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.

ObjectiveTo observe ovarian microvascular damage in rats with cold coagulation and blood stasis syndrome and to explore the mechanism by which Liangfang Wenjing decoction improves this condition in rats. MethodsFifty SPF female SD rats were randomly divided into a blank group， a model group， low-dose （8.1 g·kg^-1） and high-dose groups （16.2 g·kg^-1） of Liangfang Wenjing decoction， and a 4-phenylbutyric acid （0.1 g·kg^-1） group， with 10 rats in each group. The ice-water bath method was employed to establish the rat model of cold coagulation and blood stasis syndrome. Concurrent with modeling， Liangfang Wenjing decoction was administered continuously for 21 days， once daily. The rats' syndrome manifestations and estrous cycles were recorded. The enzyme-linked immunosorbent assay （ELISA） was used to detect serum reproductive hormone levels and levels of endothelin-1 （ET-1）， nitric oxide （NO）， thrombomodulin （TM）， and von Willebrand factor （vWF） in ovarian tissue. Prothrombin time （PT）， activated partial thromboplastin time （APTT）， thrombin time （TT）， and fibrinogen （FIB） were measured. The ovarian microcirculatory blood perfusion was detected by laser speckle contrast imaging. Hematoxylin-eosin （HE） staining was performed to observe the ovarian histopathology， flow cytometry to detect ovarian apoptosis rate， and transmission electron microscopy to observe the ultrastructure of ovarian microvascular endothelial cells. Western blot was employed to detect the protein expression of endothelial nitric oxide synthase （eNOS）， phosphorylated eNOS （p-eNOS）， Caspase-3， B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， glucose-regulated protein 78 （GRP78）， C/EBP homologous protein （CHOP）， inositol-requiring enzyme1α （IRE1α）， p-IRE1α， apoptosis signal-regulating kinase 1 （ASK1）， p-ASK1， c-Jun N-terminal kinase （JNK）， and p-JNK. Immunofluorescence was used to detect ovarian Bax and Bcl-2 expression in microvascular endothelial cells. ResultsCompared with the blank group， the model group showed signs of cold coagulation and blood stasis syndrome， prolonged estrus cycles， and reproductive hormone disorders. Histopathological results revealed a decrease in follicle counts at all stages and disorganized granulosa cell arrangement. Ovarian microcirculatory perfusion was significantly decreased （P<0.01）. PT， APTT， and TT were reduced （P<0.05， P<0.01）， while FIB levels were increased （P<0.05）. In ovarian tissue， NO content was decreased， while ET-1， vWF， and TM levels were increased significantly （P<0.01）. The apoptosis rate of ovarian cells was markedly increased （P<0.01）. Furthermore， p-eNOS/eNOS and Bcl-2 were decreased （P<0.05）， whereas Bax， cleaved-Caspase-3/Caspase-3， GRP78， CHOP， p-IRE1α/IRE1α， p-ASK1/ASK1， and p-JNK/JNK expression showed significant increases （P<0.05， P<0.01）. Compared with the model group， Liangfang Wenjing decoction intervention alleviated the symptoms of cold coagulation and blood stasis， gradually restored the estrus cycle， and improved ovarian histopathology and endothelial cell ultrastructure. Microcirculatory blood perfusion was significantly elevated （P<0.05）. NO content in ovarian tissue was elevated， while ET-1， vWF， and TM levels were significantly decreased （P<0.05， P<0.01）. The p-eNOS/eNOS ratio and Bcl-2 expression were significantly elevated （P<0.05）， while the expression of Bax， cleaved-Caspase-3/Caspase-3， GRP78， CHOP， p-IRE1α/IRE1α， p-ASK1/ASK1， and p-JNK/JNK was significantly decreased （P<0.05， P<0.01）. ConclusionLiangfang Wenjing decoction may regulate the IRE1α/ASK1/JNK signaling pathway to inhibit endoplasmic reticulum stress， attenuate apoptosis， and improve microvascular endothelial injury in ovaries of rats with cold coagulation and blood stasis syndrome.

Eight butyl-phthalides, senkyunolide K(1), senkyunolide N(2), butylphthalide(3), senkyunolide I(4), senkyunolide H(5),(Z)-butylidenephthalide(6),(Z)-ligustilide(7), and 3-butylidene-7-hydroxyphthalide(8) were isolated from the aerial part of Ligusticum sinense by column chromatography on silica gel column, ODS, Sephadex LH-20 and semi-preparative HPLC. Their structures were elucidated on the basis of spectroscopic and chemical data, especially NMR and MS. Compound 1 was a new butyl-phthalide and compounds 2-8 were isolated from the aerial part of L. sinense for the first time. Furthermore, the inhibitory activities of compounds 1-8 against the nitric oxide(NO) production induced by lipopolysaccharide(LPS) in mouse RAW264.7 macrophages in vitro were evaluated. The results showed that compounds 1-8 exerted inhibitory activities on NO production with IC_(50) of 19.34-42.16 μmol·L~(-1).
Animals ; Mice ; Nitric Oxide/biosynthesis* ; Ligusticum/chemistry* ; Benzofurans/isolation & purification* ; Drugs, Chinese Herbal/isolation & purification* ; Macrophages/immunology* ; RAW 264.7 Cells ; Molecular Structure

OBJECTIVE: To investigate the expression of CSF-1 and CSF-1R in the peripheral blood of children with immune thrombocytopenia (ITP) and its clinical significance. METHODS: Forty-four children with ITP treated in our hospital from February 2023 to January 2024 were selected as the observation group, and 40 healthy children were selected as the control group during the same period, and relevant clinical data were collected. Peripheral blood mononuclear cells (PBMC) of children with ITP and healthy children were separated, and the plasma levels of M1 macrophage-associated cytokines (TNF-α, IL-6), M2 macrophage-associated cytokines (IL-10, TGF-β), and CSF-1 were detected by ELISA in the children of both groups. The mRNA levels of M1 macrophage surface markers (CD86, iNOS), M2 macrophage surface markers (CD206, Arg-1) and CSF-1R were detected by RT-PCR in PBMC of children in both groups. Western blot was used to detect the expression of CSF-1R protein in PBMC of the two groups of children. The correlation between platelet count and CSF-1R mRNA expression in PBMC, TNF-α, IL-6, IL-10, TGF-β and CSF-1 in plasma was analyzed. RESULTS: Compared with the control group, the levels of IL-10, TGF-β, CSF-1 and platelet count in plasma of children with ITP were significantly decreased (P < 0.01), and the levels of TNF-α and IL-6 were significantly increased (P < 0.01); the mRNA levels of the M1 macrophage surface markers (CD86, iNOS) in PBMC of children with ITP were significantly increased (P < 0.05), mRNA levels of M2 macrophage surface marker CD206 in PBMC of children with ITP were decreased compared with controls but the difference was not statistically significant ( P >0.05), mRNA levels of Arg-1 were decreased, the difference was statistically significant (P < 0.05). The mRNA and protein levels of CSF-1R in PBMC of ITP children were higher than that in controls. CSF-1R expression in PBMC of ITP was positively correlated with platelet count, IL-10, CSF-1 were positively correlated (r =0.822,0.481,0.405). CONCLUSION CSF-1 is significantly reduced in the plasma of ITP, and CSF-1R mRNA and protein expression is significantly elevated in PBMC of ITP, which are involved in the regulation of macrophage M1/M2 imbalance, and could serve as a potential therapeutic target for ITP.
Humans ; Purpura, Thrombocytopenic, Idiopathic/blood* ; Macrophage Colony-Stimulating Factor/metabolism* ; Leukocytes, Mononuclear/metabolism* ; Child ; Interleukin-10/blood* ; Macrophages/metabolism* ; Tumor Necrosis Factor-alpha/blood* ; Interleukin-6/blood* ; Male ; Female ; Transforming Growth Factor beta/blood* ; Receptor, Macrophage Colony-Stimulating Factor/metabolism* ; Clinical Relevance

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection,with a high mortality rate.Sirtuin 3,a deacetylase within mitochondria,plays an important regulatory role in cellular metabolism,oxidative stress,and inflammatory responses.In recent years,significant progress has been made in the study of the function and regulatory role of sirtuin 3 in sepsis-related diseases.Research has shown that sirtuin 3 can alleviate organ damage caused by sepsis by regulating mitochondrial function,reducing oxidative stress,and inhibiting inflammatory responses.The specific mechanisms include the regulation of mitochondrial bioenergetics,activation of antioxidant enzyme systems,and inhibition of inflammatory mediator expression.In addition,sirtuin 3 plays a protective role in the pathological process of sepsis by interacting with multiple signaling pathways.This article summarizes the functions and regulatory mechanisms of sirtuin 3 in various sepsis-related diseases,aiming to provide new targets and strategies for the prevention and treatment of sepsis in the future.
Sepsis/metabolism* ; Sirtuin 3/physiology* ; Humans ; Animals ; Oxidative Stress ; Mitochondria/metabolism* ; Signal Transduction

Objective To evaluate the bioequivalence and safety of ibuprofen arginine granules test and reference formulations in Chinese healthy volunteers under fasting and postprandial conditions,and to provide evidence for consistency evaluation and clinical application of the drugs.Methods A single-center,single-dose,randomized,open-label,fasting and postprandial,two-period,two-crossover trial design was used.Twenty-four healthy Chinese volunteers were enrolled in the fasting and postprandial trial,respectively.The test preparation and reference preparation of ibuprofen arginine granules 0.4 g were taken orally in a randomized crossover single dose.Data analysis was performed using Phoenix WinNonlin 8.3.Results In the fasting group,the main pharmacokinetic parameters of ibuprofen in plasma after administration of the test and reference formulations of ibuprofen arginine granules were as follows:Cmax were(51.07±7.43)and(50.10±7.64)μg·mL-1;AUC0-,were(122.78±20.62)and(119.94±21.03)μg·h·mL-1;AUC0_∞ were(125.84±21.31)and(122.64±21.87)μg·h·mL-1,respectively.In the postprandial group,the main pharmacokinetic parameters of ibuprofen in plasma after administration of the test and reference formulations of ibuprofen arginine granules were as follows:Cmax were(17.47±3.56)and(17.89±4.47)μg·mL-1;AUC0-twere(114.33±17.12)and(122.13±29.46)μg·h·mL-1;AUC0_∞ were(134.04±36.72)and(133.96±30.35)μg·h·mL-1,respectively.The 90％confidence intervals of the geometric mean ratio of the two preparations were as follows:Cmax 97.96％-106.02％,AUC0_t 98.77％-105.14％,AUC0-∞ 99.34％-105.19％in fasting group;in postprandial group,Cmax was 92.37％-103.05％,AUC0-t was 93.31％-99.56％,AUC0-∞ was 93.89％-102.91％.Conclusion The test preparation and reference preparation of ibuprofen arginine granules in this study are bioequivalent in healthy adult Chinese volunteers.

Objective This study aimed to clarify the intervention effect of salidroside(SAL)on lung injury caused by PM2.5 in mice and illuminate the function of SIRT1-PGC-1ɑ axis. Methods Specific pathogen-free(SPF)grade male C57BL/6 mice were randomly assigned to the following groups:control group,SAL group,PM2.5 group,SAL+PM2.5 group.On the first day,SAL was given by gavage,and on the second day,PM2.5 suspension was given by intratracheal instillation.The whole experiment consist of a total of 10 cycles,lasting 20 days.At the end of treatment,blood samples and lung tissues were collected and analyzed.Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy.The expression of inflammatory,antioxidants,apoptosis,and SIRT1-PGC-1ɑ proteins were detected by Western blotting. Results Exposure to PM2.5 leads to obvious morphological and pathologica changes in the lung of mice.PM2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1,Nrf2,SOD2,SIRT1 and PGC-1ɑ,and an increase in the protein expressions of IL-6,IL-1β,Bax,caspase-9 and cleaved caspase-3.However,SAL reversed the aforementioned changes caused by PM2.5 by activating the SIRT1-PGC-1α pathway. Conclusion SAL can activate SIRT1-PGC-1ɑ to ameliorate PM2.5-induced lung injury.

Objective To investigate the best evidence application of exercise prescription in patients with chronic heart failure in clinical practice and evaluate its effectiveness.Methods The best evidence of exercise prescription for patients with chronic heart failure was summarized,and the evidence-based practice plan was developed,and it was implemented in the cardiology department of a tertiary hospital in Zhejiang Province from August to October,2022.Nurses'exercise prescription knowledge-attitude-practice level,implementation rate of review indicators,the length of hospital stay,exercise endurance,daily living ability and grip strength of both groups before and after the intervention were compared.Results After the application of the best evidence,the score of knowledge dimension was(9.34±0.98)points;the score of attitude dimension was(63.29±1.37)points;the score of practice dimension was(25.49±1.51)points,which were statistically significant compared with the scores before the application of evidence(P<0.05).After the application of the best evidence,the implementation rate of 16 review indicators was higher than that before the application of evidence(P<0.001).The length of hospital stay in the evidence application group was shorter than that in the baseline examination group(Z=-2.610,P<0.001).After intervention,the exercise endurance,daily living ability and grip strength of patients in the evidence application group were improved compared with the baseline review group,and the difference was statistically significant(P<0.05).Conclusion After the application of the best evidence of exercise prescription in patients with chronic heart failure,it can improve the level of knowledge,attitude and practice of nurses on exercise prescription,standardize the compliance of nurses'exercise prescription,reduce the number of days in the hospital,and improve patients'exercise endurance,daily living ability and grip strength.

AIM To evaluate the quality of Yanyangke Mixture.METHODS The HPLC fingerprints were established,after which cluster analysis,principal component analysis and partial least squares discriminant analysis were performed.The contents of liquiritin,rosmarinic acid,sheganoside,irisgenin,honokiol,monoammonium glycyrrhizinate,irisflorentin,isoliquiritin and magnolol were determined,the analysis was performed on a 35 ℃ thermostatic Agilent ZORBAX SB-C18 column(5 μm,250 mmx4.6 mm),with the mobile phase comprising of 0.1％phosphoric acid-acetonitrile flowing at 1 mL/min in a gradient elution manner,and multi-wavelength detection was adopted.RESULTS There were ten common peaks in the fingerprints for twelve batches of samples with the similarities of more than 0.9.Various batches of samples were clustered into three types,three principal components displayed the acumulative variance contribution rate of 87.448％,peaks 5、14(honokiol),3(liquiritin),11(monoammonium glycyrrhizinate)and 15(asarinin)were quality markers.Nine constituents showed good linear relationships within their own ranges(r＞0.999 0),whose average recoveries were 98.5％-103.6％with the RSDs of 0.92％-1.7％.CONCLUSION This stable and reliable method can provide a basis for the quality control of Yanyangke Mixture.

Gap junction(GJ),also known as gap junction,is widely found between neurons and glial cells,and can connect neighboring cells and mediate the transmission of electrical sig-nals between neighboring cells.The GJ channel,which exists between neurons and mediates intercellular electrical signaling,is also known as an electrical synapse.Connexins(Cxs)are the molecular basis of GJ,and are expressed to different degrees in different neurons and glial cells.The presence of GJ mediates different functions among neurons and glial cells,which further influences the establishment of various mature neural circuits,re-flecting the importance of GJ in the maintenance of neural cir-cuits.This review summarizes the relationship between GJ and neural circuits in relation to the effects of GJ and different Cxs on neurons and glial cells,providing new research ideas for the treatment of neuropsychiatric disorders.