AAV-mediated Gene Cocktails Enhance Supporting Cell Reprogramming and Hair Cell Regeneration.

Mammalian cochlear hair cells (HCs) are essential for hearing, and damage to HCs results in severe hearing impairment. Damaged HCs can be regenerated by neighboring supporting cells (SCs), thus the functional regeneration of HCs is the main goal for the restoration of auditory function in vivo. Here, cochlear SC trans-differentiation into outer and inner HC by the induced expression of the key transcription factors Atoh1 and its co-regulators Gfi1, Pou4f3, and Six1 (GPAS), which are necessary for SCs that are destined for HC development and maturation via the AAV-ie targeting the inner ear stem cells are successfully achieved. Single-cell nuclear sequencing and lineaging tracing results showed that the majority of new Atoh1-derived HCs are in a state of initiating differentiation, while GP (Gfi1, Pou4f3) and GPS (Gfi1, Pou4f3, and Six1) enhanced the Atoh1-induced new HCs into inner and outer HCs. Moreover, the patch-clamp analysis indicated that newborn inner HCs induced by GPAS forced expression have similar electrophysiological characteristics to those of native inner HCs. Also, GPAS can induce HC regeneration in the HC-damaged mice model. In summary, the study demonstrates that AAV-mediated co-regulation of multiple genes, such as GPAS, is an effective means to achieve functional HC regeneration in the mouse cochlea.

Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice.

BACKGROUND: Postoperative Cognitive Dysfunction (POCD) has attracted increased attention, but its precise mechanism remains to be explored. This study aimed to figure out whether HDAC6 could regulate NLRP3-induced pyroptosis by modulating the functions of HSP70 and HSP90 in microglia to participate in postoperative cognitive dysfunction in aged mice. METHODS: Animal models of postoperative cognitive dysfunction in aged mice were established by splenectomy under sevoflurane anesthesia. Morris water maze was used to examine the cognitive function and motor ability. Sixteen-months-old C57BL/6 male mice were randomly divided into six groups: control group (C group), sham surgery group (SA group), splenectomy group (S group), splenectomy + HDAC6 inhibitor ACY-1215 group (ACY group), splenectomy + HDAC6 inhibitor ACY-1215 + HSP70 inhibitor Apoptozole group (AP group), splenectomy + solvent control group (SC group). The serum and hippocampus of mice were taken after mice were executed. The protein levels of HDAC6, HSP90, HSP70, NLRP3, GSDMD-N, cleaved-Caspase-1 (P20), IL-1ß were detected by western blotting. Serum IL-1ß, IL-6 and S100ß were measured using ELISA assay, and cell localization of HDAC6 was detected by immunofluorescence. In vitro experiments, BV2 cells were used to validate whether this mechanism worked in microglia. The protein levels of HDAC6, HSP90, HSP70, NLRP3, GSDMD-N, P20, IL-1ß were detected by western blotting and the content of IL-1ß in the supernatant was measured using ELISA assay. The degree of acetylation of HSP90, the interaction of HSP70, HSP90 and NLRP3 were analyzed by coimmunoprecipitation assay. RESULTS: Splenectomy under sevoflurane anesthesia in aged mice could prolong the escape latency, reduce the number of crossing platforms, increase the expression of HDAC6 and activate the NLRP3 inflammasome to induce pyroptosis in hippocampus microglia. Using ACY-1215 could reduce the activation of NLRP3 inflammasome, the pyroptosis of microglia and the degree of spatial memory impairment. Apoptozole could inhibit the binding of HSP70 to NLRP3, reduce the degradation of NLRP3 and reverse the protective effect of HDAC6 inhibitors. The results acquired in vitro experiments closely resembled those in vivo, LPS stimulation led to the pyroptosis of BV2 microglia cells and the release of IL-1ß due to the activation of the NLRP3 inflammasome, ACY-1215 showed the anti-inflammatory effect and Apoptozole exerted the opposite effect. CONCLUSIONS: Our findings suggest that hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice.

Development and validation of serological dynamic risk score to predict outcome in gastric cancer with adjuvant chemotherapy: a multicentre, longitudinal, cohort study.

Background: Baseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests. Materials and methods: This was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters. Results: The Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy (P for interaction <0.0001). Compared with the low-low-low risk group, the low-low-high risk group of the long-term state chain (risk state at baseline, 6 months, 1 year) had the worse OS (HR, 6.91; 95%CI: 4.27, 11.19) and DFS (HR, 7.27; 95%CI: 4.55, 11.63). Conclusion: The dynamic risk score is an accurate and user-friendly serological risk assessment tool for predicting outcomes and assisting clinical decisions after gastrectomy.

A prediction model of elderly hip fracture mortality including preoperative red cell distribution width constructed based on the random survival forest (RSF) and Cox risk ratio regression.

An independent correlation between pre-RDW and 1-year mortality after surgery in elderly hip fracture can be used to predict mortality in elderly hip fracture patients and has predictive significance in anemia patients. With further research, a treatment algorithm can be developed to potentially identify patients at high risk of preoperative mortality. INTRODUCTION: Red blood cell distribution width (RDW) is an independent predictor of various disease states in elderly individuals, but its association with the prognosis of elderly hip fracture patients is controversial. This study aimed to evaluate the prognostic value of RDW in such patients, construct a prediction model containing RDW using random survival forest (RSF) and Cox regression analysis, and compare RDW in patients with and without anemia. METHODS: We retrospectively analyzed the data of elderly patients who underwent hip fracture surgery, selected the best variables using RSF, stratified the independent variables by Cox regression analysis, constructed a 1-year mortality prediction model of elderly hip fracture with RDW, and conducted internal validation and external validation. RESULTS: Two thousand one hundred six patients were included in this study. The RSF algorithm selects 12 important influencing factors, and Cox regression analysis showed that eight variables including preoperative RDW (pre-RDW) were independent risk factors for death within 1-year after hip fracture surgery in elderly patients. Stratified analysis showed that pre-RDW was still independently associated with 1-year mortality in the non-anemia group and not in the anemia group. The nomogram prediction model had high differentiation and fit, and the prediction model constructed by the total cohort of patients was also used for validation of patients in the anemia patients and obtained good clinical benefits. CONCLUSION: An independent correlation between pre-RDW and 1-year mortality after surgery in elderly hip fracture can be used to predict mortality in elderly hip fracture patients and has predictive significance in anemia patients.

Multi-Wavelength Selective and Broadband Near-Infrared Plasmonic Switches in Anisotropic Plasmonic Metasurfaces.

Anisotropic plasmonic metasurfaces have attracted broad research interest since they possess novel optical properties superior to natural materials and their tremendous design flexibility. However, the realization of multi-wavelength selective plasmonic metasurfaces that have emerged as promising candidates to uncover multichannel optical devices remains a challenge associated with weak modulation depths and narrow operation bandwidth. Herein, we propose and numerically demonstrate near-infrared multi-wavelength selective passive plasmonic switching (PPS) that encompasses high ON/OFF ratios and strong modulation depths via multiple Fano resonances (FRs) in anisotropic plasmonic metasurfaces. Specifically, the double FRs can be fulfilled and dedicated to establishing tailorable near-infrared dual-wavelength PPS. The multiple FRs mediated by in-plane mirror asymmetries cause the emergence of triple-wavelength PPS, whereas the multiple FRs governed by in-plane rotational asymmetries avail the implementation of the quasi-bound states in the continuum-endowed multi-wavelength PPS with the ability to unfold a tunable broad bandwidth. In addition, the strong polarization effects with in-plane anisotropic properties further validate the existence of the polarization-resolved multi-wavelength PPS. Our results provide an alternative approach to foster the achievement of multifunctional meta-devices in optical communication and information processing.

In Situ Preparation of Polyamine-Derived Ru Cluster@N-Doped Porous Carbon Nanoplates for Hydrogen Evolution over Wide pH Ranges.

Efficient and low-cost electrocatalysts for the hydrogen evolution reaction (HER) are required for producing hydrogen energy through water splitting. Carbon materials as HER catalyst supports are explored widely since the strong metal-support interactions are generally believed to be active and stable toward HER. Herein, we report N-doped porous carbon materials as novel substrates to stabilize the cluster metal sites through the Ru(III) polyamine complexes, which play an important role not only in efficient electron transfer but also in the increasing utilization of metallic active sites. Meanwhile, due to the strong metal-support interactions driven by Ru(III) polyamine complexes, the obtained Ru cluster with a mass loading of 3% on N-doped porous carbon nanoplates (Ru cluster@NCs) exhibits robust stability for HER at a constant voltage, proving to be a promising candidate catalyst for HER. Density functional theory calculations further indicate that the Gibbs free energy (ΔG) of adsorbed H* of Ru cluster@NCs is much closer to zero compared to Ru@(10%)NCs and Pt/C(20%), thus Ru cluster@NCs facilitate the HER process.

Synthesis, Preclinical Evaluation, and First-in-Human PET Study of [68Ga]-Labeled Biphenyl-Containing PSMA Tracers.

Radioisotope-labeled prostate-specific membrane antigen (PSMA) PET tracers have gained popularity in diagnosing prostate cancer (PCa). This study aimed to improve the affinity and tumor-targeting capabilities of new PSMA tracers by increasing the number of pharmacophores that specifically bind to PSMA. Using biphenyl as a core scaffold, we investigated the relationship among spacer segments, affinity, and pharmacokinetic properties. In preclinical PET studies on mice with 22Rv1 tumors, compared with [68Ga]Ga-PSMA-11 (SUVmax = 3.37), [68Ga]Ga-PSMA-D5 (Ki = 0.15) showed higher tumor uptake (SUVmax = 3.51) and lower renal uptake (T/K = 1.84). In the first-in-human study, [68Ga]Ga-PSMA-D5 effectively detected small PCa-associated lesions and distant metastases. The advantages of [68Ga]Ga-PSMA-D5 include high tumor uptake, straightforward synthesis, and labeling, making it a promising PSMA PET tracer. Furthermore, [68Ga]Ga-PSMA-D5 contains a DOTA chelator, allowing convenient labeling with therapeutic radionuclides such as 177Lu and 225Ac, providing the potential for targeted radioligand therapy in PCa.

Efficacy of immune checkpoint inhibitors along with chemotherapy in non-small cell lung cancer and the impact on adverse reactions and serum tumor markers.

OBJECTIVE: To examine the efficacy of immune checkpoint inhibitors along with chemotherapy in non-small cell lung cancer (NSCLC) and the effect on adverse reactions and serum tumor markers. METHODS: Data of 112 NSCLC patients admitted to Geriatric respiratory department, Xi'an International Medical Center Hospital from February 2018 to March 2021 were analyzed retrospectively. Among them, 54 patients treated with concurrent chemotherapy were labeled as the control group (CG), and 58 patients treated with PD-1/PD-L1 inhibitors in addition to chemotherapy were the observation group (OG). The two groups were compared in terms of immune function indexes, therapeutic efficacy, incidence of adverse reactions, 1-year survival rate, serum tumor markers before and after treatment, and independent risk factors affecting patients' prognosis. RESULTS: Compared to the CG, the OG exhibited significantly better therapeutic efficacy. The levels of IgG, IgA and IgM 6 months after treatment were significantly higher in both groups than those before treatment, and the elevations in the OG were more evident than those in the CG, and the OG demonstrated markedly lower Recombinant Cytokeratin Fragment Antigen 21-1 (CYFRA21-1), Carcinoembryonic antigen (CEA) and Carbohydrate antigen 125 (CA125) levels after treatment than the CG did. Between the two groups, there was no significant difference identified in the incidence of adverse reactions, but the OG was observed to have much higher 1-year survival rate. The pathological stage, differentiation and treatment regimen were independent risk factors affecting patients' prognosis. CONCLUSION: For NSCLC patients, the adoption of PD-1/PD-L1 inhibitors following chemoradiotherapy shows potential in enhancing clinical efficacy, boosting patients' immune function, and improving long-term survival rates, with premising safety profile.

A Pixel Circuit for Compensating Electrical Characteristics Variation and OLED Degradation.

In recent years, the active-matrix organic light-emitting diode (AMOLED) displays have been greatly required. A voltage compensation pixel circuit based on an amorphous indium gallium zinc oxide thin-film transistor is presented for AMOLED displays. The circuit is composed of five transistors-two capacitors (5T2C) in combination with an OLED. In the circuit, the threshold voltages of both the transistor and the OLED are extracted simultaneously in the threshold voltage extraction stage, and the mobility-related discharge voltage is generated in the data input stage. The circuit not only can compensate the electrical characteristics variation, i.e., the threshold voltage variation and mobility variation, but also can compensate the OLED degradation. Furthermore, the circuit can prevent the OLED flicker, and can achieve the wide data voltage range. The circuit simulation results show that the OLED current error rates (CERs) are lower than 3.89% when the transistor's threshold voltage variation is ±0.5V, lower than 3.49% when the mobility variation is ±30%.

Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization.

BACKGROUND: Polarization of microglia, the resident retinal immune cells, plays important roles in mediating both injury and repair responses post-retinal ischemia-reperfusion (I/R) injury, which is one of the main pathological mechanisms behind ganglion cell apoptosis. Aging could perturb microglial balances, resulting in lowered post-I/R retinal repair. Young bone marrow (BM) stem cell antigen 1-positive (Sca-1+) cells have been demonstrated to have higher reparative capabilities post-I/R retinal injury when transplanted into old mice, where they were able to home and differentiate into retinal microglia. METHODS: Exosomes were enriched from young Sca-1+ or Sca-1- cells, and injected into the vitreous humor of old mice post-retinal I/R. Bioinformatics analyses, including miRNA sequencing, was used to analyze exosome contents, which was confirmed by RT-qPCR. Western blot was then performed to examine expression levels of inflammatory factors and underlying signaling pathway proteins, while immunofluorescence staining was used to examine the extent of pro-inflammatory M1 microglial polarization. Fluoro-Gold labelling was then utilized to identify viable ganglion cells, while H&E staining was used to examine retinal morphology post-I/R and exosome treatment. RESULTS: Sca-1+ exosome-injected mice yielded better visual functional preservation and lowered inflammatory factors, compared to Sca-1-, at days 1, 3, and 7 days post-I/R. miRNA sequencing found that Sca-1+ exosomes had higher miR-150-5p levels, compared to Sca-1- exosomes, which was confirmed by RT-qPCR. Mechanistic analysis found that miR-150-5p from Sca-1+ exosomes repressed the mitogen-activated protein kinase kinase kinase 3 (MEKK3)/JNK/c-Jun axis, leading to IL-6 and TNF-α downregulation, and subsequently reduced microglial polarization, all of which contributes to reduced ganglion cell apoptosis and preservation of proper retinal morphology. CONCLUSION: This study elucidates a potential new therapeutic approach for neuroprotection against I/R injury, via delivering miR-150-5p-enriched Sca-1+ exosomes, which targets the miR-150-5p/MEKK3/JNK/c-Jun axis, thereby serving as a cell-free remedy for treating retinal I/R injury and preserving visual functioning.

Design and Characterization of Squaramic Acid-Based Prostate-Specific Membrane Antigen Inhibitors for Prostate Cancer.

Prostate-specific membrane antigen (PSMA) overexpressed on prostate cancer (PCa) cells is a satisfactory theranostic target in PCa. To seek novel non-glutamate-urea-based PSMA inhibitors by the strategy of bioisosterism, 10 ligands were designed, synthesized, and characterized. Among them, ligands 17, 18, and 21-24 bearing the squaramic acid moiety proved to be potent PSMA inhibitors, with Ki values ranging from 0.40 to 2.49 nM, which are comparable or higher in inhibitory potency compared to previously reported glutamate-urea-based inhibitors. Docking studies of 15, 17, and 19 were carried out to explore their binding mode in the active site of PSMA. Two near-infrared (NIR) probes, 23 (λEM = 650 nm) and 24 (λEM = 1088 nm), displayed favorable in vivo NIR imaging and successful NIR-II image-guided tumor resection surgery in PSMA-positive tumor-bearing mice, which demonstrated the effectiveness of these new squaramic acid-based inhibitors.

Morphology regulation of zero-valent iron nanosheets supported on microsilica for promoting peroxymonosulfate activation.

Combing the assisted dispersion strategy of support with the wet chemical reduction method, a novel nano-zero valent iron/microsilica (nZVI/M) composite was successfully fabricated, where the 2D nZVI nanosheets were uniformly anchored and covered on the surface of microsilica. The introduction of microsilica notably relieved the agglomeration effect of nZVI nanosheets, which induced the improvement of specific surface area (45.68 m2/g) and pore volume (0.172 cm3/g), and thereby exposing more active sites for bisphenol A (BPA) removal. The optimized nZVI/M-0.6 displayed the superior catalytic performance in the presence of peroxymonosulfate (PMS) with the degradation rate of BPA reached above 97% within 3 min and a higher constant rate of 0.659 min-1, which was approximately 3.9 times as high as that of nZVI/PMS system. The homogeneously dispersion of nZVI nanosheets on microsilica benefited for the assembly of the pollutants and boosting the kinetics of the catalytic degradation process. As a highly efficient PMS activator, it could well maintain the catalytic activity in different real water samples. The quenching experiments verified that SO4•- played the dominate role for BPA removal. This work offered novel insights for designing and preparing iron-based persulfate activator for wastewater treatment.

Plasmonic Sensing and Switches Enriched by Tailorable Multiple Fano Resonances in Rotational Misalignment Metasurfaces.

Fano resonances that feature strong field enhancement in the narrowband range have motivated extensive studies of light-matter interactions in plasmonic nanomaterials. Optical metasurfaces that are subject to different mirror symmetries have been dedicated to achieving nanoscale light manipulation via plasmonic Fano resonances, thus enabling advantages for high-sensitivity optical sensing and optical switches. Here, we investigate the plasmonic sensing and switches enriched by tailorable multiple Fano resonances that undergo in-plane mirror symmetry or asymmetry in a hybrid rotational misalignment metasurface, which consists of periodic metallic arrays with concentric C-shaped- and circular-ring-aperture unit cells. We found that the plasmonic double Fano resonances can be realized by undergoing mirror symmetry along the X-axis. The plasmonic multiple Fano resonances can be tailored by adjusting the level of the mirror asymmetry along the Z-axis. Moreover, the Fano-resonance-based plasmonic sensing that suffer from mirror symmetry or asymmetry can be implemented by changing the related structural parameters of the unit cells. The passive dual-wavelength plasmonic switches of specific polarization can be achieved within mirror symmetry and asymmetry. These results could entail benefits for metasurface-based devices, which are also used in sensing, beam-splitter, and optical communication systems.

Case report: Long response to PD-1 blockade after failure of trastuzumab plus chemotherapy in advanced Epstein-Barr virus-associated gastric cancer.

Background: Trastuzumab-containing chemotherapy is the first-line treatment for advanced gastric cancer (GC) with HER2 positive. Although PD-1 inhibitors significantly improved the outcome of GC patient's refractory to previous chemotherapy regimens, few studies explore the role of anti-PD-1 therapy overcomes resistance to trastuzumab plus chemotherapy in advanced Epstein-Barr Virus-associated gastric cancer (EBVaGC) with PD-L1 and HER2 positive. Case Presentation: We report a case of advanced EBVaGC in a 45-year-old man presenting with fatigue, dysphagia, and weight loss for several months. Initial endoscopy revealed a large tumor at the gastroesophageal junction. Computed tomography revealed GC accompanied by multiple lymph nodes and hepatic and pulmonary metastases. The immunohistochemistry indicated that HER-2 and PD-L1 were overexpressed, and tumor cells were positive for EBV-encoded small RNA (EBER) by in situ hybridization. Trastuzumab plus DCS was started as first-line chemotherapy with a PFS of 4 months and shifted to trastuzumab plus FOLFIRI or gemcitabine as second-/third-line therapy. After five-cycle nivolumab monotherapy, the patient received partial response and was treated with total radical gastrectomy plus sequential radiotherapy. He continued the postoperative immunotherapy over 30 cycles with a PFS of 28 months. Due to a new abdominal lymph node metastasis confirmed by PET-CT, he received toripalimab as the next-line treatment and achieved complete remission as the best objective response. Summary: We presented an advanced HER2-positive EBVaGC patient with PD-L1 high expression, refractory to trastuzumab plus chemotherapy, and had a durable clinical benefit sequence with a single dose of the PD-1 inhibitor.

Defect Engineering Modulated Iron Single Atoms with Assist of Layered Clay for Enhanced Advanced Oxidation Processes.

Single-atom catalysts (SACs) feature maximum atomic utilization efficiency; however, the loading amount, dispersibility, synthesis cost, and regulation of the electronic structure are factors that need to be considered in water treatment. In this study, kaolinite, a natural layered clay mineral, is applied as the support for g-C3 N4 and single Fe atoms (FeSA-NGK). The FeSA-NGK composite exhibits an impressive degradation performance toward the target pollutant (>98% degradation rate in 10 min), and catalytic stability across consecutive runs (90% reactivity maintained after three runs in a fluidized-bed catalytic unit) under peroxymonosulfate (PMS)/visible light (Vis) synergetic system. The introduction of kaolinite promotes the loading amount of single Fe atoms (2.57 wt.%), which is a 14.2% increase compared to using a bare catalyst without kaolinite, and improved the concentration of N vacancies, thereby optimizing the regulation of the electronic structure of the single Fe atoms. It is discovered that the single Fe atoms successfully occupied five coordinated N atoms and combined with a neighboring N vacancy. Consequently, this regulated the local electronic structure of single Fe atoms, which drives the electrons of N atoms to accumulate on the Fe centers. This study opens an avenue for the design of clay-based SACs for water purification.

Increased neutrophil-to-lymphocyte ratio is associated with unfavorable functional outcomes in acute pontine infarction.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is positively associated with unfavorable outcomes in patients with cerebral infarction. This study aimed to investigate the relationship between the NLR and the short-term clinical outcome of acute pontine infarction. METHODS: Patients with acute pontine infarction were consecutively included. Clinical and laboratory data were collected. All patients were followed up at 3 months using modified Rankin Scale (mRS) scores. An unfavorable outcome was defined as an mRS score ≥ 3. Receiver operating characteristic (ROC) curve analysis was used to calculate the optimal cutoff values for patients with acute pontine infarction. risk factors can be predictive factors for an unfavorable outcome after acute pontine infarction. RESULTS: Two hundred fifty-six patients with acute pontine infarction were included in this study. The NLR was significantly higher in the unfavorable outcome group than in the favorable outcome group (P < 0.05). Additionally, the infarct size was significantly higher in the high NLR tertile group than in the low NLR tertile group (P < 0.05). Multivariate logistic regression analysis revealed that the baseline National Institutes of Health Stroke Scale (NIHSS) score, NLR, platelet count, and fasting blood glucose (FBG) level were significantly associated with unfavorable outcomes 3 months after acute pontine infarction. The optimal cutoff value of the NLR for predicting the 3-month outcome of acute pontine infarction was 3.055. The negative and positive predictive values of NLR were 85.7% and 61.3%, respectively, and the sensitivity and specificity of NLR were 69.2% and 80.9%. CONCLUSIONS: We found that the NLR may be an independent predictive factor for the outcome of acute pontine infarction.

Kaempferol alleviates the inflammatory response and stabilizes the pulmonary vascular endothelial barrier in LPS-induced sepsis through regulating the SphK1/S1P signaling pathway.

Sepsis, a clinical syndrome causing multi-organ failure, is one of the leading causes of morbidity and mortality. The effective treatment strategies for sepsis are limited. Some studies have demonstrated the benefits of kaempferol in countering sepsis, but its specific mechanism of action is unclear. The study aimed to investigate the anti-sepsis effects and mechanisms of kaempferol via sphingosine kinase 1/sphingosine-1-phosphate (SphK1/S1P) signaling pathway in a lipopolysaccharide (LPS)-induced sepsis model. We elucidated the effect of kaempferol on sepsis in LPS-induced RAW264.7 cells, HUVECs and septic mice. In RAW264.7 cells. We found that kaempferol decreased the levels of inflammatory mediators NO and PGE2. Western blot showed that kaempferol inhibited the expression of SphK1, p-p65 and p-IκB-α. LC-MS/MS analyze showed that kaempferol decreased S1P content in RAW264.7 cells. In HUVECs, we found that kaempferol promoted the expression of SphK1 and S1P, while kaempferol increased the expression levels of VE-Cadherin and ß-catenin. In vivo, consistent with the in vitro results, kaempferol alleviated LPS-induced inflammatory responses and endothelial barrier damage. In addition, by immunofluorescence localization of F4/80, CD31 and SphK1, we found that kaempferol inhibited the expression of SphK1 in macrophages and increased the expression of SphK1 in endothelial cells. In summary, our present results not only suggested that kaempferol alleviated the inflammatory response and stabilizes the endothelial barrier in LPS-induced sepsis by regulating the SphK1/S1P signaling pathway, but also showed that kaempferol exhibited cell-specific effects on the regulation of SphK1 expression.

Prevalence and correlates of cigarette smoking among Dulong adults in China: A cross-sectional survey in 2020.

Background: The Dulong people are one of the minorities in China with the lowest population. In recent years, the lifestyle of the Dulong people has also changed drastically due to income growth and urbanization. This study aims to identify cigarette smoking prevalence and potential risk factors among Dulong adults in China. Methods: This study was conducted among 1,018 adults based on the Dulong Health Status Investigation and Evaluation (DHSIE) in Gongshan Dulong and Nu Autonomous County of Yunnan province, Southwest China. A cross-sectional design and face-to-face questionnaire were used to collect cigarette smoking habits and demographic information. Data were weighted by post-stratification weights according to the age and gender composition of Dulong resident. We also analyzed univariate and multivariate unconditional logistic regression to explore current smoking correlates. Results: The weighted prevalence of ever-smoking, currently smoking, and formerly smoking among Dulong adults is 31.3, 27.7, and 3.6%, respectively. The prevalence of ever-smoking and currently smoking among male participants (57.0 and 50.6%) is much higher than that of female participants (4.0 and 3.4%). Nearly 60% of ever-smokers and current smokers smoked more than 20 cigarettes per day, which are higher than former smokers (35.2%). Among current smokers, 33.1% relapsed, and 28.3% intend to quit smoking. By adjusting for potential confounding variables, multiple logistic regression analysis indicated that male participants (OR = 48.982, 95% CI: 25.026-95.869) and current drinkers (OR = 4.450, 95% CI: 2.556-7.746) are more likely to be current smokers. On the contrary, current smokers are also more likely to be exposed to secondhand smoke (OR = 4.269, 95% CI: 2.330-7.820) and have a higher risk of chronic respiratory disease (OR = 4.955, 95% CI: 1.669-14.706). Conclusion: Cigarette smoking is highly prevalent among the Dulong people in Southwest China. An appropriate and effective tobacco control strategy is an urgent need for this population.