RESUMEN
In skeletal-muscle regeneration, it is critical to promote efferocytosis of immune cells and differentiation of satellite cells/postnatal muscle stem cells at the damaged sites. With the optimized poloxamer 407 composition gelled at body temperature, the drugs can be delivered locally. The purpose of this study is to develop a topical injection therapeutic agent for muscle regeneration, sarcopenia, and cachexia. Herein, we construct an injectable, in situ hydrogel system consisting of CD146, IGF-1, collagen I/III, and poloxamer 407, termed CIC gel. The secreted CD146 then binds to VEGFR2 on the muscle surface and effectively induces efferocytosis of neutrophils and macrophages. IGF-1 promotes satellite cell differentiation, and biocompatible collagen evades immune responses of the CIC gel. Consequently, these combined molecules activate muscle regeneration via autophagy and suppress muscle inflammation and apoptosis. Conclusively, we provide an applicable concept of the myogenesis-activating protein formulation, broadening the thermoreversible hydrogel to protein therapeutics for damaged muscle recovery.
Asunto(s)
Hidrogeles , Nanopartículas , Antígeno CD146/metabolismo , Colágeno/metabolismo , Hidrogeles/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Músculo Esquelético , Nanopartículas/uso terapéutico , Poloxámero/farmacología , Cicatrización de HeridasRESUMEN
The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia (n = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.
Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/diagnóstico , Síndrome de Liberación de Citoquinas/diagnóstico , Proteínas de la Matriz Extracelular/inmunología , Leucocitos Mononucleares/inmunología , Neumonía Viral/diagnóstico , Procesamiento Proteico-Postraduccional , Insuficiencia Respiratoria/diagnóstico , Factor de Crecimiento Transformador beta/inmunología , Acetilación , Anticuerpos Neutralizantes/farmacología , Betacoronavirus/inmunología , Biomarcadores/sangre , COVID-19 , Estudios de Casos y Controles , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Proteínas de la Matriz Extracelular/antagonistas & inhibidores , Proteínas de la Matriz Extracelular/genética , Expresión Génica , Humanos , Unidades de Cuidados Intensivos , Recuento de Leucocitos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/patología , Leucocitos Mononucleares/virología , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Lisina/metabolismo , FN-kappa B/genética , FN-kappa B/inmunología , Pandemias , Neumonía Viral/sangre , Neumonía Viral/inmunología , Neumonía Viral/patología , Cultivo Primario de Células , Pronóstico , Insuficiencia Respiratoria/sangre , Insuficiencia Respiratoria/inmunología , Insuficiencia Respiratoria/patología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.
Asunto(s)
Betacoronavirus/patogenicidad , Colesterol/biosíntesis , Infecciones por Coronavirus/genética , Síndrome de Liberación de Citoquinas/genética , Interacciones Huésped-Patógeno/genética , Leucocitos Mononucleares/inmunología , Neumonía Viral/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Betacoronavirus/inmunología , COVID-19 , Estudios de Casos y Controles , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/mortalidad , Síndrome de Liberación de Citoquinas/virología , Regulación de la Expresión Génica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Unidades de Cuidados Intensivos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/virología , FN-kappa B/genética , FN-kappa B/inmunología , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Neumonía Viral/virología , Cultivo Primario de Células , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/inmunología , SARS-CoV-2 , Transducción de Señal , Proteína 2 de Unión a Elementos Reguladores de Esteroles/inmunología , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The larva of Allomyrina dichotoma (family Scarabaeidae) is an edible insect that is registered in the Korean Food Standards Codex as a food resource. The chemical study on the larvae of A. dichotoma resulted in the isolation of three new tetrahydroquinolines, allomyrinaines A-C (1-3), one new dopamine derivative, allomyrinamide A (4), and four known compounds (5-8). The structures were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) and MS spectroscopic data analysis. Allomyrinaines A-C (1-3) possessed three stereogenic centers at C-2, C-3, and C-4, whose relative configurations were determined by analyses of the coupling constants and the nuclear Overhauser enhancement spectroscopy (NOESY) data, as well as DP4+ calculation. The anti-inflammatory effects of compounds 1-4 were evaluated in human endothelial cells. Allomyrinaines A-C (1-3) could stabilize vascular barrier integrity on lipopolysaccharide (LPS)-induced vascular inflammation via inhibition of the nuclear factor-κB (NF-κB) pathway. The physiologically relevant concentration was confirmed by Q-TOF-MS-based quantitative analysis on allomyrinaines A-C in crude extract. This study suggests that allomyrinaines A-C (1-3) are bioactive constituents of A. dichotoma to treat vascular inflammatory disorder.