Explore the vast range of titles available.

Idiopathic pulmonary fibrosis (IPF) is a prevalent interstitial lung disease with high mortality. CD38 is a main enzyme for intracellular nicotinamide adenine dinucleotide (NAD + ) degradation in mammals. It has been reported that CD38 participated in pulmonary fibrosis through promoting alveolar epithelial cells senescence. However, the roles of endothelial CD38 in pulmonary fibrosis remain unknown. In the present study, we observed that the elevated expression of CD38 was related to endothelial-to-mesenchymal transition (EndMT) of lung tissues in IPF patients and bleomycin (BLM)-induced pulmonary fibrosis mice and also in human umbilical vein endothelial cells (HUVECs) treated with BLM. Micro-computed tomography (MCT) and histopathological staining showed that endothelial cell-specific CD38 knockout (CD38 EndKO ) remarkably attenuated BLM-induced pulmonary fibrosis. In addition, CD38 EndKO significantly inhibited TGFβ-Smad3 pathway-mediated excessive extracellular matrix (ECM), reduced Toll-like receptor4-Myeloid differentiation factor88-Mitogen-activated protein kinases (TLR4-MyD88-MAPK) pathway-mediated endothelial inflammation and suppressed nicotinamide adenine dinucleotide phosphate oxidases1 (NOX1)-mediated oxidative stress. Furthermore, we demonstrated that 3-TYP, a SIRT3-specific inhibitor, markedly reversed the protective effect of HUVECs CD38KD cells and 78 C, a CD38-specific inhibitor, on BLM-induced EndMT in HUVECs. Therefore, we concluded that CD38 EndKO significantly ameliorated BLM-induced pulmonary fibrosis through inhibiting ECM, endothelial inflammation and oxidative stress, further alleviating EndMT in mice. Our findings suggest that endothelial CD38 may be a new therapeutic target for the prevention and treatment of pulmonary fibrosis clinically. Graphical Abstract Protective role and the underlying mechanism of endothelial CD38 in bleomycin-induced pulmonary fibrosis in mice. Endothelial cells-specific CD38 knockout (CD38 EndKO ) inhibited TGFβ-Smad3-mediated ECM, ROS-mediated oxidative stress and TLR4-mediated inflammation, and in turn, suppressed endothelial-to-mesenchymal transition (EndMT), eventually, alleviated pulmonary fibrosis induced by bleomycin in mice, suggesting endothelial CD38 may be a therapeutic target for the prevention and the treatment of pulmonary fibrosis clinically

Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne infectious disease caused by a novel phlebovirus (SFTS virus, SFTSV), was listed among the top 10 priority infectious diseases by the World Health Organization due to its high fatality of 12%–50% and possibility of pandemic transmission. Currently, effective anti-SFTSV intervention remains unavailable. Here, by screening a library of FDA-approved drugs, we found that benidipine hydrochloride, a calcium channel blocker (CCB), inhibited SFTSV replication in vitro. Benidipine hydrochloride was revealed to inhibit virus infection through impairing virus internalization and genome replication. Further experiments showed that a broad panel of CCBs, including nifedipine, inhibited SFTSV infection. The anti-SFTSV effect of these two CCBs was further analyzed in a humanized mouse model in which CCB treatment resulted in reduced viral load and decreased fatality rate. Importantly, by performing a retrospective clinical investigation on a large cohort of 2087 SFTS patients, we revealed that nifedipine administration enhanced virus clearance, improved clinical recovery, and remarkably reduced the case fatality rate by >5-fold. These findings are highly valuable for developing potential host-oriented therapeutics for SFTS and other lethal acute viral infections known to be inhibited by CCBs in vitro.

Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide. Although the role of tumor programmed cell death 1 ligand 1 (PD-L1) in suppressing antitumor immunity has been validated in various malignances, the impact of PD-L2 (PD-L2/PDCD1LG2) within tumors remains elusive. Here, we examined tumor PD-L2 expression by immunohistochemical analysis and assessed its association with clinicopathological characteristics and the infiltration of intratumoral T lymphocytes in colon carcinoma patients (n = 1264). We found that tumor PD-L2 status was correlated with perineural invasion (PNI) and associated with survival outcome in colon carcinoma patients. The level of tumor PD-L2 was positively associated with tumor PD-L1 expression but inversely associated with the density of CD8 + tumor-infiltrating lymphocytes (TILs). Patients with elevated tumor PD-L2 levels had a favorable 5-year overall survival (OS) compared to patients with low PD-L2 levels (57% vs 40%, p  < 0.001), especially in advanced stage colon carcinoma patients. Low tumor PD-L2 expression was associated with an increased 5-year OS risk among advanced stage colon carcinoma patients by univariate analysis [hazard ratio (HR) = 1.69, 95% CI 1.324–2.161, p  < 0.001] and multivariate analysis [HR = 1.594, 95% CI 1.206–2.106, p  = 0.001]. Moreover, tumor PD-L2 expression was inversely associated with the lymphocytic reaction in advanced stage colon carcinoma, suggesting that PD-L2 may be upregulated by a compensatory mechanism to inhibit T cell-mediated anticancer immunity. Taken together, these results show that tumor PD-L2 expression may be an independent prognostic factor for survival outcome in patients with advanced stage colon carcinoma.

Programmed cell death-1 (PDCD1/PD-1) and its ligand programmed cell death 1 ligand 1 (CD274/PD-L1) have been reported to suppress anti-tumor T cell-mediated immune responses. However, the clinical significance of CD274 in colorectal cancer were still elusive. We aim to clarify the relationships between CD8+ intratumor-infiltrating lymphocytes (TILs) and CD274 as well as their prognostic values in stage II-III colon carcinoma. Tumor differentiation, perineural invasion (PNI), pN stage and DNA mismatch repair (MMR)-deficient were clearly correlated with CD8+ TILs counts within the tumor microenvironment ( p  < 0.0001). Furthermore, tumor differentiation and PNI were suggestively correlated with tumor CD274 expression ( p  = 0.02 and p  = 0.0195). Tumor CD274 level was significantly correlated with higher CD8+ TILs ( p  < 0.0001) but was not associated with MMR-deficient status ( p  = 0.14). High tumor CD274 expression [hazard ratio (HR) = 2.16, 95% CI = 1.63–2.86, p  < 0.0001] and CD8+ TILs [HR = 1.51, 95% CI = 1.19–1.91, p  = 0.0007] were associated with improved disease-free survival and overall survival. Additionally, the subgroup of patients who had a high CD8+ TILs/tumor CD274 have better survival outcomes compared with other subgroups (71% vs 53%; p  < 0.0001). Therefore, the CD8+ TILs counts and tumor CD274 may be prognostic factors to predict survival and therapeutic responses in stage II–III colon carcinoma patients.

Purpose/backgroundRadiotherapy has been recently reported to boost the therapeutic response of immune checkpoint blockade (ICB); however, few studies have focused on programmed cell death-ligand 1 (PD-L1) expression in locally advanced rectal cancer (LARC) patients who receive preoperative neoadjuvant chemoradiotherapy (neoCRT). The aim of the present study was to investigate the PD-L1 expression status and CD8+ intra-tumoral infiltrating lymphocytes (TILs) before and after neoCRT and its association with clinicopathological characteristics in rectal cancer.Materials and methodsImmunostainings of PD-L1 and CD8+ TILs were performed in 112 pair-matched LARC patients treated by neoCRT. Tumor PD-L1 expression and CD8+ TILs within the tumor microenvironment before and after neoCRT were evaluated via immunohistochemistry.ResultsHigh tumor PD-L1 expression was significantly increased from 50 to 63%, and high CD8+ TILs counts were also slightly increased from 32 to 35% after neoCRT treatment. High tumor PD-L1 before and after neoCRT was associated with improved disease-free survival (DFS, pre-neoCRT: p = 0.003 and post-neoCRT: p = 0.003) and overall survival (OS, pre-neoCRT: p = 0.045 and post-neoCRT: p = 0.0001). High CD8+ TILs before neoCRT was associated with improved DFS (p = 0.057), and it was significantly associated with improved DFS after neoCRT (p = 0.039). Patients with high tumor PD-L1 and CD8+ TILs before and after neoCRT were significantly associated with improved DFS (pre-neoCRT: p = 0.004 and post-neoCRT: p = 0.006).ConclusionThe present results provide evidence that tumor PD-L1 expression and recruitment of CD8+ TILs within the tumor microenvironment were increased by neoCRT treatment. Tumor PD-L1 and CD8+ TILs are prognostic biomarkers for the survival of LARC patients treated with neoCRT.

SARS-CoV-2 induced marked lymphopenia in severe patients with COVID-19. However, whether lymphocytes are targets of viral infection is yet to be determined, although SARS-CoV-2 RNA or antigen has been identified in T cells from patients. Here, we confirmed that SARS-CoV-2 viral antigen could be detected in patient peripheral blood cells (PBCs) or postmortem lung T cells, and the infectious virus could also be detected from viral antigen-positive PBCs. We next prove that SARS-CoV-2 infects T lymphocytes, preferably activated CD4 + T cells in vitro. Upon infection, viral RNA, subgenomic RNA, viral protein or viral particle can be detected in the T cells. Furthermore, we show that the infection is spike-ACE2/TMPRSS2-independent through using ACE2 knockdown or receptor blocking experiments. Next, we demonstrate that viral antigen-positive T cells from patient undergone pronounced apoptosis. In vitro infection of T cells induced cell death that is likely in mitochondria ROS-HIF-1a-dependent pathways. Finally, we demonstrated that LFA-1, the protein exclusively expresses in multiple leukocytes, is more likely the entry molecule that mediated SARS-CoV-2 infection in T cells, compared to a list of other known receptors. Collectively, this work confirmed a SARS-CoV-2 infection of T cells, in a spike-ACE2-independent manner, which shed novel insights into the underlying mechanisms of SARS-CoV-2-induced lymphopenia in COVID-19 patients.

ATP and its receptor P2RX7 exert a pivotal effect on antitumor immunity during chemotherapy-induced immunogenic cell death (ICD). Here, we demonstrated that TNFα-mediated PANX1 cleavage was essential for ATP release in response to chemotherapy in colorectal cancer (CRC). TNFα promoted PANX1 cleavage via a caspase 8/3-dependent pathway to enhance cancer cell immunogenicity, leading to dendritic cell maturation and T-cell activation. Blockade of the ATP receptor P2RX7 by the systemic administration of small molecules significantly attenuated the therapeutic efficacy of chemotherapy and decreased the infiltration of immune cells. In contrast, administration of an ATP mimic markedly increased the therapeutic efficacy of chemotherapy and enhanced the infiltration of immune cells in vivo. High PANX1 expression was positively correlated with the recruitment of DCs and T cells within the tumor microenvironment and was associated with favorable survival outcomes in CRC patients who received adjuvant chemotherapy. Furthermore, a loss-of-function P2RX7 mutation was associated with reduced infiltration of CD8 + immune cells and poor survival outcomes in patients. Taken together, these results reveal that TNFα-mediated PANX1 cleavage promotes ATP-P2RX7 signaling and is a key determinant of chemotherapy-induced antitumor immunity.

Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1 Ser616 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1 Ser616 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.

Background: Cerebral small vessel disease (CSVD) is a group of clinical syndromes covering all pathological processes of small vessels in the brain, which can cause stroke and serious dementia. However, as the pathogenesis of CSVD is not clear, so the treatment is limited. Endothelial cell dysfunction is earlier than clinical symptoms, such as hypertension and leukosis. Therefore, the treatment of endothelial cells is expected to be a new breakthrough. Quercetin, a flavonoid present in a variety of plants, has the function of anti-inflammation and anti-oxidation. This study aimed to investigate the protective effect of quercetin on endothelial cell injury and provide a basic theory for subsequent application in the clinic. Methods: Human brain microvascular endothelial cells (HBMECs) were cultured in vitro , and the injury model of endothelial cells was established by hypoxia and reoxygenation (H/R). The protective effects of quercetin on HBMECs were studied from the perspectives of cell viability, cell migration, angiogenesis and apoptosis. In order to further study the mechanism of quercetin, oxidative stress and endoplasmic reticulum stress were analyzed. What’s more, blood-brain barrier (BBB) integrity was also studied. Results: Quercetin can promote the viability, migration and angiogenesis of HBMECs, and inhibit the apoptosis. In addition, quercetin can also activate Keap1/Nrf2 signaling pathway, reduce ATF6/GRP78 protein expression. Further study showed that quercetin could increase the expression of Claudin-5 and Zonula occludens-1. Conclusions: Our experiments show that quercetin can protect HBMECs from H/R, which contains promoting cell proliferation, cell migration and angiogenesis, reducing mitochondrial membrane potential damage and inhibiting cell apoptosis. This may be related to its antioxidation and inhibition of endoplasmic reticulum stress. At the same time, quercetin can increase the level of BBB connexin, suggesting that quercetin can maintain BBB integrity.

Transposable elements (TEs) and satellite DNAs, two major categories of repetitive sequences, are expected to accumulate in non-recombining genome regions, including sex-linked regions, and contribute to sex chromosome evolution. The dioecious plant, Humulus scandens , can be used for studying the evolution of the XX/XY 1 Y 2 sex chromosomes. In this study, we thoroughly examined the repetitive components of male and female H. scandens using next-generation sequencing data followed by bioinformatics analysis and florescence in situ hybridization (FISH). The H. scandens genome has a high overall repetitive sequence composition, 68.30% in the female and 66.78% in the male genome, with abundant long terminal repeat (LTR) retrotransposons (RTs), including more Ty3/ Gypsy than Ty1/ Copia elements, particularly two Ty3/ Gypsy lineages, Tekay and Retand. Most LTR-RT lineages were found dispersed across the chromosomes, though CRM and Athila elements were predominately found within the centromeres and the pericentromeric regions. The Athila elements also showed clearly higher FISH signal intensities in the Y 1 and Y 2 chromosomes than in the X or autosomes. Three novel satellite DNAs were specifically distributed in the centromeric and/or telomeric regions, with markedly different distributions on the X, Y 1 , and Y 2 chromosomes. Combined with FISH using satellite DNAs to stain chromosomes during meiotic diakinesis, we determined the synapsis pattern and distinguish pseudoautosomal regions (PARs). The results indicate that the XY 1 Y 2 sex chromosomes of H. scandens might have originated from a centric fission event. This study improves our understanding of the repetitive sequence organization of H. scandens genome and provides a basis for further analysis of their chromosome evolution process.