Long-Acting Heterodimeric Paclitaxel-Idebenone Prodrug-Based Nanomedicine Promotes Functional Recovery after Spinal Cord Injury.

After spinal cord injury (SCI), successive systemic administration of microtubule-stabilizing agents has been shown to promote axon regeneration. However, this approach is limited by poor drug bioavailability, especially given the rapid restoration of the blood-spinal cord barrier. There is a pressing need for long-acting formulations of microtubule-stabilizing agents in treating SCI. Here, we conjugated the antioxidant idebenone with microtubule-stabilizing paclitaxel to create a heterodimeric paclitaxel-idebenone prodrug via an acid-activatable, self-immolative ketal linker and then fabricated it into chondroitin sulfate proteoglycan-binding nanomedicine, enabling drug retention within the spinal cord for at least 2 weeks and notable enhancement in hindlimb motor function and axon regeneration after a single intraspinal administration. Additional investigations uncovered that idebenone can suppress the activation of microglia and neuronal ferroptosis, thereby amplifying the therapeutic effect of paclitaxel. This prodrug-based nanomedicine simultaneously accomplishes neuroprotection and axon regeneration, offering a promising therapeutic strategy for SCI.

Balitoraanlongensis, the first cavefish species of the genus Balitora (Teleostei, Balitoridae) from Guizhou Province, southwest China.

This work describes a new species, Balitoraanlongensissp. nov., collected from a cave at Xinglong Town, Anlong County, Guzihou, China. Phylogenetic trees reconstructed based on two mitochondrial and three nuclear genes show that the new species represents an independent evolutionary lineage with large genetic differences, 7.1%-12.0% in mitochondrial gene cytochrome b and 9.2%-12.1% in cytochrome oxidase subunit 1, from congeners. Morphologically, the new species can be distinguished from the 18 species currently assigned to the genus Balitora by a combination of characters, most clearly by having two pairs of maxillary barbels; 8½ branched dorsal-fin rays; 5½ branched anal-fin rays; pectoral fin not reaching pelvic fin origin; dorsal-fin origin in front of pelvic fin origin; eye small (eye diameter approximately equal to outer maxillary barbel length); and fins lacking pigment in live fish. The new species represents the first record of Balitora inhabiting caves in China and increases the number of species in the genus Balitora in its present concept from 18 to 19. The study suggests that more evidence is needed to further clarify the taxonomic composition of the genus Balitora.

A Comparative Study between Abrus cantoniensis and Abrus mollis: Flavonoids Profiles by UPLC-Q-TOF-MS and Anti-Inflammatory Mechanism by Transcriptomics.

Abrus mollis (MJGC) has been used as a substitute herb for Abrus cantoniensis (JGC) in China. However, an in-depth comparison on their key metabolites and the mechanism of anti-inflammation between these two is not available. In this report, high pressure liquid chromatography equipped with mass spectrometry was applied to capture their flavonoid profiles; transcriptomics was adopted to analyze their anti-inflammatory mechanisms. The results showed that the main flavonoids in MJGC were vicenin-2, schaftoside and isoschaftoside, while those in JGC were vicenin-1 isomer and schaftoside isomer. The anti-inflammatory activity of JGC was slightly stronger than that of MJGC. The number of differential expression genes regulated by JGC was significantly higher than MJGC. JGC regulated 151 (42 up and 109 down) of inflammation related genes, while MJGC regulated 58 (8 up and 50 down) of inflammation related genes. The results of this study provided scientific evidence and guidance for the substitution of MJGC and JGC.

Using "Age and Total-PSA" as the Main Indicators: The Results of Taizhou Integrated Prostate Screening (No 2).

The aim of the study was to analyze population-based prostate cancer (PCa) screening and the incidence of PCa among males ≥50 years of age residing in the Luqiao district of Taizhou, China. From October to December 2020, male residents ≥50 years of age were screened for serum total prostate-specific antigen (total-PSA). If t-PSA re-test levels persisted above 4 µg/L, subjects underwent further noninvasive examinations, including digital rectal examination or multiparameter magnetic resonance imaging (mpMRI) of the prostate. Subjects underwent prostate biopsy of pathological tissue based on t-PSA and mpMRI results. A total of 3524 (49.1%) residents participated in this PCa screening study. In total, 285 (8.1%) subjects exhibited t-PSA levels ≥4.0 µg/L and 112 (3.2%) underwent noninvasive examinations. Forty-two (1.2%) residents underwent prostate biopsy, of which 16 (0.45%) were diagnosed with PCa. Of those diagnosed with PCa, three (19%) had localized PCa (cT1-cT2N0M0), six (37%) had locally advanced PCa (cT3a- cT4N0-1M0), and seven (44%) had advanced metastatic PCa (M1). Unfortunately, 3477 (48.5%) residents did not participate in the study, mainly due to lack of awareness of PCa based on feedback from local health centers. Age and t-PSA were used as primary screening indicators and, when further combined with mpMRI and prostate biopsy, confirmed the diagnosis of PCa among participating residents. Although this was a relatively economical and convenient screening method, education and knowledge should be further enhanced to increase the participation rate in PCa screening programs.

The bacterial communities in vagina of different Candida species-associated vulvovaginal candidiasis.

The incidence of vaginal infection caused by Candida species has considerably increased over the past two decades. Candida albicans is the main cause of vulvovaginal candidiasis (VVC); however, non-albicans Candida (NAC) species, such as Candida glabrata and Candida tropicalis, are now frequently identified in VVC patients. Although the vaginal microbiome (VMB) was well studied in Candida albicans-associated VVC patients, the fungal influence on bacterial communities of NAC species-associated VVC and potential microbial interplay contributing to VVC pathology remain elusive. We characterized VMB via Candida albicans and NAC species-associated VVC patients, as Candida albicans (CA, n = 16), Candida glabrata (CG, n = 16), Candida tropicalis (CT, n = 4), and recruiting healthy (CON, n = 20) women as references of dysbiosis and eubiosis. The bacterial diversity of the vagina in the CG group significantly declined. Further, all VVC patients have a higher abundance of Lactobacillus iners, especially for the CG group. Meanwhile, the predicted functions in all VVC are toned which may be associated with a disruption in the bacterial network. In conclusion, according to the taxonomic analysis, we found that the vaginal microbiome in C. glabrata-associated VVC women is different from that of other Candida species-associated VVC women, implying a different pathogenesis.

A moderated-mediation analysis of performance appraisal politics perception and counterproductive work behavior.

Politics has become a common element in the performance appraisal process, and as decision recipients in this process, those appraised tend to be more sensitive to performance appraisal politics. This paper examines the mechanisms by which performance appraisal politics perception (PAPP) affects counterproductive work behavior (CWB) from the perspective of those appraised. The mediating effect of perceived organizational justice (POJ) and the moderating effect of political skill (PS) are incorporated into a parsimonious moderated-mediation model. A quantitative research approach is employed with survey data from 460 employees of large and medium-sized enterprises in Hubei Province (China), and structural equation modeling (SEM) and bootstrap analysis are used to test the proposed hypothesized relationships. The findings demonstrate that PAPP has a positive impact on CWB, and POJ partly mediates the relationship between PAPP and CWB. The results also reveal that individual PS moderates the positive correlation between PAPP and CWB. The academic and practical implications of these findings, as well as limitations and suggestions for future research, are also discussed.

Design and Implementation of Taizhou Integrated Prostate Screening.

A community-based prostate cancer screening program was conducted to assess the morbidity and associated factors for prostate cancer among the subpopulation of men aged ≥50 years in Taizhou, China. Taizhou Integrated Prostate Screening (TIPS) is a large, observational, population-based study of prostate cancer screening data based on serum prostate-specific antigen (PSA) concentrations. A pilot census of all male residents aged 50 years or older was conducted in Luqiao District, one of the field sites of the TIPS cohort in the city of Taizhou, Zhejiang. The interviewer-administered questionnaire evaluated demographic characteristics and environmental exposure factors. A total of 1,806 out of 3,516 participants completed the questionnaire. The overall prevalence of PSA ≥4 ng/mL was 11.5%, and included participants at low risk (9.2%), moderate risk (1.7%), and high risk (0.6%). Participants aged 60-69, 70-79, and ≥80 years had a 2.7-fold, 4.2-fold, and 6.5-fold higher risk of elevated PSA, respectively, in comparison with those aged 50 to 59 years (p < .001). Eighteen patients were diagnosed with prostate cancer, of whom 11 (61.1%) underwent radical surgery. This community-based PSA screening program indicated the results for early detection of prostate cancer among men aged ≥50 years. Early screening and appropriate clinical therapy for the management of prostate cancer are essential in this subpopulation.

Microcrystals of Ketal-Linked Paliperidone Prodrugs for Long-Acting Antipsychotics.

Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics. SKP-MCs of three different sizes were prepared and systematically examined. We found that paliperidone exposure in SKP-MC-treated rats was prolonged compared with that in rats treated with the commercial antipsychotic Invega Sustenna and that the drug release rate decreased with increasing MC size. In inflammation-inhibition-model rats, paliperidone release from the SKP-MCs was considerably decreased, indicating that the immune-mediated foreign-body response after intramuscular administration boosted paliperidone release. Our findings will provide valuable insights into in vivo drug release from prodrug-based MC formulations. The ketal-linked prodrug strategy might be a new solution for developing long-acting prodrug formulations of hydroxyl-group-bearing drugs.

Discretion: Whether and How Does It Promote Street-Level Bureaucrats' Taking Charge Behavior?

The extant pieces of literature on discretion has mainly focused on its effect on policy implementation and public service delivery, but few studies have looked at its influence on street-level bureaucrats' work behavior, such as taking charge behavior (TCB), which is of great importance for government reforms, especially in developing and transitional countries. Based on the self-determination theory, this study examines whether and how discretion promotes street-level bureaucrats' TCB. Two studies were conducted among street-level bureaucrats in China. First, a survey experiment (n = 355) suggests that discretion positively predicts street-level bureaucrats' TCB. Then, a survey questionnaire study (n = 442) shows that discretion is positively related to TCB through the mediator of public service motivation (PSM). We concluded with implications for theory and practice.

Corporate social responsibility and job applicant attraction: A moderated-mediation model.

Based on the social identity theory, this study investigates the mediation and moderation mechanism of CSR on job applicant attraction. A total of 395 job seekers are recruited to join in the experiment survey. The results indicate that job seekers' perceptions of CSR positively relate to job applicant attraction, employer reputation and expected pride mediate this relationship, respectively, and the serial mediating role of employer reputation and then expected pride in the relationship between CSR and job applicant attraction. Additionally, the findings show that job applicants' materialism orientation plays a moderating role in the indirect effect of CSR on job applicant attraction via expected pride, but the moderating effect of job seekers' materialism orientation in the indirect effect of CSR on job applicant attraction via employer reputation is not statistically significant. These findings enrich the new culture-driven evidence on the impacting mechanism of CSR on job applicant's attitude and provide valuable insight into how CSR motivates job applicant attraction.

Efficacy and safety of once-weekly semaglutide in adults with overweight or obesity: a meta-analysis.

PURPOSE: This meta-analysis aimed to assess the efficacy and safety of once-weekly semaglutide among adults with overweight or obesity. METHODS: We searched multiple electronic databases for randomized controlled trials that compared once-weekly semaglutide versus placebo in adults with overweight or obesity. The primary outcomes were the percentage change and absolute change in body weight. Secondary outcomes included achievement of categorical weight loss targets (at least 5, 10, 15, or 20%), cardiometabolic risk profiles, and health-related quality of life. RESULTS: This meta-analysis included a total of four trials with 3447 patients. Once-weekly semaglutide was superior to placebo in terms of the percentage change and absolute change in body weight. Compared with placebo, once-weekly semaglutide also led to significant increases in the proportions of achievement of categorical weight reduction targets. Moreover, once-weekly semaglutide induced superior reductions in waist circumference and body-mass index compared with placebo. Furthermore, the effect on improving other cardiometabolic risk factors and health-related quality of life was more pronounced for once-weekly semaglutide relative to placebo. CONCLUSION: Among adults with overweight or obesity, once-weekly semaglutide could result in clinically meaningful weight loss, which was a promising therapy for treating overweight or obesity.

Development of a deep learning-based method to diagnose pulmonary ground-glass nodules by sequential computed tomography imaging.

BACKGROUND: Early identification of the malignant propensity of pulmonary ground-glass nodules (GGNs) can relieve the pressure from tracking lesions and personalized treatment adaptation. The purpose of this study was to develop a deep learning-based method using sequential computed tomography (CT) imaging for diagnosing pulmonary GGNs. METHODS: This diagnostic study retrospectively enrolled 762 patients with GGNs from West China Hospital of Sichuan University between July 2009 and March 2019. All patients underwent surgical resection and at least two consecutive time-point CT scans. We developed a deep learning-based method to identify GGNs using sequential CT imaging on a training set consisting of 1524 CT sections from 508 patients and then evaluated 256 patients in the testing set. Afterwards, an observer study was conducted to compare the diagnostic performance between the deep learning model and two trained radiologists in the testing set. We further performed stratified analysis to further relieve the impact of histological types, nodule size, time interval between two CTs, and the component of GGNs. Receiver operating characteristic (ROC) analysis was used to assess the performance of all models. RESULTS: The deep learning model that used integrated DL-features from initial and follow-up CT images yielded the best diagnostic performance, with an area under the curve of 0.841. The observer study showed that the accuracies for the deep learning model, junior radiologist, and senior radiologist were 77.17%, 66.89%, and 77.03%, respectively. Stratified analyses showed that the deep learning model and radiologists exhibited higher performance in the subgroup of nodule sizes larger than 10 mm. With a longer time interval between two CTs, the deep learning model yielded higher diagnostic accuracy, but no general rules were yielded for radiologists. Different densities of components did not affect the performance of the deep learning model. In contrast, the radiologists were affected by the nodule component. CONCLUSIONS: Deep learning can achieve diagnostic performance on par with or better than radiologists in identifying pulmonary GGNs.

Molecular transmission networks and pre-treatment drug resistance among individuals with acute HIV-1 infection in Baoding, China.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) genetic diversity and pre-treatment drug resistance (PDR) are major barriers to successful antiretroviral therapy (ART). In China, sexual intercourse is the most frequent route of HIV-1 transmission. However, few studies have analyzed PDR and transmission networks in detail among individuals in China with acute HIV-1 infection and their sexual contacts. METHODS: A cross-sectional study was conducted in Baoding City, Hebei Province, China from 2019-2020. CD4 T cell counts and viral loads were assessed and a HIV-1 genotypic PDR assay was developed in-house. Transmission networks were visualized using Cytoscape with a threshold genetic distance of 0.015 among HIV-1 subtypes. RESULTS: From 139 newly diagnosed and drug-naïve individuals with HIV-1, 132 pol gene sequences were obtained and revealed eight HIV-1 subtypes. Circulating recombinant form (CRF)01_AE was the most frequent subtype (53.0%, 70/132) followed by CRF07_BC (26.5%, 35/132), B (13.6%, 18/132), unique recombinant forms (2.3%, 3/132), CRF55_01B (1.5%, 2/132), CRF103_01B (1.5%, 2/132), CRF65_cpx (0.8%, 1/132), and C (0.8%, 1/132). A total of 47 pol gene sequences were used to generate 10 molecular transmission networks. The overall prevalence of PDR was 7.6% and that of PDR to non-nucleotide reverse transcriptase inhibitors was 6.1%. Of three transmission networks for PDR, two were closely associated with Beijing and Tianjin, while another was restricted to sequences determined in this study. CONCLUSIONS: These results demonstrate that during acute HIV-1 infection, PDR is transmitted in dynamic networks. This suggests that early detection, diagnosis, surveillance, and treatment are critical to effectively control HIV-1 spread.

Efficacy and Safety of Subcutaneous and Oral Semaglutide Administration in Patients With Type 2 Diabetes: A Meta-Analysis.

Background: This meta-analysis aimed to combine the data available from clinical trials to assess the effects of subcutaneous and oral semaglutide administration on glycemic control, weight management, and safety outcomes in patients with type 2 diabetes (T2D). Methods: We systematically searched for phase 3 randomized controlled trials (RCTs) that compared semaglutide with placebo or other anti-diabetic drugs in T2D patients. The primary outcome was the change from baseline in glycated hemoglobin (HbA1c) levels. Secondary efficacy endpoints included the change from baseline in body weight, achievement of HbA1c targets, and clinically significant weight loss. Key safety outcomes were also assessed. Results: In this meta-analysis, 24 trials with a total of 22185 patients were included. Subcutaneous semaglutide administration reduced HbA1c levels (weighted mean difference [WMD]: -1.14% and -1.37%, for 0.5 mg and 1 mg, respectively) and body weight (WMD: -2.73 kg and -4.09 kg, for 0.5 mg and 1 mg, respectively) when compared with placebo; its efficacy was also superior to other anti-diabetic drugs in reducing HbA1c levels (WMD: -0.71% and -0.86%, for 0.5 mg and 1 mg, respectively) and body weight (WMD: -2.65 kg and -3.78 kg, for 0.5 mg and 1 mg, respectively). Oral semaglutide administration was superior to placebo in decreasing HbA1c levels (WMD: -0.96% and -1.02%, for 7 mg and 14 mg, respectively). Moreover, oral administration of 14 mg of semaglutide also showed a significant reduction in HbA1c levels (WMD: -0.36%) compared with other anti-diabetic drugs. Furthermore, oral semaglutide administration resulted in substantial weight loss compared with other anti-diabetic drugs (WMD: -1.53 kg and -1.73 kg, for 7 mg and 14 mg, respectively). Notably, subcutaneous and oral semaglutide administration also resulted in higher numbers of patients achieving the targets of HbA1c levels and weight loss than placebo and other anti-diabetic drugs. Overall, we noted no clear evidence of detrimental effects on safety endpoints due to semaglutide treatment, except for some gastrointestinal adverse events. Conclusion: Both subcutaneous and oral semaglutide administration could enable the achievement of sufficient glycemic control and weight management without increasing the risk of hypoglycemia, which were effective and safe for the treatment of T2D.

Qualitative Study on the Toxic Triangle Integration of Leadership Ostracism.

Leadership ostracism widely exists in all types of organizations, yet specific study regarding this trend is limited. With this study, we explore the influencing mechanisms of leadership ostracism through case interview based on literature analysis and grounded theory. Results show that leadership ostracism is the integration of a triadic interaction process between subordinate performance, leadership characteristics, and organizational environment. Based on Padilla's destructive leadership toxic triangle model, we constructed a toxic triangle model of leadership ostracism. Through comparison, we found that these two triad models overlap in the areas of narcissism and power consciousness of supervisors, the self-concept of subordinates, and the management system of situational factors, indicating that leadership ostracism is itself a type of destructive leadership. In addition, the uniqueness, and differences in leadership ostracism are reflected in the model, including stereotypes, and results orientation of supervisors, political skills, job performance, and cognitive style of subordinates, the power distance, Chaxu climate, and organizational politics of the situational elements. Theoretical and practical implications are discussed in the research field that provides prospects for future orientation.

Olaparib attenuates sepsis-induced acute multiple organ injury via ERK-mediated CD14 expression.

Sepsis is characterized by persistent systemic inflammation, which can cause multi-organ dysfunction. The poly polymerase-1 inhibitor olaparib possesses anti-inflammatory properties. This study aimed to assess the effects of olaparib (pre- and post-treatments) on sepsis, and to investigate whether it could suppress CD14 expression via the ERK pathway in polymicrobial sepsis and peritoneal macrophages models. Sepsis was induced by cecal ligation and puncture in C57BL/6 male mice. Fifty mice were randomly divided into five groups: The sham group was treated with vehicle or olaparib, the cecal ligation and puncture group with vehicle or with olaparib (5 mg/kg i.p.) 1 h before or 2 h after surgery. Olaparib pretreatment significantly improved the survival of septic mice (P < 0.001). Pre- and post-treatment of mice with olaparib partly alleviated cecal ligation and puncture-induced organ injury by decreasing the amounts of the pro-inflammatory mediators TNF-α and IL-6 as well as bacterial burden in the serum, peritoneal lavage fluid, and organs (P < 0.05). The protective effect of olaparib was associated with CD14 suppression via inhibition of ERK activation. Olaparib facilitated negative regulation of ERK-mediated CD14 expression, which may contribute to multi-organ injury in sepsis.

Transurethral seminal vesiculoscopy for intractable hematospermia: experience from 144 patients.

PURPOSE: to describe the methodology of transurethral seminal vesiculoscopy and the anatomy of the area of the verumontanum, and to determine the safety of this procedure, especially in terms of postoperative complications. METHODS: This retrospective observational study enrolled 144 patients with intractable hematospermia from May 2011 and August 2019. A 4.5/6.5-Fr vesiculoscope was inserted into the seminal vesicle to deal with the positive findings. The solution of quinolones was used to rinse each seminal vesicle. RESULTS: In this study, Transurethral seminal vesiculoscopy was successfully performed in 139 patients (96.53%). Hematospermia was alleviated or disappeared in 116 (80.56%) patients by less than half a year after surgery. Common intraoperative manifestations were hemorrhage, stones, utricle polyps and cysts. The surgical approach in our study were categorized into four types, including 24 (16.7%), 73 (50.7%), 42 (29.2%), and 5 (3.5%) cases in Type A (natural opening of the ejaculatory duct), B (trans-duct fenestration), C (trans-utricle fenestration), and D (not founded), respectively. Sexual function change was recorded in 12 patients of 111 patients, all by the method of trans-utricle fenestration, including 8 (7.21%), 3 (2.70%), and 1 (0.90%) patients in shorter intravaginal ejaculatory latency time, worse erection hardness and loss of orgasm, respectively. CONCLUSION: Transurethral seminal vesiculoscopy is an effective and safe procedure for the management of hematospermia. The anatomy of the distal seminal tract should be understood more deeply and Wu'method (uncover-curtain method) needs to be promoted to verify its universality and safety. Besides, the complications of the function dysfunction should be discussed in the future in multi-center clinical trials.

Combining initial chest CT with clinical variables in differentiating coronavirus disease 2019 (COVID-19) pneumonia from influenza pneumonia.

Coronavirus disease 2019 (COVID-19) has spread in more than 100 countries and regions around the world, raising grave global concerns. COVID-19 has a similar pattern of infection, clinical symptoms, and chest imaging findings to influenza pneumonia. In this retrospective study, we analysed clinical and chest CT data of 24 patients with COVID-19 and 79 patients with influenza pneumonia. Univariate analysis demonstrated that the temperature, systolic pressure, cough and sputum production could distinguish COVID-19 from influenza pneumonia. The diagnostic sensitivity and specificity for the clinical features are 0.783 and 0.747, and the AUC value is 0.819. Univariate analysis demonstrates that nine CT features, central-peripheral distribution, superior-inferior distribution, anterior-posterior distribution, patches of GGO, GGO nodule, vascular enlargement in GGO, air bronchogram, bronchiectasis within focus, interlobular septal thickening, could distinguish COVID-19 from influenza pneumonia. The diagnostic sensitivity and specificity for the CT features are 0.750 and 0.962, and the AUC value is 0.927. Finally, a multivariate logistic regression model combined the variables from the clinical variables and CT features models was made. The combined model contained six features: systolic blood pressure, sputum production, vascular enlargement in the GGO, GGO nodule, central-peripheral distribution and bronchiectasis within focus. The diagnostic sensitivity and specificity for the combined features are 0.87 and 0.96, and the AUC value is 0.961. In conclusion, some CT features or clinical variables can differentiate COVID-19 from influenza pneumonia. Moreover, CT features combined with clinical variables had higher diagnostic performance.

The HIV protease inhibitor Saquinavir attenuates sepsis-induced acute lung injury and promotes M2 macrophage polarization via targeting matrix metalloproteinase-9.

Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.

Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis.

Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/ß, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.