Outcomes of patients in nasopharyngeal adenoid cystic carcinoma in the IMRT era: a single-center experience.

OBJECTIVE: Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with special biological features. Controversies exist regarding the treatment approach and prognostic factors in the IMRT era. This study aimed to evaluate the long-term outcomes and management approaches in NACC. METHODS: Fifty patients with NACC at our institution between 2010 and 2020 were reviewed. Sixteen patients received primary radiotherapy (RT), and 34 patients underwent primary surgery. RESULTS: Between January 2010 and October 2020, a total of 50 patients with pathologically proven NACC were included in our analysis. The median follow-up time was 58.5 months (range: 6.0-151.0 months). The 5-year overall survival rate (OS) and progression-free survival rate (PFS) were 83.9% and 67.5%, respectively. The 5-year OS rates of patients whose primary treatment was surgery and RT were 90.0% and 67.3%, respectively (log-rank P = 0.028). The 5-year PFS rates of patients whose primary treatment was surgery or RT were 80.8% and 40.7%, respectively (log-rank P = 0.024). Multivariate analyses showed that nerve invasion and the pattern of primary treatment were independent factors associated with PFS. CONCLUSIONS: Due to the relative insensitivity to radiation, primary surgery seemed to provide a better chance of disease control and improved survival in NACC. Meanwhile, postoperative radiotherapy should be performed for advanced stage or residual tumours. Cranial nerve invasion and treatment pattern might be important factors affecting the prognosis of patients with NACC.

Targeting EFHD2 Inhibits Interferon-γ Signaling and Ameliorates Non-Alcoholic Steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of nonalcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. This study investigates the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in NASH pathogenesis. METHODS: Hepatic EFHD2 expression was characterized in NASH patients and two diet-induced NASH mouse models. Single-cell RNA-sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma (HCC) were assessed. Molecular mechanisms underlying EFHD2 function were investigated, along with its potential as a therapeutic target by chemical and genetic means. RESULTS: EFHD2 expression was significantly elevated in liver tissue macrophages/monocytes in both NASH patients and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related HCC. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of interferon-γ receptor-2 (IFNγR2) onto the plasma membrane. This interaction mediates IFNγ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a developed stapled α-helical peptide targeting EFHD2 demonstrated its efficacy in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all NAFLD patients progress to NASH. A key challenge is identifying the factors triggering inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of IFNγ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings suggest EFHD2 as a promising target for drug development aimed at NASH treatment.

Targeted metabolomic profiles of serum amino acids are independently correlated with malnutrition in older adults.

BACKGROUND: Malnutrition is a common geriatric syndrome that is closely associated with adverse clinical outcomes and poses significant harm to older adults. Early assessment of nutritional status plays a crucial role in preventing and intervening in cases of malnutrition. However, there is currently a lack of measurable methods and biomarkers to evaluate malnutrition in older adults accurately. The aim of this study is to investigate the independent correlation between serum levels of amino acids and malnutrition in older adults, and to identify effective metabolomics biomarkers that can aid in the early detection of geriatric malnutrition. METHODS: A total of 254 geriatric medical examination participants from Beijing Hospital were included in the study, consisting of 182 individuals with normal nutritional status (Normal group) and 72 patients at risk of malnutrition or already malnourished (MN group). Malnutrition was assessed using the Mini-Nutritional Assessment Short-Form (MNA-SF). Demographic data were collected, and muscle-related and lipid indexes were determined. Serum amino acid concentrations were measured using isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS). The correlation between serum amino acid levels and malnutrition was analyzed using non-parametric tests, partial correlation analysis, linear regression, and logistic regression. RESULTS: The geriatric MN group exhibited significantly lower serum aromatic amino acid levels (P < 0.05) compared to the normal group. A positive correlation was observed between serum aromatic amino acid levels and the MNA-SF score (P = 0.002), as well as with known biomarkers of malnutrition such as body mass index (BMI) (P < 0.001) and hemoglobin (HGB) (P = 0.005). Multivariable logistic or linear regression analyses showed that aromatic amino acid levels were negatively correlated with MN and positively correlated with the MNA-SF score, after adjusting for some confounding factors, such as age, gender, BMI, smoking status, history of dyslipidemia, diabetes mellitus and frailty. Stratified analyses revealed that these trends were more pronounced in individuals without a history of frailty compared to those with a history of frailty, and there was an interaction between aromatic amino acid levels and frailty history (P = 0.004). CONCLUSION: Our study suggests that serum aromatic amino acids are independently associated with malnutrition in older adults. These results have important implications for identifying potential biomarkers to predict geriatric malnutrition or monitor its progression and severity, as malnutrition can result in poor clinical outcomes.

MiRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrated that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cells balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of RA patients. Overall, the unique characteristics, including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues, position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

Ailanthone inhibits non-small cell lung cancer growth and metastasis through targeting UPF1/GAS5/ULK1 signaling pathway.

BACKGROUND: Targeting long non-coding RNAs (LncRNAs) is a novel and promising approach in cancer therapy. In our previous study, we investigated the effects of ailanthone (aila), the main active compound derived from the stem barks of Ailanthus altissima (Mill.) Swingle, on the growth of non-small cell lung cancer (NSCLC) cells. Although we observed significant inhibition of NSCLC cell growth of aila, the underlying mechanisms involving LncRNAs, specifically LncRNA growth arrest specific 5 (GAS5), remain largely unknown. METHODS: To further explore the impact of aila on NSCLC, we performed a series of experiments. Firstly, we confirmed the inhibitory effect of aila on NSCLC cell growth using multiple assays, including MTT, wound healing, transwell assay, as well as subcutaneous and metastasis tumor mice models in vivo. Next, we utilized cDNA microarray and RT-QPCR to identify GAS5 as the primary target of aila. To verify the importance of GAS5 in aila-induced tumor inhibition, we manipulated GAS5 expression levels by constructing GAS5 over-expression and knockdown NSCLC cell lines. Furthermore, we investigated the upstream and downstream signaling pathways of GAS5 through western blot and RT-QPCR analysis. RESULTS: Our results showed that aila effectively increased GAS5 expression, as determined by microarray analysis. We also observed that aila significantly enhanced GAS5 expression in a dose- and time-dependent manner across various NSCLC cell lines. Notably, over-expression of GAS5 led to a significant suppression of NSCLC cell tumor growth; while aila had minimal inhibitory effect on GAS5-knockdown NSCLC cells. Additionally, we discovered that aila inhibited ULK1 and autophagy, and this inhibition was reversed by GAS5 knockdown. Moreover, we found that aila up-regulated GAS5 expression by suppressing UPF1-mediated nonsense-mediated mRNA decay (NMD). CONCLUSION: In summary, our findings suggest that aila promotes GAS5 expression by inhibiting UPF1-mediated NMD, leading to the repression of ULK1-mediated autophagy and subsequent inhibitory effects on NSCLC cells. These results indicate that aila is a potent enhancer of GAS5 and holds promising potential for application in NSCLC therapy. However, our research is currently focused only on NSCLC. It remains to be determined whether aila can also inhibit the growth of other types of tumors through the UPF1/GAS5/ULK1 signaling pathway. In future studies, we can further investigate the mechanisms by which aila suppresses other types of tumors and potentially broaden the scope of its application in cancer therapy.

Effects of folic acid supplementation on cognitive impairment: A meta-analysis of randomized controlled trials.

OBJECTIVE: With the increasing number of patients with cognitive impairment, nonpharmacological ways to delay cognitive impairment have attracted people's attention, such as lifestyle changes and nutritional supplementation. Folic acid supplementation appears to be a promising treatment option. However, it remains controversial whether folic acid supplementation is effective in delaying adult's cognitive impairment. Therefore, we conducted a meta-analysis to analyze the effects of folic acid supplementation on different cognitive impairments. METHODS: We systematically searched PubMed, Web of Science, EMbase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI), WanFang and VIP databases for randomized controlled trials on January 22, 2024. The included population comprised those diagnosed with cognitive impairment. We included trials that compared folic acid treatment with placebo, other dosing regimens, or other intervention controls. Conducting quality evaluation of included studies according to the Cochrane Risk of Bias tool. Statistical analyses were performed using Review Manager software. RESULTS: Twenty-two trials, including 3604 participants, met inclusion criteria. Compared with controls, the cognitive function of Alzheimer's disease (AD) patients showed improvement with folic acid supplementation: supplementation with < 3 mg (standardized mean differences (SMD) = 0.15, 95% confidence interval (CI) -0.10 to 0.41), and supplementing with ≥ 3 mg folic acid could improve cognitive function in AD patients (SMD = 1.03, 95% CI 0.18 to 1.88). Additionally, it reduced homocysteine (HCY) levels (mean differences (MD) = -4.74, 95% CI -8.08 to -1.39). In mild cognitive impairment (MCI) patients, cognitive function improved with folic acid supplementation: supplementation with > 400 µg (SMD = 0.38, 95% CI 0.13 to 0.63), and supplementation with ≤ 400 µg (SMD = 1.10, 95% CI 0.88 to 1.31). It also reduced HCY levels at intervention ≤ 6 months (MD = -3.93, 95% CI -5.05 to -2.82) and intervention > 6 months (MD = -4.38, 95% CI -5.15 to -3.61). However, supplementing with folic acid did not improve cognitive function in vascular cognitive impairment (VCI) patients, with folic acid supplements < 3 mg (SMD = -0.07, 95% CI -0.23 to -0.08), folic acid supplements ≥ 3 mg (SMD = 0.46, 95% CI -0.57 to 1.49), however, it reduced HCY levels at intervention > 6 months (MD = -5.91, 95% CI -7.13 to -4.69) and intervention ≤ 6 months (MD = -11.15, 95% CI -12.35 to -9.95). CONCLUSIONS: Supplement folic acid is beneficial to the cognitive profile of patients with MCI, supplementation with ≥ 3 mg folic acid can improve cognitive function in AD patients.

The discovery of three-dimensional Van Hove singularity.

Arising from the extreme/saddle point in electronic bands, Van Hove singularity (VHS) manifests divergent density of states (DOS) and induces various new states of matter such as unconventional superconductivity. VHS is believed to exist in one and two dimensions, but rarely found in three dimension (3D). Here, we report the discovery of 3D VHS in a topological magnet EuCd2As2 by magneto-infrared spectroscopy. External magnetic fields effectively control the exchange interaction in EuCd2As2, and shift 3D Weyl bands continuously, leading to the modification of Fermi velocity and energy dispersion. Above the critical field, the 3D VHS forms and is evidenced by the abrupt emergence of inter-band transitions, which can be quantitatively described by the minimal model of Weyl semimetals. Three additional optical transitions are further predicted theoretically and verified in magneto-near-infrared spectra. Our results pave the way to exploring VHS in 3D systems and uncovering the coordination between electronic correlation and the topological phase.

Recyclable Fe3O4@UiO-66-PDA core-shell nanomaterials for extensive metal ion adsorption: Batch experiments and theoretical analysis.

With the ever-increasing challenge of heavy metal pollution, the imperative for developing highly efficient adsorbents has become apparent to remove metal ions from wastewater completely. In this study, we introduce a novel magnetic core-shell adsorbent, Fe3O4@UiO-66-PDA. It features a polydopamine (PDA) modified zirconium-based metal-organic framework (UiO-66) synthesized through a simple solvothermal method. The adsorbent boasts a unique core-shell architecture with a high specific surface area, abundant micropores, and remarkable thermal stability. The adsorption capabilities of six metal ions (Fe3+, Mn2+, Pb2+, Cu2+, Hg2+, and Cd2+) were systematically investigated, guided by the theory of hard and soft acids and bases. Among these, three representative metal ions (Fe3+, Pb2+, and Hg2+) were scrutinized in detail. The activated Fe3O4@UiO-66-PDA exhibited exceptional adsorption capacities for these metal ions, achieving impressive values of 97.99 mg/g, 121.42 mg/g, and 130.72 mg/g, respectively, at pH 5.0. Moreover, the adsorbent demonstrated efficient recovery from aqueous solution using an external magnet, maintaining robust adsorption efficiency (>80%) and stability even after six cycles. To delve deeper into the optimized adsorption of Hg2+, density functional theory (DFT) analysis was employed, revealing an adsorption energy of -2.61 eV for Hg2+. This notable adsorption capacity was primarily attributed to electron interactions and coordination effects. This study offers valuable insights into metal ion adsorption facilitated, by magnetic metal-organic framework (MOF) materials.

The cyclooxygenase-2 upregulation mediates production of PGE2 autacoid to positively regulate interleukin-6 secretion in chronic rhinosinusitis with nasal polyps and polyp-derived fibroblasts.

Chronic rhinosinusitis (CRS) can be traditionally classified as CRSwNP [with nasal polyps (NPs)] and CRSsNP (without NPs) based on the clinical phenotypes but recently suggested to be classified by the endotypes. We have identified overexpression of the cyclooxygenase-2 (COX-2) gene in NP tissues of Taiwanese CRSwNP patients. Therefore, in this study, we sought to investigate its protein expression/location/distribution in NP specimens and explore its roles in nasal polyposis. The COX-2 protein and mRNA expression was found higher in NPs than that in the control and CRSsNP patients' nasal tissues, mainly located at the epithelium and subepithelial stroma. Consistently, the CRS-related peptidoglycan (PGN) and bradykinin provoked COX-2 mRNA and protein upregulation in the human NP-derived fibroblasts and caused PGE2, thromboxane A2 (TXA2), and interleukin (IL-6) secretion in culture medium. Further analysis revealed that the PI3K/Akt activation and COX-2 induction were necessarily required for PGN-induced IL-6 production/secretion and the induced PGE2, but not TXA2, was speculated to affect IL-6 protein trafficking and production. Finally, the IL-6 increase observed in vitro could also be detected in NP tissues. Collectively, we demonstrated here that COX-2 protein and IL-6 are overexpressed in human NP tissues. In response to PGN challenge, the PI3K/Akt activation and COX-2-mediated PGE2 autacoid correlates with extracellular IL-6 protein trafficking/production in NP-derived fibroblasts, which can additionally contribute to the production of Th17-related cytokines such as IL-17 and TNF-α. This study also suggests COX-2 as a special biomarker for CRSwNP endotyping and may highlight the importance of COX-2 inhibitors in treating CRSwNP.

Impacts of microplastic contamination on the rheology properties of sediments in a eutrophic shallow lake.

Microplastic (MP) contamination is a growing global concern, with lake sediments serving as a significant sink for MP due to both anthropogenic and natural activities. Given the increasing evidence of MP accumulation in sediments, it was crucial to assess their influence on sediment erosion resistance, which directly affected sediment resuspension. To fill this gap, this study focused on the effect of MP on the sediments rheological properties. After 60-day experiments, it was found that MP addition into sediments reduced sediment viscosity, yield stress, and flow point shear stress. Meanwhile, MPs also significantly altered sediment properties and extracellular polymer composition. MP addition reduced extracellular polymeric substances production and cation exchange capacity, which then worked together and led to a weak sediment structure. Seemingly, MPs changed fluid sediment characteristics and caused stronger fluidity under less shear force. Consequently, the accumulation of MP might facilitate the resuspension of sediments under smaller wind and wave disturbances. This study provided novel insights into the direct impact of MPs on sediment physical properties using rheology, thereby enhancing our understanding of the environmental behavior of MPs in lake ecosystems.

Construction of an instrument to enable the assessment of the risk of falls in older outpatients: A quantitative methodological study.

OBJECTIVES: To develop an instrument to facilitate the risk assessment of falls in older outpatients. DESIGN: A quantitative methodological study using the cross-sectional data. METHODS: This study enrolled 1988 older participants who underwent comprehensive geriatric assessment (CGA) in an outpatient clinic from May 2020 to November 2022. The history of any falls (≥1 falls in a year) and recurrent falls (≥2 falls in a year) were investigated. Potential risk factors of falls were selected by stepwise logistic regression, and a screening tool was constructed based on nomogram. The tool performance was compared with two reference tools (Fried Frailty Phenotype; CGA with 10 items, CGA-10) by using receiver operating curves, sensitivity (Sen), specificity (Spe), and area under the curve (AUC). RESULTS: Age, unintentional weight loss, depression measured by the Patient Health Questionnaire-2, muscle strength measured by the five times sit-to-stand test, and stand balance measured by semi- and full-tandem standing were the most important risk factors for falls. A fall risk screening tool was constructed with the six measurements (FRST-6). FRST-6 showed the best AUC (Sen, Spe) of 0.75 (Sen = 0.72, Spe = 0.69) for recurrent falls and 0.65 (Sen = 0.74, Spe = 0.48) for any falls. FRST-6 was comparable to CGA-10 and outperformed FFP in performance. CONCLUSIONS: Age, depression, weight loss, gait, and balance were important risk factors of falls. The FRST-6 tool based on these factors showed acceptable performance in risk stratification. IMPACT: Performing a multifactorial assessment in primary care clinics is urgent for falls prevention. The FRST-6 provides a simple and practical way for falls risk screening. With this tool, healthcare professionals can efficiently identify patients at risk of falling and make appropriate recommendations in resource-limited settings. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution was received, due to our study design.

Protective role of curcumin in disease progression from non-alcoholic fatty liver disease to hepatocellular carcinoma: a meta-analysis.

Background: Pathological progression from non-alcoholic fatty liver disease (NAFLD) to liver fibrosis (LF) to hepatocellular carcinoma (HCC) is a common dynamic state in many patients. Curcumin, a dietary supplement derived from the turmeric family, is expected to specifically inhibit the development of this progression. However, there is a lack of convincing evidence. Methods: The studies published until June 2023 were searched in PubMed, Web of Science, Embase, and the Cochrane Library databases. The SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) approach was used to evaluate the certainty of evidence. StataSE (version 15.1) and Origin 2021 software programs were used to analyze the critical indicators. Results: Fifty-two studies involving 792 animals were included, and three disease models were reported. Curcumin demonstrates a significant improvement in key indicators across the stages of NAFLD, liver fibrosis, and HCC. We conducted a detailed analysis of common inflammatory markers IL-1ß, IL-6, and TNF-α, which traverse the entire disease process. The research results reveal that curcumin effectively hinders disease progression at each stage by suppressing inflammation. Curcumin exerted hepatoprotective effects in the dose range from 100 to 400 mg/kg and treatment duration from 4 to 10 weeks. The mechanistic analysis reveals that curcumin primarily exerts its hepatoprotective effects by modulating multiple signaling pathways, including TLR4/NF-κB, Keap1/Nrf2, Bax/Bcl-2/Caspase 3, and TGF-ß/Smad3. Conclusion: In summary, curcumin has shown promising therapeutic effects during the overall progression of NAFLD-LF-HCC. It inhibited the pathological progression by synergistic mechanisms related to multiple pathways, including anti-inflammatory, antioxidant, and apoptosis regulation.

Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.

L-Serine enables reducing the virulence of Acinetobacter baumannii and modulating the SIRT1 pathway to eliminate the pathogen.

The emergence of high-virulent Acinetobacter baumannii strains increases the mortality of patients and seriously affects their prognosis, which motivates us to explore novel ways to control such infections. In this study, gas chromatography-mass spectrometry was adopted to explore the metabolic difference between high- and low-virulent A. baumannii strains, and the decreased L-serine levels were identified as the most crucial biomarker in low-virulent A. baumannii strains. In vitro, L-serine reduced the virulence of A. baumannii to Beas 2B cells and inhibited the activation of NLRP3 inflammasome via decreasing the generation of ROS and mtROS and the release of inflammatory cytokines (IL-18 and IL-1ß) through upregulating SIRT1. In vivo, the Galleria mellonella model was adopted. L-serine downregulated the levels of virulence genes (ompA, carO, and omp33-36), reduced the mortality of A. baumannii to G. mellonella, and decreased the blacking speed as well as the degree of G. mellonella after infection. Taken together, we found that L-serine can reduce the virulence of A. baumannii and enhance the host's defense against the pathogen, providing a novel strategy for the treatment of infections caused by A. baumannii.IMPORTANCEAcinetobacter baumannii has become one of the most common and severe opportunistic pathogens in hospitals. The high-virulent A. baumannii strains pose a great threat to patients and increase the risk of nosocomial infection. However, the mechanism of virulence in A. baumannii is still not well understood. In the present study, we identified potential biomarkers in low-virulent A. baumannii strains. Our analysis revealed the effect of L-serine on reducing the virulence of A.baumannii. This discovery suggests that targeting L-serine could be a promising strategy for the treatment or adjunctive treatment of A. baumannii infections. The development of treatments targeting virulence may provide a substitute for the increasingly failed traditional antibacterial treatment.

Silica Nanoparticles Shed Light on Intriguing Cellular Pathways in Human Tracheal Smooth Muscle Cells: Revealing COX-2/PGE2 Production through the EGFR/Pyk2 Signaling Axis.

The use of manufactured silica nanoparticles (SiNPs) has become widespread in everyday life, household products, and various industrial applications. While the harmful effects of crystalline silica on the lungs, known as silicosis or chronic pulmonary diseases, are well understood, the impact of SiNPs on the airway is not fully explored. This study aimed to investigate the potential effects of SiNPs on human tracheal smooth muscle cells (HTSMCs). Our findings revealed that SiNPs induced the expression of cyclooxygenase-2 (COX-2) mRNA/protein and the production of prostaglandin E2 (PGE2) without causing cytotoxicity. This induction was transcription-dependent, as confirmed by cell viability assays and COX-2 luciferase reporter assays. Further analysis, including Western blot with pharmacological inhibitors and siRNA interference, showed the involvement of receptor tyrosine kinase (RTK) EGF receptor (EGFR), non-RTK Pyk2, protein kinase Cα (PKCα), and p42/p44 MAPK in the induction process. Notably, EGFR activation initiated cellular signaling that led to NF-κB p65 phosphorylation and translocation into the cell nucleus, where it bound and stimulated COX-2 gene transcription. The resulting COX-2 protein triggered PGE2 production and secretion into the extracellular space. Our study demonstrated that SiNPs mediate COX-2 up-regulation and PGE2 secretion in HTSMCs through the sequential activation of the EGFR/Pyk2/PKCα/p42/p44MAPKs-dependent NF-κB signaling pathway. Since PGE2 can have both physiological bronchodilatory and anti-inflammatory effects, as well as pathological pro-inflammatory effects, the increased PGE2 production in the airway might act as a protective compensatory mechanism and/or a contributing factor during airway exposure to SiNPs.

Super-tetragonal Sr4Al2O7 as a sacrificial layer for high-integrity freestanding oxide membranes.

Identifying a suitable water-soluble sacrificial layer is crucial to fabricating large-scale freestanding oxide membranes, which offer attractive functionalities and integrations with advanced semiconductor technologies. Here, we introduce a water-soluble sacrificial layer, "super-tetragonal" Sr4Al2O7 (SAOT). The low-symmetric crystal structure enables a superior capability to sustain epitaxial strain, allowing for broad tunability in lattice constants. The resultant structural coherency and defect-free interface in perovskite ABO3/SAOT heterostructures effectively restrain crack formation during the water release of freestanding oxide membranes. For a variety of nonferroelectric oxide membranes, the crack-free areas can span up to a millimeter in scale. This compelling feature, combined with the inherent high water solubility, makes SAOT a versatile and feasible sacrificial layer for producing high-quality freestanding oxide membranes, thereby boosting their potential for innovative device applications.

Tim-3 deficiency aggravates cadmium nephrotoxicity via regulation of NF-κB signaling and mitochondrial damage.

Kidney is the target organ of serious cadmium injury. Kidney damage caused by cadmium exposure is greatly influenced by the inflammatory response and mitochondrial damage. T cell immunoglobulin domain and mucin domain 3 (Tim-3) is an essential protein that functions as a negative immunological checkpoint to regulate inflammatory responses. Mice were given cadmium treatments at various dosages (0, 1.5, 3, 4.5 mg/kg) and times (0, 3, 5, 7 days) to assess the effects of cadmium on kidney damage. We found that the optimal way to induce kidney injury in mice was to inject 4.5 mg/kg of cadmium intraperitoneally for five days. It is interesting that giving mice 4.5 mg/kg of cadmium intravenously for seven days drastically lowered their survival rate. After cadmium exposure, Tim-3 knockout mice exhibited higher blood concentrations of urea nitrogen and creatinine compared to control mice. Tim-3 impacted the expression of oxidative stress-associated genes such as UDP glucuronosyltransferase family 1 member A9 (Ugt1a9), oxidative stress-induced growth inhibitor 2 (Osgin2), and S100 calcium binding protein A8 (S100a8), according to RNA-seq and real-time RT-PCR data. Tim-3 deficiency also resulted in activated nuclear factor-kappa B (NF-κB) signaling pathway. The NF-κB inhibitor 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) significantly alleviated cell apoptosis, oxidative stress response, and renal tubule inflammation in Tim-3 knockout mice exposed to cadmium. Furthermore, cadmium caused obvious B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) translocation from cytoplasm to mitochondria, which can be inhibited by TPCA-1. In conclusion, Tim-3 prevented mitochondrial damage and NF-κB signaling activation, hence providing protection against cadmium nephrotoxicity.

Cornus officinalis var. koreana Kitam extracts alleviate cadmium-induced renal fibrosis by targeting matrix metallopeptidase 9.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis var. koreana Kitam (Cornus officinalis) is a commonly used Chinese herbal medicine and has a good clinical efficacy in kidney and liver diseases. Recent years, a number of studies reported the significant effects of Cornus officinalis on renal fibrosis. However, it is still unclear about the underlying specific mechanism, the bioactive ingredients, and the target gene regulatory network. AIM OF THE STUDY: We investigated the impact of Cornus officinalis extract on cadmium-induced renal fibrosis, screened the bioactive ingredients of Cornus officinalis using a pharmacological sub-network analysis, and explored the regulatory effects of Cornus officinalis extracts on target gene matrix metallopeptidase 9 (MMP9). METHODS: Male C57BL/6N mice were treated with single or combinatorial agents such as saline, cadmium chloride, Cornus officinalis, Isoginkgetin and FSL-1. Isoginkgetin is a compound with anti-MMP9 activity. FSL-1 can induce MMP9 expression. Masson staining and Western blot and immunohistochemistry analyses were used for assessing renal fibrosis. In addition, wound healing model was established using BUMPT (Boston university mouse proximal tubular) cells to investigate how Cornus officinalis affected cadmium-induced cell migration. The main Cornus officinalis bioactive compounds were identified by UHPLC-MS (Ultra-high-performance liquid chromatography - mass spectrometry). The MMP9 target for Cornus officinalis active ingredients were confirmed through a pharmacological sub-network analysis. RESULTS: Aqueous extracts of Cornus officinalis protected from renal dysfunction and kidney fibrosis induced by cadmium chloride in mice. In vitro experiments validated that Cornus officinalis extracts inhibited cell migration ability especially in cadmium chloride condition. The sub-network analysis and chemical components profiling technique revealed the active compounds of Cornus officinalis. Cellular thermal shift assay verified the binding abilities of three active components Daidzein, N-Acetyl-L-tyrosine or Swertisin with matrix metalloproteinase-9. Gelatin zymography assay revealed that the activity of MMP9 was inhibited by the three active components. We further confirmed that MMP9 was involved in the process of Cornus officinalis extracts reducing renal fibrosis. Cornus officinalis attenuated the cadmium-induced renal fibrosis was correlated with decreased expression of MMP9, collagen I, α-SMA (alpha-smooth muscle actin) and vimentin. CONCLUSIONS: This study demonstrated that Cornus officinalis extracts could alleviate the cadmium chloride-induced renal fibrosis by targeting MMP9, and might provide new insights into the mechanism of treating renal fibrosis by Cornus officinalis.

Infusion of GMSCs relieves autoimmune arthritis by suppressing the externalization of neutrophil extracellular traps via PGE2-PKA-ERK axis.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B × N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis. OBJECTIVES: To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis. METHODS: The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B × N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments. RESULTS: We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation. CONCLUSION: Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory diseases.

Interplay of IL-33 and IL-35 Modulates Th2/Th17 Responses in Cigarette Smoke Exposure HDM-Induced Asthma.

Cigarette smoke (CS) facilitates adverse effects on the airway inflammation and treatment of asthma. Here, we investigated the mechanisms by which CS exacerbates asthma. The roles of IL-33 and IL-35 in asthma development were examined by treatment with IL-33 knockout (IL-33 KO) or transfection of adenovirus encoding IL-35 (Ad-IL-35) in a murine model of cigarette smoke-exposure asthma. Furthermore, the involvement of IL-33 and IL-35 in regulating DCs and Th2/Th17 cells was examined in a coculture system of DCs with CD4+ T cells. Additionally, we observed the effect of CpG-ODNs on the balance of IL-33 and IL-35. We show that CS and house dust mite (HDM) exposure induced IL-33 and suppressed IL-35 levels in cigarette smoke-exposure asthma in vivo and in vitro. Treatment with IL-33 KO or Ad-IL-35 significantly attenuated airway hyperreactivity, goblet hyperplasia, airway remodelling, and eosinophil and neutrophil infiltration in the lung tissues from asthmatic mice. Furthermore, we demonstrated reciprocal regulation between CS and HDM-modulated IL-33 and IL-35. Mechanistically, IL-33 KO (or anti-ST2) and Ad-IL-35 attenuated Th2- and Th17-associated inflammation by downregulating TSLP-DC signalling. Finally, administration of CpG-ODNs suppressed the expression of IL-33/ST2 and elevated the levels of IL-35, which is mainly derived from CD4+Foxp+ Tregs, to alleviate Th2- and Th17-associated inflammation by inhibiting the activation of BMDCs. Taken together, the IL-33/ST2 pathway drives the DC-Th2 and Th17 responses of cigarette smoke-exposure asthma, while IL-35 has the opposite effect. CpG-ODNs represent a potential therapeutic strategy for modulating the balance of IL-33 and IL-35 to suppress allergic airway inflammation.