OBJECTIVES: To explore the role of berberine (BBR) in ameliorating coronary endothelial cell injury in Kawasaki disease (KD) by regulating the complement and coagulation cascade. METHODS: Human coronary artery endothelial cells (HCAEC) were divided into a healthy control group, a KD group, and a BBR treatment group (n=3 for each group). The healthy control group and KD group were supplemented with 15% serum from healthy children and KD patients, respectively, while the BBR treatment group received 15% serum from KD patients followed by the addition of 20 mmol/L BBR. Differential protein expression was analyzed and identified using isobaric tags for relative and absolute quantitation technology and liquid chromatography-tandem mass spectrometry, followed by GO functional enrichment analysis and KEGG signaling pathway enrichment analysis of the differential proteins. Western blot was used to detect differential protein expression. RESULTS: A total of 518 differential proteins were identified between the KD group and the healthy control group (300 upregulated proteins and 218 downregulated proteins). A total of 422 differential proteins were identified between the BBR treatment group and the KD group (221 upregulated proteins and 201 downregulated proteins). Bioinformatics analysis showed that compared to the healthy control group, the differential proteins in the KD group were enriched in the complement and coagulation cascade and ribosome biogenesis in eukaryotes. Compared to the KD group, the differential proteins in the BBR treatment group were also enriched in the complement and coagulation cascade and ribosome biogenesis in eukaryotes. Western blot results indicated that compared to the healthy control group, the expression of complement C1q subcomponent subunit C (C1QC), kininogen-1 (KNG1), complement C1s subcomponent (C1S), and C4b-binding protein alpha chain (C4BPA) was increased in the KD group (P<0.05). Compared to the KD group, the expression of KNG1, C1S, C1QC, and C4BPA was decreased in the BBR treatment group (P<0.05). CONCLUSIONS The complement and coagulation cascade may be involved in the regulation of BBR treatment for coronary injury in KD, and C1QC, KNG1, C1S, and C4BPA may serve as biomarkers for this treatment.
Mucocutaneous Lymph Node Syndrome/blood* ; Humans ; Endothelial Cells/pathology* ; Complement System Proteins/physiology* ; Coronary Vessels/drug effects* ; Male ; Blood Coagulation/drug effects* ; Berberine/therapeutic use* ; Female ; Child, Preschool ; Infant

Objective:This study aims to investigate the influence of microvessel density（MVD） and microlymphatic vessel density（MLVD） on the prognosis of patients with hypopharyngeal squamous cell carcinoma（HPSCC） and to develop a nomogram prediction model for prognosis based on pathological characteristics. Methods:A retrospective analysis was conducted on clinicopathological and follow-up data from HPSCC patients who underwent surgical treatment at our institution between June 2010 and June 2020. Immunohistochemical staining was performed on tumor tissues and adjacent normal margin tissues to evaluate MVD and MLVD. The associations among MVD, MLVD, and clinicopathological features were analyzed. Univariate and multivariate Cox regression analyses were conducted to identify independent risk factors affecting overall survival（OS）. Based on these findings, a nomogram model was constructed and its predictive accuracy was assessed using C-index, receiver operating characteristic（ROC） curve, and calibration curve. Results:Both MVD and MLVD were significantly higher in HPSCC tumor tissues compared to normal tissues. Patients in the high MVD and high MLVD groups exhibited significantly lower OS rates than those in the low MVD and low MLVD groups. Multivariate Cox regression analysis revealed that N stage, recurrence, nerve invasion, lymph node capsule invasion, MVD, and MLVD were independent prognostic factors of OS. Based on these factors, a nomogram prognosis model was successfully constructed. The nomograms demonstrated superior performance in terms of C-index, area under the ROC curve, and calibration, outperforming the AJCC TNM staging system. Conclusion:Elevated MVD and MLVD levels are associated with poorer prognosis in HPSCC patients. The nomogram model based on pathological features provides valuable insights for clinical assessment and decision-making.
Humans ; Hypopharyngeal Neoplasms/blood supply* ; Prognosis ; Retrospective Studies ; Microvascular Density ; Nomograms ; Lymphatic Vessels/pathology* ; Male ; Female ; Middle Aged ; Carcinoma, Squamous Cell/blood supply* ; Microvessels/pathology* ; Lymphatic Metastasis ; Survival Rate

Type 2 diabetes (T2D) increases the risk for cerebrovascular disease (CVD) and dementia. The underlying molecular mechanisms remain elusive, which hampers the development of treatment or/and effective prevention strategies. Recent studies suggest that dyshomeostasis of amylin, a satiety hormone that forms pancreatic amyloid in patients with T2D, promotes accumulation of amylin in cerebral small blood vessels and interaction with Alzheimer's disease (AD) pathology. Overexpression of human amylin in rodents (rodent amylin does not form amyloid) leads to late-life onset T2D and neurologic deficits. In this Review, we discuss clinical evidence of amylin pathology in CVD and AD and identify critical characteristics of animal models that could help to better understand molecular mechanisms underlying the increased risk of CVD and AD in patients with prediabetes or T2D.
Alzheimer Disease ; Amyloid ; Blood Vessels ; Cerebrovascular Disorders ; Dementia ; Diabetes Complications ; Diabetes Mellitus, Type 2 ; Humans ; Islet Amyloid Polypeptide ; Models, Animal ; Neurologic Manifestations ; Pathology ; Prediabetic State ; Rodentia

PURPOSE: Intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease (KD). However, there is still no standard treatment for IVIG-resistant KD. This study aimed to evaluate the efficacy of low-dose methotrexate (MTX) as a treatment for IVIG-resistant KD. MATERIALS AND METHODS: We retrospectively analyzed 10-year data for patients with IVIG-resistant KD who were administered MTX at Severance Children's Hospital. RESULTS: The subjects included 75 patients with KD aged 5 months to 9.2 years who had been administered MTX. Their maximum body temperatures decreased significantly within 24 h of therapy. The patients' C-reactive protein levels were significantly lower 1 week after administering the first dose of MTX than those before treatment. No adverse effect for MTX was observed. CONCLUSION: MTX treatment of IVIG-resistant KD resulted in rapid defervescence, improvement of clinical symptoms, and normalization of acute-phase reactants in all patients. Thus, MTX could be a candidate treatment for IVIG-resistant KD.
C-Reactive Protein/analysis ; Child ; Child, Preschool ; Coronary Vessels/pathology ; Demography ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Infant ; Male ; Methotrexate/administration & dosage ; Methotrexate/therapeutic use ; Mucocutaneous Lymph Node Syndrome/blood ; Mucocutaneous Lymph Node Syndrome/drug therapy ; Retrospective Studies ; Steroids/therapeutic use ; Treatment Outcome

Behçet's disease is a systemic vasculitis of unknown etiology characterized by recurrent oral and genital ulcers and uveitis. The vascular involvement of Behçet's disease affects arteries, veins, and blood vessels of all sizes, and it can include venous or arterial thrombosis and arterial aneurysms. There are only a few reports of an aortic aneurysm invading a vertebral body in a patient with Behçet's disease. Here, we report the case of a 45-year-old man who was initially diagnosed with vertebral invasion of a mycotic aneurysm. He underwent vascular surgery and received empirical antibiotics, but all cultures were negative. However, he had persistent, recurrent deep vein thrombosis and elevated inflammatory markers. After reviewing the pathology, a final diagnosis of Behçet's disease was made. He was successfully treated with corticosteroids. This report presents a rare case of Behçet's disease mimicking vertebral invasion of a mycotic aneurysm.
Adrenal Cortex Hormones ; Aneurysm ; Aneurysm, Infected* ; Anti-Bacterial Agents ; Aortic Aneurysm ; Arteries ; Behcet Syndrome ; Blood Vessels ; Diagnosis ; Humans ; Middle Aged ; Osteomyelitis ; Pathology ; Systemic Vasculitis ; Thrombosis ; Ulcer ; Uveitis ; Veins ; Venous Thrombosis

OBJECTIVETo study the expression of serum cytokines, interleukin-38 (IL-38) and interleukin-1β (IL-1β) in the acute phase of Kawasaki disease (KD) in children and the association of IL-38 and IL-1β with inflammatory response in the acute phase and the development of coronary artery lesion (CAL).

METHODSA total of 40 children with KD who were hospitalized in the hospital between July 2015 and June 2016 were enrolled, with 21 children in the CAL group and 19 in the non-CAL (NCAL) group. Thirty healthy children and 19 children with infection and pyrexia, who were matched for sex and age, were enrolled as healthy control group and pyrexia control group respectively. ELISA was used to measure the serum levels of IL-38 and IL-1β in the 40 children in the acute phase of KD. Spearman's rank correlation analysis was used to investigate the correlations of IL-1β and IL-38 with interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), N-terminal pro-brain natriuretic peptide (NT-proBNP), triglyceride (TG), and total cholesterol (TC).

RESULTSThe serum level of IL-38 in the children in the acute phase of KD was significantly lower than that in the healthy control group (P<0.05), but significantly higher than that in the pyrexia control group (P<0.05). There was no significant difference in the level of IL-38 between the CAL and NCAL groups (P>0.05). The children in the acute phase of KD had a significantly higher level of IL-1β than the healthy control group (P<0.05), while there was no significant difference between this group and the pyrexia control group (P>0.05). There was also no significant difference in the level of IL-1β between the CAL and NCAL groups (P>0.05). Serum IL-1β and IL-38 levels were not correlated with serum levels of CRP, ESR, PCT, IL-6, and NT-ProBNP or blood lipids (TG and TC) (P>0.05).

CONCLUSIONSIL-38 is involved in an inflammatory response in the acute phase of KD and may exert an anti-inflammatory effect, which is opposite to the effect of IL-1β to promote inflammatory response. However, there is no significant correlation between these two cytokines and the development of CAL in KD.

Acute Disease ; Atrial Natriuretic Factor ; blood ; Blood Sedimentation ; C-Reactive Protein ; metabolism ; Case-Control Studies ; Child ; Child, Preschool ; Cholesterol ; blood ; Coronary Artery Disease ; blood ; etiology ; pathology ; Coronary Vessels ; pathology ; Female ; Humans ; Infant ; Interleukin-1beta ; blood ; Interleukins ; blood ; Male ; Mucocutaneous Lymph Node Syndrome ; blood ; complications ; Procalcitonin ; blood ; Protein Precursors ; blood ; Triglycerides ; blood

OBJECTIVEThis study aimed at investigating whether notoginsenoside R1 (R1), a unique saponin found in Panax notoginseng could promote angiogenic activity on human umbilical vein endothelial cells (HUVECs) and elucidate their potential molecular mechanisms. In addition, vascular restorative activities of R1 was assessed in a chemically-induced blood vessel loss model in zebrafish.

METHODSThe in vitro angiogenic effect of R1 was compared with other previously reported angiogenic saponins Rg1 and Re. The HUVECs proliferation in the presence of R1 was determined by cell proliferation kit II (XTT) assay. R1, Rg1 and Re-induced HUVECs invasion across polycarbonate membrane was stained with Hoechst-33342 and quantified microscopically. Tube formation assay using matrigelcoated wells was performed to evaluate the pro-angiogenic actions of R1. In order to understand the mechanism underlying the pro-angiogenic effect, various pathway inhibitors such as SU5416, wortmannin (wort) or L-Nω-nitro- L-arginine methyl ester hydrochloride (L-NAME), SH-6 were used to probe the possible involvement of signaling pathway in the R1 mediated HUVECs proliferation. In in vivo assays, zebrafish embryos at 21 hpf were pre-treated with vascular endothelial growth factor (VEGF) receptor kinase inhibitor II (VRI) for 3 h only and subsequently post-treated with R1 for 48 h, respectively. The intersegmental vessels (ISVs) in zebrafish were assessed for the restorative effect of R1 on defective blood vessels.

RESULTSR1 could stimulate the proliferation of HUVECs. In the chemoinvasion assay, R1 significantly increased the number of cross-membrane HUVECs. In addition, R1 markedly enhanced the tube formation ability of HUVECs. The proliferative effects of these saponins on HUVECs were effectively blocked by the addition of SU5416 (a VEGF-KDR/Flk-1 inhibitor). Similarly, pre-treatment with wort [a phosphatidylinositol 3-kinase (PI3K)-kinase inhibitor], L-NAME [an endothelial nitric oxide synthase (eNOS) inhibitor] or SH-6 (an Akt pathway inhibitor) significantly abrogated the R1 induced proliferation of HUVECs. In chemicallyinduced blood vessel loss model in zebrafish, R1 significantly rescue the damaged ISVs.

CONCLUSIONR1, similar to Rg1 and Re, had been showed pro-angiogenic action, possibly via the activation of the VEGF-KDR/Flk-1 and PI3K-Akt-eNOS signaling pathways. Our findings also shed light on intriguing pro-angiogenic effect of R1 under deficient angiogenesis condition in a pharmacologic-induced blood vessels loss model in zebrafish. The present study in vivo and in vitro provided scientific evidence to explain the ethnomedical use of Panax notoginseng in the treatment of cardiovascular diseases, traumatic injuries and wound healing.

Animals ; Blood Vessels ; pathology ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Collagen ; pharmacology ; Disease Models, Animal ; Drug Combinations ; Ginsenosides ; chemistry ; pharmacology ; Human Umbilical Vein Endothelial Cells ; cytology ; drug effects ; enzymology ; physiology ; Humans ; Laminin ; pharmacology ; Neovascularization, Physiologic ; drug effects ; Phosphatidylinositol 3-Kinases ; metabolism ; Protein Kinase Inhibitors ; pharmacology ; Proteoglycans ; pharmacology ; Proto-Oncogene Proteins c-akt ; metabolism ; Vascular Endothelial Growth Factor Receptor-2 ; metabolism ; Zebrafish

OBJECTIVE: To assess magnetic resonance imaging (MRI) features of coronary microembolization in a swine model induced by small-sized microemboli, which may cause microinfarcts invisible to the naked eye. MATERIALS AND METHODS: Eleven pigs underwent intracoronary injection of small-sized microspheres (42 microm) and catheter coronary angiography was obtained before and after microembolization. Cardiac MRI and measurement of cardiac troponin T (cTnT) were performed at baseline, 6 hours, and 1 week after microembolization. Postmortem evaluation was performed after completion of the imaging studies. RESULTS: Coronary angiography pre- and post-microembolization revealed normal epicardial coronary arteries. Systolic wall thickening of the microembolized regions decreased significantly from 42.6 +/- 2.0% at baseline to 20.3 +/- 2.3% at 6 hours and 31.5 +/- 2.1% at 1 week after coronary microembolization (p < 0.001 for both). First-pass perfusion defect was visualized at 6 hours but the extent was largely decreased at 1 week. Delayed contrast enhancement MRI (DE-MRI) demonstrated hyperenhancement within the target area at 6 hours but not at 1 week. The microinfarcts on gross specimen stained with nitrobluetetrazolium chloride were invisible to the naked eye and only detectable microscopically. Increased cTnT was observed at 6 hours and 1 week after microembolization. CONCLUSION: Coronary microembolization induced by a certain load of small-sized microemboli may result in microinfarcts invisible to the naked eye with normal epicardial coronary arteries. MRI features of myocardial impairment secondary to such microembolization include the decline in left ventricular function and myocardial perfusion at cine and first-pass perfusion imaging, and transient hyperenhancement at DE-MRI.
Animals ; Coronary Angiography/*methods ; Coronary Vessels/*pathology ; Disease Models, Animal ; Embolism/*pathology ; Female ; Heart/radiography ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging/*methods ; Microspheres ; Myocardial Contraction/physiology ; Myocardial Infarction/*pathology ; Myocardium/pathology ; Nitroblue Tetrazolium ; Staining and Labeling ; Swine ; Troponin T/blood ; Ventricular Function, Left

To explore the protective effects of right coronary artery ischemic preconditioning and post-conditioning on myocardial ischemia reperfusion injury in rabbit heart.
 Methods: A total of 30 rabbits were randomly divided into 4 groups: a control group (n=7), an ischemia reperfusion group (IR group, n=8), an ischemic preconditioning group (IPC group, n=8) and an ischemic post-conditioning group (IPO group, n=7). Venous blood samples were taken at pre-operation, 1 and 6 h post-operation, and the concentration of serum creatine kinase isoenzyme (CK-MB) and cardiac troponin-T (cTn-T) were measured. The infarct area of cardiac muscle was calculated.
 Results: Compared with the IR group, the levels of CK-MB and cTn-T at 1 and 6 h post-operation in the IPC group and the IPO group were reduced (all P<0.05). Compared with the IR group, the infarct size in the IPC group and the IPO group was significantly decreased, with significant difference (both P<0.05) .
 Conclusion: Right coronary artery ischemic preconditioning and post-conditioning exert significant protective effects on the myocardial ischemia reperfusion injury in New Zealand rabbits.
Animals ; Coronary Vessels ; Creatine Kinase, MB Form ; blood ; Heart ; Ischemia ; Ischemic Postconditioning ; Ischemic Preconditioning ; Ischemic Preconditioning, Myocardial ; Myocardial Infarction ; etiology ; pathology ; physiopathology ; prevention & control ; Myocardial Ischemia ; complications ; therapy ; Myocardial Reperfusion Injury ; prevention & control ; Myocardium ; Rabbits ; Troponin T ; blood

We aimed to evaluate the histologic components of primary mediastinal mixed germ cell tumors. A total of 221 patients diagnosed with a mediastinal germ cell tumor (GCT) were retrospectively reviewed. Among them, 14 patients underwent surgical resection after chemotherapy and 8 patients were diagnosed with mixed GCT, who were then selected for further evaluation. Clinical chart review and histologic review of biopsy and surgical specimens of 8 patients were performed. All 8 patients were young males and showed a mature teratoma or a mature teratoma with a focal immature teratoma in the resected specimens. Serum alpha-feto protein was variably elevated. Seven patients experienced an increase in tumor size after the chemotherapy. In 5 patients, a variable amount of vasculoconnective tissue was found along with the mature teratoma occupying average 66.3% of resected mass, and 3 of them showed an identical vasculoconnective component on biopsy before chemotherapy. We suggest that vasculoconnective tissue might be the intrinsic component of primary mediastinal mixed GCT. When vasculoconnective tissue is obtained on small biopsy of an anterior mediastinal mass of a young male, the possibility of underlying mixed GCT should be considered and further clinical work up should be performed.
Adolescent ; Adult ; Blood Vessels/*pathology ; Connective Tissue/*pathology ; Diagnosis, Differential ; Humans ; Male ; Mediastinal Neoplasms/*pathology ; Middle Aged ; Neoplasms, Germ Cell and Embryonal/*pathology ; Teratoma/*pathology ; Young Adult