Explore the vast range of titles available.

Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia and has one of the poorest prognosis. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined that IL-24, an IL-20 subfamily cytokine member, was increased both in the serum of IPF patients and the bronchoalveolar lavage fluid (BALF) of mice following bleomycin (BLM)-induced pulmonary fibrosis. As a result, IL-24 deficiency protected mice from BLM-induced lung injury and fibrosis. Specifically, loss of IL-24 significantly attenuated transforming growth factor β1 (TGF-β1) production and reduced M2 macrophage infiltration in the lung of BLM-induced mice. Mechanistically, IL-24 alone did not show a perceptible impact on the induction of M2 macrophages, but it synergized with IL-4 to promote M2 program in macrophages. IL-24 suppressed IL-4-induced expression of suppressor of cytokine signaling 1 (SOCS1) and SOCS3, through which it enhanced signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma (STAT6/PPARγ) signaling, thereby promoting IL-4-induced production of M2 macrophages. Collectively, our data support that IL-24 synergizes with IL-4 to promote macrophage M2 program contributing to the development of pulmonary fibrosis.

Background Insulin resistance (IR) has been linked to the development of gout. The triglyceride glycemic (TyG) index is a useful biomarker of IR, and the evidences between TyG and gout are limited. Therefore, this study aimed to examine the association between the TyG index and gout in the United States (U.S). Methods The cross-sectional study was conducted among adults with complete TyG index and gout data in the 2007–2017 National Health and Nutrition Examination Survey (NHANES). The TyG index was calculated as fasting triglycerides (mg/dl) * fasting glucose (mg/dl)/2. Gout was assessed by self-report questionnaire (MCQ160n). Weighted chi-squared and weighted Student’s t-test were used to assess group differences. Weighted multivariable logistic regression analysis, subgroup analysis, and interaction tests were used to examine the TyG index and gout association. Results The final participants were 11,768; 5910 (50.32%) were female, 7784 (73.26%) were 18–60 years old, 5232 (69.63%) were white, and 573 (5.12%) had gout. After adjusting for all covariates, the TyG index was positively associated with gout; each unit increase in TyG index was associated with 40% higher odds of gout (odds ratio (OR), 1.40; 95% CI: 1.82–2.66; p  < 0.0001). Participants in the highest TyG index tertile group were at high risk of gout (odds ratio (OR), 1.64; 95% CI: 1.06–2.54, p  = 0.03) versus those in the lowest tertile group. Interaction tests showed no significant effect of age, race, marital status, PIR level, education, BMI, smoking status, drinking status, hypertension, and DM on this association between TyG index and gout ( p  for interaction > 0.05). Conclusions In this large cross-sectional study, our results suggested that a higher TyG index was associated with an increased likelihood of gout in U.S. adults. Our findings highlight that the TyG index is a reliable biomarker of IR; management of IR among adults may prevent or alleviate the development of gout; meanwhile, the TyG index may be a simple and cost-effective method to detect gout.

Kdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a ( LysM- Cre- Kdm2a f/f , Kdm2a −/− ) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a −/− increased H3K36me2 levels at the Pparg locus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a −/− mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a −/− macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a −/− mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.

Background Negative pressure wards are used to admit patients with respiratory infectious diseases. Most of the negative pressure wards are currently reconstructed, and the standard disinfection protocol has not yet been established. Methods In this study, we adopted the Delphi method to develop a disinfection protocol for negative pressure wards. First, we constructed a draft disinfection protocol based on literature analysis, theoretical analysis and investigation of the status quo. Then, we conducted two rounds of consultation through letters with fifteen experts in the management and disinfection of negative pressure wards from 6 provinces and cities around China. Results The final disinfection protocol of negative pressure wards contains 8 primary indicators, including air disinfection, surface disinfection, disinfection management of special hardware facilities, fabric disinfection, disinfection of secretions/excretions/vomitus, monitoring of disinfection effectiveness, management of cleaning and disinfection tools, and management of medical waste, along with 20 secondary indicators and 46 tertiary indicators. Conclusions The disinfection protocol for the negative pressure wards developed in this study is scientifically sound and highly operable, providing a reference for medical institutions equipped with negative pressure wards.

HIV-1 capsid plays multiple key roles in viral replication, and inhibition of capsid assembly is an attractive target for therapeutic intervention. Here, we report the atomic-resolution structure of capsid protein (CA) tubes, determined by magic-angle spinning NMR and data-guided molecular dynamics simulations. Functionally important regions, including the NTD β-hairpin, the cyclophilin A-binding loop, residues in the hexamer central pore, and the NTD-CTD linker region, are well defined. The structure of individual CA chains, their arrangement in the pseudo-hexameric units of the tube and the inter-hexamer interfaces are consistent with those in intact capsids and substantially different from the organization in crystal structures, which feature flat hexamers. The inherent curvature in the CA tubes is controlled by conformational variability of residues in the linker region and of dimer and trimer interfaces. The present structure reveals atomic-level detail in capsid architecture and provides important guidance for the design of novel capsid inhibitors.Structures of HIV-1 capsid protein (CA) in tubular assemblies, determined by MAS-NMR, reveal the basis of CA’s conformational plasticity.

Objectives Hypoxia is an important risk factor for pulmonary arterial remodelling in pulmonary arterial hypertension (PAH), and the Janus kinase 2 (JAK2) is believed to be involved in this process. In the present report, we aimed to investigate the role of JAK2 in vascular smooth muscle cells during the course of PAH. Methods Smooth muscle cell (SMC)‐specific Jak2 deficient mice and their littermate controls were subjected to normobaric normoxic or hypoxic (10% O2) challenges for 28 days to monitor the development of PAH, respectively. To further elucidate the potential mechanisms whereby JAK2 influences pulmonary vascular remodelling, a selective JAK2 inhibitor was applied to pre‐treat human pulmonary arterial smooth muscle cells (HPASMCs) for 1 hour followed by 24‐hour hypoxic exposure. Results Mice with hypoxia‐induced PAH were characterized by the altered JAK2/STAT3 activity in pulmonary artery smooth muscle cells. Therefore, induction of Jak2 deficiency in SMCs protected mice from hypoxia‐induced increase of right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodelling. Particularly, loss of Jak2 significantly attenuated chronic hypoxia‐induced PASMC proliferation in the lungs. Similarly, blockade of JAK2 by its inhibitor, TG‐101348, suppressed hypoxia‐induced human PASMC proliferation. Upon hypoxia‐induced activation, JAK2 phosphorylated signal transducer and activator of transcription 3 (STAT3), which then bound to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC proliferation. Conclusions Our studies support that JAK2 could be a culprit contributing to the pulmonary vascular remodelling, and therefore, it could be a viable target for prevention and treatment of PAH in clinical settings.

Urban flooding threatens urban resilience and challenges SDGs 11 and 13. This study assesses urban building flood risk in Guangzhou by integrating flood susceptibility with building function vulnerability. Using a Random Forest (RF) model, it predicts flood susceptibility based on flood records, hydrological, topographical, and anthropogenic features. The Categorical Boosting (CatBoost) model identifies building functions using POI and AOI data. Results reveal significant spatial variations: central districts exhibit higher flood susceptibility, while peripheral areas remain less affected. Over half of the buildings are moderately vulnerable, with only a small fraction highly vulnerable. Based on flood susceptibility and functional vulnerability, Guangzhou is classified into three district types: central urban (Type I), intermediate urban (Type II), and suburban/rural (Type III). The study underscores the need for tailored flood risk management strategies to address these disparities and mitigate climate change-induced water hazards.

Object This study aims to investigate the molecular mechanism of NDRG2 (N-myc downstream-regulated gene 2) in the cell senescence of lens endothelial cells. Methods Lens endothelial cells (SRA01/04) were irradiated with UVB at different times. Cell viability was measured by CCK-8 kit and cell cycle was detected by flow cytometry. Cell senescence was detected using SA-β-gal staining. Western blot was utilized to detect the expressions of p53, p21 and NDRG2. TUNEL staining and flow cytometry were used to detect apoptosis and pyroptosis. Results UVB-irradiation significantly induces cell senescence and the expression of NDRG2, p53 and p21 in SRA01/04 cells was up-regulated. Down-regulation of NDRG2 inhibited UVB-induced cell senescence, significantly reversed pyroptosis and promoted cell proliferation. UVB-induced pyroptosis is closely related to caspase-1/NLRP3 axis. Conclusion Our study confirmed downregulation of NDRG2 significantly inhibited UVB radiation-induced cell senescence by regulating caspase-1/NLRP3-mediated pyroptosis.

Background Pulmonary fibrosis (PF) is an irreversible, progressive, chronic and fatal interstitial lung disease with limited therapeutic options. Dehydrocorydaline (DHC), derived from the traditional Chinese medicinal plant Corydalis yanhusuo , has exhibited a variety of pharmacological properties. Nevertheless, the potential function and mechanism of DHC in the management of PF have yet to be elucidated. Purpose To evaluate the therapeutical efficacy of DHC in different PF models and elucidate its underlying mechanism. Methods A well-established Bleomycin-induced PF mouse model and human precision-cut lung slices (hPCLS) following fibrosis-inducing cocktail stimulation were employed. The antifibrotic effects of DHC on PF were measured by histopathological manifestation, immunofluorescent staining and expression levels of fibrosis related markers. Human primary pulmonary fibroblasts (HPFs) were used to explore the impact of DHC on fibroblast function and the underlying mechanism. Results Here, we demonstrated that DHC exhibited a therapeutic efficacy in Bleomycin-induced PF mouse model with a dose dependent, as well as in hPCLS after fibrosis-inducing cocktail stimulation, as evidenced by histopathological staining, decrease of Fibronectin, Collagen 1 and α-SMA expression. Additionally, in vitro experiments indicated that DHC effectively suppressed fibroblast to myofibroblast transition, but had no significant effect on the proliferation and migration of fibroblast. Mechanistic studies revealed that the inhibitory effect of DHC on fibroblast activation was dependent on the endoplasmic reticulum stress, thereby inhibiting TGF-β/SMAD signal pathway. Conclusions Our study implied that DHC hold a promise therapeutic approach against PF by suppressing fibroblast activation. The safety and efficacy of DHC have been preliminary demonstrated in a mouse model. Graphical Abstract

Background Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it’s unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. Methods To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. Results In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO 2 -induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO 2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-β/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. Conclusion In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.