An in-depth comprehension of the molecular mechanisms behind the targeted eradication of cancer cells through cell death represents a requisite for effective anticancer treatments. However, the precise mechanism by which cell divisionrelated factors interact with intracellular organelles in the context of cancer cell death remains unclear. Mitotic arrest deficiency 2 (MAD2/MAD2L1), a pivotal component of the spindle assembly checkpoint (SAC), and its overexpression also resulted in many types of cancer. Here we show that the depletion of a microtubule-binding protein, tumor susceptibility gene 101 (TSG101), causes synthetic dosage lethality (SDL) in MAD2-overexpressing cells, and we term this cell death MAD2- overexpressing interphase cell death (MOID). MOID induction is p53-independent but AIFM1-dependent and caspase-activated cell death. The induction of MOID depends on PML and DAXX mediating mitochondrial AIFM1-release. C-terminal phosphorylations of TSG101 and closed (C-)MAD2-overexpression are required to induce MOID. Additionally, a part of MAD2 colocalizes with PML at PML nuclear bodies (PML NBs), and the PML release from PML NBs through PML deSUMOylation is required to induce MOID. The post-transcriptional/translational cell death machinery and the non-canonical transcriptional regulation of oxidative stress and ATM/ATR-mediated DNA double-strand breaks (DSB) - DNA damage response (DDR) are intricately linked to MOID. MOID is also associated with the activation of ROS and autophagy. PML localized at the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), i.e., ER-MAM, may serve as a crucial intersection for MOID signaling.

BACKGROUND: This study aims to explore whether Xuebijing (XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism. METHODS: A rat model of sepsis was established by cecal ligation and puncture (CLP). A total of 30 male SD rats were divided into four groups: sham group, CLP group, XBJ + axitinib group, and XBJ group. XBJ was intraperitoneally injected 2 h before CLP. Hemodynamic data (blood pressure and heart rate) were recorded. The intestinal microcirculation data of the rats were analyzed via microcirculation imaging. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum levels of interleukin-6 (IL -6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha) in the rats. Histological analysis and transmission electron microscopy were used to analyze the injury of small intestinal microvascular endothelial cells and small intestinal mucosa in rats. The expression of vascular endothelial growth factor A (VEGF-A), phosphoinositide 3 -kinase (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (Akt), and phosphorylated Akt (p -Akt) in the small intestine was analyzed via Western blotting. RESULTS: XBJ improved intestinal microcirculation dysfunction in septic rats, alleviated the injury of small intestinal microvascular endothelial cells and small intestinal mucosa, and reduced the systemic inflammatory response. Moreover, XBJ upregulated the expression of VEGF-A, p-PI3K/total PI3K, and p-Akt/total Akt in the rat small intestine. CONCLUSION: XBJ may improve intestinal microcirculation dysfunction in septic rats possibly through the VEGF-A/PI3K/Akt signaling pathway.

OBJECTIVE:Asthma stands as one of the most prevalent chronic respiratory conditions in children, with its pathogenesis tied to the actived antigen presentation by dendritic cells (DCs) and the imbalance within T cell subgroups. This study seeks to investigate the role of the transcription factor EB (TFEB) in modulating the antigen presentation process of DCs and its impact on the differentiation of T cell subgroups.METHODS:Bone marrow dendritic cells (BMDCs) were activated using house dust mites (HDM) and underwent RNA sequencing (RNA-seq) to pinpoint differentially expressed genes. TFEB mRNA expression levels were assessed in the peripheral blood mononuclear cells (PBMCs) of both healthy children and those diagnosed with asthma. In an asthma mouse model induced by HDM, the TFEB expression in lung tissue DCs was evaluated. Further experiments involved LV-shTFEB BMDCs co-cultured with T cells to explore the influence of TFEB on DCs' antigen presentation, T cell subset differentiation, and cytokine production.RESULTS:Transcriptomic sequencing identified TFEB as a significantly differentially expressed gene associated with immune system pathways and antigen presentation. Notably, TFEB expression showed a significant increase in the PBMCs of children diagnosed with asthma compared to healthy counterparts. Moreover, TFEB exhibited heightened expression in lung tissue DCs of HDM-induced asthmatic mice and HDM-stimulated BMDCs. Silencing TFEB resulted in the downregulation of MHC II, CD80, CD86, and CD40 on DCs. This action reinstated the equilibrium among Th1/Th2 and Th17/Treg cell subgroups, suppressed the expression of pro-inflammatory cytokines like IL-4, IL-5, IL-13, and IL-17, while augmenting the expression of the anti-inflammatory cytokine IL-10.CONCLUSION:TFEB might have a vital role in asthma's development by impacting the antigen presentation of DCs, regulating T cell subgroup differentiation, and influencing cytokine secretion. Its involvement could be pivotal in rebalancing the immune system in asthma. These research findings could potentially unveil novel therapeutic avenues for treating asthma.

To assess the impacts of high-dose intravenous methylprednisolone pulse (IVMP) therapy in survival and the occurrences of treatment-related infection of patients with anti-melanoma differentiation-associated gene 5 antibody-related rapidly progressive interstitial lung disease (MDA5-RPILD). Patients with MDA5-RPILD from June 2017 to August 2022 in our hospital were retrospectively reviewed. IVMP therapy was defined as intravenous methylprednisolone (mPSL) 0.5g/day for 3 consecutive days during hospitalization or 7 days prior to admission and patients were divided into IVMP group and non-IVMP group based on who had ever received IVMP therapy. All-cause mortality and the incidence of adverse events during treatment were compared between the two groups. Sixty-four patients with MDA5-RPILD were enrolled. Among them, twenty-three (35.9

Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a severe complication of sepsis characterized by acute respiratory distress, hypoxemia, and diffuse bilateral pulmonary infiltrates. The regulation of RIPK1 is an important part of the inflammatory response, and cIAP1/2 serves as the E3 ubiquitin ligase for RIPK1. In this study, we investigated the effect and mechanism of cIAP1/2 inhibition on sepsis-induced lung injury. Our results showed that cIAP1/2 inhibition can alleviate sepsis-induced lung injury and reduce the inflammatory response, which is accompanied by downregulation of RIPK1 phosphorylation and ubiquitination. Additionally, cIAP1/2 inhibition led to the up-regulation of programmed cell death, including apoptosis, necroptosis, and pyroptosis, and inhibiting these three cell death pathways can further reduce the inflammatory response, which is similar to the recently discovered programmed cell death pathway PANoptosis. Our findings suggest that cIAP1/2 and PANoptosis inhibition may be a new strategy for treating sepsis-induced lung injury and provide important references for further exploring the mechanism of sepsis-induced lung injury and identifying new therapeutic targets.

Mitochondria, pivotal organelles governing cellular biosynthesis, energy metabolism, and signal transduction, maintain dynamic equilibrium through processes such as biogenesis, fusion, fission, and mitophagy. Growing evidence implicates mitochondrial dysfunction in a spectrum of respiratory diseases including acute lung injury/acute respiratory distress syndrome, bronchial asthma, pulmonary fibrosis, chronic obstructive pulmonary disease, and lung cancer. Consequently, identifying methods capable of ameliorating damaged mitochondrial function is crucial for the treatment of pulmonary diseases. Extracellular vesicles (EVs), nanosized membrane vesicles released by cells into the extracellular space, facilitate intercellular communication by transferring bioactive substances or signals between cells or organs. Recent studies have identified abundant mitochondrial components within specific subsets of EVs, termed mitochondrial extracellular vesicles (mitoEVs), whose contents and compositions vary with disease progression. Moreover, mitoEVs have demonstrated reparative mitochondrial functions in injured recipient cells. However, a comprehensive understanding of mitoEVs is currently lacking, limiting their clinical translation prospects. This Review explores the biogenesis, classification, functional mitochondrial cargo, and biological effects of mitoEVs, with a focus on their role in pulmonary diseases. Emphasis is placed on their potential as biological markers and innovative therapeutic strategies in pulmonary diseases, offering fresh insights for mechanistic studies and drug development in various pulmonary disorders.

目的 为临床医师诊治肺诺卡菌病提供参考,并探讨宏基因组二代测序技术(mNGS)对肺诺卡菌病的临床诊断价值.方法 对 2017 年 1 月至 2022 年 10 月南京大学医学院附属鼓楼医院通过mNGS检测诊断的 13 例肺诺卡菌患者进行回顾性分析,并进行相关文献复习.结果 13 例患者中,男 9 例,女 4 例,年龄 35～79 岁,平均(57±10)岁;10 例伴有基础疾病,4 例使用激素或免疫抑制剂.临床表现主要为咳嗽、咳痰、发热、气喘、咯血、消瘦等.胸部CT表现为结节、肺实变、胸膜增厚、空洞、肿块、胸腔积液、支气管扩张、纵隔及腋窝淋巴结肿大、磨玻璃影.通过经支气管镜肺泡灌洗液行mNGS检测确诊9 例,经支气管镜肺活检组织行mNGS检测确诊 1 例,经皮肺穿刺活检组织行mNGS检测确诊 3 例,标本均未培养出诺卡菌.入院至确诊中位时间为 8 d(3.50～15.00 d).治疗药物以复方磺胺甲噁唑为主,分别联合利奈唑胺、阿米卡星、亚胺培南、美罗培南、莫西沙星等抗菌药物.11 例随访病情好转,1 例随访无好转,3 个月后确诊为肺癌,1 例自动出院,未继续治疗.结论 肺诺卡菌病的临床表现及影像学无明显特异性,容易漏诊、误诊.肺诺卡菌感染可能合并其他潜在病因,需密切随访以免漏诊.相较于传统细菌培养法,mNGS对于肺诺卡菌病是一种敏感高效的诊断方法,有很好的应用前景.

Aberrant intestinal epithelial barrier function is the primary pathology of Ulcerative colitis (UC), making it a desirable drug target. In this study, our small-molecule compound AI-34 exerted a significant protective effect in an LPS-induced epithelial barrier injury model. In vitro, AI-34 treatment significantly decreased cell permeability, increased transmembrane resistance, and maintained the junctional protein (ZO-1 and E-cadherin) levels in monolayer cells. Using the LiP-small molecule mapping approach (LiP-SMap), we demonstrated that AI-34 binds to 14-3-3ζ. AI-34 promoted the interaction between 14-3-3ζ and β-catenin, decreasing the ubiquitination of β-catenin and thus maintaining intestinal epithelial barrier function. Finally, AI-34 triggered the stabilization of β-catenin mediated by 14-3-3ζ, provoking a significant improvement in the DSS-induced colitis model. Our findings suggest that AI-34 may be a promising candidate for UC treatment.

Aberrant intestinal epithelial barrier function is the primary pathology of Ulcerative colitis (UC), making it a desirable drug target. In this study, our small-molecule compound AI-34 exerted a significant protective effect in an LPS-induced epithelial barrier injury model. In vitro, AI-34 treatment significantly decreased cell permeability, increased transmembrane resistance, and maintained the junctional protein (ZO-1 and E-cadherin) levels in monolayer cells. Using the LiP-small molecule mapping approach (LiPSMap), we demonstrated that AI-34 binds to 14-3-3z. AI-34 promoted the interaction between 14-3-3z and (3-catenin, decreasing the ubiquitination of (3-catenin and thus maintaining intestinal epithelial barrier function. Finally, AI-34 triggered the stabilization of (3-catenin mediated by 14-3-3z, provoking a significant improvement in the DSS-induced colitis model. Our findings suggest that AI-34 may be a promising candidate for UC treatment.& COPY; 2023 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

报道1例胸部CT以双肺间质纤维化改变为主要表现的原发性肺癌患者.临床主要表现为咳嗽、咳痰、胸闷、气喘,胸部CT主要表现为双肺间质纤维化改变伴结节影,通过外科胸腔镜肺活检明确病理,诊断为肺腺癌.以双肺间质纤维化改变为主要表现的原发性肺腺癌临床罕见,易误诊为间质性肺疾病,为提高临床医生对该类型肺癌的影像学认识,以免延误诊治,报道如下.

Background: Idiopathic pulmonary fibrosis (IPF) is a heterogeneous and progressive fibrosing interstitial lung disease with a poor prognosis. However, there are currently no effective biomarker that can reliably predict the prognosis for IPF in clinic. The serum level of soluble suppression of tumorigenicity-2 (sST2), which is involved in the immune response, has proven to be a prognostic predictor for various diseases. Previous studies have confirmed that the immune dysfunction plays an important role in the pathogenesis of IPF and the serum sST2 concentrations in patients with IPF are elevated. However, the relationship between sST2 and the prognosis of IPF remains unknown. Methods: A total of 83 patients with IPF and 20 healthy controls from 2016 to 2021 were enrolled and demographic variables, indices of lung function testing as well as the biomarkers including the sST2 were obtained at baseline. During follow-up, the primary endpoint was defined as all-cause death and clinical deterioration. Cox hazard models and Kaplan-Meier method were used to assess the prognostic value of various indices including sST2. Results: Mean duration of follow-up was 29 months, during which 49 patients had an event, and of them, 35 patients died. The sST2 level was higher in the IPF patients compared with the healthy controls. Although the sST2 level did not directly predict all-cause death in the present study, it was proved to be an independent predictor of event-free survival. Multivariate forward stepwise model which was adjusted by age, sex, and body surface area (BSA) showed that the overexpression of sST2 increased the hazard ratio [1.005, 95% confidence interval (CI): 1.001–1.010]. A higher sST2 serum level heralded more deterioration and the poor outcomes. Moreover, the effect of sST2 on the prognosis of IPF may not necessarily involve the development of IPF-related pulmonary hypertension (PH). Conclusions: In our study, the sST2 serum level was significantly elevated and a higher serum level of sST2 predicted more deterioration and poor outcomes in patients with IPF. Thus, sST2 can serve as a valuable prognostic biomarker for the outcome of IPF. However, further multicenter clinical trials of larger sample size are needed in the future.

肺康复治疗( pulmonary rehabilitation,PR)是通过对患者进行全面评估、为患者制定特异性的综合治疗方案,以达到减轻患者呼吸困难症状、改善呼吸功能、提高运动耐力,同时保持良好的心理状态进而提高患者生存质量的目的.肺康复治疗最早源于国外的呼吸康复,兴起于20 世纪中后期,经过多次更新,在2013年美国胸科学会( American Thoracic So-ciety,ATS)和欧洲呼吸学会( European Respiratory Society,ERS)发表的声明中[1] ,肺康复已经发展成为涵盖了运动训练、行为改变和协作性自我管理、骨骼肌的流失和干预、身体活动、肺康复治疗的时机、长期维持肺康复的好处、以患者为中心的转归、肺康复流程的优化、卫生经济学评价等诸多方面的综合性干预治疗方案.

Inflammatory injury is a hallmark of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). However, the mechanisms underlying inflammatory injury remain obscure. Here, we developed the novel strategy to suppress lung inflammation through maintaining microvascular endothelial barrier integrity. VE-cadherin is the main adherens junction protein that interacts with β-catenin and forms a complex. We found that lung inflammation was accompanied by decreased VE-cadherin expression and increased β-catenin activity in animal models and human pulmonary microvascular endothelial cells (HPMECs), illuminating the relationship among VE-cadherin/β-catenin complex, microvascular endothelial barrier integrity, and inflammation. Furthermore, we showed that the VE-cadherin/β-catenin complex dissociated upon lung inflammation, while Sirt3 promoted the stability of such a complex. Sirt3 was decreased during lung inflammation in vivo and in vitro. Sirt3 deficiency not only led to the downregulation of VE-cadherin but also enhanced the transcriptional activity of β-catenin that further increased β-catenin target gene MMP-7 expression, thereby promoting inflammatory factor COX-2 expression. Sirt3 overexpression promoted VE-cadherin expression, inhibited β-catenin transcriptional activity, strengthened the stability of the VE-cadherin/β-catenin complex, and suppressed inflammation in HPMECs. Notably, Sirt3 deficiency significantly damaged microvascular endothelial barrier integrity and intensified lung inflammation in animal model. These results demonstrated the role of Sirt3 in modulating microvascular endothelial barrier integrity to inhibit inflammation. Therefore, strategies that aim at enhancing the stability of endothelial VE-cadherin/β-catenin complex are potentially beneficial for preventing sepsis-induced lung inflammation.

Pneumonia is a common illness that continues to be the major killer of remaining to be a significant source of morbidity and mortality in the patient population. Many microorganisms cause pneumonia, and now concern is turning to the importance of the cause the new therapies for viral pneumonia. In the current study, we report the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on poly I: C-induced pneumonia. Andrographolide sulfonate was administrated through intraperitoneal injection to mice with poly I: C-induced pneumonia. Recruitment of airway inflammatory cells, alteration of lung histological induced by Poly I: C were significantly ameliorated by andrographolide sulfonate. The protein levels of pro-inflammatory cytokines in bronchoalveolar fluid (BALF) and serum were reduced by andrographolide sulfonate treatment. The levels of MUC5AC and MUC5B in lung tissue were also suppressed. These results reveal that andrographolide sulfate remarkably alleviated pneumonia induced by poly I:C in mice. Moreover, andrographolide sulfonate markedly inhibited the activation of nuclear factor-κB (NF-κB). Taken together, we demonstrated that andrographolide sulfonate ameliorated poly I: C-induced pneumonia in mice, suggesting the possible use of andrographolide sulfonate for virus-induced pneumonia in clinical.

Inflammatory bowel disease could result in diarrhea and abdominal pain, as well as potential complications such as tissue fibrosis. The therapeutic effect of andrographolide sulfonate on acute murine experimental colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) has been confirmed. In the study here, chronic colitis triggered by repeated intrarectal administration of TNBS was established and the effect of andrographolide sulfonate was examined. Repeated TNBS administration induced substantial mice death, which was significantly decreased by andrographolide sulfonate treatment. The elevation of inflammatory cytokines including IL-6, IL-17A, TNF-α as well as IFN-γ in colonic tissues levels were decreased after administration of andrographolide sulfonate. Next, CD4+ T cell and macrophage infiltration was found to descend. The subset of pathogenic CD4+ T cell subset including CD4+IFN-γ+ (Th1) and CD4+IL-17A+ (Th17) were also suppressed by andrographolide sulfonate. Further, the restrain of p38 and p65 activation were also observed after andrographolide sulfonate administration. Finally, TNBS-induced colonic epithelial damage as well as fibrosis were significantly mitigated by andrographolide sulfonate. Based on the results got here, we can make a conclusion that andrographolide sulfonate could decrease inflammation and epithelial damage as well as fibrosis thus ameliorating chronic colitis in mice. Our study suggest the possible use of andrographolide sulfonate for chronic colitis treatment in clinical.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a serious respiratory disease, the mechanism is unclear. This paper revealed the mechanism of ganoderic acid B (BB) on lipopolysaccharide-induced pneumonia in mice. Pneumonia model was induced by LPS in mice and A549 cells. Lung dry/wet weight (W/D) and myeloperoxidase (MPO) activity in lung were examined. Lung histopathological changes was observed by HE staining. Superoxide dismutase (SOD), malondialdehyde (MDA) and proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in mice and A549 cells were detected. Rho/NF-κB pathway in mice and A549 cells were examined by Western Blot. BB significantly reduced W/D and MPO activity, restored lung histopathological changes. BB also increased SOD, decreased MDA, TNF-α, IL-1β and IL-6 in mice and A549 cells. In addition, BB inhibited Rho/NF-κB pathway in mice and A549 cells. BB has protective effect on LPS-induced pneumonia in mice, and its mechanism is related to the regulation of Rho/NF-κB signaling pathway.

A 52-year-old man presented with repeated cough and worsening exertional dyspnea for 5 years. Long-term oral prednisone had been administered with little effect. He denied chest pain, hemoptysis, or nighttime paroxysmal dyspnea. His medical history included chronic hepatitis B, liver cirrhosis, splenomegaly, diabetes insipidus, and hypertension. He denied consuming alcohol or illicit drugs. He was a never smoker. His family history was noncontributory.

Inflammatory bowel disease (IBD) is a worldwide prototypical complex disease, owing to its multifactorial causes, relapsing and remitting condition and high incidence. Thus, effective therapeutic approaches need to be developed for patients with IBD. Currently, we reported the improving effect of magnesium isoglycyrrhizinate on colitis induced by dextran sulfate sodium (DSS). We found that magnesium isoglycyrrhizinate treatment significantly alleviated DSS-induced acute and chronic colitis by inhibiting the inflammatory response characterized by reduce of the infiltrations of immune cell and the level of pro-inflammatory cytokines. Besides, magnesium isoglycyrrhizinate treatment significantly inhibited the level of ROS and decreased the gut barrier destruction after DSS treatment. Furthermore, the results also showed that administration of magnesium isoglycyrrhizinate significantly reduced the colonic fibrosis. Taken together, these results revealed the potency of magnesium isoglycyrrhizinate on the intestinal inflammation, by which points to the possible use of magnesium isoglycyrrhizinate for IBD therapy in clinical applications.

The present study aimed to investigate the protective effects of ganoderic acid A (GAA) on lipopolysaccharide (LPS)-induced acute lung injury. In mouse model of LPS-induced acute lung injury, we found that GAA led to significantly lower lung wet-to-dry weight ratio and lung myeloperoxidase activity, and attenuated pathological damages. In addition, GAA increased superoxide dismutase activity, but decreased malondialdehyde content and proinflammatory cytokines levels in the bronchoalveolar lavage fluid. Mechanistically, GAA reduced the activation of Rho/ROCK/NF-κB pathway to inhibit LPS-induced inflammation. In conclusion, our study suggests that GAA attenuates acute lung injury in mouse model via the inhibition of Rho/ROCK/NF-κB pathway.