model group, the medium-dose group of Naoxintong Capsules showed significantly lower neurological function scores, increased grip strength, and prolonged time on the rotarod. Pathological damage in brain and heart tissue was reduced, with increased and more orderly arranged mitochondria in neurons and cardiomyocytes. Apoptosis in brain neuronal cells was decreased, and ROS levels in cardiomyocytes were reduced. The microvascular density and endothelial cells of new blood vessels in brain and heart tissue increased, with increased overlapping regions of CD31 and Ki67 expression. The relative protein and mRNA expression levels of HIF-1α, VEGF, VEGFR2, Src, Ang-1, Tie-2, and bFGF were elevated in brain tissue and myocardial tissue. Naoxintong Capsules may improve multiple cerebral infarctions and myocardial injury by mediating HIF-1α/VEGF expression to promote angiogenesis.
Animals ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Rats ; Cerebral Infarction/genetics* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Vascular Endothelial Growth Factor A/genetics* ; Capsules ; Signal Transduction/drug effects* ; Humans ; Brain/metabolism* ; Myocardium/metabolism* ; Apoptosis/drug effects*

This study investigates the mechanism by which Xintong Granules improve myocardial ischemia-reperfusion injury(MIRI) through the regulation of gut microbiota and their metabolites, specifically short-chain fatty acids(SCFAs). Rats were randomly divided based on body weight into the sham operation group, model group, low-dose Xintong Granules group(1.43 g·kg~(-1)·d~(-1)), medium-dose Xintong Granules group(2.86 g·kg~(-1)·d~(-1)), high-dose Xintong Granules group(5.72 g·kg~(-1)·d~(-1)), and metoprolol group(10 mg·kg~(-1)·d~(-1)). After 14 days of pre-administration, the MIRI rat model was established by ligating the left anterior descending coronary artery. The myocardial infarction area was assessed using the 2,3,5-triphenyltetrazolium chloride(TTC) staining method. Apoptosis in tissue cells was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay. Pathological changes in myocardial cells and colonic tissue were observed using hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), creatine kinase MB isoenzyme(CK-MB), and cardiac troponin T(cTnT) in rat serum were quantitatively measured using enzyme-linked immunosorbent assay(ELISA) kits. The activities of lactate dehydrogenase(LDH), creatine kinase(CK), and superoxide dismutase(SOD) in myocardial tissue, as well as the level of malondialdehyde(MDA), were determined using colorimetric assays. Gut microbiota composition was analyzed by 16S rDNA sequencing, and fecal SCFAs were quantified using gas chromatography-mass spectrometry(GC-MS). The results show that Xintong Granules significantly reduced the myocardial infarction area, suppressed cardiomyocyte apoptosis, and decreased serum levels of pro-inflammatory cytokines(TNF-α, IL-1β, and IL-6), myocardial injury markers(CK-MB, cTnT, LDH, and CK), and oxidative stress marker MDA. Additionally, Xintong Granules significantly improved intestinal inflammation in MIRI rats, regulated gut microbiota composition and diversity, and increased the levels of SCFAs(acetate, propionate, isobutyrate, etc.). In summary, Xintong Granules effectively alleviate MIRI symptoms. This study preliminarily confirms that Xintong Granules exert their inhibitory effects on MIRI by regulating gut microbiota imbalance and increasing SCFA levels.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Myocardial Reperfusion Injury/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Apoptosis/drug effects* ; Humans ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6/genetics* ; Malondialdehyde/metabolism*

OBJECTIVE: To explore the mechanism by which the extract of Semen Ziziphi Spinosae extract promotes bone growth in mice by modulation of the expression of miR-34a-5p in brain tissue. METHODS: Mice were assigned to four experimental groups:a normal control group, a drug administration group (receiving 0.320 mg·g^-1 body weight of Semen Ziziphi Spinosae extract via intragastric administration), a positive control group (receiving 0.013 mg·g^-1 body weight of jujube seed saponin via intragastric administration), and a combination group administration with Semen Ziziphi Spinosae extract plus a 5-hydroxytryptamine 2A receptor (5-HT2AR) agonist (intragastric administration of Semen Ziziphi Spinosae extract combined with intracerebroventricular injection of 8 μg P-MPPF per mice for the final three days of the experiment). Following a 20-day administration period, the effects of the interventions on bone growth, serum growth hormone (GH) levels, and 5-HT2AR expression in brain tissue were evaluated. MicroRNAs (miRNAs) that were differentially expressed in the brain tissues of mice exhibiting bone growth induced by Semen Ziziphi Spinosae extract, as compared to those in normal mice, were identified using a gene chip approach. The interaction between miR-34a-5p and 5-HT2AR was subsequently validated through quantitative reverse transcription polymerase chainreaction (RT-qPCR) and dual-luciferase reporter gene assays. Subsequently, by utilizing the miR-34a-5p inhibitor group and mimics group, along with the normal control group, the drug administration group, the positive control group, and the drug administration combined with miR-34a-5p inhibitor group, the variations in 5-HT2AR expression in mouse brain tissue across all groups were examined, and the binding activity of 5-hydroxytryptamine (5-HT) to the 5-hydroxytryptamine 1A receptor (5-HT1AR) in mice was assessed. RESULTS: The body lengths of the normal control group and the drug administration group were(8.9±0.3) and(10.4±0.4) cm;femur lengths were (8.5±0.3) and (9.1±0.5) mm;tibia lengths were (10.7±0.3) and (11.2±0.4) mm, respectively. The contents of GH levels were (58.6±8.2) and (72.9±6.1) ng·ml-1;and the contents of 5-HT2AR were (32.0±5.0) and (21.9± 5.5) ng·ml-1, respectively. Compared with the normal control group, the drug administration group promoted the growth of body length, femur, and tibia in mice, and increased GH secretion, showing statistically significant differences (P<0.05). Additionally, it significantly reduced the content of 5-HT2AR in brain tissue, with statistical significance (P<0.01). The gene chip analysis identified a total of 16 differentially expressed miRNAs, of which 13 were up-regulated and 3 were down-regulated. Bioinformatics analysis predicted that the up-regulated miR-34a-5p could regulate the expression of 5-HT2AR, a prediction that was confirmed through a dual-luciferase reporter gene assay, demonstrating a direct regulatory interaction between the two. Furthermore, in vivo experiments in mice revealed that overexpression and silencing of miR-34a-5p resulted in corresponding changes in the expression levels of 5-HT2AR in brain tissues/cells, as well as in the binding activity between 5-HT and 5-HT1AR. CONCLUSION The Semen Ziziphi Spinosae extract promotes animal bone growth by enhancing miR-34a-5p expression in brain tissue, downregulating the expression level of 5-HT2AR, improving the binding activity between 5-HT and 5-HT1AR, and extending slow-wave sleep duration, thereby stimulating GH secretion.
Animals ; MicroRNAs/metabolism* ; Mice ; Male ; Brain/metabolism* ; Ziziphus/chemistry* ; Bone Development/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Plant Extracts/pharmacology*

OBJECTIVE: To investigate the relationship between angiotensin Ⅱ type 1 receptor autoantibody (AT1-AA) and semen parameters. Methods： The semen samples of 820 male patients who were treated in the Reproductive Medicine Center of Taiyuan Central Hospital from August 2022 to August 2023 were retrospectively analyzed. The levels of AT1-AA and Ang Ⅱ of semen were detected by ELISA, and the function of AT1-AA was detected by cardiomyocyte beating assay in suckling rats. The patients were divided into low group, median group and high group according to the OD values of AT1-AA. The differences in general data and semen parameters between different groups were analyzed. And the correlation between AT1-AA level and semen parameters in semen of all study subjects was analyzed by the method of Spearman analysis. And the relationships between AT1-AA OD value, Ang Ⅱ level and semen parameters in the AT1-AA high value group were analyzed as well. RESULTS: AT1-AA was present in semen with good function. There was no significant difference in the general data of patients in different AT1-AA levels (P>0.05). In the comparison of semen parameters among the groups with different levels of AT1-AA, there were differences in sperm concentration, PR concentration, NP％, and ALH among the three groups (P<0.05). And AT1-AA OD value was positively correlated with total sperm count, sperm concentration, PR concentration, and NP％, and negatively correlated with semen volume (P<0.05). In the AT1-AA high value group, the OD value of AT1-AA in semen was negatively correlated with inactive sperm, and positively correlated with total motility (［PR+NP］％), curve rate, mean path rate, and ALH. However, there was no correlation between the level of Ang Ⅱ in semen and semen parameters (P>0.05). CONCLUSION The presence of AT1-AA in semen may be associated with the promotion of sperm motility.
Male ; Humans ; Autoantibodies ; Sperm Motility ; Semen ; Retrospective Studies ; Receptor, Angiotensin, Type 1/immunology* ; Animals ; Rats ; Angiotensin II ; Adult ; Sperm Count ; Semen Analysis ; Receptor, Angiotensin, Type 2/immunology*

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

Seven triterpenoids were isolated and purified from the 95% aqueous EtOH extract whole plants of P. villosa by various chromatographic techniques, such as silica gel, ODS, Sephadex LH-20 gel column chromatography and preparative high performance liquid chromatography. Based on physicochemical properties and spectral analyses, the structures of the seven compounds were identified as 29-acetoxyoleanolic acid-3-O-α-L-arabinopyranoside (1), oleanolic acid (2), 3β-hydroxy-24-norursa-4(23),12,20(30)-trien-28-oic acid (3), 3β-hydroxy-24-nor-urs-4(23),12-dien-28-oic acid (4), ursolic acid (5), hederagenin (6), oleanolic acid 3-O-arabinoside (7). Compound 1 is a new compound. Compounds 3, 4, 6, and 7 are isolated from P. villosa for the first time. All compounds were assayed for their anti-inflammatory activity by the prodution of NO in lipopolysaccharide-stimulated RAW 264.7 cells. The results showed that compounds 1, 2, 3, 4, 6, and 7 significantly inhibited the NO release.