Myocardial fibrosis is a serious cause of heart failure and even sudden cardiac death. However, the mechanisms underlying myocardial ischemia-induced cardiac fibrosis remain unclear. Here, we identified that the expression of sterile alpha and TIR motif containing 1 (SARM1), was increased significantly in the ischemic cardiomyopathy patients, dilated cardiomyopathy patients (GSE116250) and fibrotic heart tissues of mice. Additionally, inhibition or knockdown of SARM1 can improve myocardial fibrosis and cardiac function of myocardial infarction (MI) mice. Moreover, SARM1 fibroblasts-specific knock-in mice had increased deposition of extracellular matrix and impaired cardiac function. Mechanically, elevated expression of SARM1 promotes the deposition of extracellular matrix by directly modulating P4HA1. Notably, by using the Click-iT reaction, we identified that the increased expression of ZDHHC17 promotes the palmitoylation levels of SARM1, thereby accelerating the fibrosis process. Based on the fibrosis-promoting effect of SARM1, we screened several drugs with anti-myocardial fibrosis activity. In conclusion, we have unveiled that palmitoylated SARM1 targeting P4HA1 promotes collagen deposition and myocardial fibrosis. Inhibition of SARM1 is a potential strategy for the treatment of myocardial fibrosis. The sites where SARM1 interacts with P4HA1 and the palmitoylation modification sites of SARM1 may be the active targets for anti-fibrosis drugs.

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

OBJECTIVE: To determine the role of Tripterygium wilfordii multiglycoside (TGW) in the treatment of psoriatic dermatitis from a cellular immunological perspective. METHODS: Mouse models of psoriatic dermatitis were established by imiquimod (IMQ). Twelve male BALB/c mice were assigned to IMQ or IMQ₊TGW groups according to a random number table. Histopathological changes in vivo were assessed by hematoxylin and eosin staining. Ratios of immune cells and cytokines in mice, as well as PAM212 cell proliferation in vitro were assessed by flow cytometry. Pro-inflammatory cytokine expression was determined using reverse transcription quantitative polymerase chain reaction. RESULTS: TGW significantly ameliorated the severity of IMQ-induced psoriasis-like mouse skin lesions and restrained the activation of CD45⁺ cells, neutrophils and T lymphocytes (all P<0.01). Moreover, TGW significantly attenuated keratinocytes (KCs) proliferation and downregulated the mRNA levels of inflammatory cytokines including interleukin (IL)-17A, IL-23, tumor necrosis factor α, and chemokine (C-X-C motif) ligand 1 (P<0.01 or P<0.05). Furthermore, it reduced the number of γ δ T17 cells in skin lesion of mice and draining lymph nodes (P<0.01). CONCLUSIONS TGW improved psoriasis-like inflammation by inhibiting KCs proliferation, as well as the associated immune cells and cytokine expression. It inhibited IL-17 secretion from γ δ T cells, which improved the immune-inflammatory microenvironment of psoriasis.
Male ; Animals ; Mice ; Tripterygium ; Psoriasis/drug therapy* ; Keratinocytes ; Skin Diseases/metabolism* ; Cytokines/metabolism* ; Imiquimod/metabolism* ; Dermatitis/pathology* ; Disease Models, Animal ; Mice, Inbred BALB C ; Skin/metabolism*

Pyroptosis is the programmed death of cells accompanied by an inflammatory response and is widely involved in the development of a variety of diseases, such as infectious diseases, cardiovascular diseases, and neurodegeneration. It has been shown that cellular scorching is involved in the pathogenesis of pulmonary arterial hypertension ( PAH) in cardiovascular diseases. Patients with PAH have perivascular inflammatory infiltrates in lungs, pulmonary vasculopathy exists in an extremely inflam-matory microenvironment, and pro-inflammatory factors in cellular scorching drive pulmonary vascular remodelling in PAH patients. This article reviews the role of cellular scorch in the pathogenesis of PAH and the related research on drugs for the treatment of PAH, with the aim of providing new ideas for clinical treatment of PAH.

Objective To explore the role of mitochondrial autophagy in ovarian inflammation associated with poly-cystic ovary syndrome(PCOS)based on the NOD-like receptor thermoprotein domain-related protein 3(NLRP3)pathway.Methods Human ovarian granulosa cell line SVOG was treated with 25 nmol/L dihydrotestosterone(DHT)for 24 h to establish PCOS cell model.SVOG cells were transfected with adenovirus carrying NLRP3(Ad-NLRP3)and negative vector(Ad-EV)or NLRP3 shRNA(sh-NLRP3)and negative control(sh-NC)to overex-press or knockdown NLRP3.Mito-Tracker staining and GFP-LC3 staining were used to evaluate mitochondrial auto-phagy in cells.TUNEL staining,JC-1 staining and Mito-SOX staining were used to analyze the apoptosis,mito-chondrial membrane potential and mitochondrial-derived superoxide production.32 female BALB/c mice were ran-domly divided into three groups:control(Con)group,DHEA group,DHEA+sh-NC group and DHEA+sh-NL-RP3 group,with 8 mice in each group.Except the control group,all other groups treated mice with dehydroepi-androsterone(DHEA)to establish PCOS mouse model.DHEA+sh-NLRP3 group and DHEA+sh-NC group were administrated with sh-NLRP3 or sh-NC encapsulated in lentivirus at a concentration of 1 x 109 TU/ml via tail vein injection.The ultrastructure of mitochondria in ovarian tissue of mice in each group was observed by transmission e-lectron microscope.Results Compared with DHT+sh-NC group,the level of NLRP3 of SVOG cells in DHT+sh-NLRP3 group decreased(P＜0.05).The co-location of GFP-LC3 and mitochondria in SVOG cells in DHT+sh-NLRP3 group was higher than that in DHT+sh-NC group(P＜0.05).Compared with DHT+sh-NC group,the number of TUNEL positive cells and Mito-SOX fluorescence density of SVOG cells in DHT+sh-NLRP3 group de-creased,and the ratio of polymer JC-1 to monomer JC-1 increased(P＜0.05).Compared with Con+Ad-EV group,the level of NLRP3,the number of TUNEL-positive cells and the fluorescence density of mito-SVOG in Con+Ad-NLRP3 group increased(P＜0.05),and the co-location level of GFP-LC3 and mitochondria decreased;the ratio of polymer JC-1 to monomer JC-1 decreased(P＜0.05).Compared with the control group,TUNEL positive cells,relative ROS intensity and percentage of damaged mitochondria in the ovarian tissue of mice in DHEA group increased(P＜0.05).Compared with DHEA+sh-NC group,TUNEL positive cells,relative ROS intensity and percentage of damaged mitochondria in DHEA+SH-NLRP group decreased(P＜0.05).Conclusion Inhibition of mitochondrial autophagy induced by activation of NLRP3 leads to mitochondrial dysfunction and promotes mito-chondrial-related apoptosis in GCs.Knockdown of NLRP3 is beneficial to mitochondrial homeostasis and improves the resistance of GCs to oxidative stress injury,thus promoting the recovery of PCOS.

Objective To investigate the correlation between the imaging manifestations and pathological classification of congeni-tal cystic adenomatoid malformation of the lung(CCAM).Methods A retrospective analysis was conducted on the clinical and radiologic data of nine patients with pathologically confirmed CCAM,and all data were compared with Stocker pathological classification,respec-tively.Results The CT images of all nine patients demonstrated cysts filled with either gas or fluid,which corresponded exactly with their gross pathological outcomes.Four cases of large cystic CCAM(cyst diameter exceeding 2 cm)were consistent with Stocker type Ⅰ.CT findings showed single or multiple capsular cavities occupying the thoracic cavity,with gas or fluid mainly in the cyst.Two cases exhibited mass effect and expansion of the involved lung lobes,while two cases showed localized decreased density around the lesion.The pathological features of these large cystic CCAM included single or multiple thick-walled cysts,with pseudostratified ciliated colum-nar epithelium lining the cyst lumen observed under microscopy.The other five cases of small cystic CCAM(cyst diameter less than 2 cm)matched Stocker type Ⅱ.CT findings showed multiple thin-walled cellular cysts confined to a single lung lobe,and none of these patients had significant mass effect or expansion of the involved lung lobes.Pathologically,these cases were characterized by multiple small cysts with septa,and the cysts were primarily lined with ciliated columnar or cuboidal epithelium upon microscopy.Conclusion CT imaging of CCAM has specific manifestations,with accurately displaying the distribution range and morphological characteristics of the lesions and reflecting the internal histological characteristics.There is a significant correlation between the CT manifestations of CCAM and their pathological classification.

Objective This study aimed to evaluate whether the onset of the plateau phase of slow hepatitis B surface antigen decline in patients with chronic hepatitis B treated with intermittent interferon therapy is related to the frequency of dendritic cell subsets and expression of the costimulatory molecules CD40,CD80,CD83,and CD86. Method This was a cross-sectional study in which patients were divided into a natural history group(namely NH group),a long-term oral nucleoside analogs treatment group(namely NA group),and a plateau-arriving group(namely P group).The percentage of plasmacytoid dendritic cell and myeloid dendritic cell subsets in peripheral blood lymphocytes and monocytes and the mean fluorescence intensity of their surface costimulatory molecules were detected using a flow cytometer. Results In total,143 patients were enrolled(NH group,n = 49;NA group,n = 47;P group,n = 47).The results demonstrated that CD141/CD1c double negative myeloid dendritic cell(DNmDC)/lymphocytes and monocytes(%)in P group(0.041[0.024,0.069])was significantly lower than that in NH group(0.270[0.135,0.407])and NA group(0.273[0.150,0.443]),and CD86 mean fluorescence intensity of DNmDCs in P group(1832.0[1484.0,2793.0])was significantly lower than that in NH group(4316.0[2958.0,5169.0])and NA group(3299.0[2534.0,4371.0]),Adjusted P all<0.001. Conclusion Reduced DNmDCs and impaired maturation may be associated with the onset of the plateau phase during intermittent interferon therapy in patients with chronic hepatitis B.

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators. Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),anti-infective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed. Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group. Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-α and IL-6 may partake the inflammatory process of DILI.