Pyrroloquinoline Quinone Alleviates Mitochondria Damage in Radiation-Induced Lung Injury in a MOTS-c-Dependent Manner.

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy and accidental radiation exposure. Pyrroloquinoline quinone (PQQ), a novel vitamin B, plays a crucial role in delaying aging, antioxidation, anti-inflammation, and antiapoptosis. This study aims to investigate the protective effect and mechanisms of PQQ against RILI. C57BL/6 mice were exposed to a 20 Gy dose of X-ray radiation on the entire thorax with or without daily oral administration of PQQ for 2 weeks. PQQ effectively mitigated radiation-induced lung tissue damage, inflammation, oxidative stress, and epithelial cell apoptosis. Additionally, PQQ significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells. Mechanistically, PQQ upregulated the mRNA and protein levels of MOTS-c in irradiated lung tissue and MLE-12 cells. Knockdown of MOTS-c by siRNA substantially attenuated the protective effects of PQQ on oxidative stress, inflammation, and apoptosis. In conclusion, PQQ alleviates RILI by preserving mitochondrial function through a MOTS-c-dependent mechanism, suggesting that PQQ may serve as a promising nutraceutical intervention against RILI.

Deletion of BTB and CNC homology 1 protects against Staphylococcus aureus-induced acute lung injury.

BTB and CNC homology 1 (BACH1) plays a crucial role in the pathogenesis of acute lung injury (ALI) caused by gram-negative bacteria. However, its exact mechanisms and roles in Staphylococcus aureus (SA)-induced ALI, a gram-positive bacterial infection, remain incompletely understood. In this study, we generated a BACH1-knockout mouse model (BACH1-/-) to investigate the role of BACH1 and its underlying mechanisms in regulating the development of sepsis-induced acute lung injury (ALI). Elevated levels of BACH1 were observed in both serum samples from septic patients and mouse models. Deletion of BACH1 alleviated ALI symptoms induced by sepsis. In bone marrow-derived macrophages, BACH1 deletion or knockdown suppressed NF-κB p65 phosphorylation and the induction of pro-inflammatory cytokines. Mechanistic studies demonstrated that BACH1 downregulated tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) mRNA expression by binding to its promoter region. These findings uncover inhibiting BACH1 may be a promising therapeutic strategy for treating gram-positive bacteria-induced ALI.

MiR-196a-5p hinders vascular smooth muscle cell proliferation and vascular remodeling via repressing BACH1 expression.

Hyperproliferation of vascular smooth muscle cells (VSMCs) is a driver of hypertensive vascular remodeling. This study aimed to uncover the mechanism of BTB and CNC homology 1 (BACH1) and microRNAs (miRNAs) in VSMC growth and hypertensive vascular remodeling. With the help of TargetScan, miRWalk, miRDB, and miRTarBase online database, we identified that BACH1 might be targeted by miR-196a-5p, and overexpressed in VSMCs and aortic tissues from spontaneously hypertensive rats (SHRs). Gain- and loss-of-function experiments demonstrated that miR-196a-5p suppressed VSMC proliferation, oxidative stress and hypertensive vascular remodeling. Double luciferase reporter gene assay and functional verification showed that miR-196a-5p cracked down the transcription and translation of BACH1 in both Wistar Kyoto rats (WKYs) and SHRs. Silencing BACH1 mimicked the actions of miR-196a-5p overexpression on attenuating the proliferation and oxidative damage of VSMCs derived from SHRs. Importantly, miR-196a-5p overexpression and BACH1 knockdown cooperatively inhibited VSMC proliferation and oxidative stress in SHRs. Furthermore, miR-196a-5p, if knocked down in SHRs, aggravated hypertension, upregulated BACH1 and promoted VSMC proliferation, all contributing to vascular remodeling. Taken together, targeting miR-196a-5p to downregulate BACH1 may be a promising strategy for retarding VSMC proliferation and hypertensive vascular remodeling.

Sophoricoside ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury by inhibiting Bach1/Akt pathway.

BACKGROUND: The lack of effective treatments for methicillin-resistant Staphylococcus aureus (MRSA) infection, which often leads to severe acute lung injury (ALI), poses a grave threat to human life. Sophoricoside (SOP), an isoflavone glycoside abundant in the fruit of traditional Chinese herbal Sophora japonica l., showed anti-inflammatory effects against atopic dermatitis, allergic inflammation, and lipopolysaccharide-induced ALI. However, its effect and underlying mechanism on MRSA-induced ALI remain unclear. PURPOSE: The aim of this study is to assess the protective effect of SOP in MRSA-induced ALI and elucidate its underlying molecular mechanisms. METHODS: In vivo experiments were conducted using wild-type mice to establish MRSA-induced ALI mouse model, and the effects of SOP on ALI were evaluated by hematoxylin-eosin staining, flow cytometry, quantitative real-time polymerase chain reaction, and several biochemical indicators. Adoptive transfer experiments and BTB and CNC homology 1 knockout (Bach1-/-) mice were also utilized in this study. In vitro studies employed murine macrophages RAW264.7 cells, primary bone marrow-derived macrophages (BMDMs), and primary lung macrophages to explore the underlying molecular mechanisms. RESULTS: The administration of SOP ameliorated MRSA-induced ALI by improving pulmonary histological damages, reducing neutrophil infiltration, suppressing oxidative stress levels, and decreasing the expression of inflammatory cytokines. In isolation experiments with ALI mouse lung macrophages and macrophage adoptive transfer experiments, SOP prevented macrophage activation, thereby reducing the production of proinflammatory cytokines. In vitro experiments demonstrated that SOP decreased the expression of inflammatory mediators in lipoteichoic acid (LTA)-stimulated RAW264.7 cells, BMDMs, and primary lung macrophages. Additionally, SOP inhibited protein kinase B (Akt) phosphorylation and treatment with MK2206-a specific inhibitor of Akt-eliminated SOP's ability to suppress LTA-stimulated macrophage inflammation. Furthermore, stimulation with LTA or MRSA up-regulated Bach1 expression; however, deletion of Bach1 abolished the inhibitory effect of SOP on p-Akt activation as well as inflammation and ALI development. CONCLUSION: This study provides the first evidence that SOP effectively mitigates MRSA-induced ALI via suppressing macrophage activation through the inhibition of Bach1/Akt pathway. These findings highlight the potential of SOP as a novel therapeutic agent for treating MRSA-induced ALI.

Nrf2 deficiency exacerbated pulmonary pyroptosis in maternal hypoxia-induced intrauterine growth restriction offspring mice.

Maternal prenatal hypoxia is an important contributor to intrauterine growth restriction (IUGR), which impedes fetal lung maturation and leads to the development of chronic lung diseases. Although evidence suggests the involvement of pyroptosis in IUGR, the molecular mechanism of pyroptosis is still unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been found to potentially interact with gasdermin D (GSDMD), the key protein responsible for pyroptosis, indicating its crucial role in inhibiting pyroptosis. Therefore, we hypothesized that Nrf2 deficiency is a key molecular responsible for lung pyroptosis in maternal hypoxia-induced IUGR offspring mice. Pregnant WT and Nrf2-/- mice were exposed to hypoxia (10.5 % O2) to mimic IUGR model. We assessed body weight, lung histopathology, pulmonary angiogenesis, oxidative stress levels, as well as mRNA and protein expressions related to inflammation in the 2-week-old offspring. Additionally, we conducted a dual-luciferase reporter assay to confirm the targeting relationship between Nrf2 and GSDMD. Our findings revealed that offspring with maternal hypoxia-induced IUGR exhibited reduced birth weight, catch-up growth delay, and pulmonary dysplasia. Furthermore, we observed impaired nuclear translocation of Nrf2 and increased GSDMD-mediated pyroptosis in these offspring with IUGR. Moreover, the dual-luciferase reporter assay demonstrated that Nrf2 could directly inhibit GSDMD transcription; deficiency of Nrf2 exacerbated pyroptosis and pulmonary dysplasia in offspring with maternal hypoxia-induced IUGR. Collectively, our findings suggest that Nrf2 deficiency induces GSDMD-mediated pyroptosis and pulmonary dysplasia in offspring with maternal hypoxia-induced IUGR; thus highlighting the potential therapeutic approach of targeting Nrf2 for treating prenatal hypoxia-induced pulmonary dysplasia in offspring.

The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism.

Radiation pneumonitis (RP) is a prevalent and fatal complication of thoracic radiotherapy due to the lack of effective treatment options. RP primarily arises from mitochondrial injury in lung epithelial cells. The mitochondrial-derived peptide MOTS-c has demonstrated protective effects against various diseases by mitigating mitochondrial injury. C57BL/6 mice were exposed to 20 Gy of lung irradiation (IR) and received daily intraperitoneal injections of MOTS-c for 2 weeks. MOTS-c significantly ameliorated lung tissue damage, inflammation, and oxidative stress caused by radiation. Meanwhile, MOTS-c reversed the apoptosis and mitochondrial damage of alveolar epithelial cells in RP mice. Furthermore, MOTS-c significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells and primary mouse lung epithelial cells. Mechanistically, MOTS-c increased the nuclear factor erythroid 2-related factor (Nrf2) level and promoted its nuclear translocation. Notably, Nrf2 deficiency abolished the protective function of MOTS-c in mice with RP. In conclusion, MOTS-c alleviates RP by protecting mitochondrial function through an Nrf2-dependent mechanism, indicating that MOTS-c may be a novel potential protective agent against RP.

BCL6 attenuates hyperoxia-induced lung injury by inhibiting NLRP3-mediated inflammation in fetal mouse.

BACKGROUND: The transcriptional repressor B-cell lymphoma 6 (BCL6) has been reported to inhibit inflammation. So far, experimental evidence for the role of BCL6 in bronchopulmonary dysplasia (BPD) is lacking. Our study investigated the roles of BCL6 in the progression of BPD and its downstream mechanisms. METHODS: Hyperoxia or lipopolysaccharide (LPS) was used to mimic the BPD mouse model. To investigate the effects of BCL6 on BPD, recombination adeno-associated virus serotype 9 expressing BCL6 (rAAV9-BCL6) and BCL6 inhibitor FX1 were administered in mice. The pulmonary pathological changes, inflammatory chemokines and NLRP3-related protein were observed. Meanwhile, BCL6 overexpression plasmid was used in human pulmonary microvascular endothelial cells (HPMECs). Cell proliferation, apoptosis, and NLRP3-related protein were detected. RESULTS: Either hyperoxia or LPS suppressed pulmonary BCL6 mRNA expression. rAAV9-BCL6 administration significantly inhibited hyperoxia-induced NLRP3 upregulation and inflammation, attenuated alveolar simplification and dysregulated angiogenesis in BPD mice, which were characterized by decreased mean linear intercept, increased radical alveolar count and alveoli numbers, and the upregulated CD31 expression. Meanwhile, BCL6 overexpression promoted proliferation and angiogenesis, inhibited apoptosis and inflammation in hyperoxia-stimulated HPMECs. Moreover, administration of BCL6 inhibitor FX1 arrested growth and development. FX1-treated BPD mice exhibited exacerbation of alveolar pathological changes and pulmonary vessel permeability, with upregulated mRNA levels of pro-inflammatory cytokines and pro-fibrogenic factors. Furthermore, both rAAV9-BCL6 and FX1 administration exerted a long-lasting effect on hyperoxia-induced lung injury (≥4 wk). CONCLUSIONS: BCL6 inhibits NLRP3-mediated inflammation, attenuates alveolar simplification and dysregulated pulmonary vessel development in hyperoxia-induced BPD mice. Hence, BCL6 may be a target in treating BPD and neonatal diseases.

A novel model for predicting prognosis and response to immunotherapy in nasopharyngeal carcinoma patients.

Blood-based biomarkers of immune checkpoint inhibitors (ICIs) response in patients with nasopharyngeal carcinoma (NPC) are lacking, so it is necessary to identify biomarkers to select NPC patients who will benefit most or least from ICIs. The absolute values of lymphocyte subpopulations, biochemical indexes, and blood routine tests were determined before ICIs-based treatments in the training cohort (n = 130). Then, the least absolute shrinkage and selection operator (Lasso) Cox regression analysis was developed to construct a prediction model. The performances of the prediction model were compared to TNM stage, treatment, and Epstein-Barr virus (EBV) DNA using the concordance index (C-index). Progression-free survival (PFS) was estimated by Kaplan-Meier (K-M) survival curve. Other 63 patients were used for validation cohort. The novel model composed of histologic subtypes, CD19+ B cells, natural killer (NK) cells, regulatory T cells, red blood cells (RBC), AST/ALT ratio (SLR), apolipoprotein B (Apo B), and lactic dehydrogenase (LDH). The C-index of this model was 0.784 in the training cohort and 0.735 in the validation cohort. K-M survival curve showed patients with high-risk scores had shorter PFS compared to the low-risk groups. For predicting immune therapy responses, the receiver operating characteristic (ROC), decision curve analysis (DCA), net reclassifcation improvement index (NRI) and integrated discrimination improvement index (IDI) of this model showed better predictive ability compared to EBV DNA. In this study, we constructed a novel model for prognostic prediction and immunotherapeutic response prediction in NPC patients, which may provide clinical assistance in selecting those patients who are likely to gain long-lasting clinical benefits to anti-PD-1 therapy.

Association of pre-/early pregnancy high blood pressure and pregnancy outcomes: a systemic review and meta-analysis.

BACKGROUND: Maternal high blood pressure (BP) was associated with adverse pregnancy outcomes. This study aimed to synthesize evidence on the association between high BP prior to or in early pregnancy with maternal and fetal complications. METHODS: We searched the cohort studies assessing the effect of high BP in the Medline, Embase, Web of Science and China National Knowledge Internet databases. A random-effects model was used to estimate the pooled odds ratios (ORs) with 95% confidence intervals (CIs). The protocol was registered in PROSPERRO (CRD 42023414945). RESULTS: 23 eligible studies were identified. High BP prior to or in early pregnancy was associated with higher odds of hypertensive disorders of pregnancy (OR 2.90, 95% CI 1.91-3.89), gestational hypertension (2.56, 2.01-3.12), preeclampsia (3.20, 2.66-3.74), gestational diabetes mellitus (1.71, 1.36-2.06), preterm birth (1.66, 1.39-1.93), stillbirth (2.01, 1.45-2.58) and neonatal intensive care unit admission (1.22, 1.08-1.37). Subgroup analyses indicated that pre-hypertension could significantly increase the odds of these outcomes except for stillbirth, though the odds were lower than hypertension. CONCLUSIONS: High BP prior to or in early pregnancy was associated with adverse pregnancy outcomes and this association increased with hypertension severity. The findings emphasized an urgent need for heightened surveillance for maternal BP, especially pre-hypertensive status.

Nrf2/PHB2 alleviates mitochondrial damage and protects against Staphylococcus aureus-induced acute lung injury.

Staphylococcus aureus (SA) is a major cause of sepsis, leading to acute lung injury (ALI) characterized by inflammation and oxidative stress. However, the role of the Nrf2/PHB2 pathway in SA-induced ALI (SA-ALI) remains unclear. In this study, serum samples were collected from SA-sepsis patients, and a SA-ALI mouse model was established by grouping WT and Nrf2-/- mice after 6 h of intraperitoneal injection. A cell model simulating SA-ALI was developed using lipoteichoic acid (LTA) treatment. The results showed reduced serum Nrf2 levels in SA-sepsis patients, negatively correlated with the severity of ALI. In SA-ALI mice, downregulation of Nrf2 impaired mitochondrial function and exacerbated inflammation-induced ALI. Moreover, PHB2 translocation from mitochondria to the cytoplasm was observed in SA-ALI. The p-Nrf2/total-Nrf2 ratio increased in A549 cells with LTA concentration and treatment duration. Nrf2 overexpression in LTA-treated A549 cells elevated PHB2 content on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division. Bioinformatic analysis and dual-luciferase reporter assay confirmed direct binding of Nrf2 to the PHB2 promoter, resulting in increased PHB2 expression. In conclusion, Nrf2 plays a role in alleviating SA-ALI by directly regulating PHB2 transcription and maintaining mitochondrial function in lung cells.

Elamipretide(SS-31) Attenuates Idiopathic Pulmonary Fibrosis by Inhibiting the Nrf2-Dependent NLRP3 Inflammasome in Macrophages.

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal lung disease with a limited therapeutic strategy. Mitochondrial oxidative stress in macrophages is directly linked to IPF. Elamipretide(SS-31) is a mitochondrion-targeted peptide that has been shown to be safe and beneficial for multiple diseases. However, whether SS-31 alleviates IPF is unclear. In the present study, we used a bleomycin (BLM)-induced mouse model followed by SS-31 injection every other day to investigate its role in IPF and explore the possible mechanism. Our results showed that SS-31 treatment significantly suppressed BLM-induced pulmonary fibrosis and inflammation, with improved histological change, and decreased extracellular matrix deposition and inflammatory cytokines release. Impressively, the expression percentage of IL-1ß and IL-18 was downregulated to lower than half with SS-31 treatment. Mechanistically, SS-31 inhibited IL-33- or lipopolysaccharide(LPS)/IL-4-induced production of IL-1ß and IL-18 in macrophages by suppressing NOD-like receptor thermal protein domain associated protein 3(NLRP3) inflammasome activation. Nuclear factor erythroid 2-related factor 2(Nrf2) was dramatically upregulated along with improved mitochondrial function after SS-31 treatment in activated macrophages and BLM-induced mice. Conversely, there was no significant change after SS-31 treatment in Nrf2-/- mice and macrophages. These findings indicated that SS-31 protected against pulmonary fibrosis and inflammation by inhibiting the Nrf2-mediated NLRP3 inflammasome in macrophages. Our data provide initial evidence for the therapeutic efficacy of SS-31 in IPF.

A Hospital-Based Study on Congenital Heart Defects - Haidian District, Beijing Municipality, China, 2013-2022.

What is already known about this topic?: Congenital heart defects (CHDs) represent the most prevalent birth defects in China, exhibiting significant mortality and morbidity rates. Recent years have witnessed a steady increase in the occurrence of CHDs, highlighting a crucial need for rigorous research focus. What is added by this report?: The cumulative birth prevalence of CHDs in Haidian District from 2013 to 2022 was 80.77 per 10,000 births, reflective of an upward trend primarily influenced by the diagnosis of minor, non-critical congenital defects (non-CCHDs). This increase can be attributed to advancements in diagnostic methodologies. Despite the progress in detection, the survival rate for CHDs did not correspondingly improve. What are the implications for public health practice?: Policies need to be formulated to promote the graded management of CHDs. There should be timely updates to the diagnostic criteria to align with advancements in diagnostic techniques. Moreover, in instances where therapeutic abortion is not required, the provision of appropriate medical consultation post-diagnosis should be enhanced.

Trends in the Prevalence of Births with Chromosomal Abnormalities - Haidian District, Beijing Municipality, China, 2013-2022.

What is already known about this topic?: The primary causes of early miscarriage and stillbirth are chromosomal abnormalities (CAs) whose prevalence has been observed to increase in recent years. What is added by this report?: According to data received from a hospital-based birth-defect surveillance system in the Haidian District, Beijing, there was a significant increase in the prevalence of CAs along with most subtypes from 2013 to 2022. This noted increase in the reported prevalence is potentially attributable to factors such as a rise in maternal age, alongside the enhanced detection efficacy resulting from the utilization of noninvasive prenatal testing. What are the implications for public health practice?: The escalating prevalence of sex CAs and other previously rare CAs pose novel challenges for genetic counseling and healthcare practitioners. These professionals are tasked with the accurate evaluation and interpretation of detection data, which must then be conveyed appropriately to patients. Furthermore, it is imperative to intensify health education efforts to assist women in making informed treatment decisions, considering the diverse prognoses associated with different CAs.

Elevated levels of neutrophil related chemokine citrullinated histone H3, interleukin-8 and C-reaction protein in patients with immune checkpoint inhibitor therapy: predictive biomarkers for response to treatment.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has been used in various tumors. The biomarkers predictive of a response to ICI treatment remain unclear, and additional and combined biomarkers are urgently needed. Secreted factors related to the tumor microenvironment (TME) have been evaluated to identify novel noninvasive predictive biomarkers. METHODS: We analyzed 85 patients undergoing ICI therapy as the primary cohort. The associations between ICI response and all biomarkers were evaluated. A prediction model and a nomogram were developed and validated based on the above factors. RESULTS: Seventy-seven patients were enrolled in the validation cohort. In the primary cohort, the baseline serum levels of H3Cit, IL-8 and CRP were significantly higher in nonresponder patients. A model based on these three factors was developed, and the "risk score" of an ICI response was calculated with the formula: "risk score" = 3.4591×H3Cit + 2.5808×IL8 + 2.0045 ×CRP- 11.3844. The cutoff point of the "risk score" was 0.528, and patients with a "risk score" lower than 0.528 were more likely to benefit from ICI treatment (AUC: 0.937, 95% CI: 0.886-0.988, with sensitivity 80.60%, specificity 91.40%). The AUC was 0.719 (95% CI: 0.600-0.837, P = 0.001), with a sensitivity of 70.00% and specificity of 65.20% in the validation cohort. CONCLUSIONS: A model incorporating H3Cit, IL-8 and CRP has an excellent prediction ability for ICI response; thus, patients with a lower "risk score" selectively benefit from ICI treatment, which may have significant clinical implications for the early detection of an ICI response.

Multiple TMA-aided CRISPR/Cas13a platform for highly sensitive detection of IL-15 to predict immunotherapeutic response in nasopharyngeal carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs)-based treatments have been recommended as the first line for refractory recurrent and/or metastatic nasopharyngeal carcinoma (NPC) patients, yet responses vary, and predictive biomarkers are urgently needed. We selected serum interleukin-15 (sIL-15) out of four interleukins as a candidate biomarker, while most patients' sIL-15 levels were too low to be detected by conventional methods, so it was necessary to construct a highly sensitive method to detect sIL-15 in order to select NPC patients who would benefit most or least from ICIs. METHODS: Combining a primer exchange reaction (PER), transcription-mediated amplification (TMA), and a immuno-PER-TMA-CRISPR/Cas13a system, we developed a novel multiple signal amplification platform with a detection limit of 32 fg/mL, making it 153-fold more sensitive than ELISA. RESULTS: This platform demonstrated high specificity, repeatability, and versatility. When applied to two independent cohorts of 130 NPC sera, the predictive value of sIL-15 was accurate in both cohorts (area under the curve: training, 0.882; validation, 0.898). Additionally, lower sIL-15 levels were correlated with poorer progression-free survival (training, HR: 0.080, p<0.0001; validation, HR: 0.053, p<0.0001). CONCLUSION: This work proposes a simple and sensitive approach for sIL-15 detection to provide insights for personalized immunotherapy of NPC patients.

MiR-155-5p Attenuates Vascular Smooth Muscle Cell Oxidative Stress and Migration via Inhibiting BACH1 Expression.

The malfunction of vascular smooth muscle cells (VSMCs) is an initiating factor in the pathogenesis of pathological vascular remodeling, including hypertension-related vascular lesions. MicroRNAs (miRNAs) have been implicated in the pathogenesis of VSMC proliferation and migration in numerous cases of cardiovascular remodeling. The evidence for the regulatory role of miR-155-5p in the development of the cardiovascular system has been emerging. However, it was previously unclear whether miR-155-5p participated in the migration of VSMCs under hypertensive conditions. Thus, we aimed to define the exact role and action of miR-155-5p in VSMC migration by hypertension. Here, we detected that the level of miR-155-5p was lower in primary VSMCs from spontaneously hypertensive rats (SHRs). Its overexpression attenuated, while its depletion accelerated, the migration and oxidative damage of VSMCs from SHRs. Our dual-luciferase reporter assay showed that miRNA-155-5p directly targeted the 3'-untranslated region (3'-UTR) of BTB and CNC homology 1 (BACH1). The miR-155-5p mimic inhibited BACH1 upregulation in SHR VSMCs. By contrast, the deletion of miR-155-5p further elevated the upregulation of BACH1 in SHR-derived VSMCs. Importantly, the overexpression of miR-155-5p and knockdown of BACH1 had synergistic effects on the inhibition of VSMCs in hypertension. Collectively, miR-155-5p attenuates VSMC migration and ameliorates vascular remodeling in SHRs, via suppressing BACH1 expression.

4-OI ameliorates bleomycin-induced pulmonary fibrosis by activating Nrf2 and suppressing macrophage-mediated epithelial-mesenchymal transition.

OBJECTIVES: Pulmonary fibrosis (PF) is a chronic and refractory interstitial lung disease with limited therapeutic options. 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, has been shown to have anti-oxidative and anti-inflammatory properties. However, the effect and the underlying mechanism of 4-OI on PF are still unknown. METHODS: WT or Nrf2 knockout (Nrf2-/-) mice were intratracheally injected with bleomycin (BLM) to establish PF model and then treated with 4-OI. The mechanism study was performed by using RAW264.7 cells, primary macrophages, and conditional medium-cultured MLE-12 cells. RESULTS: 4-OI significantly alleviated BLM-induced PF and EMT process. Mechanism studies have found that 4-OI can not only directly inhibit EMT process, but also can reduce the production of TGF-ß1 by restraining macrophage M2 polarization, which in turn inhibits EMT process. Moreover, the effect of 4-OI on PF and EMT depends on Nrf2. CONCLUSION: 4-OI ameliorates BLM-induced PF in an Nrf2-dependent manner, and its role in alleviating PF is partly due to the direct inhibition on EMT, and partly through indirect inhibition of M2-mediated EMT. These findings suggested that 4-OI has great clinical potential to develop as a new anti-fibrotic agent for PF therapy.

Staphylococcal virulence factor HlgB targets the endoplasmic-reticulum-resident E3 ubiquitin ligase AMFR to promote pneumonia.

Staphylococcus aureus invades cells and persists intracellularly, causing persistent inflammation that is notoriously difficult to treat. Here we investigated host-pathogen interactions underlying intracellular S. aureus infection in macrophages and discovered that the endoplasmic reticulum (ER) is an important cellular compartment for intracellular S. aureus infection. Using CRISPR-Cas9 guide RNA library screening, we determined that the autocrine motility factor receptor (AMFR), an ER-resident E3 ubiquitin ligase, played an essential role in mediating intracellular S. aureus-induced inflammation. AMFR directly interacted with TAK1-binding protein 3 (TAB3) in the ER, inducing K27-linked polyubiquitination of TAB3 on lysine 649 and promoting TAK1 activation. Moreover, the virulence factor γ-haemolysin B (HIgB) of S. aureus bound to the AMFR and regulated TAB3. Our findings highlight an unknown role of AMFR in intracellular S. aureus infection-induced pneumonia and suggest that pharmacological interruption of AMFR-mediated TAB3 signalling cascades and HIgB targeting may prevent invasive staphylococci-mediated pneumonia.

Establishment and validation of a novel prognostic model for non-virus-related hepatocellular carcinoma.

OBJECTIVE: The incidence of non-virus-related hepatocellular carcinoma (NV-HCC) in hepatocellular carcinoma (HCC) is steadily increasing. The aim of this study was to establish a prognostic model to evaluate the overall survival (OS) of NV-HCC patients. METHODS: Overall, 261 patients with NV-HCC were enrolled in this study. A prognostic model was developed by using LASSO-Cox regression analysis. The prognostic power was appraised by the concordance index (C-index), and the time-dependent receiver operating characteristic curve (TD-ROC). Kaplan-Meier (K-M) survival analysis was used to evaluate the predictive ability in the respective subgroups stratified by the prognostic model risk score. A nomogram for survival prediction was established by integrating the prognostic model, TNM stage, and treatment. RESULTS: According to the LASSO-Cox regression results, the number of nodules, lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), alkaline phosphatase (ALP), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (SLR) and C-reactive protein (CRP) were included for prognostic model construction. The C-index of the prognostic model was 0.759 (95% CI 0.723-0.797) in the development cohort and 0.796 (95% CI 0.737-0.855) in the validation cohort, and its predictive ability was better than TNM stage and treatment. The TD-ROC showed similar results. K-M survival analysis showed that NV-HCC patients with low risk scores had a better prognosis (P < 0.05). A nomogram based on the prognostic model, TNM stage, and treatment was constructed with sufficient discriminatory power with C-indexes of 0.78 and 0.85 in the development and validation cohort, respectively. CONCLUSION: For NV-HCC, this prognostic model could predict an OS benefit for patients, which may assist clinicians in designing individualized therapeutic strategies.