HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.

Objective:To evaluatethe therapeutic efficacy and underlying mechanism of sodium houttuyfonate in treating airway inflammation in allergic asthma induced by co-exposure to the environmental pollutant benzo[a] pyrene (BaP) and ovalbumin (OVA).Methods:Thirty BALB/c mice were randomly divided into five groups with six mice in each group using a block randomization method: control, BaP, asthma model (OVA), BaP-exacerbated asthma (BaP+ OVA), and sodium houttuyfonate-treated BaP-exacerbated asthma (BaP+ OVA+ SH) groups. A mouse model of exacerbated asthma induced by co-exposure to BaP and OVA was established. Airway hyperresponsiveness, leukocyte distribution in bronchoalveolar lavage fluid (BALF), expression of cytokines such as IL-4, IL-13, IL-25, IL-33, thymic stromal lymphopoietin (TSLP) and IFN-γ, serum OVA-specific antibodies (IgE, IgG2a and IgG1), levels of malondialdehyde and superoxide dismutase (SOD) in lung tissues, and histopathological changes in lung tissues were evaluated. Western blot and RT-qPCR were used to detect the protein and mRNA expression levels of suppression of tumorigenicity 2 (ST2), extracellular regulated protein kinases (ERK), and phosphorylated ERK (p-ERK). Statistical analysis was conducted using analysis of variance and other statistical methods.Results:Compared with the BaP+ OVA group, the mice in the BaP+ OVA+ SH group showed significantly reduced airway hyperresponsiveness ( P<0.01), decreased numbers of total leukocytes ( P<0.01), neutrophils ( P<0.05), and lymphocytes ( P<0.01) in BALF, significantly downregulated secretion of IL-4, IL-13, IL-25, IL-33 and TSLP ( P<0.01), and inhibited production of IgE ( P<0.01) and IgG1 ( P<0.05). Additionally, sodium houttuyfonate treatment significantly decreased the malondialdehyde levels in lung tissues of mice with BaP-exacerbated asthma ( P<0.05) and reduced airway inflammatory cell infiltration, mucus secretion, and collagen fiber proliferation. Sodium houttuyfonate could supress the expression of ST2 and ERK ( P<0.05), inhibit ERK phosphorylation ( P<0.01), alleviate oxidative stress injury, and reduce collagen fiber proliferation in mouse lung tissues, thereby blocking the progression of BaP-exacerbated asthmatic inflammation. Conclusions:BaP exacerbates OVA-sensitized asthmatic airway inflammation in mice by inducing airway remodeling through the IL-33-ST2/ERK pathway. Sodium houttuyfonate inhibits this pathway, thereby preventing the progression of BaP-exacerbated asthma inflammation. This study provides new insights into the prevention and treatment of different phenotypes of asthma.

Objective:To investigate the relationship between the changes in extracellular vesicles (EVs) size distribution before and after cardiopulmonary bypass (CPB) cardiac surgery and postoperative coagulation function.Methods:A total of 103 patients undergoing cardiac surgery with CPB were enrolled. Venous blood samples were collected at preoperation, postoperative 12 h and 3 days. Additionally, 50 age- and gender-matched healthy volunteers served as a control group. EVs were isolated using gradient centrifugation, and their size distribution was assessed by dynamic light scattering (DLS). The relationship between EV size characteristics, including peak diameter, peak height, and interquartile range( IQR), and postoperative coagulation function was analyzed. Results:Compared to patients with normal postoperative coagulation function, those with postoperative coagulation dysfunction had lower size at peak and IQR, and significantly higher peak intensity. Logistic regression analysis indicated that elevated peak intensity and lower size at peak and IQR were risk factors for coagulation dysfunction. The area under the curve ( AUC) for diagnosing coagulation dysfunction with 12 h postoperative EVs peak intensity was 0.76, with a positive predictive value of 85% at the optimal cutoff of 8.2; the AUC for IQR was 0.84, with a sensitivity of 83%, specificity of 82%, and negative predictive value of 86% at the optimal cutoff of 125.05 nm. Conclusion:The size distribution of circulating EVs show a correlation with coagulation function after cardiac surgery with CPB and may serve as a novel biomarker to predict postoperative coagulation dysfunction.

Objective:To analyze the therapeutic efficacy and long-term outcomes of wire-assisted dynamic traction with corrective device for congenital nipple inversion.Methods:A retrospective study was conducted on 22 female patients (42 nipples) with congenital nipple inversion treated at the Department of Plastic Surgery, Peking Union Medical College Hospital from January to December 2017. The patients′ age was 18-54 (27.6±1.9) years. All patients underwent wire-assisted dynamic traction correction. Postoperative indicators including numerical rating scale (NRS) pain scores, nipple skin microcirculatory disorders, and traction duration were recorded. Follow-up assessments via telephone interviews were completed by September 20, 2022; mean follow-up time was (63.68±3.73) months. Evaluating questions included nipple retraction, fertility status and breastfeeding outcomes.Results:Pain in the operative area was non-radiating, and the pain level decreased over time. Mean NRS were (5.4±1.5) scores on surgery day, decreasing to (4.4±1.2) scores at postoperative day 1 and (3.3±1.7) scores at day 2. Microcirculatory assessments revealed Grade 0-I (intact skin) in 78.6% (33/42), Grade II (skin ulceration) in 14.3% (6/42), and Grade III (partial necrosis) in 7.1% (3/42) of the nipples, with no Grade IV necrosis observed. Successful device placement was achieved in all cases (42/42), with traction duration ranging 6-15 (9.6±0.6) months. Follow-up data from 12 patients (23 nipples) showed mild retraction in 3 nipples. Three patients subsequently delivered infants and successfully achieved breastfeeding.Conclusion:The wire-assisted dynamic traction method with corrective device demonstrates satisfactory therapeutic outcomes for congenital nipple inversion patients with favorable long-term maintenance and breastfeeding compatibility.

Hypertrophic cardiomyopathy, a genetic hereditary disease, is highly regarded in clinical practice due to its unique pathophysiological changes, course characteristics, and hemodynamic features. With the continuous advance of treatment methods such as medications and surgeries, the prevention, treatment and prognosis of hypertrophic cardiomyopathy has gradually improved. However, inappropriate use of positive inotropic drugs may lead to serious consequences that are difficult to reverse. Therefore, how to smoothly navigate through the perioperative period and ensure clinical safety poses a great challenge for anesthesiologists. This paper discusses the perioperative management of patients with hypertrophic cardiomyopathy, with the hope of enhancing anesthesiologists' management capabilities for this type of disease.

Objective To investigate the effects of long non coding RNA MAGI2 antisense chain RNA3(LncRNA MAGI2-AS3)on the migration,invasion,and epithelial mesenchymal transition(EMT)of gastric cancer(GCa)cells by regulating the miR-194-5 p/caveolin-1(CAV1)axis.Methods Fifty-two GCa patients who underwent surgical resection in our hospital from August 2022 to December 2023 were selected.Cancer and adjacent tissues were collected,and AGS,MKN45,HGC-27,and GES1 cells were cultured in vitro.The expression of MAGI2-AS3,miR-194-5p,and CAV1 in tissue samples and cell lines was analyzed.AGS cells were randomly separated into AGS group,sh-AGS group sh-MAGI2-AS3 group,miR-NC group,and in miR-194-5p group.The proliferation,apoptosis,migration,and invasion of cells in each group were compared.Immunoblotting was applied to analyze the expression of E-cadherin,CAV1,proliferating cell nuclear antigen(PCNA),N-cadherin,Bax,matrix metalloproteinase 2(MMP2),and vimentin of cells in each group.Dual luciferase assay was applied to analyze the relationship between MAGI2-AS3 and miR-194-5p,and between miR-194-5p and CAV1.Results The expression of MAGI2-AS3 mRNA,CAV1 mRNA,and positive expression rate of CAV1 protein in GCa tissue increased,while the expression of miR-194-5p mRNA decreased(P＜0.05).The expression of MAGI2-AS3 mRNA,CAV1 mRNA,and CAV1 protein in HGC-27,MKN45,and AGS cells was higher than that of GES1 cells,the expression of miR-194-5p mRNA was lower than that of GES1 cells(P＜0.05).Compared with the AGS and sh-AGS groups,the cell absorbance,number of clones,invasion and migration,expression of CAV1,PCNA,N-cadherin,MMP2,and vimentin in sh-MAGI2-AS3 group decreased,the apoptosis rate,expression of E-cadherin,and Bax increased(P＜0.05).Compared with the miR-NC group and sh-MAGI2-AS3 group,the cell absorbance,number of clones,invasion and migration,expression of CAV1,PCNA,N-cadherin,MMP2,and vimentin in in-miR-194-5p group increased,the apoptosis rate,expression of E-cadherin,and Bax reduced(P＜0.05).ENCORI database found that there were multiple binding sites between MAGI2-AS3 and miR-194-5p,and between miR-194-5p and CAV1.Compared with the WT-MAGI2-AS3+miR-NC group,the luciferase activity in the WT-MAGI2-AS3+miR-194-5p group decreased(P＜0.05),while compared with the WT-CAV1+miR-NC group,the luciferase activity in the WT-CAV1+miR-194-5p group decreased(P＜0.05).Conclusion LncRNA MAGI2-AS3 silencing can target miR-194-5p to downregulate CAV1,thereby inhibiting GCa cell migration,invasion,and EMT.

Objective To investigate the effects of long non coding RNA MAGI2 antisense chain RNA3(LncRNA MAGI2-AS3)on the migration,invasion,and epithelial mesenchymal transition(EMT)of gastric cancer(GCa)cells by regulating the miR-194-5 p/caveolin-1(CAV1)axis.Methods Fifty-two GCa patients who underwent surgical resection in our hospital from August 2022 to December 2023 were selected.Cancer and adjacent tissues were collected,and AGS,MKN45,HGC-27,and GES1 cells were cultured in vitro.The expression of MAGI2-AS3,miR-194-5p,and CAV1 in tissue samples and cell lines was analyzed.AGS cells were randomly separated into AGS group,sh-AGS group sh-MAGI2-AS3 group,miR-NC group,and in miR-194-5p group.The proliferation,apoptosis,migration,and invasion of cells in each group were compared.Immunoblotting was applied to analyze the expression of E-cadherin,CAV1,proliferating cell nuclear antigen(PCNA),N-cadherin,Bax,matrix metalloproteinase 2(MMP2),and vimentin of cells in each group.Dual luciferase assay was applied to analyze the relationship between MAGI2-AS3 and miR-194-5p,and between miR-194-5p and CAV1.Results The expression of MAGI2-AS3 mRNA,CAV1 mRNA,and positive expression rate of CAV1 protein in GCa tissue increased,while the expression of miR-194-5p mRNA decreased(P＜0.05).The expression of MAGI2-AS3 mRNA,CAV1 mRNA,and CAV1 protein in HGC-27,MKN45,and AGS cells was higher than that of GES1 cells,the expression of miR-194-5p mRNA was lower than that of GES1 cells(P＜0.05).Compared with the AGS and sh-AGS groups,the cell absorbance,number of clones,invasion and migration,expression of CAV1,PCNA,N-cadherin,MMP2,and vimentin in sh-MAGI2-AS3 group decreased,the apoptosis rate,expression of E-cadherin,and Bax increased(P＜0.05).Compared with the miR-NC group and sh-MAGI2-AS3 group,the cell absorbance,number of clones,invasion and migration,expression of CAV1,PCNA,N-cadherin,MMP2,and vimentin in in-miR-194-5p group increased,the apoptosis rate,expression of E-cadherin,and Bax reduced(P＜0.05).ENCORI database found that there were multiple binding sites between MAGI2-AS3 and miR-194-5p,and between miR-194-5p and CAV1.Compared with the WT-MAGI2-AS3+miR-NC group,the luciferase activity in the WT-MAGI2-AS3+miR-194-5p group decreased(P＜0.05),while compared with the WT-CAV1+miR-NC group,the luciferase activity in the WT-CAV1+miR-194-5p group decreased(P＜0.05).Conclusion LncRNA MAGI2-AS3 silencing can target miR-194-5p to downregulate CAV1,thereby inhibiting GCa cell migration,invasion,and EMT.

Objective:To evaluatethe therapeutic efficacy and underlying mechanism of sodium houttuyfonate in treating airway inflammation in allergic asthma induced by co-exposure to the environmental pollutant benzo[a] pyrene (BaP) and ovalbumin (OVA).Methods:Thirty BALB/c mice were randomly divided into five groups with six mice in each group using a block randomization method: control, BaP, asthma model (OVA), BaP-exacerbated asthma (BaP+ OVA), and sodium houttuyfonate-treated BaP-exacerbated asthma (BaP+ OVA+ SH) groups. A mouse model of exacerbated asthma induced by co-exposure to BaP and OVA was established. Airway hyperresponsiveness, leukocyte distribution in bronchoalveolar lavage fluid (BALF), expression of cytokines such as IL-4, IL-13, IL-25, IL-33, thymic stromal lymphopoietin (TSLP) and IFN-γ, serum OVA-specific antibodies (IgE, IgG2a and IgG1), levels of malondialdehyde and superoxide dismutase (SOD) in lung tissues, and histopathological changes in lung tissues were evaluated. Western blot and RT-qPCR were used to detect the protein and mRNA expression levels of suppression of tumorigenicity 2 (ST2), extracellular regulated protein kinases (ERK), and phosphorylated ERK (p-ERK). Statistical analysis was conducted using analysis of variance and other statistical methods.Results:Compared with the BaP+ OVA group, the mice in the BaP+ OVA+ SH group showed significantly reduced airway hyperresponsiveness ( P<0.01), decreased numbers of total leukocytes ( P<0.01), neutrophils ( P<0.05), and lymphocytes ( P<0.01) in BALF, significantly downregulated secretion of IL-4, IL-13, IL-25, IL-33 and TSLP ( P<0.01), and inhibited production of IgE ( P<0.01) and IgG1 ( P<0.05). Additionally, sodium houttuyfonate treatment significantly decreased the malondialdehyde levels in lung tissues of mice with BaP-exacerbated asthma ( P<0.05) and reduced airway inflammatory cell infiltration, mucus secretion, and collagen fiber proliferation. Sodium houttuyfonate could supress the expression of ST2 and ERK ( P<0.05), inhibit ERK phosphorylation ( P<0.01), alleviate oxidative stress injury, and reduce collagen fiber proliferation in mouse lung tissues, thereby blocking the progression of BaP-exacerbated asthmatic inflammation. Conclusions:BaP exacerbates OVA-sensitized asthmatic airway inflammation in mice by inducing airway remodeling through the IL-33-ST2/ERK pathway. Sodium houttuyfonate inhibits this pathway, thereby preventing the progression of BaP-exacerbated asthma inflammation. This study provides new insights into the prevention and treatment of different phenotypes of asthma.

Objective:To investigate the relationship between the changes in extracellular vesicles (EVs) size distribution before and after cardiopulmonary bypass (CPB) cardiac surgery and postoperative coagulation function.Methods:A total of 103 patients undergoing cardiac surgery with CPB were enrolled. Venous blood samples were collected at preoperation, postoperative 12 h and 3 days. Additionally, 50 age- and gender-matched healthy volunteers served as a control group. EVs were isolated using gradient centrifugation, and their size distribution was assessed by dynamic light scattering (DLS). The relationship between EV size characteristics, including peak diameter, peak height, and interquartile range( IQR), and postoperative coagulation function was analyzed. Results:Compared to patients with normal postoperative coagulation function, those with postoperative coagulation dysfunction had lower size at peak and IQR, and significantly higher peak intensity. Logistic regression analysis indicated that elevated peak intensity and lower size at peak and IQR were risk factors for coagulation dysfunction. The area under the curve ( AUC) for diagnosing coagulation dysfunction with 12 h postoperative EVs peak intensity was 0.76, with a positive predictive value of 85% at the optimal cutoff of 8.2; the AUC for IQR was 0.84, with a sensitivity of 83%, specificity of 82%, and negative predictive value of 86% at the optimal cutoff of 125.05 nm. Conclusion:The size distribution of circulating EVs show a correlation with coagulation function after cardiac surgery with CPB and may serve as a novel biomarker to predict postoperative coagulation dysfunction.