IL-21/IL-21R Signaling Aggravated Respiratory Inflammation Induced by Intracellular Bacteria through Regulation of CD4+ T Cell Subset Responses.

The IL-21/IL-21R interaction plays an important role in a variety of immune diseases; however, the roles and mechanisms in intracellular bacterial infection are not fully understood. In this study, we explored the effect of IL-21/IL-21R on chlamydial respiratory tract infection using a chlamydial respiratory infection model. The results showed that the mRNA expression of IL-21 and IL-21R was increased in Chlamydia muridarum-infected mice, which suggested that IL-21 and IL-21R were involved in host defense against C. muridarum lung infection. IL-21R-/- mice exhibited less body weight loss, a lower bacterial burden, and milder pathological changes in the lungs than wild-type (WT) mice during C. muridarum lung infection. The absolute number and activity of CD4+ T cells and the strength of Th1/Th17 responses in IL-21R-/- mice were significantly higher than those in WT mice after C. muridarum lung infection, but the Th2 response was weaker. Consistently, IL-21R-/- mice showed higher mRNA expression of Th1 transcription factors (T-bet/STAT4), IL-12p40, a Th17 transcription factor (STAT3), and IL-23. The mRNA expression of Th2 transcription factors (GATA3/STAT6), IL-4, IL-10, and TGF-ß in IL-21R-/- mice was significantly lower than that in WT mice. Furthermore, the administration of recombinant mouse IL-21 aggravated chlamydial lung infection in C57BL/6 mice and reduced Th1 and Th17 responses following C. muridarum lung infection. These findings demonstrate that IL-21/IL-21R may aggravate chlamydial lung infection by inhibiting Th1 and Th17 responses.

IL-27/IL-27R Mediates Protective Immunity against Chlamydial Infection by Suppressing Excessive Th17 Responses and Reducing Neutrophil Inflammation.

IL-27, a heterodimeric cytokine of the IL-12 family, has diverse influences on the development of multiple inflammatory diseases. In this study, we identified the protective role of IL-27/IL-27R in host defense against Chlamydia muridarum respiratory infection and further investigated the immunological mechanism. Our results showed that IL-27 was involved in C. muridarum infection and that IL-27R knockout mice (WSX-1-/- mice) suffered more severe disease, with greater body weight loss, higher chlamydial loads, and more severe inflammatory reactions in the lungs than C57BL/6 wild-type mice. There were excessive IL-17-producing CD4+ T cells and many more neutrophils, neutrophil-related proteins, cytokines, and chemokines in the lungs of WSX-1-/- mice than in wild-type mice following C. muridarum infection. In addition, IL-17/IL-17A-blocking Ab treatment improved disease after C. muridarum infection in WSX-1-/- mice. Overall, we conclude that IL-27/IL-27R mediates protective immunity during chlamydial respiratory infection in mice by suppressing excessive Th17 responses and reducing neutrophil inflammation.

New molecular prognostic factors of adult diffuse lower-grade gliomas in post-2016 molecular era: a retrospective analysis from single center.

BACKGROUND AND OBJECTIVE: Several studies have examined the prognostic significance of IDH1/2 mutation, 1p/19q codeletion and MGMT promoter methylation in lower-grade gliomas but most of these used the 2007 fourth edition of the WHO classification. We evaluate prognostic significance of these indicators in the 2016 WHO updated fourth edition of CNS tumor classification. METHODS: A total of 180 intracranial glioma patients diagnosed according WHO 2016 edition between December 2016 and December 2018 Jinling Hospital (Nanjing, China) were reviewed retrospectively. We performed survival analysis on 109 patients with complete molecular pathology and follow-up data. RESULTS: Histologically, 52 were diagnosed as astrocytoma (WHO grade II and III), 17 as oligodendrogliomas (WHO grade II and III) and 40 as GBMs. At last follow-up, 50.5% patients had experienced tumor progression and 34.9% had died. Among grade II and III cases 36.2% experienced tumor progression and 27.5% died. In univariate Kaplan-Meier analysis, multifocal tumor, EGFR mutation or amplification, PIK3CA mutation and IDHwt/TERTpwt group were associated with shorter PFS (p < 0.001, p = 0.003, p = 0.005, p < 0.001, respectively) and OS (p = 0.010, p = 0.020, p = 0.018, p < 0.001, respectively) as were older age (≥55 years), multifocal tumor, IDH1/2 wild type, 1p/19q non-codeletion and negative methylation in the MGMT promoter region. A Cox proportional hazards model was created demonstrating that single tumor (HR = 0.180, p = 0.04), MGMTp methylation (HR = 0.095, p = 0.003) and chemoradiotherapy (HR = 0.006, p = 0.002) were independent prognostic factors for OS. CONCLUSIONS: Beyond histological classification as well as IDH1/2 mutation, 1p/19q codeletion status, we could incorporate IDH1/2mt combined with TERTpmt, EGFR mutation or amplification and PIK3CA mutation into the diagnostic criteria for DLGGs to supplement WHO 2016 pathological criteria.

IL-21/IL-21R Regulates the Neutrophil-Mediated Pathologic Immune Response during Chlamydial Respiratory Infection.

IL-21/IL-21R was documented to participate in the regulation of multiple infection and inflammation. During Chlamydia muridarum (C. muridarum) respiratory infection, our previous study had revealed that the absence of this signal induced enhanced resistance to infection with higher protective Th1/Th17 immune responses. Here, we use the murine model of C. muridarum respiratory infection and IL-21R deficient mice to further identify a novel role of IL-21/IL-21R in neutrophilic inflammation. Resistant IL-21R-/- mice showed impaired neutrophil recruitment to the site of infection. In the absence of IL-21/IL-21R, pulmonary neutrophils also exhibited reduced activation status, including lower CD64 expression, MPO activity, and neutrophil-produced protein production. These results correlated well with the decrease of neutrophil-related chemokines (KC and MIP-2), inflammatory cytokines (IL-6, IL-1ß, and TNF-α), and TLR/MyD88 pathway mediators (TLR2, TLR4, and MyD88) in infected lungs of IL-21R-/- mice than normal mice. Complementarily, decreased pulmonary neutrophil infiltration, activity, and levels of neutrophilic chemotactic factors and TLR/MyD88 signal in infected lungs can be corrected by rIL-21 administration. These results revealed that IL-21/IL-21R may aggravate the neutrophil inflammation through regulating TLR/MyD88 signal pathway during chlamydial respiratory infection.

Targeted therapy with anlotinib for a H3K27M mutation diffuse midline glioma patient with PDGFR-α mutation: a case report.

H3K27M-mutant diffuse midline glioma (H3K27M-mt DMG) was a novel entity, which was defined by K27M mutations in H3F3A or HIST1H3B/C in the 2016 WHO updated fourth edition of the central nervous system (CNS) tumor classification. There is an urgent need for effective therapeutic strategies. Anlotinib is a multitarget tyrosine kinase inhibitor, which has not been reported for H3K27M-mt DMG treatment. Here, we firstly reported an adult multifocal H3K27M-mt DMG patient benefiting from anlotinib. This report provides a promising treatment option for H3K27M-mt DMG patients.

Pre-treatment with compound Danshen dripping pills prevents lipid infusion-induced microvascular dysfunction in mice.

CONTEXT: Recent studies have shown compound Danshen dripping pills (CDDP) could improve microcirculation in ischemic/reperfusion injury and other microvascular disorders. The mechanism for CDDP's role in microcirculation is not clear. OBJECTIVE: To explore the protective effects of CDDP on microvascular dysfunction. MATERIALS AND METHODS: C57BL/6 male mice (6-8 weeks) were randomized into control, model and CDDP groups (n = 10), which were treated with normal saline or CDDP (105.30 mg/kg), respectively. Then, lipid emulsion and heparin were infused via mice jugular vein to establish systemic microvascular dysfunction model. Coronary flow reserve (CFR) and leukocytes adhesion on microvascular wall were measured. Relative CD11b and CD62L expression levels on neutrophils were measured by flow cytometric analysis. Expression level of forkhead box transcription factor O1 (FOXO1) mRNA was identified by real-time PCR. RESULTS: Lipid infusion significantly attenuated the CFR (1.84 ± 0.14 vs. 2.65 ± 0.02) and increased the number of leukocytes adherent to microvascular wall in cremaster (4067.00 ± 581.20 cells/mm2 vs. 10.67 ± 4.81 cells/mm2). The expression level of CD11b and FOXO1 in neutrophils was also up-regulated by lipid infusion. Pre-treatment with CDDP significantly improved CFR (2.57 ± 0.29 vs. 1.84 ± 0.14), decreased the number of leukocytes adherent to microvascular wall (2500.00 ± 288.70 cells/mm2 vs. 4067.00 ± 581.20 cells/mm2) and down-regulated CD11b and FOXO1 expression. Discussion and conclusions: Pre-treatment with CDDP could prevent lipid infusion-induced systemic microvascular disorder including coronary and peripheral microvascular dysfunction. Down-regulated FOXO1 and decreased leukocyte adhesion might play an important role in the mechanisms of CDDP's efficacy.

Endogenous IL-17A mediated neutrophil infiltration by promoting chemokines expression during chlamydial lung infection.

Chlamydia is an obligate intracellular bacteria, which can infect cervix, urethra, conjunctiva, joints, lungs and so on. Neutrophils are important in host protection against microbial invasion during the early phase of infection. Here, to investigate the mechanism of IL-17A in recruiting neutrophils during Chlamydia muridarum (Cm) lung infection, we introduced IL-17A antibodies and IL-17-/- mice to confirm the effect of IL-17A on influencing neutrophil attractants expressions. From the analysis of the data, we found that showed that Cm infection could upregulate the expression of neutrophil-related chemokines such as KC, MIP-2 and IL-6, as well as adhesion molecules including ICAM-1 and VCAM-1. With blocking endogenous IL-17A, the upregulated MIP-2 and IL-6 were decreased, which induced less neutrophil recruitment in lung. Comparing to WT mice, IL-17-/- mice showed decreased infiltration of neutrophils in lung during the early phase of Cm infection, which were accordant with decreased chemokines, such as KC, MIP-2 and IL-6 expression. Whereas, the expression of adhesion molecules including ICAM and VCAM-1 in lungs were significantly increased in IL-17-/- mice comparing to WT mice during Cm lung infection. The results demonstrated that IL-17A influenced neutrophil infiltration by affecting expression of chemokines and adhesion molecules during the early phase of chlamydial lung infection.

Effect of acidosis on adipose-derived stem cell impairment and gene expression.

Based on disappointing results of stem cell-based application in clinical trials for patients with critical limb ischemia, we hypothesized that the acidic environment might be the key factor limiting cell survival and function. In the present study, we used microdialysis to determine presence of acidosis and metabolic imbalance in critical ischemia. Moreover, we explored the effect of extracellular acidosis on adipose-derived stem cells (ADSCs) at molecular and transcriptional level. Our data demonstrate that low pH negatively regulates cell proliferation and survival, also, it results in cell cycle arrest, mitochondrial dynamics disorder, DNA damage as well as the impairment of proangiogenic function in a pH-dependent manner. Further transcriptome profiling identified the pivotal signaling pathways and hub genes in response to acidosis. Collectively, these findings provide strong evidences for a critical role of acidosis in ADSCs impairment with ischemic condition and suggest treatments focus on tissue pH balance and acidosis-mediated hub genes may have therapeutic potential in stem cell-based application.

Predicting rice productivity for ground data-sparse regions: A transferable framework and its application to North Korea.

The use of observation-dependent methods for crop productivity and food security assessment is challenging in data-sparse regions. This study presents a transferable framework and applies it to North Korea (NK) to assess rice productivity based on climate similarity, transferable machine-learning techniques, and extendable multi-source data. We initially divided the primary phenological stages of rice in the study region and extracted dynamic rice distributions based on Moderate Resolution Imaging Spectroradiometer products and phenological observations. We compared the performances of four representative environmentally driven models (Linear Regression, back-propagation Neural Network, Support Vector Machine, and Random Forest) in simulating rice productivity using an extensive dataset that included multi-angle vegetation monitoring, climate variables, and planting distribution information. The framework integrated an optimal environmentally driven model with agricultural management practices for transferability to predict rice productivity in NK over multiple years. Additionally, two crop growth scenarios (whole growth period (WGP) and seeding-heading period (SHP)) were compared to assess pre-harvest forecasting capabilities and identify dominant factors. Finally, independent datasets from the Food and Agriculture Organization, World Food Program, and Global Gridded Crop Models were used to validate the magnitude and spatial distribution of the predicted results. The results showed that phenological identification based on remote sensing can accurately capture rice growth characteristics and map rice distribution. Random Forest outperformed other models in simulating rice productivity variation, with r-squares of 0.87 and 0.83 in the WGP and SHP, respectively. The solar-induced chlorophyll fluorescence, maximum temperature, and evapotranspiration collectively determined approximately 40 % of the variation in yield simulated using Random Forest. Conversely, planting areas contributed over 42 % of the variation in rice production. Compared to Food and Agriculture Organization statistics, the environmentally driven framework explained 78.72 % and 76.89 % of the production variation and 69.42 % and 71.15 % of the yield variation in NK under the WGP and SHP, respectively. Moreover, the environmental management-driven framework captured over 90 % of the yield variation. The predicted spatial pattern of rice productivity exhibited significant concordance with the World Food Program and Global Gridded Crop Model reports. In summary, the proposed transferable framework for crop productivity assessment contributes to early warnings of production reduction and has the potential for scalability across various crops and data-sparse regions.

Circ_0006949 as a potential non-invasive diagnosis biomarker promotes the proliferation of NSCLC cells via miR-4673/GLUL axis.

The 5-year survival for non-small cell lung cancer (NSCLC) remains <20 %, primarily due to the early symptoms of lung cancer are inconspicuous. Prompt identification and medical intervention could serve as effective strategies for mitigating the death rate. We therefore set out to identify biomarkers to help diagnose NSCLC. CircRNA microarray and qRT-PCR reveal that sputum circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC, which can enhance the proliferation and clone formation, regulate the cell cycle, and accelerate the migration and invasion of NSCLC cells. Circ_0006949 and miR-4673 are predominantly co-localized in the cytoplasm of NSCLC cell lines and tissues; it upregulates GLUL by adsorption of miR-4673 through competing endogenous RNAs mechanism. The circ_0006949/miR-4673/GLUL axis exerts pro-cancer effects in vitro and in vivo. Circ_0006949 can boost GLUL catalytic activity, and they are highly expressed in NSCLC tissues and correlate with poor prognosis. In summary, circ_0006949 is a potential biomarker for the early diagnosis and therapy of NSCLC. This novel sputum circRNA is statistically more predictive than conventional serum markers for NSCLC diagnosis. Non-invasive detection of patients with early-stage NSCLC using sputum has shown good potential for routine diagnosis and possible screening.

SUV39H1 Inhibits Angiogenesis in Limb Ischemia of Mice.

Peripheral arterial disease (PAD), characterized by atherosclerosis of the peripheral arteries or even amputation, has threatened public life and health. However, the underlying mechanism remains largely obscure. SUV39H1, a histone methyltransferase, could specifically methylate lysine 9 of histone H3 and act as a repressor in transcriptional activity. The study aimed to investigate the role of SUV39H1 in limb ischemia. C57BL/6 male mice were randomly divided into Sham or Model groups to investigate the expression of SUV39H1 in the ischemic limbs. Then, pharmaceutical inhibition or genetic deletion of SUV39H1 in the limb ischemia mice model was performed to confirm its effect on limb ischemia. The blood perfusion was quantified by laser speckle contrast imaging (LSCI). Capillary density and muscle edema were measured by CD31 immunohistochemical staining and HE staining. The expressions of SUV39H1 and Catalase were confirmed by western blot. Transcriptome sequencing of siSUV39H1 in human umbilical vein endothelial cells (HUVECs) was used to explore the regulation mechanism of SUV39H1 on angiogenesis. The results showed that SUV39H1 was highly expressed in the ischemic muscle tissue of the mice. Pharmaceutical inhibition or genetic deletion of SUV39H1 significantly improved blood perfusion, capillary density, and angiogenesis in ischemic muscle tissue. Cell experiments showed that SUV39H1 knockdown promoted cell migration, tube formation, and mitochondrial membrane potential in endothelial cells under oxidative stress. The transcriptome sequencing results unmasked mechanisms of the regulation of angiogenesis induced by SUV39H1. Finally, Salvianolic acid B and Astragaloside IV were identified as potential drug candidates for the improvement of endothelial function by repressing SUV39H1. Our study reveals a new mechanism in limb ischemia. Targeting SUV39H1 could improve endothelial dysfunction and thus prevent limb ischemia.

Concordance analysis of cerebrospinal fluid with the tumor tissue for integrated diagnosis in gliomas based on next-generation sequencing.

Purpose: The driver mutations of gliomas have been identified in cerebrospinal fluid (CSF). Here we compared the concordance between CSF and tumor tissue for integrated diagnosis in gliomas using next-generation sequencing (NGS) to evaluate the feasibility of CSF detection in gliomas. Patients and methods: 27 paired CSF/tumor tissues of glioma patients were sequenced by a customized gene panel based on NGS. All CSF samples were collected through lumbar puncture before surgery. Integrated diagnosis was made by analysis of histology and tumor DNA molecular pathology according to the 2021 WHO classification of the central nervous system tumors. Results: A total of 24 patients had detectable circulating tumor DNA (ctDNA) and 22 had at least one somatic mutation or chromosome alteration in CSF. The ctDNA levels varied significantly across different ages, Ki-67 index, magnetic resonance imaging signal and glioma subtypes (p < 0.05). The concordance between integrated ctDNA diagnosis and the final diagnosis came up to 91.6% (Kappa, 0.800). We reclassified the clinical diagnosis of 3 patients based on the results of CSF ctDNA sequencing, and 4 patients were reassessed depending on tumor DNA. Interestingly, a rare IDH1 R132C was identified in CSF ctDNA, but not in the corresponding tumor sample. Conclusion: This study demonstrates a high concordance between integrated ctDNA diagnosis and the final diagnosis of gliomas, highlighting the practicability of NGS based detection of mutations of CSF in assisting integrated diagnosis of gliomas, especially glioblastoma.

Establishment of FAP-overexpressing Cells for FAP-targeted Theranostics.

OBJECTIVE: Fibroblast activation protein (FAP) has been widely studied and exploited for its clinical applications. One of the difficulties in interpreting reports of FAP-targeted theranostics is due to the lack of accurate controls, making the results less specific and less confirmative. This study aimed to establish a pair of cell lines, in which one highly expresses FAP (HT1080-hFAP) and the other has no detectable FAP (HT1080-vec) as control, to accurately evaluate the specificity of the FAP-targeted theranostics in vitro and in vivo. METHODS: The cell lines of the experimental group (HT1080-hFAP) and no-load group (HT1080-vec) were obtained by molecular construction of the recombinant plasmid pIRES-hFAP. The expression of hFAP in HT1080 cells was detected by PCR, Western blotting and flow cytometry. CCK-8, Matrigel transwell invasion assay, scratch test, flow cytometry and immunofluorescence were used to verify the physiological function of FAP. The activities of human dipeptidyl peptidase (DPP) and human endopeptidase (EP) were detected by ELISA in HT1080-hFAP cells. PET imaging was performed in bilateral tumor-bearing nude mice models to evaluate the specificity of FAP. RESULTS: RT-PCR and Western blotting demonstrated the mRNA and protein expression of hFAP in HT1080-hFAP cells but not in HT1080-vec cells. Flow cytometry confirmed that nearly 95% of the HT1080-hFAP cells were FAP positive. The engineered hFAP on HT1080 cells had its ability to retain enzymatic activities and a variety of biological functions, including internalization, proliferation-, migration-, and invasion-promoting activities. The HT1080-hFAP xenografted tumors in nude mice bound and took up 68GA-FAPI-04 with superior selectivity. High image contrast and tumor-organ ratio were obtained by PET imaging. The HT1080-hFAP tumor retained the radiotracer for at least 60 min. CONCLUSION: This pair of HT1080 cell lines was successfully established, making it feasible for accurate evaluation and visualization of therapeutic and diagnostic agents targeting the hFAP.

In Vivo Evaluation of a Gallium-68-Labeled Tumor-Tracking Cyanine Dye for Positron Emission Tomography/Near-Infrared Fluorescence Carcinoma Imaging, Image-Guided Surgery, and Photothermal Therapy.

Positron emission tomography (PET)/near-infrared fluorescence (NIRF) dual-modal imaging presents an enticing prospect for tumor diagnosis and surgical navigation. In this study, we developed a novel probe IR808-DOTA for tumor-targeted PET/NIRF imaging, image-guided surgery, and photothermal therapy. This construct had better water solubility and pharmacokinetics than IR808 and had similar photophysical properties, tumor targeting ability, and photothermal anticancer effect to IR808. By a simple labeling process, IR808-DOTA was labeled with gallium-68 and applied as a PET probe for tumor imaging in MCF-7 tumor xenografted mice. IR808-DOTA itself acted as an NIRF imaging agent in the following surgery for intraoperative navigation to aid surgeons in the delineation of tumor margins and visualizing sentinel lymph nodes to facilitate a more thorough tumor resection. Irradiation by laser, IR808-DOTA could prominently inhibit tumor growth in MCF-7 subcutaneous tumor model mice by directly ablating tumor cells, inhibiting tumor proliferation, and promoting tumor cell apoptosis. In summary, 68Ga-DOTA-IR808 could enable a convenient and user-friendly workflow for tumor imaging and guided surgery, and therefore, it may have great prospects for clinical translation as a PET/NIRF dual-modal probe.

A bibliometric analysis of acute myocardial infarction in women from 2000 to 2022.

Background: Plenty of publications had been written in the last several decades on acute myocardial infarction (AMI) in women. However, there are few bibliometric analyses in such field. In order to solve this problem, we attempted to examine the knowledge structure and development of research about AMI in women based on analysis of related publications. Method: The Web of Science Core Collection was used to extract all publications regarding AMI in women, ranging from January 2000 to August 2022. Bibliometric analysis was performed using VOSviewer, Cite Space, and an online bibliometric analysis platform. Results: A total of 14,853 publications related to AMI in women were identified from 2000 to 2022. Over the past 20 years, the United States had published the most articles in international research and participated in international cooperation the most frequently. The primary research institutions were Harvard University and University of Toronto. Circulation was the most cited journal and had an incontrovertible academic impact. 67,848 authors were identified, among which Harlan M Krumholz had the most significant number of articles and Thygesen K was co-cited most often. And the most common keywords included risk factors, disease, prognosis, mortality, criteria and algorithm. Conclusion: The research hotspots and trends of AMI in women were identified and explored using bibliometric and visual methods. Researches about AMI in women are flourishing. Criteria and algorithms might be the focus of research in the near future, which deserved great attentions.

Simultaneous Delivery of Dual Inhibitors of DNA Damage Repair Sensitizes Pancreatic Cancer Response to Irreversible Electroporation.

Pancreatic ductal adenocarcinoma (PDAC) is an abysmal disease refractory to most standard therapies. Irreversible electroporation (IRE) is a local ablative technique for the clinical treatment of solid tumors, including locally advanced and unresectable PDAC, by intratumorally delivering high-intensity electric pulses to permanently disrupt cell membranes and induce cell death. But the distribution of electric field is uneven within the tumor, and in some regions, tumor cells only experience temporary perturbation to their cell membrane, a phenomenon denoted as reversible electroporation (RE). These tumor cells may survive and therefore are the main culprit of tumor relapse after IRE. We herein showed that RE, although not killing tumor cells, induced DNA double-strand breaks and activated DNA damage repair (DDR) responses. Using reactive oxygen species-sensitive polymeric micelles coloaded with Olaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and AZD0156, an inhibitor of ataxia telangiectasia mutated (ATM), the resultant nanoformulation (M-TK-OA) disrupted both homologous recombination and nonhomologous end joining signaling of the DDR response and impaired colony formation in pancreatic cancer cells after RE. The combination of IRE and M-TK-OA significantly prolonged animal survival in both subcutaneous and orthotopic murine PDAC models and elicited CD8+ T cell-mediated antitumor immunity with a sustained antitumor memory. The efficacy of combined IRE and M-TK-OA treatments was partially attributed to the activation of cyclic GMP-AMP synthase-stimulator of interferon genes innate immune responses. Our study suggests that dual inhibition of PARP and ATM with nanomedicine is a promising strategy to enhance the pancreatic cancer response to IRE.

Salvianolic Acid B Alleviates Limb Ischemia in Mice via Promoting SIRT1/PI3K/AKT Pathway-Mediated M2 Macrophage Polarization.

Salvianolic acid B (Sal B) is an effective treatment agent for ischemic disease in China. However, Sal B's effects on peripheral arterial disease (PAD) and its mechanism remains poorly understood. Macrophage polarization plays a crucial role in PAD. Nevertheless, treatment modalities that increase the population of anti-inflammatory (M2) macrophages are limited. This study aimed to explore the protective effects of Sal B on limb perfusion and investigate the mechanism of Sal B-induced macrophage polarization. C57BL/6 male mice (6 weeks) were randomized into control, Model + NS, and Model + Sal B groups (n = 5). Then, we established a hind limb ischemia mouse model to assess the Sal B's role (15 mg/kg/d) in PAD. We quantified the blood perfusion via laser speckle contrast imaging (LSCI) and measured the capillary density and muscle edema with CD31 and H&E staining. The Sal B-induced macrophage polarization was confirmed by qPCR and ELISA. The results showed that the Sal B group exhibited a significant improvement in the blood perfusion, capillary density, muscle edema, and M2 markers gene expressions. Cell migration and tube formation were promoted in the endothelial cells stimulated with a culture supernatant from Sal B-treated macrophages. In contrast, endothelial functions improved by Sal B-treated macrophages were impaired in groups treated with SIRT1 and PI3K inhibitors. These findings provide evidence for Sal B's protective role in PAD and demonstrate the enhancement of macrophage polarization via the SIRT1/PI3K/AKT pathway.

Impact of Iodinated Contrast Media in Patients Received Percutaneous Coronary Intervention: Focus on Thyroid Disease.

Background: With the rapid advance in percutaneous coronary intervention (PCI) technology, patients absorb large volume of iodinated contrast media (ICM). Recent studies suggested that ICM may lead to hyperthyroidism, but the association between ICM volume and thyroid is still unclear. We sought to evaluate the long-term influence of ICM on thyroid dysfunction and disease in patients received PCI. Methods: This single-center retrospective study included consecutive coronary artery disease (CAD) patients. A covariance (ANCOVA) model was performed to evaluate the change of serum TSH, FT3 and FT4 before and one-year after the PCI procedure. Restricted cubic splines and logistic regression were performed to evaluate the association between ICM volume and thyroid disease. Results: 2062 patients met inclusion criteria (1381 patients in the low-volume group and 681 patients in the high-volume group). The high-volume group was 0.238 ± 0.092 pmol/L higher than the low-volume group (P = 0.010) in the serum FT4. Restricted cubic splines show that there were linear dose-response relationships for ICM volume and composite endpoint and hyperthyroidism. In all models, there were significant differences in composite endpoint between the two groups. (OR 1.75, 95% CI (1.05, 2.92), P = 0.032, OR 1.73, 95% CI (1.01-2.96), P= 0.032 and OR 1.83, 95% CI (1.09-3.06), P= 0.022, respectively). The positive results were also showed for hyperthyroidism in all models (OR 2.35, 95% CI (1.14-4.84), P = 0.021, OR 10.36, 95% CI (1.20-89.00), P = 0.033 and OR 2.35, 95% CI (1.13-4.87), P = 0.022, respectively). Conclusion: The present analysis gives an overview that ICM volume is associated with an increased risk of thyroid dysfunction and thyroid disease.