The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8+ T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8+ T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8+ T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8+ cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (TTSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-TTSM cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-TTSM cells could be harnessed to potentiate anti-tumor immunotherapy.

Exploring the bi-directional relationship between periodontitis and dyslipidemia: a comprehensive systematic review and meta-analysis.

AIM: As periodontitis and dyslipidemia are diseases that occur with high incidence, the relationship between them has attracted much attention. Previous studies on these diseases have tended to focus on lipid parameters and periodontitis, we aimed to investigate the relationship between dyslipidemia and periodontitis. MATERIALS AND METHODS: A comprehensive search to identify the studies investigating the relationship between dyslipidemia and periodontitis was performed on PubMed, Web of Science and Cochrane Library before the date of August, 2023. Studies were considered eligible if they contained data on abnormal blood lipid parameters and periodontitis. Studies that reported mean differences and 95% confidence intervals or odds ratios were used. RESULTS: A total of 73 publications were included in the meta-analysis. Hyper total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL) and lower high-density lipoprotein (HDL) levels are risk factors for periodontitis. Periodontal disease is a risk factor for high TG and low HDL levels. Three months after periodontal treatment, the levels of TC, TG and HDL were significantly improved, and statin treatment only improved gingival index (GI) levels compared to that of the dietary control. CONCLUSIONS: The findings reported here suggest that the mutual promotion of periodontitis and dyslipidemia can be confirmed. Non-surgical periodontal therapy may improve lipid abnormalities. It can't be demonstrated whether systematic application of statins have a better effect on the improvement in periodontal status in patients with dyslipidemia compared to that of the control.

Efficiency and safety of high-power ablation guided by Lesion size index: An ex vivo porcine heart study.

BACKGROUND: Although Lesion size index (LSI) has been reported to highly predict radiofrequency lesion size in vitro, its accuracy in lesion size and steam pop estimation has not been well investigated for every possible scenario. METHODS: Initially, radiofrequency ablations were performed on porcine myocardial slabs at various power, CF, and time settings with blinded LSI. Subsequently, radiofrequency power at 20, 30, 40, 50, and 60 W was applied at CF values of 5, 10, 20, and 30 g to reach target LSIs of 4, 5, 6, and 7. Lesion size and steam pops were recorded for each ablation. RESULTS: Lesion size was positively correlated with LSI regardless of power settings (p < 0.001). The linear correlation coefficients of lesion size and LSI decreased at higher power settings. At high power combined with high CF settings (50 W/20 g), lesion depth and LSI showed an irrelevant correlation (p = 0.7855). High-power ablation shortened ablation time and increased the effect of resistive heating. LSI could predict the risk of steam pops at high-power settings with the optimal threshold of 5.65 (sensitivity, 94.1%; specificity, 46.1%). The ablation depth of the heavy heart was shallower than that of the light heart under similar ablation settings. CONCLUSIONS: LSI could predict radiofrequency lesion size and steam pops at high power settings in vitro, while synchronous high power and high CF should be avoided. Lighter hearts require relatively lower ablation settings to create appropriate ablation depth.

The interaction of CD300lf and ceramide reduces the development of periodontitis by inhibiting osteoclast differentiation.

AIM: The regulation of osteoclasts (OCs) by inhibitory immunoreceptors maintains bone homeostasis and is considered an important determinant of the extent of periodontal pathology. The aim of this study was to investigate the role of the inhibitory immunoreceptor CD300lf and its ligand ceramide in osteoclastogenesis in periodontitis. MATERIALS AND METHODS: The expression of CD300lf was measured in vitro and in a ligature-induced periodontitis model. The effect of CD300lf ablation on osteoclastogenesis was examined in ligature-retained and ligature removal periodontitis models. The effect of ceramide, the ligand of CD300lf, was examined in osteoclastogenesis in vitro and in vivo by smearing 20 µg of ceramide dissolved in carboxymethylcellulose on teeth and gingiva every other day in an experimental periodontitis model and ligature removal model. RESULTS: CD300lf expression was downregulated during osteoclastogenesis. Ablation of CD300lf in the ligature-induced periodontitis model increased the number of OCs and exacerbated bone damage. Bone resorption caused by CD300lf ablation was reversible following ligature removal. CD300lf-ceramide binding suppressed osteoclastogenesis in vitro and inhibited alveolar bone loss in a mouse periodontitis model. CONCLUSIONS: Our findings reveal that CD300lf-ceramide binding plays a critical negative role in alveolar bone loss in periodontitis by inhibiting OCs differentiation.

Lafutidine Ameliorates Indomethacin-Induced Small Intestinal Damage in Rats by Modifying the Intestinal Mucosal Barrier, Inflammation, and Microbiota.

INTRODUCTION: Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage is a serious and escalating clinical problem without effective treatment. Lafutidine (LAF) is a novel histamine H2 receptor antagonist with a mucosal protective action. This study aimed to investigate the protective effect of LAF on indomethacin (IND)-induced enteropathy in rats. METHODS: Rats were treated with LAF for 10 days with concomitant IND treatment on the final 5 days. Changes in metabolism and hematological and biochemical parameters were measured, and intestinal damage was blindly scored. Intestinal mucosal tissue and luminal contents were collected for transcriptome and microbiota sequencing. Intestinal inflammation and barrier function were also evaluated. RESULTS: LAF treatment prevented anorexia and weight loss in rats and ameliorated reductions in hemoglobin, hematocrit, total protein, and albumin levels. LAF reduced the severity of IND-induced intestinal damage including macroscopic and histopathological damage score. Transcriptome sequencing results indicated that LAF might have positive effects on intestinal inflammation and the intestinal mucosal barrier. Further research revealed that LAF decreased neutrophil infiltration, and IL-1ß and TNF-α expression in intestinal tissue. Besides, the treatment increased mucus secretion, MUC2, Occludin, and ZO-1 expression, and decreased serum D-lactate levels. LAF treatment also ameliorates microbial dysbiosis in small intestine induced by IND and increased the abundance of Lactobacillus acidophilus. CONCLUSION: LAF may protect against NSAID enteropathy via enhancing the intestinal mucosal barrier, inhibiting inflammation, and regulating microbiota.

ATF3/SPI1/SLC31A1 Signaling Promotes Cuproptosis Induced by Advanced Glycosylation End Products in Diabetic Myocardial Injury.

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2 or elesclomol-CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe-S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.

Development and validation of the Health Education Adherence Scale for Stroke Patients: a cross-sectional study.

BACKGROUND: Due to the lack of health education adherence assessment tools for stroke patients, the assessment of health education adherence in this population is insufficient, which hinders the prevention and rehabilitation of stroke. This study aims to develop and validate a Health Education Adherence Scale for Stroke Patients (HEAS-SP). METHODS: A cross-sectional design with a purposive sampling method was used for this study. Six hundred and fifty-four eligible participants completed the demographic questionnaire and the HEAS-SP. The data collection lasted for 7 months, from March 1stto September 30th in 2019. Item analysis and exploratory and confirmatory factor analysis were employed to develop and validate the HEAS-SP. RESULTS: The item analysis, exploratory and confirmatory factor analysis resulted in a 20-item HEAS-SP with 4 domains: medication adherence, diet adherence, rehabilitation exercise adherence, and healthy lifestyle adherence. The four-domain model demonstrated acceptable model fit indexes and the 20-item HEAS-SP demonstrated acceptable reliability and validity. CONCLUSION: The 20-item HEAS-SP was shown to have acceptable reliability and validity for assessing health education adherence with respect to diet, medication, rehabilitation exercise and healthy lifestyle in stroke patients, making it a potential basis for developing targeted interventions for stroke patients.

Editorial for special issue on advances in Actuarial Science and quantitative finance.

This article provides an overview of all papers published on the special issue, Advances in Actuarial Science and Quantitative Finance. The special issue is intended to collect articles that reflect the latest development and emerging topics in these closely related two areas. Topics included in this special issue range from actuarial and risk theory, to optimal control for finance and insurance, to statistical inferences of financial and insurance models, to pricing, valuation and reserving.

Enhanced Sensitivity of Hydrogenated Cu0.27Co2.73O4 Nanooctahedrons Having {111} Facets and the Sensing Mechanism of 3-Coordinated Co/Cu Atoms as Active Centers.

Cu0.27Co2.73O4 nanooctahedrons enclosed by polar {111} planes have been prepared through the selective adsorption of Cl-. Hydrogenation has been successfully used to enhance the responses of the Cu0.27Co2.73O4 nanooctahedron sensors to acetone, ethanol, and n-butylamine. The enhancement of the response results from the increase in the number of 3-coordinated Co/Cu atoms (Co3c/Cu3c) at the (111) plane of Cu0.27Co2.73O4 through removing O-H groups and Cl- ions at the surface by hydrogenation. The Co3c/Cu3c atoms on the (111) plane of Cu0.27Co2.73O4 are considered to function as the gas response active centers. These Co3c/Cu3c active atoms have three functions: generating electrons, adsorbing oxygen from air, and catalyzing the sensing reactions. The hydrogenation polar surface approach can be applied to improve the performances of other sensing materials. Such sensing mechanisms of the Co3c/Cu3c unsaturated atoms as the active centers can be conducive to understanding the gas-sensing essence and the development of sensing materials with high performances.

Inhibition of Interleukin-6/glycoprotein 130 signalling by Bazedoxifene ameliorates cardiac remodelling in pressure overload mice.

The role of IL-6 signalling in hypertensive heart disease and its sequelae is controversial. Our group demonstrated that Bazedoxifene suppressed IL-6/gp130 signalling in cancer cells but its effect on myocardial pathology induced by pressure overload is still unknown. We explored whether Bazedoxifene could confer benefits in wild-type C57BL/6J mice suffering from transverse aortic constriction (TAC) and the potential mechanisms in H9c2 myoblasts. Mice were randomized into three groups (Sham, TAC, TAC+Bazedoxifene, n = 10). Morphological and histological observations suggested TAC aggravated myocardial remodelling while long-term intake of Bazedoxifene (5 mg/kg, intragastric) attenuated pressure overload-induced pathology. Echocardiographic results indicated Bazedoxifene rescued cardiac function in part. We found Bazedoxifene decreased the mRNA expression of IL-6, MMP2, Col1A1, Col3A1 and periostin in murine hearts after 8-week surgery. By Western blot detection, we found Bazedoxifene exhibited an inhibition of STAT3 activation in mice three hours and 8 weeks after TAC. Acute TAC stress (3 hours) led to down-regulated ratio of LC3-Ⅱ/LC3-Ⅰ, while in mice after long-term (8 weeks) TAC this ratio becomes higher than that in Sham mice. Bazedoxifene inverted the autophagic alteration induced by TAC at both two time-points. In H9c2 myoblasts, Bazedoxifene suppressed the IL-6-induced STAT3 activation. Moreover, IL-6 reduced the ratio of LC3-Ⅱ/LC3-Ⅰ, promoted P62 expression but Bazedoxifene reversed both changes in H9c2 cells. Our data suggested Bazedoxifene inhibited IL-6/gp130 signalling and protected against cardiac remodelling together with function deterioration in TAC mice.

Bazedoxifene exhibits growth suppressive activity by targeting interleukin-6/glycoprotein 130/signal transducer and activator of transcription 3 signaling in hepatocellular carcinoma.

The interleukin (IL)-6/glycoprotein (GP)130/signal transducer and activator of transcription (STAT)3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL-6 binds to IL-6R, forming a binary complex, which further combines with GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL-6 and GP130 may inhibit the IL-6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that bazedoxifene acetate (BAZ), a selective estrogen receptor modulator approved by the US Food and Drug Administration, could inhibit IL-6/GP130 protein-protein interactions. Western blot, immunofluorescence staining, wound healing and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V-FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P-STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P-STAT3 induced by IL-6, but not by leukemia inhibitory factor. BAZ inhibited P-STAT1 and P-STAT6 less significantly as elicited by interferon-α, interferon-γ and IL-4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL-6. BAZ inhibited cell viability, wound healing and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that BAZ inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy.

Treatment recommendations for small gastric gastrointestinal stromal tumors: positive endoscopic resection.

Objectives: To evaluate the safety and efficacy of endoscopic resection and discuss the treatment strategy of small gastric gastrointestinal stromal tumors (GISTs) less than 2 cm. Material and methods: The data of 713 patients, who underwent endoscopic submucosal dissection (ESD) for gastric submucosal tumors (SMTs), were retrospectively analyzed. We investigated the clinicopathological features and analyzed the risk potential of small gastric GISTs, and documented therapeutic and follow-up outcomes. We also compared the follow-up results between operated patients and 58 patients who were suspected of small gastric GISTs and underwent regular surveillance under endoscopic ultrasound (EUS) in the same period. Results: GISTs were the most common gastric SMTs (289 cases, 40.5%), of which small GISTs were found in 250 cases. The mitotic index was less than 5 in all cases. However, 122 out of 250 cases (48.8%) had adverse factors under EUS, which were related to tumor size (p < .01). ESD was successfully performed in all patients, and no serious complication or perioperative death occurred. The follow-up period for 42.07 ± 22.49 months revealed improvement of symptoms in 80.2% patients and showed no recurrence or metastasis. Of the 58 patients selected for EUS surveillance, 48 (82.8%) presented with gastrointestinal symptoms and 41 out of 48 (85.4%) were not relieved during follow-up and 16 (27.6%) with severe psychological problems. Conclusions: ESD is a safe and effective treatment for small GISTs, which helps to confirm the diagnosis, improve symptoms and reduce the psychological pressure. Thus, we recommend endoscopic resection is a good option for small gastric GISTs once diagnosed.

Applicability and cross-cultural validation of the Chinese version of the Warwick-Edinburgh mental well-being scale in patients with chronic heart failure.

BACKGROUND: The mental well-being of patients with chronic heart failure is likely to influence their health-related quality of life and decrease the utilization of public health resources. This study assessed the mental well-being of patients with chronic heart failure and evaluated the reliability and validity of the Warwick-Edinburgh Mental Well-Being Scale. METHODS: We conducted a cross-sectional survey from July 2016 to July 2017 among 191 patients with chronic heart failure, and examined psychometric properties of the Warwick-Edinburgh Mental Well-Being Scale, such as internal consistency, reliability, test-retest reliability, and factorial validity of the Chinese version of the Warwick-Edinburgh Mental Well-Being Scale. RESULTS: One-dimensional construct validity was demonstrated by confirmatory factor analysis. The psychometric properties of the Chinese version of the Warwick-Edinburgh Mental Well-Being Scale were satisfactory in our sample of patients with chronic heart failure. The internal consistency reliability was .948 and the test-retest reliability .925. The item-total correlations ranged from .405 to .872. There was a strong correlation (r = .79) between the Chinese version of the Warwick-Edinburgh Mental Well-Being Scale and the five-item World Health Organization Well-Being Index. The Chinese version of the Warwick-Edinburgh Mental Well-Being Scale appears acceptable for use in patients with chronic heart failure, and we were able to verify its reliability and validity with our sample. CONCLUSIONS: The Chinese version of the Warwick-Edinburgh Mental Well-Being Scale is a reliable quantitative tool for evaluating mental well-being in patients with chronic heart failure in clinical settings, and this has important implications for overall assessments of mental well-being in patients with chronic heart failure.

Eavesdropping on wastewater pollution: Detecting discharge events from river outfalls via fiber-optic distributed acoustic sensing.

Wastewater discharge from outfall pipes can significantly impact river water quality and aquatic ecosystems. Effective outfall monitoring is critical for controlling pollution and protecting public health. This study demonstrates a novel distributed acoustic sensing (DAS) approach for detecting wastewater discharge events from outfall pipes located along rivers. Controlled field experiments were conducted in an industrial park river to systematically evaluate DAS performance. DAS detects vibrational signals imparted to suspended fiber-optic cables by turbulent wastewater flows, predominantly within 10-30 Hz, enabling continuous monitoring along entire river lengths. Vibrational power analysis locates outfalls with meter-level accuracy, while time-frequency techniques discern discharge timing and characteristics. Cable type and outfall-fiber separation influence on detection capability was assessed. Thermoplastic-jacketed tight buffer cables optimized detection through enhanced vibrational coupling. Vibrational energy decreased exponentially with separation, highlighting benefits of proximal deployment for sensitivity. However, detection range scales with discharge flow rate. Frequency centroid proved a robust feature with potential for automated discharge identification. Overall, DAS enables high spatiotemporal resolution monitoring to pinpoint concealed outfalls minimally invasively. This positions DAS as a promising tool supporting improved water governance through early pollution warnings and rapid source localization via outfall vibrational signatures emanating across river networks.

The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD.

Metabolic-associated fatty liver disease (MAFLD) is a globally prevalent chronic hepatic disease. Previous studies have indicated that the activation of the signal transducer and activator of transcription3 (STAT3) plays a vital role in MAFLD progression at the very beginning. However, the specific association between STAT3 and abnormal hepatic metabolism remains unclear. In this study, activated inflammation was observed to induce abnormal glucolipid metabolic disorders in the hepatic tissues of high-fat diet (HFD)-fed ApoE-/- mice. Furthermore, we found that the activation of STAT3 induced by HFD might function as a transcriptional factor to suppress the expression of VAV3, which might participate in intracellular glucolipid metabolism and the regulation of glucose transporter 4 (GLUT4) storage vesicle traffic in the development of MAFLD both in vitro and in vivo. We verified that VAV3 deficiency could retard the GLUT4 membrane translocation and impair the glucose homeostasis. Additionally, VAV3 participates in cholesterol metabolism in hepatocytes, eventually resulting in the accumulation of intracellular cholesterol. Moreover, rAAV8-TBG-VAV3 was conducted to restore the expression of VAV3 in HFD-fed ApoE-/- mice. VAV3 overexpression was observed to improve glucose homeostasis as well as attenuate hepatic cholesterol accumulation in vivo. In conclusion, the STAT3/VAV3 signaling pathway might play a significant role in MAFLD by regulating glucose and cholesterol metabolism, and VAV3 might be a potential therapeutic strategy which could consequently ameliorate MAFLD.

Development of an "on-off-on" fluoroprobe utilizing an anthrylimidazole-based fluorescent ionic liquid for sensitive Cr(VI) and ascorbic acid detection.

Developing a rapid detection method of Cr(VI) and ascorbic acid (AA) is vital in the food and environmental fields. Herein, an anthrylimidazole-based fluorescent ionic liquid (AI-FIL) with the advantageous fluorescent properties was successfully prepared and used to construct a promising "on-off-on" fluoroprobe for rapid/sensitive Cr(VI) and AA detection. Cr(VI) could effectively quench the fluorescence of AI-FIL owing to the inner-filter effect and photoinduced electron-transfer process. However, the decreased fluorescence could be rapidly recovered by AA owing to the redox reaction between AA and Cr(VI). For Cr(VI) detection, a satisfactorily linear response (0.03-300 µM) was achieved with the corresponding detection limit of 9 nM. For AA detection, a good linearity from 1 to 1000 µM was obtained with the resultant detection limit of 0.3 µM. Moreover, the AI-FIL based fluoroprobe was successfully utilized for Cr(VI) and AA detection in food and water samples with satisfactory accuracy and precision.

Barrier function and ultrastructure characteristics of epidermis in patients with primary cutaneous amyloidosis.

Previous studies on primary cutaneous amyloidosis (PCA) have mainly focused on exploring genetic mutation and components of amyloid in patients with PCA. However, studies on skin barrier function in PCA patients are scarce. Here, we detected the skin barrier function in PCA patients and healthy people by using noninvasive techniques and characterized ultrastructural features of PCA lesions compared with healthy people using transmission electron microscopy (TEM). The expression of proteins related to skin barrier function was examined by immunohistochemistry staining. A total of 191 patients with clinically diagnosed PCA and 168 healthy individuals were enrolled in the study. Our analysis revealed that all investigated lesion areas displayed higher transepidermal water loss and pH values, and lower Sebum levels and stratum corneum hydration levels in PCA patients compared with the same site area in healthy individuals. The TEM results showed that the intercellular spaces between the basal cells were enlarged and the number of hemidesmosomes decreased in PCA lesions. Immunohistochemical staining showed that the expression of integrin α6 and E-cadherin in PCA patients was less than that in healthy controls, while no differences in the expression of loricrin and filaggrin were observed. Our study revealed that individuals with PCA displayed skin barrier dysfunction, which may be related to alterations in epidermal ultrastructure and a decrease in the skin barrier-related protein E-cadherin. However, the molecular mechanisms underlying skin barrier dysfunction in PCA remain to be elucidated.

Characterization of Epidermal Function in Individuals with Primary Cutaneous Amyloidosis.

Purpose: To compare epidermal biophysical properties, indicators of epidermal function, in individuals with and without primary cutaneous amyloidosis (PCA). Patients and Methods: This study incorporated 189 patients with PCA and 166 healthy individuals. The GPSkin Barrier was employed to measure transepidermal water loss (TEWL) rates and hydration levels of the stratum corneum. The Sebumeter and the Skin pH Meter were utilized to determine the skin surface's sebum content and pH, respectively. The severity of pruritus in participants was evaluated using the visual analog scale (VAS). Results: Compared to the control group without PCA, individuals with PCA displayed a notable increase in skin surface pH and TEWL and a decrease in the hydration levels of the stratum corneum (p<0.0001 for all parameters). Additionally, the sebum content was markedly lower in those with PCA than in the controls (p<0.0001). Of particular note, both TEWL and skin surface pH at the lesion sites on the back and the shin were more elevated in lichenoid amyloidosis (LA) and in macular amyloidosis (MA), whereas hydration levels of the stratum corneum and sebum levels were diminished in LA compared to MA (p<0.05). In conclusion, both hydration levels of the stratum corneum and sebum content exhibited an inverse relationship with pruritus severity, whereas TEWL and skin surface pH demonstrated a positive correlation with pruritus intensity. Conclusion: The function of the epidermis is compromised in individuals diagnosed with PCA. However, the mechanisms underlying these changes await further investigation.

Porphyromonas gingivalis Gingipains Destroy the Vascular Barrier and Reduce CD99 and CD99L2 Expression To Regulate Transendothelial Migration.

Porphyromonas gingivalis is an important periodontal pathogen that can cause vascular injury and invade local tissues through the blood circulation, and its ability to evade leukocyte killing is critical to its distal colonization and survival. Transendothelial migration (TEM) is a series of that enable leukocytes to squeeze through endothelial barriers and migrate into local tissues to perform immune functions. Several studies have shown that P. gingivalis-mediated endothelial damage initiates a series of proinflammatory signals that promote leukocyte adhesion. However, whether P. gingivalis is involved in TEM and thus influences immune cell recruitment remains unknown. In our study, we found that P. gingivalis gingipains could increase vascular permeability and promote Escherichia coli penetration by downregulating platelet/endothelial cell adhesion molecule 1 (PECAM-1) expression in vitro. Furthermore, we demonstrated that although P. gingivalis infection promoted monocyte adhesion, the TEM capacity of monocytes was substantially impaired, which might be due to the reduced CD99 and CD99L2 expression on gingipain-stimulated endothelial cells and leukocytes. Mechanistically, gingipains mediate CD99 and CD99L2 downregulation, possibly through the inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway. In addition, our in vivo model confirmed the role of P. gingivalis in promoting vascular permeability and bacterial colonization in the liver, kidney, spleen, and lung and in downregulating PECAM-1, CD99, and CD99L2 expression in endothelial cells and leukocytes. IMPORTANCE P. gingivalis is associated with a variety of systemic diseases and colonizes in distal locations in the body. Here, we found that P. gingivalis gingipains degrade PECAM-1 to promote bacterial penetration while simultaneously reducing leukocyte TEM capacity. A similar phenomenon was also observed in a mouse model. These findings established P. gingivalis gingipains as the key virulence factor in modulating the permeability of the vascular barrier and TEM processes, which may provide a new rationale for the distal colonization of P. gingivalis and its associated systemic diseases.

Notopterol Ameliorates Hyperuricemia-Induced Cardiac Dysfunction in Mice.

Notopterol is a naturally occurring furanocoumarin compound found in the root of Notopterygium incisum. Hyperuricemia involves the activation of chronic inflammation and leads to cardiac damage. Whether notopterol has cardioprotective potential in hyperuricemia mice remains elusive. The hyperuricemic mouse model was constructed by administration of potassium oxonate and adenine every other day for six weeks. Notopterol (20 mg/kg) and allopurinol (10 mg/kg) were given daily as treatment, respectively. The results showed that hyperuricemia dampened heart function and reduced exercise capacity. Notopterol treatment improved exercise capacity and alleviated cardiac dysfunction in hyperuricemic mice. P2X7R and pyroptosis signals were activated both in hyperuricemic mice and in uric acid-stimulated H9c2 cells. Additionally, it was verified that inhibition of P2X7R alleviated pyroptosis and inflammatory signals in uric acid-treated H9c2 cells. Notopterol administration significantly suppressed expression levels of pyroptosis associated proteins and P2X7R in vivo and in vitro. P2X7R overexpression abolished the inhibition effect of notopterol on pyroptosis. Collectively, our findings suggested that P2X7R played a critical role in uric acid-induced NLRP3 inflammatory signals. Notopterol inhibited pyroptosis via inhibiting the P2X7R/NLRP3 signaling pathway under uric acid stimulation. Notopterol might represent a potential therapeutic strategy against pyroptosis and improve cardiac function in hyperuricemic mice.