Onnamide A suppresses the severe acute respiratory syndrome-coronavirus 2 infection without inhibiting 3-chymotrypsin-like cysteine protease.

Given the continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the development of new inhibitors is necessary to enhance clinical efficacy and increase the options for combination therapy for the coronavirus disease 2019. Because marine organisms have been a resource for the discovery of numerous bioactive molecules, we constructed an extract library of marine invertebrates collected from the Okinawa Islands. In this study, the extracts were used to identify antiviral molecules against SARS-CoV-2. Using a cytopathic effect (CPE) assay in VeroE6/TMPRSS2 cells, an extract from the marine sponge Theonella swinhoei was found to reduce virus-induced CPE. Eventually, onnamide A was identified as an antiviral compound in the extract using column chromatography and NMR analysis. Onnamide A inhibited several SARS-CoV-2 variant-induced CPEs in VeroE6/TMPRSS2 cells as well as virus production in the supernatant of infected cells. Moreover, this compound blocked the entry of SARS-CoV-2 pseudo-virions. Taken together, these results demonstrate that onnamide A suppresses SARS-CoV-2 infection, which may be partially related to entry inhibition, and is expected to be a candidate lead compound for the development of anti-SARS-CoV-2 drugs.

[Placement of An Expandable Metallic Stent for Malignant Tracheal Stenosis: A Case Report].

The utility of stent placements has been widely reported. We performed a thought-provoking stent placement for malignant tracheal stenosis recently. A 90-year-old woman who was admitted to our hospital because of a urinary tract infection was treated with a course of antibiotics, but she demonstrated a rapidly progressive course with dyspnea. Chest computed tomography showed severe tracheal stenosis due to an upper mediastinal mass. She was put on noninvasive positive pressure ventilation (NPPV) because of severe respiratory failure. Bronchoscopy showed severe tracheal stenosis due to direct invasion by the upper mediastinal mass. An expandable metallic stent (EMS) was placed in the trachea, after which a bronchoscopy showed a widely patent airway, and she got off NPPV. Then she did not need supplemental oxygen. She could seat herself, and have an enough meal, independently. However, takotsubo cardiomyopathy occurred and she died 11 days after the placement of the EMS. Since a malignant airway complication can be fatal, tracheal stent placement is a useful treatment in the management of malignancy with airway stenosis. In this case, it was thought that an early intervention of airway stenosis would have reduced the risk of takotsubo cardiomyopathy in a patient with severe symptoms of airway stenosis and stress.

Comorbidities frequency in Takotsubo syndrome: an international collaborative systematic review including 1109 patients.

BACKGROUND: To identify predisposing factors that can result in the onset of takotsubo syndrome, we performed an international, collaborative systematic review focusing on clinical characteristics and comorbidities of patients with takotsubo syndrome. METHODS: We searched and reviewed cited references up to August 2013 to identify relevant studies. Corresponding authors of selected studies were contacted and asked to provide additional quantitative details. Data from each study were extracted by 2 independent reviewers. The cumulative prevalence of presenting features and comorbidities was assessed. Nineteen studies whose authors sent the requested information were included in the systematic review, with a total of 1109 patients (951 women; mean age, 59-76 years). Evaluation of risk factors showed that obesity was present in 17% of patients (range, 2%-48%), hypertension in 54% (range, 27%-83%), dyslipidemia in 32% (range, 7%-59%), diabetes in 17% (range, 4%-34%), and smoking in 22% (range, 6%-49%). Emotional stressors preceded takotsubo syndrome in 39% of patients and physical stressors in 35%. The most common comorbidities were psychological disorders (24%; range, 0-49%), pulmonary diseases (15%; range, 0-22%), and malignancies (10%; range, 4%-29%). Other common associated disorders were neurologic diseases (7%; range, 0-22%), chronic kidney disease (7%; range, 2%-27%), and thyroid diseases (6%; range, 0-37%). CONCLUSIONS: Patients with takotsubo syndrome have a relevant prevalence of cardiovascular risk factors and associated comorbidities. Such of associations needs to be evaluated in further studies.

Topical E6005, a novel phosphodiesterase 4 inhibitor, attenuates spontaneous itch-related responses in mice with chronic atopy-like dermatitis.

Atopic dermatitis is a chronic inflammatory cutaneous disease with difficult-to-treat pruritus. Although phosphodiesterase (PDE) 4 inhibitors have an anti-inflammatory effect on inflammatory skin diseases, such as atopic dermatitis, their acute antipruritic activities remain unclear. Therefore, in this study, we examined whether E6005, a novel PDE4 inhibitor, has antipruritic activity in dermatitis, using a mouse model of atopic dermatitis (NC/Nga mice). A single topical application of E6005 inhibited spontaneous hind-paw scratching, an itch-associated response and spontaneous activity of the cutaneous nerve in mice with chronic dermatitis. The cutaneous concentration of cAMP was significantly decreased in mice with chronic dermatitis, and this decrease was reversed by topical E6005 application. These results suggest that E6005 increases the cutaneous concentration of cAMP to relieve dermatitis-associated itching. Thus, E6005 may be a useful therapy for pruritic dermatitis such as atopic dermatitis.

Assessment of a polymorphism of SDK1 with hypertension in Japanese Individuals.

BACKGROUND: Hypertension is a major risk factor for cardiovascular disease. Although genetic studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. The purpose of the present study was to identify genetic variants that confer susceptibility to hypertension in Japanese individuals. METHODS: A total of 5,734 Japanese individuals from two independent populations were examined: subject panel A comprised 2,066 hypertensive individuals and 824 controls; and subject panel B comprised 834 hypertensive individuals and 2,010 controls. The 150 polymorphisms examined in the present study were selected by genome-wide association studies of myocardial infarction and ischemic stroke with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS: The chi(2)-test revealed that 10 polymorphisms were significantly (P < 0.05) related to the prevalence of hypertension in subject panel A. To validate the relations, these polymorphisms were examined in subject panel B. The A-->G polymorphism (rs645106) of SDK1 and the C-->G polymorphism (rs12078839) of RABGAP1L were significantly associated with hypertension in subject panel B. Multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that the A-->G polymorphism of SDK1 was significantly associated with hypertension in both subject panels A and B, with the G allele protecting against this condition. CONCLUSIONS: SDK1 may be a susceptibility gene for hypertension in Japanese individuals, although the functional relevance of the identified polymorphism was not determined.

Association of gene polymorphisms with chronic kidney disease in Japanese individuals.

Chronic kidney disease (CKD) is recognized as a risk factor not only for end-stage renal disease but also for cardiovascular disease. Early detection and treatment of CKD is a likely key factor for prevention of its complications. Although genetic linkage analyses and association studies have implicated several loci and candidate genes in predisposition to CKD, the genes that underlie genetic susceptibility to this condition have remained largely unknown. The purpose of the present study was to identify genetic variants that confer susceptibility to CKD in Japanese individuals. The study population comprised 4,829 Japanese individuals (2,697 men, 2,132 women), including 757 subjects with CKD [464 men, 293 women; estimated glomerular filtration rate (eGFR) <50 ml min 1.73 m(-2)] and 4,072 controls (2,233 men, 1,839 women; eGFR >or=60 ml min 1.73 m(-2)). The genotypes for 40 polymorphisms of 39 candidate genes were determined. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that six polymorphisms of F10, PITRM1, PCSK2, JPH3, MYO7B, and AKAP12 were related (P<0.05) to the prevalence of CKD. Among these polymorphisms, the Cright curved arrow T polymorphism of F10 (rs5962) was most significantly associated with this condition. Determination of genotypes for the Cright curved arrow T polymorphism of F10 may prove informative for assessment of genetic risk for CKD in Japanese individuals.

Assessment of genetic risk factors for thoracic aortic aneurysm in hypertensive patients.

BACKGROUND: Conventional risk factors for thoracic aortic aneurysm including dissection (TAA) are thought to include age, arteriosclerosis, and hypertension. In addition, evidence suggests that genetic factors play a role in the development of this condition. The purpose of the present study was to identify genetic variants that confer susceptibility to TAA in hypertensive subjects. METHODS: Study subjects comprised 1,351 hypertensive individuals: 88 patients with TAA and 1,263 subjects without this condition. The genotypes for 142 polymorphisms of 119 candidate genes were determined by a method that combines the PCR and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: Evaluation of genotype distributions by the chi2-test and subsequent multivariable logistic regression analysis with adjustment for covariates revealed that the 3949T-->G (3' untranslated region) polymorphism of the thrombospondin-2 gene (THBS2; odds ratio, 4.6), the -110A-->C polymorphism of the heat shock 70-kDa protein 8 gene (HSPA8; odds ratio, 0.4), the C-->T (Pro198Leu) polymorphism of the glutathione peroxidase 1 gene (GPX1; odds ratio, 0.3), the -6G-->A polymorphism of the angiotensinogen gene (AGT; odds ratio, 0.3), and the -850C-->T polymorphism of the tumor necrosis factor gene (TNF; odds ratio, 0.5) were significantly (P < 0.05) associated with TAA. CONCLUSIONS: The variant allele of THBS2 is a risk factor for TAA in hypertensive patients, whereas the variant alleles of HSPA8, GPX1, AGT, and TNF are protective against this condition. Determination of genotypes for these polymorphisms may prove informative for assessment of the genetic risk for TAA.

Association of genetic variants with atherothrombotic cerebral infarction in Japanese individuals with metabolic syndrome.

Metabolic syndrome is a risk factor for cardiovascular disease. The aim of the present study was to identify genetic variants that confer susceptibility to atherothrombotic cerebral infarction among individuals with metabolic syndrome in order to allow prediction of genetic risk for this condition. The study population comprised 1284 unrelated Japanese individuals with metabolic syndrome, including 313 subjects with atherothrombotic cerebral infarction and 971 controls. The genotypes for 296 polymorphisms of 202 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. The Chi-square test, multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of hypertension, hypercholesterolemia, and diabetes mellitus, as well as a stepwise forward selection procedure revealed that the 2445G-->A (Ala54Thr) polymorphism (rs1799883) of FABP2, the -108/3G-->4G polymorphism of IPF1 (S82168), the A-->G (Thr94Ala) polymorphism (rs2241883) of FABP1, the G-->A (Asp2213Asn) polymorphism (rs529038) of ROS1, the -11377C-->G polymorphism (rs266729) of ADIPOQ, the 162A-->C polymorphism (rs4769055) of ALOX5AP, the -786T-->C polymorphism (rs2070744) of NOS3, and the 3279C-->T polymorphism (rs7291467) of LGALS2 were associated (P<0.05) with the prevalence of atherothrombotic cerebral infarction. Among these polymorphisms, the 2445G-->A (Ala54Thr) polymorphism of FABP2 was most significantly associated with this condition. Our results suggest that FABP2, IPF1, FABP1, ROS1, ADIPOQ, ALOX5AP, NOS3, and LGALS2 are susceptibility loci for atherothrombotic cerebral infarction among Japanese individuals with metabolic syndrome. Genotypes for these polymorphisms, especially for the 2445G-->A (Ala54Thr) polymorphism of FABP2, may prove informative for the prediction of genetic risk for atherothrombotic cerebral infarction among such individuals.

Association of polymorphisms of ABCA1 and ROS1 with hypertension in Japanese individuals.

Although various environmental factors, such as a high-salt diet, a smoking habit, excessive alcohol intake, and physical inactivity, influence the development of hypertension, genetic variation also contributes to an individual's susceptibility to this condition. The purpose of the present study was to identify gene polymorphisms that confer susceptibility or resistance to hypertension, and thereby contribute to the prediction of the genetic risk for this condition. The study population comprised 2752 unrelated Japanese individuals (1370 men, 1382 women), including 1276 subjects with hypertension (774 men, 502 women) and 1476 controls (596 men, 880 women). The genotypes for 50 polymorphisms of 35 candidate genes were determined by a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Evaluation of genotype distributions by the Chi-square test and subsequent multivariable logistic regression analysis with adjustment for age, sex, body mass index, smoking status, and the prevalence of diabetes mellitus and hypercholesterolemia revealed that the -14C-->T polymorphism of ABCA1, the C-->G (Ser2229Cys) polymorphism of ROS1, the C-->T (Asn591Asn) polymorphism of LDLR, the 13989A-->G (Ile118Val) polymorphism of CYP3A4, the C-->G and A-->C polymorphisms of ADIPOR1, and the -519A-->G polymorphism of MMP1 were significantly (P<0.05) associated with the prevalence of hypertension. Systolic and diastolic blood pressure differed significantly among genotypes for the -14C-->T polymorphism of ABCA1 and the C-->G (Ser2229Cys) polymorphism of ROS1, with the variant T and G alleles, respectively, being related to increased blood pressure. These results suggest that polymorphisms of ABCA1 and ROS1 are determinants of blood pressure and the development of hypertension in Japanese individuals. Determination of genotypes for ABCA1 and ROS1 may thus prove informative for the prediction of the genetic risk for hypertension.

A pathophysiologic study of tako-tsubo cardiomyopathy with F-18 fluorodeoxyglucose positron emission tomography.

UNLABELLED: AIMS; Our study aims to investigate the pathophysiologic mechanism underlying tako-tsubo cardiomyopathy using F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET). METHODS AND RESULTS: Fifteen patients with tako-tsubo cardiomyopathy were enrolled in this study. Plasma catecholamines, cardiac troponin T (cTnT), and D-dimer were serially evaluated in all patients. Thallium-201 ((201)Tl) single-photon emission computed tomography (SPECT) and F-18 FDG PET were performed in 10 and eight patients, respectively. Emotional or physical stress occurred in 12 (80.0%) patients. ST-T segment abnormalities existed in all patients. Thirteen patients exhibited mildly elevated cTnT, although coronary angiography did not reveal significant stenosis in any patient. Endomyocardial biopsy specimens (n = 9) demonstrated contraction-band necrosis (n = 4) and mononuclear cell infiltration (n = 3). The levels of norepinephrine and epinephrine peaked on admission (744 +/- 452 and 140 +/- 166 pg/mL, respectively). There was severely reduced uptake at the apex on F-18 FDG PET image, despite slightly reduced uptake of (201)Tl. Elevation of D-dimer was observed in nine patients. CONCLUSION: The extent of metabolic defect involving apical akinetic area was more severe than perfusion abnormality. Our data suggest that sudden emotional or physical stress may cause a catecholamine-induced metabolic disorder in the myocardium, which is probably central to this syndrome.