RESUMEN

Vascular inflammation and endothelial dysfunction contribute to vascular diseases. While neutrophil extracellular traps (NETs) participate in some vascular pathologies, their roles in lower limb ischemia remain poorly defined. This study investigated the functional significance of NETs in vascular inflammation and remodeling associated with limb ischemia. Single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed neutrophil activation and upregulated NETs formation in human limb ischemia, with immunofluorescence confirming IL-1ß-induced release of NETs for vascular inflammation. Endothelial cell activation was examined via scRNA-seq and western blotting, indicating enhanced proliferation, expression of adhesion molecules (VCAM-1, ICAM-1), inflammatory cytokines (IL-1ß, IL-6) and decreased expression of VE-cadherin, that could be mediated by NETs to exacerbate endothelial inflammation. Mechanistically, NETs altered endothelial cell function via increased pSTAT1/STAT1 signaling. Vascular inflammation and subsequent ischemia were alleviated in vivo by NETosis or IL-1ß inhibition in ischemic mice. IL-1ß-NETs induce endothelial activation and inflammation in limb ischemia by stimulating STAT1 signaling. Targeting NETs may thus represent a novel therapeutic strategy for inflammatory vascular diseases associated with limb ischemia. Graphical abstract of NETs regulation of the development of vascular inflammation in lower limb ischemia via pSTAT1/STAT1 signaling pathway.

Asunto(s)

Trampas Extracelulares , Interleucina-1beta , Isquemia , Trampas Extracelulares/metabolismo , Interleucina-1beta/metabolismo , Isquemia/metabolismo , Isquemia/fisiopatología , Animales , Humanos , Ratones , Masculino , Factor de Transcripción STAT1/metabolismo , Endotelio Vascular/metabolismo , Ratones Endogámicos C57BL , Neutrófilos , Transducción de Señal , Extremidad Inferior/irrigación sanguínea , Células Endoteliales/metabolismo

RESUMEN

OBJECTIVE: To report demographics and clinical, laboratory, and imaging features of acute renal infarction (ARI) due to symptomatic isolated spontaneous renal artery dissection (SISRAD) and to analyze outcomes after the initial therapy for SISRAD. METHODS: Thirteen patients with ARI due to SISRAD between January 2016 and March 2021 were enrolled in this retrospective study. We reviewed the demographics, clinical, laboratory, and imaging features (location of the infarct kidney, the branch artery involved by dissection, true lumen stenosis, false lumen thrombosis, and aneurysm), treatment modalities, and follow-up results; analyzed the difference between SISRAD and other causes of ARI; and propose an appropriate therapy strategy for SISRAD based on our data and literature. RESULT: Patients with ARI due to SISRAD were mostly young men (43 [24-53] years; 12/13 [92%]). No patients had atrial fibrillation or acute kidney injury at admission (0/13). All 13 patients received conservative treatment as the initial treatment. Sixty-two percent (8/13) of patients progressed, and 88% (7/8) of them had dissection aneurysm on the admission computed tomographic angiography (CTA) image. Seventy-five percent (6/8) of patients underwent endovascular intervention as follows, stent placement in 1 patient, renal artery embolization in 1, and stent placement with embolization in 4. Two patients with disease progression died: 1 during the conservative treatment period and 1 after the stent placement. Thirty-eight percent (5/13) of patients in remission continued to receive conservative treatment, none of whom had dissection aneurysm on the admission CTA. CONCLUSION: Symptomatic isolated spontaneous renal artery dissection is a rare and fatal disease. For young ARI patients with no previous history of tumors and cardiogenic diseases, CTA examination is recommended to exclude SISRAD. Dissection aneurysm seems to be a risk of progression for SISRAD in this series. Conservative treatment, a recognized initial treatment, has a good effect on patients without dissection aneurysm, and we recommend endovascular intervention as the initial treatment for the patient with dissection aneurysm at admission. Multicenter clinical studies are needed to explore a more-appropriate treatment for patients with SISRAD. CLINICAL IMPACT: This article report the related factors, risks, demographics and laboratory data of Acute renal infarction (ARI) due to Symptomatic isolated spontaneous renal artery dissection (SISRAD) and explore a better initial therapy strategy for SISRAD. It will help improve the effectiveness of SISRAD treatment and reduce the mortality rate from this rare but lethal disease.

RESUMEN

Chronic hepatitis C (CHC) is a major liver disease caused by the hepatitis C virus. The current standard of care for CHC can achieve cure rates above 95%; however, the drugs in current use are administered for a period of 8-16 weeks. A combination of safe and effective drugs with a shorter treatment period is highly desirable. We report synthesis and biological evaluation of a series of 2',3'- and 2',4'-substituted guanosine nucleotide analogues. Their triphosphates exhibited potent inhibition of the HCV NS5B polymerase with IC50 as low as 0.13 µM. In the HCV replicon assay, the phosphoramidate prodrugs of these analogues demonstrated excellent activity with EC50 values as low as 5 nM. A lead compound AL-611 showed high levels of the nucleoside 5'-triphosphate in vitro in primary human hepatocytes and in vivo in dog liver following oral administration.

Asunto(s)

Antivirales/farmacología , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Nucleótidos de Guanina/farmacología , Hepacivirus/efectos de los fármacos , Profármacos/farmacología , Animales , Antivirales/síntesis química , Antivirales/toxicidad , Perros , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/toxicidad , Femenino , Nucleótidos de Guanina/síntesis química , Nucleótidos de Guanina/toxicidad , Humanos , Masculino , Profármacos/síntesis química , Profármacos/toxicidad , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos

RESUMEN

We report the synthesis and biological evaluation of a series of 4'-fluoro-2'- C-substituted uridines. Triphosphates of the uridine analogues exhibited a potent inhibition of hepatitis C virus (HCV) NS5B polymerase with IC50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrugs of these uridine analogues demonstrated a very potent activity with EC50 values as low as 20 nM. A lead compound AL-335 (53) demonstrated high levels of the nucleoside triphosphate in vitro in primary human hepatocytes and Huh-7 cells as well as in dog liver following a single oral dose. Compound 53 was selected for the clinical development where it showed promising results in phase 1 and 2 trials.

Asunto(s)

Alanina/análogos & derivados , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Profármacos/farmacología , Nucleótidos de Uracilo/farmacología , Uridina/análogos & derivados , Alanina/síntesis química , Alanina/farmacología , Animales , Antivirales/síntesis química , Línea Celular Tumoral , Perros , Hepacivirus/enzimología , Hepatitis C/tratamiento farmacológico , Humanos , Inhibidores de la Síntesis del Ácido Nucleico/síntesis química , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Fosforamidas , Profármacos/síntesis química , Replicón/efectos de los fármacos , Nucleótidos de Uracilo/síntesis química , Nucleótidos de Uracilo/metabolismo , Uridina/síntesis química , Uridina/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores

RESUMEN

Influenza viruses are responsible for seasonal epidemics and occasional pandemics which cause significant morbidity and mortality. Despite available vaccines, only partial protection is achieved. Currently, there are two classes of widely approved anti-influenza drugs: M2 ion channel blockers and neuraminidase inhibitors. However, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs, particularly with a different mechanism of action. Favipiravir (T-705), a broad-spectrum antiviral agent, has shown potent anti-influenza activity in cell-based assays, and its riboside (2) triphosphate inhibited influenza polymerase. In one of our approaches to treat influenza infection, we designed, prepared, and tested a series of C-nucleoside analogues, which have an analogy to 2 and were expected to act by a similar antiviral mechanism as favipiravir. Compound 3c of this report exhibited potent inhibition of influenza virus replication in MDCK cells, and its triphosphate was a substrate of and demonstrated inhibitory activity against influenza A polymerase. Metabolites of 3c are also presented.

Asunto(s)

Antivirales/farmacología , Nucleósidos/farmacología , Orthomyxoviridae/efectos de los fármacos , Piridazinas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Células de Riñón Canino Madin Darby/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Piridazinas/síntesis química , Piridazinas/química , Piridinas/síntesis química , Piridinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad

RESUMEN

Pure enantiomers of carboxylic acids are a class of important biomolecules, chiral drugs, chiral reagents, etc. Analysis of the enantiomers usually needs expensive instrument or complex chiral receptors. However, to develop simple and reliable methods for the enantiomer analysis of acids is difficult. In this paper, chiral recognition of 2,3-dibenzoyltartaric acid and mandelic acid was first carried out by aggregation-induced emission molecules bearing optically pure aminol group, which was easily synthesized. The chiral recognition is not only seen by naked eyes but also measured by fluorophotometer. The difference of fluorescence intensity between the two enantiomers of the acids aroused by the aggregation-induced emission molecules was up to 598. The chiral recognition could be applied to quantitative analysis of enantiomer content of chiral acids. More chiral AIE amines need to be developed for enantiomer analysis of more carboxylic acids.

Asunto(s)

Ácidos Carboxílicos/análisis , Ácidos Carboxílicos/química , Fenómenos Ópticos , Aminas/química , Espectrometría de Fluorescencia , Estereoisomerismo

RESUMEN

Novel chiral AIE compounds bearing a tartaric acid group were synthesized. They selectively aggregated with one enantiomer of a number of chiral amines, such that one enantiomer led to strong fluorescence and another enantiomer showed no or only weak fluorescence. This was used for the quantitative analysis of enantiomeric composition.

RESUMEN

A chiral calix[4]arene bearing l-2,3-dibenzoyltartaric acid groups at the lower rim was synthesized and could enantioselectively self-assemble to result in a gel or suspension only with one enantiomer of chiral amines; as revealed by electron microscopy, the resultant gel was of nanofibers with a high aspect ratio but the suspension was composed of nanospheres.