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.

Psoriasis is a chronic inflammatory skin disease, and its pathogenesis is largely modulated by abnormal angiogenesis. Previous research has indicated that AlkB homolog 5 (ALKBH5), an important demethylase affecting N⁶-methyladenosine (m⁶A) modification, plays a role in regulating angiogenesis in cardiovascular and eye diseases. Our present study found that ALKBH5 was upregulated and co-localized with cluster of differentiation 31 (CD31) in the skin of IMQ group compared with control group. ALKBH5-deficient mice decreased IMQ-induced psoriatic dermatitis and exhibited histological improvements, including decreased epidermal thickness, hyperkeratosis, numbers of dermal capillary vessels and inflammatory cell infiltration. ALKBH5-KO mice alleviated angiogenesis in psoriatic lesions by downregulating the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Additionally, the expression of ALKBH5 was significantly upregulated in IL-17A-induced human umbilical vein endothelial cells (HUVECs), which further promoted the expression of angiogenesis-related cytokines and endothelial cell proliferation. Cell proliferation and angiogenesis were suppressed in ALKBH5 knockdown group, whereas ALKBH5 overexpression promoted these processes. The regulation of angiogenesis in HUVECs by ALKBH5 was facilitated through the AKT-mTOR pathway. Collectively, ALKBH5 plays a pivotal role in psoriatic dermatitis and angiogenesis, which may offer a new potential targets for treating psoriasis.
Animals ; Psoriasis/chemically induced* ; Mice ; Humans ; Neovascularization, Pathologic/genetics* ; Human Umbilical Vein Endothelial Cells/metabolism* ; AlkB Homolog 5, RNA Demethylase/genetics* ; Proto-Oncogene Proteins c-akt/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Cell Proliferation ; Mice, Knockout ; Disease Models, Animal ; Signal Transduction ; Male ; Skin/blood supply* ; Mice, Inbred C57BL ; Angiogenesis

Objective To investigate the effect of Tan Ⅰ on SA-AKI in rats by mediating Wnt/β-catenin signaling pathway.Methods Sprague-Dawley rats were randomly divided into the following groups(n=8 per group,including 2 reserve animals per group):Sham,SA-AKI,SA-AKI+5 mg/kg Tan I,SA-AKI+10 mg/kg Tan I,SA-AKI+15 mg/kg Tan I(SA-AKI+Tan I),SA-AKI+salinomycin sodium(SS,Wnt signal inhibitor,SA-AKI+SS),SA-AKI+SS+Tan I,SA-AKI+laduviglusib(LG,Wnt signal activator,SA-AKI+LG),and SA-AKI+LG+Tan I.Rat SA-AKI model was induced by cecal ligation and puncture(CLP),with Tan I,SS,and LG administered via intraperitoneal injection.Hematoxylin-eosin and TUNEL staining were used to observe renal tissue pathological damage.Enzyme-linked immunosorbent assay was used to detect serum concentrations of neutrophil gelatinase-associated lipocalin(NGAL),IL-1β,IL-8,IL-6,and TNF-α.Creatinine(Cre)and blood urea nitrogen(BUN)kit were used to detect serum Cre and BUN concentrations.Western blot and immunofluorescence staining were used to detect the expression and fluorescence intensity of Wnt1,GSK3β,and β-catenin.Results Administration of Tan I at doses of 10 mg/kg and 15 mg/kg significantly attenuated renal injury in rats with SA-AKI(P<0.05),suppressed the levels of SA-AKI biomarkers NGAL,Cre,and BUN and pro-inflammatory cytokines(P<0.05),reduced apoptosis,and downregulated Wnt1 and GSK3β while upregulating β-catenin expression(P<0.05).Although Tan I at 5 mg/kg exhibited a modest protective effect against SA-AKI in rats,no statistically significant difference was observed compared to the sham group(P>0.05).SS weakened CLP-induced kidney injury and the production of inflammatory cytokines in rats(P<0.05),and LG further aggravated CLP-induced kidney injury in rats(P<0.05).Tan Ⅰ reversed the promoting effect of LG on kidney injury in SA-AKI rats(P<0.05).Conclusion Tan Ⅰ provides a protective effect on CLP-induced SA-AKI rat by inhibiting Wnt/β-catenin signaling pathway.

Objectives:Primary cardiac involvement (SSc-PHI) in systemic sclerosis is an important prognostic factor. We aimed to characterize and identify subclinical SSc-PHI using cardiovascular MRI to determine whether disease severity and serum biomarkers are associated with subclinical SSc-PHI.Methods:A total of 26 patients with SSc who had no history of cardiovascular disease or pulmonary hypertension underwent 3 T-enhanced cardiovascular MRI. Measurements included native T 1, extracellular volume, advanced gadolinium enhancement, T 2 mapping, and left ventricular volume function. Troponin T and N telencephalic natriuretic peptide precursors were also determined. Results:LGE was observed in 13 of 26 patients (50.0%), suggesting focal fibrosis, and T 2 mapping was significantly higher in the dcSSc group than in the lcSSc group ( P=0.009). Left ventricular volume and function were within the normal range in all patients, but final systolic left ventricular volume was significantly higher in dcSSc than in lcSSc ( P=0.021). The modified Rodnan skin score (mRSS) was significantly higher in patients with LGE focal fibrosis ( P=0.019). Logistic regression analysis confirmed the association between mRSS and LGE ( OR=1.224, P=0.037). In multivariate analysis, T 2 mapping was negatively correlated with disease course, and was correlated with dcSSc and fingertip ulcer ( R2=0.711, P=0.018, P=0.013, P=0.030). Troponin T was correlated with T 2 mapping ( r=0.555, P=0.049). Conclusions:Subclinical SSc-PHI is characterized by diffuse and focal myocardial fibrosis, but preserves myocardial systolic function. Subclinical SSC-Phi is associated with TNT, SSc disease severity, and complex peripheral vascular disease. These data provide information for identifying individuals at risk of SSc-PHI.

Objective To analyze the influencing factors of survival of patients with airway stenosis requiring clinical interventions after lung transplantation. Methods Clinical data of 66 patients with airway stenosis requiring clinical interventions after lung transplantation were retrospectively analyzed. Univariate and multivariate Cox’s regression models were adopted to analyze the influencing factors of survival of all patients with airway stenosis and those with early airway stenosis. Kaplan-Meier method was used to calculate the overall survival and delineate the survival curve. Results For 66 patients with airway stenosis, the median airway stenosis-free time was 72 (52,102) d, 27% (18/66) for central airway stenosis and 73% (48/66) for distal airway stenosis. Postoperative mechanical ventilation time [hazard ratio (HR) 1.037, 95% confidence interval (CI) 1.005-1.070, P=0.024] and type of surgery (HR 0.400, 95%CI 0.177-0.903, P=0.027) were correlated with the survival of patients with airway stenosis after lung transplantation. The longer the postoperative mechanical ventilation time, the higher the risk of mortality of the recipients. The overall survival of airway stenosis recipients undergoing bilateral lung transplantation was better than that of their counterparts after single lung transplantation. Subgroup analysis showed that grade 3 primary graft dysfunction (PGD) (HR 4.577, 95%CI 1.439-14.555, P=0.010) and immunosuppressive drugs (HR 0.079, 95%CI 0.022-0.287, P<0.001) were associated with the survival of patients with early airway stenosis after lung transplantation. The overall survival of patients with early airway stenosis after lung transplantation without grade 3 PGD was better compared with that of those with grade 3 PGD. The overall survival of patients with early airway stenosis after lung transplantation treated with tacrolimus was superior to that of their counterparts treated with cyclosporine. Conclusions Long postoperative mechanical ventilation time, single lung transplantation, grade 3 PGD and use of cyclosporine may affect the survival of patients with airway stenosis after lung transplantation.

The phenomenon of coronary artery ectasia is typically discovered incidentally during coronary angiography.As a relatively uncommon manifestation of coronary arteries,it has attracted the interest of numerous researchers.However,despite extensive research on coronary artery ectasia,substantial controversies persist regarding both its etiology and treatment modalities.This article provides a comprehensive summary of recent research on coronary artery ectasia,elucidates various aspects of research progress,with the aim of offering substantive support and guidance for subsequent investigations.

As the final resolution for end-stage lung disease, lung transplantation can not only significantly prolong the survival, but also remarkably improve the quality of life of recipients. In recent decades, with the advancement of surgical techniques, immunosuppressants and post-transplantation management, the quantity of lung transplantation has been surged around the globe. However, the shortage of donor lung has severely restricted the development of lung transplantation. It is necessary to develop innovative approaches to expand the donor pool. The number of donors and effective preservation and functional maintenance of potential donor lungs play a key role in expanding the donor pool. The quality of donor lung is a critical precondition to ensure the long-term survival of lung transplant recipients. Preservation and functional maintenance of donor lung are of significance for guaranteeing the quality of lung allograft. In this article, research progresses on the management and maintenance of donor lung before procurement, the procurement of donor lung and the preservation and functional maintenance of lung allograft were reviewed, aiming to provide reference for the development of lung transplantation in clinical practice.

AIM: To investigate the effect of autophagy on cell ferroptosis in intestinal ischemia-reperfusion injury. METHODS: Twenty-four SPF grade Wistar rats weighing 200-220 g were divided into 4 groups (n = 6): sham operation group (sham group), ischemia group (I group), ischemia-reperfusion group (I/R group),and ischemia-reperfusion + autophagy inhibitor group (I/R + 3-MA group). The ischemia model was established by clamping the superior mesenteric artery for 1 hour, and the intestinal ischemia-reperfusion injury model was established by reperfusion for 2 hours. HE staining was used to observe the pathological changes of intestinal mucosa and Chiu score under light microscope. Fe

Alphapapillomavirus ; Humans ; Lupus Erythematosus, Systemic ; Papillomavirus Infections/prevention & control* ; Vaccination

Objective:To investigate the clinical effect of "mutual support" framework in costal cartilage rhinoplasty.Methods:From June 2020 to December 2021, the patients were enrolled and undergone rhinoplasty with bilateral lower lateral cartilage margin incision combined with nasal columnar incision in the Department of Plastic & Reconstructive Surgery of Zhejiang Provincial People’s Hospital. During the operation, the sixth costal cartilage was made into the nasal columella support graft(strut) and the nasal tip graft integrated scaffold, and the septal extension grafts (SEG). The strut and SEG were sutured in the same plane to construct the framework to correct the aesthetic defects of the nose. Abode Photoshop CS 6.0 was used to measure a series of aesthetics index before and 6 months after surgery, including nasofrontal angle, nasorostral angle, nasolabial angle, columella lobular angle, ratio of tip projection to the length of the nose and ratio of the length of the infratip lobule to the length of the nasal columella to evaluate the surgical effect. Visual analogue scale (VAS) and rhinoplasty outcome evaluation (ROE) were used to investigate the patients’ satisfaction. Paired t-test was used for data analysis and P<0.05 was considered statistically significant. Results:A total of 53 patients were enrolled, including 4 males and 49 females, aged from 18 to 45 years (average age: 25.6 years). Forty-nine cases were primary rhinoplasty and 4 cases were secondary rhinoplasty. No short-term complications including hemorrhage and infection occurred in 53 patients. All patients were followed up for 6-12 months. There were statistically significant differences in nasofrontal angle, nasorostral angle, nasolabial angle, columella lobular angle, ratio of tip projection to the length of the nose and ratio of the length of the infratip lobule to the length of the nasal columella( P<0.01), which sugguested that aesthetic defects of the nose were corrected and no obvious deflection and rotation of nasal tip occured. VAS score and ROE score postoperatively were 7.6±0.4 and 21.3±2.1, respectively, which were significantly higher than preoperatively( 6.1±0.5, 10.5±1.6)( P< 0.01). Postoperative satisfaction survey showed that swelling disappeared within 4-6 weeks after surgery, and no obvious ventilatory disorder, paresthesia and hyposmia symptoms occurred. Most patients were satisfied with the aesthetic and functional results. Conclusions:The "mutual support" framework in costal cartilage rhinoplasty can reduce the risk of framework deflection and nasal tip rotation and obtain satisfactory nasal columella shape.