Sodium tanshinone IIA sulfonate protects vascular relaxation in ApoE-knockout mice by inhibiting the SYK-NLRP3 inflammasome-MMP2/9 pathway.

BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Identification of 16SrXXX-A Phytoplasma Associated with Salt cedar (Tamarix chinensis Lour.) witches'-broom (SCWB) in Southern Xinjiang of China.

Salt cedar is an ornamental shrub/moderate tree species native to Asia and East Europe, and grows in salt-alkali soil, desert and other dry areas, which plays an important role in wind prevention and sand fixation as well as maintaining ecological balance. Salt cedar witches'-broom (SCWB), which was extremely pernicious to Salt cedar. It was first observed and reported in Xi'an, China in 2005 (Zhao et al.2005). Witches' broom symptoms were observed on 20 out of 150 (13.3%) salt plants surveyed from the Alar region and 10 out of 86 (11.6%) plants from the Akesu region in southern of Xinjiang in May 2020. The damaged plants compared with asymptomatic plants (Fig.1A), the major symptoms included branches clustered, intersegment shorten and coarsen, giving rise to the formation of clusters (Fig.1B). Total plant DNA was extracted from phloem tissues with asymptomatic symptoms and phloem tissues with witches'-broom symptoms by a CTAB-based DNA extraction method (Green et al.1999). The 16S rRNA gene and the phytoplasma universal primers P1/P7 and rpF1/rpR1 of the rp (ribosomal protein) gene were used for Polymerase chain reaction (PCR) amplification by using the extracted plant total DNA as the template. The PCR product was used as the template and the R16F2n/R16R2 prmer was used for nested PCR amplification of the 16S rRNA gene after the amplification was completed. The results show that no product was obtained in asymptomatic plants. When DNA samples from witches'-broom symptomatic plants were used as templates, fragments with lengths 1219 bp and 1174 bp, corresponding to 16S rRNA gene and rp gene, were obtained. 16S rRNA gene was sequenced and deposited in GenBank under accession number MW447513. BLAST analysis revealed that the partial 16S rRNA sequence of the phytoplasma associated with P. aphylla witches' broom showed highest sequence identity (99.67%) to salt cedar witches' broom phytoplasma, 'Candidatus Phytoplasma tamaricis' (Accession Number: FJ432664). Phylogenetic and molecular evolutionary analyses were conducted using MEGA-X (Kumar et al., 2018). Results showed taht the SCWB and 16S rXXX group's'Candidatus Phytoplasma tamaricis', (GenBank accession: FJ432664) have the highest affinity (Fig.2A). A virtual restriction fragment length polymorphism(RFLP) was done to determinethe subgroup ( Zhao et al. 2009). The 16S rDNA sequence from the Tamarix chinensis plant showed 99.3% similarity with that of the "Candidatus Phytoplasma tamaricis" reference strain (GenBank accession: FJ432664), suggesting that the phytoplasma in this study belongs to "Candidatus Phytoplasma tamaricis"-related strain. Therefore, it can be stated that SCWB belongs to the 16S rXXX group. The partial rp sequences only shared 84.74% sequence similarity with that of 'Candidatus Phytoplasma prunorum' (MG383523) of Apple proliferation group, a known subgroup 16S rX. Blast analysis based on the partial rp sequences showed that it shares less than 90% similarity with that of any known phytoplasma (Fig 2B), we suspect that this is due to a lack of sequenced rp gene sequences for the 16S rXXX group. To our knowledge, this is the first report of Salt Cedar Witches' Broom phytoplasma in Xinjiang province, China. As a consequence, we guess the SCWB phytoplasma rp gene belongs to 16S rXXX-rp group, which is also the first report about the 16SrXXX-rp group. Because SCWB1 is the only strain in the 16S rXXX group, and it is the representative strain of the 16S rXXX-A subgroup (Zhao et al. 2009). So, the SCWB disease we found in southern Xinjiang belongs to the 16S rXXX-A subgroup.

Impact of the posttransplant lymphoproliferative disorder subtype on survival.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of solid organ transplantation. Histologic heterogeneity and a lack of treatment standards have made evaluating clinical outcomes in specific patient populations difficult. This systematic literature review investigated the impact of the PTLD histologic subtype on survival in a large data set. METHODS: Case series were identified on PubMed with the search terms post-transplant lymphoproliferative disorder/disease, PTLD, and solid organ transplantation, with additional publications identified through reference lists. The patient characteristics, immunosuppressive regimen, treatment, survival, and follow-up time for 306 cases were extracted from 94 articles, and these cases were combined with 11 cases from Emory University Hospital. Patients with a recorded subtype were included in a Kaplan-Meier survival analysis (n = 234). Cox proportional hazards regression analyses identified predictors of overall survival (OS) for each subtype and B-cell subgroup. RESULTS: OS differed significantly between monomorphic T-cell neoplasms (median, 9 months) and polymorphic, monomorphic B-cell, and Hodgkin-type neoplasms, for which the median OS was not reached (P = .0001). Significant differences in OS among B subgroups were not detected, but there was a trend toward decreased survival for patients with Burkitt-type PTLD. Kidney transplantation and a reduction of immunosuppression were associated with increased OS for patients with B-cell neoplasms in a multivariate analysis. Immunosuppression with azathioprine was associated with decreased OS for patients with T-cell neoplasms, whereas radiotherapy was associated with improved OS for patients with that subtype. CONCLUSIONS: The histologic subtype represents an important prognostic factor in PTLD, with patients with T-cell neoplasms exhibiting very poor OS. Possibly lower survival for certain subsets of patients with B-cell PTLD should be explored further and suggests the need for subtype-specific therapies to improve outcomes. Cancer 2018;124:2327-36. © 2018 American Cancer Society.

Sodium Tanshinone IIA Sulfonate alleviates vascular senescence in diabetic mice by modulating the A20-NFκB-NLRP3 inflammasome-catalase pathway.

Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence ß-Galactosidase Staining (SA-ß-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-ß-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.

Meta-Analysis of Interleukin-2 Receptor Antagonists as the Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Corticosteroid is the first-line treatment for aGVHD, but its response rate is only approximately 50%. At present, no uniformly accepted treatment for steroid-refractory aGVHD (SR-aGVHD) is available. Blocking interleukin-2 receptors (IL-2Rs) on donor T cells using pharmaceutical antagonists alleviates SR-aGVHD. This meta-analysis aimed to compare the efficacy and safety of four commercially available IL-2R antagonists (IL-2RAs) in SR-aGVHD treatment. A total of 31 studies met the following inclusion criteria (1): patients of any race, any sex, and all ages (2); those diagnosed with SR-aGVHD after HSCT; and (3) those using IL-2RA-based therapy as the treatment for SR-aGVHD. The overall response rate (ORR) at any time after treatment with basiliximab and daclizumab was 0.81 [95% confidence interval (CI): 0.74-0.87)] and 0.71 (95% CI: 0.56-0.82), respectively, which was better than that of inolimomab 0.54 (95% CI: 0.39-0.68) and denileukin diftitox 0.56 (95% CI: 0.35-0.76). The complete response rate (CRR) at any time after treatment with basiliximab and daclizumab was 0.55 (95% CI: 0.42-0.68) and 0.42 (95%CI: 0.29-0.56), respectively, which was better than that of inolimomab 0.30 (95% CI: 0.16-0.51) and denileukin diftitox 0.37 (95% CI: 0.24-0.52). The ORR and CRR were better after 1-month treatment with basiliximab and daclizumab than after treatment with inolimomab and denileukin diftitox. The incidence of the infection was higher after inolimomab treatment than after treatment with the other IL-2RAs. In conclusion, the efficacy and safety of different IL-2RAs varied. The response rate of basiliximab was the highest, followed by that of daclizumab. Prospective, randomized controlled trials are needed to compare the efficacy and safety of different IL-2RAs.

[The angiographic features of exercise-induced ST-segment elevation in patients without myocardial infarction].

OBJECTIVE: To explore the incidence and angiographic features of exercise-induced ST-segment elevation in patients without prior myocardial infarction. METHODS: Exercise-induced ST-segment elevation occurred in 15 out of 4601 consecutive patients without prior myocardial infarction underwent treadmill exercise testing during a 2-year period. The coronary angiographic features of the 15 patients (13 males, aged between 40 - 75 years) were analyzed. RESULTS: Coronary angiography revealed one hemodynamically relevant stenotic vessel in 6 patients, two hemodynamically relevant stenotic vessels in 6 patients, three hemodynamically relevant stenotic vessels in 3 patients. Left anterior descending (LAD) coronary artery was affected in 12 patients. Left main coronary artery (LMCA) stenosis was evidenced in 1 patient and right coronary artery stenosis in 7 patients. Severe (90% - 100%) occlusions were visualized in 8 out of 13 patients with LAD or LMCA lesions. Elevated ST-segment leads were consistent with the ischemic area where the blood supply of myocardium was affected by diseased vessels. CONCLUSIONS: The incidence of exercise induced ST-segment elevation in patients without prior myocardial infarction is very low and mostly due to severe fixed coronary artery stenosis, especially in LAD. The location of ischemic myocardium can be suggested by ST-segment elevation leads during exercise.

Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling.

The goal of allogeneic bone marrow transplantation (allo-BMT) is elimination of leukemia cells through the graft-versus-leukemia (GvL) activity of donor cells, while limiting graft-versus-host disease (GvHD). Immune checkpoint pathways regulate GvL and GvHD activities, but blocking antibodies or genetic inactivation of these pathways can cause lethal GVHD. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that regulates coinhibitory pathways; its role in allo-BMT has not been studied. We found VIP transiently expressed in donor NK, NK-T, dendritic cells, and T cells after allo transplant, as well as host leukocytes. A peptide antagonist of VIP signaling (VIPhyb) increased T-cell proliferation in vitro and reduced IL10 expression in donor T cells. Treatment of allo-BMT recipients with VIPhyb, or transplanting donor grafts lacking VIP (VIP-KO), activated donor T-cells in lymphoid organs, reduced T-cell homing to GvHD target organs, and enhanced GvL without increasing GvHD in multiple allo-BMT models. Genetic or ex vivo depletion of donor NK cells or CD8+ T cells from allografts abrogated the VIPhyb-enhanced GvL activity. VIPhyb treatment led to downregulation of PD-1 and PD-L1 expression on donor immune cells, increased effector molecule expression, and expanded oligoclonal CD8+ T cells that protected secondary allo transplant recipients from leukemia. Blocking VIP signaling thus represents a novel pharmacologic approach to separate GvL from GvHD and enhance adaptive T-cell responses to leukemia-associated antigens in allo-BMT. Cancer Res; 76(23); 6802-15. ©2016 AACR.

Gastric wall implantation metastasis of retroperitoneal extraskeletal osteosarcoma: A case report and review of the literature.

Retroperitoneal extraskeletal osteosarcoma (ESOS) is a rare and highly invasive tumor that is usually diagnosed at an advanced stage due to the insidious onset. The present study analyses a case of retroperitoneal ESOS and its clinical, radiological and therapeutic conditions, and also provides a review of the literature. A 52-year-old male was diagnosed with retroperitoneal ESOS. The patient succumbed to the condition one year after the initial surgery. During treatment, the patient underwent two additional surgeries and two courses of chemotherapy. In the present case, a peritoneal metastatic lesion of ESOS was shed from the peritoneum and implanted into the outer membrane of the stomach and metastasis was identified, this has rarely been reported in the literature. Retroperitoneal ESOS should be considered in the differential diagnosis of a retroperitoneal mass in order to facilitate the management of surgery and help determine the appropriate treatment of the disease.