RESUMO
High-density lipoprotein (HDL) mediates reverse cholesterol transport and is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional regulator ATF3, as an HDL-inducible target gene in macrophages that downregulates the expression of Toll-like receptor (TLR)-induced proinflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of new HDL-based therapies.
Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Aterosclerose/terapia , Colesterol/metabolismo , Inflamação/terapia , Lipoproteínas HDL/uso terapêutico , Macrófagos/efeitos dos fármacos , Fator 3 Ativador da Transcrição/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Imunoprecipitação da Cromatina , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lipoproteínas HDL/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Biologia de Sistemas , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologiaRESUMO
BACKGROUND: The effect of low serum uric acid (sUA) levels on kidney function is unclear. This study aimed to clarify the relationship between low sUA levels and the rapid decline in kidney function. METHODS: We examined the relationship between sUA levels and kidney function decline in health check-up examinees. A total of 10,547 participants were enrolled using data from the Yuport Medical Checkup Center Study between 1998 and 2002 for baseline and data from 2002 to 2006 as the follow-up period in Japan. According to sUA level (mg/dL), we classified the participants into the following six groups: (1) 2.0-2.9 (n = 247), (2) 3.0-3.9 (n = 1457), (3) 4.0-4.9 (n = 2883), (4) 5.0-5.9 (n = 2899), (5) 6.0-6.9 (n = 2010), and (6) 7.0-7.9 (n = 1,051). The relationship between sUA level and rapid decline in estimated glomerular filtration rate (ΔeGFR ≥ 3 mL/min/1.73 m2/year) was examined using a logistic regression model. RESULTS: During study period (5.4 ± 1.6 years), the incidence of rapid eGFR decline for the respective sUA groups (2.0-2.9, 3.0-3.9, 4.0-4.9, 5.0-5.9, 6.0-6.9, 7.0-7.9) were as follows: 4.5%, 4.0%, 2.4%, 3.3%, 3.1%, 3.4%. The crude and adjusted odds ratios (OR) for rapid eGFR decline were significantly higher in the 2.0-2.9 (OR:1.93 and 1.86) and 3.0-3.9 (OR:1.72 and 1.73) groups than in the 4.0-4.9 groups (reference). Stratified analysis of age differences revealed that the detrimental effect of low sUA was not evident in older adults (age ≥ 65 years). CONCLUSION: A lower normal sUA level is related to an increased risk for a rapid decline in kidney function.
Assuntos
Insuficiência Renal Crônica , Ácido Úrico , Pessoa de Meia-Idade , Humanos , Idoso , Fatores de Risco , Taxa de Filtração Glomerular , Testes de Função Renal , RimRESUMO
Seriniquinone was isolated as a melanoma-selective anti-cancer agent from a culture broth of the marine-derived bacterium Serinicoccus marinus CNJ927 in 2014. It targets the unique small protein, dermcidin, which affects the drug resistance of cancer cells. Due to its significant activity against cancer cells, particularly melanoma, and its unique target, seriniquinone has been developed as a new pharmacophore. However, it has the disadvantage of poor solubility in drug discovery research, which needs to be resolved. A new seriniquinone glycoside (1) was synthesized by the biological transformation of seriniquinone using the deep sea-derived bacterium Bacillus licheniformis KDM612. Compound 1 exhibited selective anti-cancer activity against melanoma, similar to seriniquinone, and was 50-fold more soluble in DMSO than seriniquinone.
Assuntos
Antineoplásicos , Bacillus licheniformis , Glicosídeos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Glicosídeos/farmacologia , Glicosídeos/química , Glicosídeos/isolamento & purificação , Bacillus licheniformis/metabolismo , Humanos , Biotransformação , Solubilidade , QuinonasRESUMO
Two new cyclic dipeptides, paranazzamides A (1) and B (2) containing a C7-prenylated tryptophan, were isolated from a culture broth of snake fungal disease-isolate Paranannizziopsis sp. UH-21. This is the first report on the new secondary metabolites from Paranannizziopsis sp. The planar structures of 1 and 2 were elucidated using various spectroscopic techniques including MS and 1D/2D NMR. The absolute configuration of 1 was assigned by comparison with the synthesized compound. Compounds 1 and 2 exhibited no antifungal activity, no antibacterial activity, and no cytotoxic activity even at a concentration of 128 µg ml-1, whereas 1 and 2 exhibited amphotericin B potentiating activity against Candida auris in combination treatment.
Assuntos
Dipeptídeos , Peptídeos Cíclicos , Triptofano , Triptofano/química , Triptofano/metabolismo , Dipeptídeos/química , Dipeptídeos/isolamento & purificação , Dipeptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/isolamento & purificação , Animais , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Candida/efeitos dos fármacos , Prenilação , Anfotericina B/farmacologia , Estrutura Molecular , HumanosRESUMO
Nectriatide 1a, a naturally occurring cyclic tetrapeptide, has been reported to a potentiator of amphotericin B (AmB) activity. In order to elucidate its structure-activity relationships, we synthesized nectriatide derivatives with different amino acids in solution-phase synthesis and evaluated AmB-potentiating activity against Candida albicans. Among them, C-and N-terminal protected linear peptides were found to show the most potent AmB-potentiating activity.
Assuntos
Anfotericina B , Antifúngicos , Anfotericina B/química , Antifúngicos/química , Candida albicans , Peptídeos , Testes de Sensibilidade MicrobianaRESUMO
[This corrects the article DOI: 10.1039/D4MD00599F.].
RESUMO
The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the anti-schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability. Therefore, the discovery of a new class of anti-schistosomal agents is imperative. To address this challenge, we introduce a pioneering method for the synthesis of 1,2,5-oxadiazinane derivatives through the cycloaddition of nitrones with N,N,N',N'-tetraalkyldiaminomethane in the presence of an IrIII complex photosensitizer. This transformative reaction offers a streamlined route to various kinds of 1,2,5-oxadiazinanes that is characterized by mild reaction conditions and broad substrate scope. Mechanistic investigations suggest that the photoredox pathway underlies the [3 + 3] photocycloaddition process. Thus, based on bioisosteric replacement, we identified a remarkable molecule as a new chemotype of a potent anti-schistosomal compound that not only exhibits superior solubility, but also retains the potent biological activity inherent to PZQ.
RESUMO
The patient was a 72-year-old male who had locally advanced squamous cell carcinoma(10×7 cm)in his buttocks that developed 18 months prior to admission. The lesion was unresectable because of the size and its invasion to the sacrum. We performed concomitant chemoradiotherapy with curative intent. External beam radiotherapy(68 Gy)was given with weekly carboplatin(AUC 2)and paclitaxel(30mg/m2). Because he developed cellulites in the irradiated skin, the concurrent chemotherapy was stopped during treatment(at 10 Gy). After improvement of the cellulites, paclitaxel was switched to S-1(80 mg/body/day)and concurrent chemoradiotherapy was completed without further toxicities. Progression of the tumor outside the irradiated field was seen 4 months after the treatment. Four courses of carboplatin (AUC 5)+infusional 5-FU(1, 000mg/m2 day 1-4)was administered as the tumor regressed. He died of sepsis 36 months post-treatment but the tumor remained stable without progression. Chemoradiotherapy may be an option for locally advanced non-melanoma skin cancer.
Assuntos
Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Quadril/patologia , Neoplasias Cutâneas/terapia , Idoso , Carcinoma de Células Escamosas/patologia , Humanos , Masculino , Indução de Remissão , Neoplasias Cutâneas/patologiaRESUMO
A new antibiotic named haneummycin (1) was isolated from a culture broth of marine-derived Streptomyces sp. KM77-8 by solvent extraction and HPLC using a C4 column. The structure of 1 was elucidated including relative stereochemistry as a new 22-membered macrolide lactam associated with a cyclopentanone and three sugars by various spectroscopic analyses, such as MS and NMR. Compound 1 displayed significant antibacterial activities against Gram-positive bacteria including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) with both MIC values of 8.0 µg ml-1.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Streptomyces , Lactamas/farmacologia , Streptomyces/química , Antibacterianos/química , Macrolídeos/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
New indanones, designated celludinones A ((±)-1) and B (2), were isolated from the culture broth of the fungal strain Talaromyces cellulolyticus BF-0307. The structures of celludinones were elucidated by spectroscopic data, including 1D and 2D NMR. Celludinone A was found to be a mixture of racemic isomers ((±)-1), which were isolated by a chiral column. Compounds (+)-1 and (-)-1 inhibited the sterol O-acyltransferase (SOAT) 1 and 2 isozymes in a cell-based assay using SOAT1- and SOAT2-expressing Chinese hamster ovary (CHO) cells, while 2 selectively inhibited the SOAT2 isozyme.
Assuntos
Inibidores Enzimáticos/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Talaromyces/química , Animais , Células CHO , Chlorocebus aethiops , Cricetinae , Cricetulus , Inibidores Enzimáticos/química , Fermentação , Humanos , Isoenzimas/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Estereoisomerismo , Esterol O-Aciltransferase 2RESUMO
Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma with an aggressive clinical course characterized by proliferation of large lymphoma cells within the lumina of the small vessels. Because of its varied clinical symptoms and the absence of lymphadenopathy, diagnosis of IVL is extremely difficult and requires histological confirmation. We report here 6 consecutive patients with IVL, admitted to Kameda General Hospital, Kamogawa-shi, Japan, from June 7, 2006, to February 28, 2007, whose IVL was diagnosed by random skin biopsy of healthy-appearing skin. Three patients presented with progressive neurological deterioration and 2 others with hypoxemia with interstitial infiltration on chest radiography. One patient presented with confusion and severe hypoxia without apparent interstitial infiltration. Two patients showed localized skin involvement. Irrespective of the presence of skin lesions, almost all skin biopsy specimens showed obliteration of small vessels of subcutaneous fat tissues by lymphoma cells, allowing a prompt diagnosis of IVL. Early institution of rituximab-based chemotherapy induced favorable responses in all patients treated. Because diagnosis based on tissue other than skin is usually difficult in patients with suspected IVL, random skin biopsy should be considered even in patients with no evident skin lesions.
Assuntos
Biópsia/métodos , Linfoma Difuso de Grandes Células B/patologia , Pele/irrigação sanguínea , Pele/patologia , Neoplasias Vasculares/patologia , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Estudos RetrospectivosRESUMO
Nickel(0)-catalyzed asymmetric three-component coupling of 1,3-dienes, aldehydes, and silanes has been realized utilizing a chiral N-heterocyclic carbene as a ligand. On the basis of the screening of various NHC precursors, an imidazolium salt having 1-(2,4,6-trimethylphenyl)propyl groups on the nitrogen was designed and synthesized. In this reaction, various coupling products were produced in good yields with high regio-, diastereo- (anti selective in the case of the internal 1,3-diene), and enantioselectivities (up to 97% ee).
Assuntos
Aldeídos/química , Compostos Heterocíclicos/química , Níquel/química , Silanos/química , Catálise , Ligantes , EstereoisomerismoRESUMO
Administration of Toll-like receptor ligands (TLRLs) is known to cause liver injury in D-galN-sensitized mice. In the present study, we aimed to complement preceding reports on the TLRL/D-galN system by analyzing comparisons among TLRLs, mouse strain dependence, effects on serum levels of cytokines, and effects of sequential administrations of different TLRLs. In a preliminary set of analyses, we first confirmed that liver failure can be induced by diverse TLRLs, including LTA and R848 in combination with D-galN. Analysis using TLR4-deficient mice excluded potential confounding effects of endogenous TLR4Ls that include those referred to as DAMPs in CpG DNA/D-galN hepatotoxicity. Subsequently, we showed that LTA pretreatment could prevent mortality in both CpG DNA/D-galN- and R848/D-galN-treated mice compared to without pretreatment. Incidentally, we observed that without the LTA pretreatment, CpG DNA/D-galN showed relatively higher liver-specific toxicity whereas R848/D-galN showed more symptoms of multiple organ failure. These findings suggest that, in D-galN-sensitized mice, different TLRLs not only show similarity in the ability to induce hepatic injury but also exhibit distinctive abilities in inducing systemic inflammation and multiple organ failure. These findings also suggest the potential usefulness of cross-tolerance induction using LTA in the prevention of organ failure in TLRL-mediated acute inflammation.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Citocinas/metabolismo , Inflamação/imunologia , Glicoproteínas de Membrana/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Feminino , Galactosamina/imunologia , Imidazóis/administração & dosagem , Tolerância Imunológica , Imunização , Lectinas/administração & dosagem , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Receptor Cross-TalkRESUMO
Thirteen cases of diffuse alveolar hemorrhage (DAH) were encountered in our Hospital between January 1996 and October 2001. Eight patients were men and five were women, their mean age being 59.5 +/- 19.2 years (range, 18-88 years). Three patients had systemic lupus erythematosus (SLE), three (23%) had polyarteritis nodosa (including microscopic PN), one (7.7%) had allergic granulomatous angitis, one (7.7%) had Goodpasture syndrome, one (7.7%) had MPO-ANCA-associated vasculitis, one (7.7%) had Behçet's disease, one (7.7%) had chronic heart failure caused by mitral stenosis, one (7.7%) had chronic renal failure (etiology unknown), and the last had no particular disorder. Nine episodes (69%) had occurred as complications of primary diseases, four (31%) as the first symptoms of underlying diseases. Prognosis was poor in the former cases but in the latter, the prognosis was relatively favorable.