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TNF receptor-associated factor 6 (TRAF6)-BECN1 signaling axis plays a pivotal role in autophagy induction through ubiquitination of BECN1, thereby inducing lung cancer migration and invasion in response to toll-like receptor 4 (TLR4) stimulation. Herein, we provide novel molecular and cellular mechanisms involved in the negative effect of ubiquitin-specific peptidase 15 (USP15) on lung cancer progression. Clinical data of the TCGA and primary non-small cell lung cancer (NSCLC) patients ( n  = 41) revealed that the expression of USP15 was significantly downregulated in lung cancer patients. Importantly, USP15 -knockout ( USP15 KO) A549 and USP15 KO H1299 lung cancer cells generated with CRISPR-Cas9 gene-editing technology showed increases in cancer migration and invasion with enhanced autophagy induction in response to TLR4 stimulation. In addition, biochemical studies revealed that USP15 interacted with BECN1, but not with TRAF6, and induced deubiquitination of BECN1, thereby attenuating autophagy induction. Notably, in primary NSCLC patients ( n  = 4) with low expression of USP15 , 10 genes ( CCNE1, MMP9, SFN, UBE2C, CCR2, FAM83A, ETV4, MYO7A, MMP11, and GSDMB ) known to promote lung cancer progression were significantly upregulated, whereas 10 tumor suppressor genes ( FMO2, ZBTB16, FCN3, TCF21, SFTPA1B, HPGD, SOSTDC1, TMEM100, GDF10 , and WIF1 ) were downregulated, providing clinical relevance of the functional role of USP15 in lung cancer progression. Taken together, our data demonstrate that USP15 can negatively regulate the TRAF6-BECN1 signaling axis for autophagy induction. Thus, USP15 is implicated in lung cancer progression.

Neutrophils are critical mediators of both the initiation and resolution of inflammation after myocardial infarction (MI). Overexuberant neutrophil signaling after MI exacerbates cardiomyocyte apoptosis and cardiac remodeling while neutrophil apoptosis at the injury site promotes macrophage polarization toward a pro-resolving phenotype. Here, we describe a nanoparticle that provides spatiotemporal control over neutrophil fate to both stymie MI pathogenesis and promote healing. Intravenous injection of roscovitine/catalase-loaded poly(lactic-co-glycolic acid) nanoparticles after MI leads to nanoparticle uptake by circulating neutrophils migrating to the infarcted heart. Activated neutrophils at the infarcted heart generate reactive oxygen species, triggering intracellular release of roscovitine, a cyclin-dependent kinase inhibitor, from the nanoparticles, thereby inducing neutrophil apoptosis. Timely apoptosis of activated neutrophils at the infarcted heart limits neutrophil-driven inflammation, promotes macrophage polarization toward a pro-resolving phenotype, and preserves heart function. Modulating neutrophil fate to tune both inflammatory and reparatory processes may be an effective strategy to treat MI. Neutrophils are involved in both the initiation and resolution of cardiac inflammation post myocardial infarction (MI). Here, the authors show that intravenously injected nanoparticles can modulate cardiac neutrophils to inhibit inflammation and promote repair for MI therapy.

Cellular senescence contributes to inflammatory kidney disease via the secretion of inflammatory and profibrotic factors. Protease‐activating receptor 2 (PAR2) is a key regulator of inflammation in kidney diseases. However, the relationship between PAR2 and cellular senescence in kidney disease has not yet been described. In this study, we found that PAR2‐mediated metabolic changes in renal tubular epithelial cells induced cellular senescence and increased inflammatory responses. Using an aging and renal injury model, PAR2 expression was shown to be associated with cellular senescence. Under in vitro conditions in NRK52E cells, PAR2 activation induces tubular epithelial cell senescence and senescent cells showed defective fatty acid oxidation (FAO). Cpt1α inhibition showed similar senescent phenotype in the cells, implicating the important role of defective FAO in senescence. Finally, we subjected mice lacking PAR2 to aging and renal injury. PAR2‐deficient kidneys are protected from adenine‐ and cisplatin‐induced renal fibrosis and injury, respectively, by reducing senescence and inflammation. Moreover, kidneys lacking PAR2 exhibited reduced numbers of senescent cells and inflammation during aging. These findings offer fresh insights into the mechanisms underlying renal senescence and indicate that targeting PAR2 or FAO may be a promising therapeutic approach for managing kidney injury. This study uncovers the role of protease‐activating receptor 2 (PAR2) in promoting cellular senescence and inflammation in kidney disease. PAR2 activation induces metabolic changes leading to cellular senescence in renal tubular epithelial cells, highlighting its significance in renal pathophysiology. Mice lacking PAR2 exhibit reduced senescence and inflammation, suggesting PAR2 and fatty acid oxidation (FAO) as potential therapeutic targets for managing kidney injury.

Background Toll-like receptor 7 (TLR7) is an endosomal TLR activated by single-stranded RNA, including endogenous microRNAs. Although TLR7 is known to promote inflammatory responses in pathophysiological conditions, its role in renal fibrosis has not been investigated. Here, we aim to investigate the inflammatory roles of TLR7 in kidney inflammation and fibrosis. Methods TLR7 knockout mice ( Tlr7   −/− ) subjected to AD-induced kidney injury were utilized to examine the role of TLR7 in kidney fibrosis. To elucidate the role of TLR7 in renal epithelial cells, NRK52E rat renal tubule epithelial cells were employed. Results Under fibrotic conditions induced by an adenine diet (AD), TLR7 was significantly increased in damaged tubule epithelial cells, where macrophages were highly infiltrated. TLR7 deficiency protected against AD-induced tubular damage, inflammation, and renal fibrosis. Under in vitro conditions, TLR7 activation increased NF-κB activity and induced chemokine expression, whereas TLR7 inhibition effectively blocked NF-κB activation. Furthermore, among the known TLR7 endogenous ligands, miR-21 was significantly upregulated in the tubular epithelial regions. In NRK52E cells, miR-21 treatment induced pro-inflammatory responses, which could be blocked by a TLR7 inhibitor. When the TLR7 inhibitor, M5049, was administered to the AD-induced renal fibrosis model, TLR7 inhibition significantly attenuated AD-induced renal inflammation and fibrosis. Conclusions Overall, activation of TLR7 by endogenous miR-21 in renal epithelial cells contributes to inflammatory responses in a renal fibrosis model, suggesting a possible therapeutic target for the treatment of renal fibrosis. 8V5xz8c9tzre9tDnxLpjTT Video Abstract

Soft electronic devices that are bendable and stretchable require stretchable electric or electronic components. Nanostructured conducting materials or soft conducting polymers are one of the most promising fillers to achieve high performance and durability. Here, we report silver nanoparticles (AgNPs) embedded with single-walled carbon nanotubes (SWCNTs) synthesized in aqueous solutions at room temperature, using NaBH 4 as a reducing agent in the presence of highly oxidized SWCNTs as efficient nucleation agents. Elastic composite films composed of the AgNPs-embedded SWCNTs, Ag flake, and polydimethylsiloxane are irradiated with radiation from a Xenon flash lamp within a time interval of one second for efficient sintering of conductive fillers. Under high irradiation energy, the stretchable electrodes are created with a maximum conductivity of 4,907 S cm −1 and a highly stretchable stability of over 10,000 cycles under a 20% strain. Moreover, under a low irradiation energy, strain sensors with a gauge factor of 76 under a 20% strain and 5.4 under a 5% strain are fabricated. For practical demonstration, the fabricated stretchable electrode and strain sensor are attached to a human finger for detecting the motions of the finger.

Clinical courses of acute myocarditis are heterogeneous in populations and geographic regions. There is a dearth of long-term outcomes data for acute myocarditis prior to the coronavirus disease pandemic, particularly in the older and female population. This study aimed to provide the nationwide epidemiologic approximates of clinically suspected acute myocarditis across adults of all ages over the long term. From the nationwide governmental health insurance database, a retrospective cohort comprised all patients aged 20-79 who were hospitalized for clinically suspected acute myocarditis without underlying cardiac diseases from 2006 to 2018. The complicated phenotype was defined as requiring hemodynamic or major organ support. Over 10 years, all-cause mortality and index event-driven excess mortality were evaluated according to young-adult (20-39 years), mid-life (40-59 years), and older-adult (60-79 years) age groups. Among 2,988 patients (51.0±16.9 years, 46.2% women), 362 (12.1%) were of complicated phenotype. Of these, 163 (45.0%) had died within 1 month. All-cause death at 30 days occurred in 40 (4.7%), 52 (4.8%), and 105 (10.0%) patients in the young-adult, mid-life, and older-adult groups, respectively. For 10 years of follow-up, all-cause death occurred in 762 (25.5%). Even in young adult patients with non-complicated phenotypes, excess mortality remained higher compared to the general population. In hospitalized patients with clinically suspected acute myocarditis, short-term mortality is high both in young and older adults, particularly those with comorbidities and severe clinical presentation. Furthermore, excess mortality remains high for at least 10 years after index hospitalization in young adults.

The progression of tuberculosis from a latent, subclinical infection to active disease that culminates in the transmission of infectious bacilli is determined locally at the level of the granuloma. This progression takes place even in the face of a robust immune response that, although it contains infection, is unable to eliminate the bacterium. The factors or environmental conditions that influence this progression remain to be determined. Recent advances have indicated that pathogen-induced dysregulation of host lipid synthesis and sequestration serves a critical role in this transition. The foamy macrophage seems to be a key participant in both sustaining persistent bacteria and contributing to the tissue pathology that leads to cavitation and the release of infectious bacilli.

With increasing technological demand for portable electronic and photovoltaic devices, it has become critical to ensure the electrical and mechano-electric reliability of electrodes in such devices. However, the limited flexibility and high processing costs of traditional electrodes based on indium tin oxide undermine their application in flexible devices. Among various alternative materials for flexible electrodes, such as metallic/carbon nanowires or meshes, silver nanowire (Ag NW) networks are regarded as promising candidates owing to their excellent electrical, optical, and mechano-electric properties. In this context, there have been tremendous studies on the physico-chemical and mechano-electric properties of Ag NW networks. At the same time, it has been a crucial job to maximize the device performance (or their mechano-electric performance) by reconciliation of various properties. This review discusses the properties and device applications of Ag NW networks under dynamic motion by focusing on notable findings and cases in the recent literature. Initially, we introduce the fabrication (deposition process) of Ag NW network-based electrodes from solution-based coating processes (drop casting, spray coating, spin coating, etc.) to commercial processes (slot-die and roll-to-roll coating). We also discuss the electrical/optical properties of Ag NW networks, which are governed by percolation, and their electrical contacts. Second, the mechano-electric properties of Ag NW networks are reviewed by describing individual and combined properties of NW networks with dynamic motion under cyclic loading. The improved mechano-electric properties of Ag NW network-based flexible electrodes are also discussed by presenting various approaches, including post-treatment and hybridization. Third, various Ag NW-based flexible devices (electronic and optoelectronic devices) are introduced by discussing their operation principles, performance, and challenges. Finally, we offer remarks on the challenges facing the current studies and discuss the direction of research in this field, as well as forthcoming issues to be overcome to achieve integration into commercial devices.

Background Free fatty acid receptors (FFARs) and toll-like receptors (TLRs) recognize microbial metabolites and conserved microbial products, respectively, and are functionally implicated in inflammation and cancer. However, whether the crosstalk between FFARs and TLRs affects lung cancer progression has never been addressed. Methods We analyzed the association between FFARs and TLRs using The Cancer Genome Atlas (TCGA) lung cancer data and our cohort of non-small cell lung cancer (NSCLC) patient data (n = 42), and gene set enrichment analysis (GSEA) was performed. For the functional analysis, we generated FFAR2-knockout ( FFAR2 KO) A549 and FFAR2 KO H1299 human lung cancer cells and performed biochemical mechanistic studies and cancer progression assays, including migration, invasion, and colony-formation assays, in response to TLR stimulation. Results The clinical TCGA data showed a significant down-regulation of FFAR2, but not FFAR1, FFAR3, and FFAR4, in lung cancer, and a negative correlation with TLR2 and TLR3. Notably, GSEA showed significant enrichment in gene sets related to the cancer module, the innate signaling pathway, and the cytokine-chemokine signaling pathway in FFAR2 Down TLR2 Up TLR3 Up lung tumor tissues (LTTs) vs. FFAR2 up TLR2 Down TLR3 Down LTTs. Functionally, treatment with propionate (an agonist of FFAR2) significantly inhibited human A549 or H1299 lung cancer migration, invasion, and colony formation induced by TLR2 or TLR3 through the attenuation of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB. Moreover, FFAR2 KO A549 and FFAR2 KO H1299 human lung cancer cells showed marked increases in cell migration, invasion, and colony formation in response to TLR2 or TLR3 stimulation, accompanied by elevations in NF-κB activation, cAMP levels, and the production of C-C motif chemokine ligand (CCL)2, interleukin (IL)-6, and matrix metalloproteinase (MMP) 2 cytokines. Conclusion Our results suggest that FFAR2 signaling antagonized TLR2- and TLR3-induced lung cancer progression via the suppression of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB, and its agonist might be a potential therapeutic agent for the treatment of lung cancer.

Fisetin is a flavonoid found in plants and has been reported to be effective in various human diseases. However, the effective mechanisms of ultraviolet-A (UVA)-mediated skin damage are not yet clear. In this study, we investigated the protective mechanisms of fisetin regarding UVA-induced human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) damages. Fisetin showed a cytoprotective effect against UVA irradiation and suppressed matrix metalloproteinases (MMPs), MMP-1, and MMP-3 expression. In addition, fisetin was rescued, which decreased mRNA levels of pro-inflammatory cytokines, reactive oxygen species production, and the downregulation of MAPK/AP-1 related protein and NADPH oxidase (NOX) mRNA levels. Furthermore, UVA-induced MMP-1 and MMP-3 were effectively inhibited by siRNAs to NOX 1 to 5 in HDFs and HEKs. These results indicate that fisetin suppresses UVA-induced damage through the NOX/ROS/MAPK pathway in HDFs and HEKs.