RESUMEN
Background: A high-fat diet (HFD) contributes to various metabolic disorders and obesity, which are major contributors to cardiovascular disease. As an essential regulator for heart homeostasis, cardiac resident macrophages may go awry and contribute to cardiac pathophysiology upon HFD. Thus, to better understand how HFD induced cardiac dysfunction, this study intends to explore the transcriptional and functional changes in cardiac resident macrophages of HFD mice. Methods: C57BL/6J female mice that were 6 weeks old were fed with HFD or normal chow diet (NCD) for 16 weeks. After an evaluation of cardiac functions by echocardiography, mouse hearts were harvested and cardiac resident CCR2- macrophages were sorted, followed by Smart sequencing. Bioinformatics analysis including GO, KEGG, and GSEA analyses were employed to elucidate transcriptional and functional changes. Results: Hyperlipidemia and obesity were observed easily upon HFD. The mouse hearts also displayed more severe fibrosis and diastolic dysfunction in HFD mice. Smart sequencing and functional analysis revealed metabolic dysfunctions, especially lipid-related genes and pathways. Besides this, antigen-presentation-related gene such as Ctsf and inflammation, particularly for NF-κB signaling and complement cascades, underwent drastic changes in cardiac resident macrophages. GO cellular compartment analysis was also performed and showed specific organelle enrichment trends of the involved genes. Conclusion: Dysregulated metabolism intertwines with inflammation in cardiac resident macrophages upon HFD feeding in mice, and further research on crosstalk among organelles could shed more light on potential mechanisms.
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Dieta Alta en Grasa , Macrófagos , Ratones Endogámicos C57BL , Miocardio , Animales , Dieta Alta en Grasa/efectos adversos , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Femenino , Miocardio/metabolismo , Miocardio/inmunología , Obesidad/inmunología , Obesidad/metabolismo , Hiperlipidemias/inmunología , Hiperlipidemias/metabolismoRESUMEN
Dyslipidemia is the most prevalent independent risk factor for patients with chronic kidney disease (CKD). Lipid-induced NLRP3 inflammasome activation in kidney-resident cells exacerbates renal injury by causing sterile inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox balance; however, the exact role of Nrf2 signaling and its regulation of the NLRP3 inflammasome in hyperlipidemia-induced kidney injury are poorly understood. In this study, we demonstrated that activation of the mtROS-NLRP3 inflammasome pathway is a critical contributor to renal tubular epithelial cell (RTEC) apoptosis under hyperlipidemia. In addition, the Nrf2/ARE signaling pathway is activated in renal tubular epithelial cells under hyperlipidemia conditions both in vivo and in vitro, and Nrf2 silencing accelerated palmitic acid (PA)-induced mtROS production, mitochondrial injury, and NLRP3 inflammasome activation. However, the activation of Nrf2 with tBHQ ameliorated mtROS production, mitochondrial injury, NLRP3 inflammasome activation, and cell apoptosis in PA-induced HK-2 cells and in the kidneys of HFD-induced obese rats. Furthermore, mechanistic studies showed that the potential mechanism of Nrf2-induced NLRP3 inflammasome inhibition involved reducing mtROS generation. Taken together, our results demonstrate that the Nrf2/ARE signaling pathway attenuates hyperlipidemia-induced renal injury through its antioxidative and anti-inflammatory effects through the downregulation of mtROS-mediated NLRP3 inflammasome activation.
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Células Epiteliales , Hiperlipidemias , Inflamasomas , Túbulos Renales , Factor 2 Relacionado con NF-E2 , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Hiperlipidemias/metabolismo , Hiperlipidemias/complicaciones , Hiperlipidemias/inmunología , Células Epiteliales/metabolismo , Ratas , Humanos , Túbulos Renales/patología , Túbulos Renales/metabolismo , Masculino , Línea Celular , Apoptosis , Elementos de Respuesta Antioxidante , Mitocondrias/metabolismo , Modelos Animales de Enfermedad , Ratas Sprague-DawleyRESUMEN
Atherosclerosis is an inflammatory disease of blood vessels involving the immune system. Natural killer T (NKT) cells, as crucial components of the innate and acquired immune systems, play critical roles in the development of atherosclerosis. However, the mechanism and clinical relevance of NKT cells in early atherosclerosis are largely unclear. The study investigated the mechanism influencing NKT cell function in apoE deficiency-induced early atherosclerosis. Our findings demonstrated that there were higher populations of NKT cells and interferon-gamma (IFN-γ)-producing NKT cells in the peripheral blood of patients with hyperlipidemia and in the aorta, blood, spleen, and bone marrow of early atherosclerotic mice compared with the control groups. Moreover, we discovered that the infiltration of CD80+ macrophages and CD1d expression on CD80+ macrophages in atherosclerotic mice climbed remarkably. CD1d expression increased in CD80+ macrophages stimulated by oxidized low-density lipoprotein (ox-LDL) ex vivo and in vitro. Ex vivo coculture of macrophages with NKT cells revealed that ox-LDL-induced CD80+ macrophages presented lipid antigen α-Galcer (alpha-galactosylceramide) to NKT cells via CD1d, enabling NKT cells to express more IFN-γ. Furthermore, a greater proportion of CD1d+ monocytes and CD1d+CD80+ monocytes were found in peripheral blood of hyperlipidemic patients compared with that of healthy donors. Positive correlations were found between CD1d+CD80+ monocytes and NKT cells or IFN-γ+ NKT cells in hyperlipidemic patients. Our findings illustrated that CD80+ macrophages stimulated NKT cells to secrete IFN-γ via CD1d-presenting α-Galcer, which may accelerate the progression of early atherosclerosis. Inhibiting lipid antigen presentation by CD80+ macrophages to NKT cells may be a promising immune target for the treatment of early atherosclerosis.NEW & NOTEWORTHY This work proposed the ox-LDL-CD80+ monocyte/macrophage-CD1d-NKT cell-IFN-γ axis in the progression of atherosclerosis. The proinflammatory IFN-γ+ NKT cells are closely related to CD1d+CD80+ monocytes in hyperlipidemic patients. Inhibiting CD80+ macrophages to present lipid antigens to NKT cells through CD1d blocking may be a new therapeutic target for atherosclerosis.
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Antígenos CD1d , Aterosclerosis , Antígeno B7-1 , Hiperlipidemias , Lipoproteínas LDL , Macrófagos , Células T Asesinas Naturales , Animales , Humanos , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Antígenos CD1d/metabolismo , Antígenos CD1d/inmunología , Antígenos CD1d/genética , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Hiperlipidemias/inmunología , Hiperlipidemias/metabolismo , Lipoproteínas LDL/inmunología , Lipoproteínas LDL/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Antígeno B7-1/metabolismo , Antígeno B7-1/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Ratones Endogámicos C57BL , Femenino , Persona de Mediana EdadRESUMEN
We performed a panoramic analysis on both human nonalcoholic steatohepatitis (NASH) microarray data and microarray/RNA-seq data from various mouse models of nonalcoholic fatty liver disease NASH/NAFLD with total 4249 genes examined and made the following findings: (i) human NASH and NAFLD mouse models upregulate both cytokines and chemokines; (ii) pathway analysis indicated that human NASH can be classified into metabolic and immune NASH; methionine- and choline-deficient (MCD)+high-fat diet (HFD), glycine N-methyltransferase deficient (GNMT-KO), methionine adenosyltransferase 1A deficient (MAT1A-KO), and HFCD (high-fat-cholesterol diet) can be classified into inflammatory, SAM accumulation, cholesterol/mevalonate, and LXR/RXR-fatty acid ß-oxidation NAFLD, respectively; (iii) canonical and noncanonical inflammasomes play differential roles in the pathogenesis of NASH/NAFLD; (iv) trained immunity (TI) enzymes are significantly upregulated in NASH/NAFLD; HFCD upregulates TI enzymes more than cytokines, chemokines, and inflammasome regulators; (v) the MCD+HFD is a model with the upregulation of proinflammatory cytokines and canonical and noncanonical inflammasomes; however, the HFCD is a model with upregulation of TI enzymes and lipid peroxidation enzymes; and (vi) caspase-11 and caspase-1 act as upstream master regulators, which partially upregulate the expressions of cytokines, chemokines, canonical and noncanonical inflammasome pathway regulators, TI enzymes, and lipid peroxidation enzymes. Our findings provide novel insights on the synergies between hyperlipidemia and hypomethylation in establishing TI and promoting inflammation in NASH and NAFLD progression and novel targets for future therapeutic interventions for NASH and NAFLD, metabolic diseases, transplantation, and cancers.
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Hiperlipidemias/inmunología , Inflamación/inmunología , Animales , Caspasa 1/metabolismo , Caspasas/metabolismo , Citocinas/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Glicina N-Metiltransferasa/genética , Humanos , Inmunidad , Mediadores de Inflamación/metabolismo , Metionina Adenosiltransferasa/genética , Metilación , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no AlcohólicoRESUMEN
Atherosclerosis is a widespread and progressive chronic arterial disease that remains the leading cause of mortality and morbidity worldwide. It is generally accepted that atherosclerosis is a multifactorial disease characterized by dyslipidemia and inflammation in the vessel walls. Nonpharmacological interventions to treat chronic diseases like atherosclerosis have gained considerable attention in recent years. Thymoquinone (TQ), the major bioactive constituent of Nigella sativa seeds, presents one such example of a natural therapeutic agent that has captured the attention of many researchers due to its wide array of medicinal properties, including its potent anti-atherosclerotic effects. Various in vitro and in vivo studies support the potential of TQ in ameliorating hyperlipidemia, hypercholesterolemia, oxidative stress, and inflammation, all of which are key hallmarks of atherosclerosis. However, to date, no review has been conducted to substantiate the role of TQ in preventing and/or treating atherosclerosis. This comprehensive review aims to examine recent in vitro and in vivo experimental findings reported on the potential anti-atherosclerotic effects of TQ. The roles of TQ in combatting hyperlipidemia, oxidative stress, and inflammation in atherosclerosis are highlighted. We also shed light on the role of TQ in preventing foam cell formation by decreasing low-density lipoprotein (LDL) availability and oxidation. Moreover, recent findings on the protective role of TQ on early markers of atherosclerosis, including homocysteinemia and endothelial dysfunction, are also underscored. Experimental evidence suggests that TQ can potentially be employed as a natural therapeutic agent with minimal side effects against the development and/or progression of atherosclerosis and its associated complications.
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Aterosclerosis/tratamiento farmacológico , Benzoquinonas/farmacología , Hiperlipidemias/tratamiento farmacológico , Nigella sativa/química , Animales , Aterosclerosis/sangre , Aterosclerosis/inmunología , Benzoquinonas/uso terapéutico , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/inmunología , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Estrés Oxidativo/efectos de los fármacos , Semillas/química , Resultado del TratamientoRESUMEN
Regulatory T cells (Tregs) play a critical role in maintaining self-tolerance and controlling inflammation. However, physiologically relevant conditions that alter Treg function and drive disease pathogenesis are poorly understood and few have been defined. We have previously shown that induction of hyperlipidemia in mice results in changes in Tregs that reduce their function. Here, we set out to examine mechanisms by which hyperlipidemia alters Tregs. Using live-cell metabolic assays, we observed that induction of hyperlipidemia increases metabolism in Tregs but not conventional T cells. Increased metabolism resulted from preferential activation of the serine/threonine kinase Akt2 (PKB-ß). Expression of a constitutively activated form of Akt2 in CD4 T cells was sufficient to increase glycolysis in Tregs and drive changes in Treg subsets. Induction of hyperlipidemia did not alter Treg metabolism in mice lacking Akt2. Activation of Akt2 was sufficient to drive the production of inflammatory cytokines by Tregs. We suggest that hyperlipidemia alters Treg function through effects on metabolism via Akt2 activation thereby promoting plasticity and decreased function of FoxP3+ T cells.
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Hiperlipidemias/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Ratones , Proteínas Proto-Oncogénicas c-akt/inmunologíaRESUMEN
Statins could be of potential therapeutic effect in asthma due to their pleiotropic effects on inflammation process. This study aimed to examine the possible interaction of serum lipids, and evaluate the effect of rosuvastatin treatment on asthma. Seven groups of rats, namely control (C), asthmatic (A), hyperlipidemic (H), asthmatic-hyperlipidemic (AH), rosuvastatin (40 mg/kg)-treated asthmatic (AR), rosuvastatin-treated hyperlipidemic (HR), and rosuvastatin-treated hyperlipidemic-asthmatic (AHR) groups, were studied. Total and differential WBC counts, serum oxidative stress markers, and bronchoalveolar lavage fluid (BALF) levels of IL-6 and IL-10 were evaluated. In the A and AH groups, total and differential WBC counts, and IL-6 and IL-10 levels were higher than in the C group (p<0.05 to p<0.001). An increase in nitrite and malondialdehyde concentrations and a decrease in total thiol content and superoxide dismutase and catalase activities were observed in the A, H, and AH groups compared to the C group (p<0.05 to p<0.001). Beyond lipid lowering, rosuvastatin treatment reduced total and differential WBC counts in the A and AH groups (p<0.05 to p<0.001), IL-6 level in the AH group (p<0.05), and IL-10 level in all treated groups (p<0.05). Rosuvastatin reduced oxidative stress by decreasing nitrite and malondialdehyde concentrations, and increasing total thiol content in all treated groups as well as superoxide dismutase and catalase activities in the H and AH groups (p<0.05 to p<0.01). Rosuvastatin reduced airway inflammation and oxidation through regulating NOS and reducing pro-inflammatory cytokine and inflammatory cells, which indicate a novel insight into the pleiotropic effects of rosuvastatin in treatment of asthma.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Asma/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hiperlipidemias/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Pulmón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Rosuvastatina Cálcica/farmacología , Animales , Asma/inmunología , Asma/metabolismo , Modelos Animales de Enfermedad , Hiperlipidemias/inmunología , Hiperlipidemias/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Lípidos/sangre , Pulmón/inmunología , Pulmón/metabolismo , Masculino , Óxido Nítrico Sintasa/metabolismo , Ratas WistarRESUMEN
The calcium sensing receptor (CaSR) is a G-protein coupled receptor that especially plays an important role in the sensing of extracellular calcium to maintain its homeostasis. Several in-vitro studies demonstrated that CaSR plays a role in adipose tissue metabolism and inflammation, resulting in systemic inflammation and contributing to atherosclerosis development. The aim of this study was to investigate whether adipocyte CaSR plays a role in adipose tissue inflammation in-vivo and atherosclerosis development. By using a newly established conditional mature adipocyte specific CaSR deficient mouse on a hyperlipidemic and atherosclerosis prone Apoe-/- background it could be shown that CaSR deficiency in adipocytes does neither contribute to initiation nor to progression of atherosclerotic plaques as judged by the unchanged lesion size or composition. Additionally, CaSR deficiency did not influence gonadal visceral adipose tissue (vAT) inflammation in-vivo, although a small decrease in gonadal visceral adipose cholesterol content could be observed. In conclusion, adipocyte CaSR seems not to be involved in vAT inflammation in-vivo and does not influence atherosclerosis development in hyperlipidemic Apoe-/- mice.
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Adipocitos/metabolismo , Hiperlipidemias/complicaciones , Grasa Intraabdominal/patología , Placa Aterosclerótica/inmunología , Receptores Sensibles al Calcio/deficiencia , Animales , Modelos Animales de Enfermedad , Humanos , Hiperlipidemias/genética , Hiperlipidemias/inmunología , Inflamación/inmunología , Inflamación/patología , Grasa Intraabdominal/citología , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Ratones , Ratones Noqueados para ApoE , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Receptores Sensibles al Calcio/genéticaRESUMEN
OBJECTIVE: Apolipoprotein C-III (Apoc3) is a key component of triglyceride-rich lipoproteins (TRL). The Apoc3-transgenic mice are characterized by high levels of plasma triglyceride and free fatty acids (FFAs). Apoc3 stimulates human monocytes via activation of the NLRP3 inflammasome. Considering the NK cell downregulation in obese individuals and the possible stimulatory-effects of macrophages, variations of NK cell functions and underlying mechanisms were investigated in mice with Apoc3-induced hyperlipidemia. METHODS: Variations of activities and glycolipid metabolism in NK cells of the Apoc3-transgenic mice with hyperlipidemia were detected. Molecular mechanisms of lipid-induced metabolic-reprogramming in NK cells were analyzed based on the transcriptome sequencing. Finally, effects of DCs in mice with hyperlipidemia on NK cell functions were determined. RESULTS: Impaired number and function of NK cells in Apoc3TG mice was involved with the increased fatty acid oxidation and decreased glycolysis. Increased uptake of FFAs in Apoc3TG-NK cells contributed to the peroxisome proliferator-activated receptor (PPAR) activation and the downstream PTEN-AKT-mTOR/FOXO1 signaling pathway. Inhibition of PPAR or CPT1α only partly reversed the IFN-γ production of Apoc3TG-NK cells, but completely restored IFN-γ secretion by palmitic acid-treated NK cells ex vivo, indicating that other factors contributed to the Apoc3TG-NK cell downregulation. Meanwhile, Apoc3TG-DCs, which contained more lipids in the cytoplasm, depended on reactive oxygen species (ROS) to increase the expressions PD-L1, TGF-ß1, and NKG2D ligands and suppress NK cell activities. DCs of the Apoc3TG-CD36-/+ hybrid mice with less intracellular lipids and ROS production could not inhibit NK cells, indicating that intracellular FFAs promoted the immune-modulatory function of DCs. CONCLUSIONS: The downregulation of NK cell activities in individuals with Apoc3-induced hyperlipidemia was due to the increased fatty acid oxidation in NK cells and the bystander suppression caused by lipid-laden DCs. The dual recovery function of NK cells and DCs would improve the prognosis of patients with metabolic syndrome.
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Células Dendríticas/fisiología , Hiperlipidemias/inmunología , Células Asesinas Naturales/fisiología , Animales , Apolipoproteína C-III/genética , Efecto Espectador/genética , Comunicación Celular/inmunología , Reprogramación Celular/genética , Células Dendríticas/metabolismo , Regulación hacia Abajo , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Metabolismo de los Lípidos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Transgénicos , Triglicéridos/metabolismoRESUMEN
Cordycepin (CRD), an adenosine analog derived from traditional Chinese medicine, is an active component in Cordyceps militaris. It has been shown to have many protective effects during liver injury and ameliorate liver disease progression, but little is known about its effect on non-alcoholic fatty liver disease (NAFLD). This study aims to explore the effects of CRD on obesity-induced NAFLD. In this experiment, C57BL/6 J mice were randomly assigned into normal control group (NC), high fat diet group (HFD) and HFD + CRD group for 8 weeks. The body weights were recorded weekly, at the end of the experiments, the liver and serum samples were collected. We found that CRD administration reduced body weight and decreased the weight of adipose and liver, and CRD relieved liver injure through diminishing of histopathological changes and decreasing serum levels of AST, ALT, TG, TC, LDL-C and increased the level of HDL-C. Furthermore, treatment with CRD significantly alleviated expression of inflammatory factors (TNF-α, IL-6 and Il-1ß) and macrophage markers (MCP1, MIP2, mKC and VCAM1). On the other hand, compared with HFD group, the CRD treated group markedly down-regulated relative proteins of lipid anabolism (SREBP1-c, ACC, SCD-1, LXRα and CD36) and up-regulated relative proteins of ß-oxidation (p-AMPK, AMPK, CPT-1 and PPARα). In summary, our results suggest that CRD can be a potential therapeutic agent in the prevention and treatment of NAFLD, which may be closely related to its effect on lipid metabolism and inflammatory responses.
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Antiinflamatorios/farmacología , Desoxiadenosinas/farmacología , Hipolipemiantes/farmacología , Mediadores de Inflamación/metabolismo , Lípidos/sangre , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Regulación hacia Abajo , Hiperlipidemias/inmunología , Hiperlipidemias/metabolismo , Hiperlipidemias/prevención & control , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/inmunología , Obesidad/metabolismo , Obesidad/prevención & control , Oxidación-ReducciónAsunto(s)
Angioedema/virología , Infecciones por Coronavirus/virología , Diabetes Mellitus Tipo 2/virología , Hiperlipidemias/virología , Obesidad/virología , Neumonía Viral/virología , Insuficiencia Respiratoria/virología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Adulto , Alanina/análogos & derivados , Alanina/uso terapéutico , Ampicilina/uso terapéutico , Angioedema/inmunología , Angioedema/fisiopatología , Angioedema/terapia , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/terapia , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/terapia , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Hiperlipidemias/inmunología , Hiperlipidemias/fisiopatología , Hiperlipidemias/terapia , Intubación Intratraqueal , Obesidad/inmunología , Obesidad/fisiopatología , Obesidad/terapia , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/fisiopatología , Neumonía Viral/terapia , Respiración Artificial , Insuficiencia Respiratoria/inmunología , Insuficiencia Respiratoria/fisiopatología , Insuficiencia Respiratoria/terapia , SARS-CoV-2 , Resultado del TratamientoRESUMEN
The initial cases of novel coronavirus disease-19 (COVID-19) in a country are of utmost importance given their impact on healthcare providers, the country's preparedness response, and the initial molding of the public perception toward this pandemic. In Bhutan, the index case was a 76-year-old immunocompromised man who had traveled from the United States and entered Bhutan as a tourist. He presented initially with vague gastrointerestinal symptoms and later a cough. His atypical presentation led to a delay in diagnosis, but ultimately he was isolated and tested. On confirming the diagnosis of COVID-19, the patient was isolated in a separate hospital with a dedicated medical care team. All contacts were traced and quarantined. The patient's respiratory status deteriorated despite broad-spectrum antivirals, antibiotics, and intensive supportive care. He required intubation and was given a trial of intravenous immunoglobulin to modulate his likely aberrant immune response. Subsequently, the patient's clinical status improved, and after 8 days of hospitalization, he was transferred out of the country, where he recovered. This was a learning experience for the treating medical staff, the government, and the people of Bhutan.
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Betacoronavirus/patogenicidad , Infecciones por Coronavirus/diagnóstico por imagen , Hiperlipidemias/diagnóstico por imagen , Hipertensión/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Neumonía Viral/diagnóstico por imagen , Anciano , Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Bután , COVID-19 , Trazado de Contacto , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Humanos , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/inmunología , Hiperlipidemias/patología , Hipertensión/tratamiento farmacológico , Hipertensión/inmunología , Hipertensión/patología , Huésped Inmunocomprometido , Inmunoglobulinas Intravenosas/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Masculino , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Neumonía Viral/patología , SARS-CoV-2 , Tomografía Computarizada por Rayos X , Viaje , Resultado del Tratamiento , Ultrasonografía , Estados UnidosRESUMEN
Lymphatic vessels serve as conduits through which immune cells traffic. Because lymphatic vessels are also involved in lipid transport, their function is vulnerable to abnormal metabolic conditions such as obesity and hyperlipidemia. Exactly how these conditions impact immune cell trafficking, however, is not well understood. Here, we found higher numbers of LYVE-1-positive lymphatic endothelial cells and CD3-positive T cells in the lymph nodes of mice fed high-cholesterol or high-fat diets compared with those of mice fed a normal chow diet. To confirm the effect of fat content on immune cell trafficking, the lymphatic endothelial SVEC4-10 cell line was treated with palmitic acid at a 100 µM concentration. After 24 h, palmitic acid-treated cells exhibited increased expression of podoplanin and vascular growth-associated molecules (VEGFC, VEGFD, VEGFR3, and NRP2) and enhanced tube formation. Microarray analysis showed an increase in pro-inflammatory cytokine and chemokine transcription after palmitic acid treatment. Finally, transwell migration assay confirmed that T cell line moved toward medium previously cultured with palmitic acid-treated SVEC4-10 cells. Together, our results suggest that hyperlipidemia drives lymphatic vessel remodeling and T cell migration toward lymphatic endothelial cells.
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Movimiento Celular , Células Endoteliales/patología , Hiperlipidemias/inmunología , Hiperlipidemias/patología , Ganglios Linfáticos/patología , Linfocitos T/patología , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Quimiocinas/metabolismo , Dieta , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Hiperlipidemias/fisiopatología , Masculino , Ratones Endogámicos C57BL , Neovascularización Fisiológica/efectos de los fármacos , Ácido Palmítico/toxicidad , Linfocitos T/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
To investigate the prevention of cardiac remodelling and inflammatory immune response after myocardial infarction (MI) via ACEI regulating dendritic cells (DCs), we explored whether the protective effect of ACEI was repressed under hyperlipidemic environment. In vivo, the survival rate and left ventricular function of the mice were recorded on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were assessed for Ang II concentration, inflammatory cytokines and DCs expression. In vitro, DCs were treated with ox-LDL + Ang II, simulating the internal environment of MI in ApoE-/- mice to explore the mechanism involved in the DCs maturation and inflammation. Under hyperlipidemic circumstances, we found that the cardioprotective effect of ACEI was attenuated through regulating DCs maturation and inflammation after MI, affecting survival rate and left ventricular function. Effects of lisinopril on the release of spleen-derived DCs and myocardial infiltration were also reduced under hyperlipidemic conditions. In vitro, immune maturation and inflammation of DCs were further induced by ox-LDL on the basis of Ang II treatment, as indicated by the upregulation of CD83, CD86, and the expressions of cytokines and chemokines. Furthermore, ox-LDL could activate TLR4-MyD88 signalling pathway, promoting IRAK-4 and NF-κB. The present study demonstrated that ACEI reduced the recruitment of DCs to the infarct site, leading to a higher survival rate and improved function. However, this effect was inhibited under hyperlipidemic environment. TLR4-MyD88 signalling pathway may be responsible for the molecular mechanism involved in the immune maturation and inflammation of DCs induced by ox-LDL.
Asunto(s)
Apolipoproteínas E/genética , Lisinopril/farmacología , Factor 88 de Diferenciación Mieloide/genética , Infarto del Miocardio/tratamiento farmacológico , Receptor Toll-Like 4/genética , Angiotensina II/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/patología , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Humanos , Hiperlipidemias/complicaciones , Hiperlipidemias/genética , Hiperlipidemias/inmunología , Hiperlipidemias/patología , Lipoproteínas LDL/genética , Ratones , Ratones Noqueados , Infarto del Miocardio/complicaciones , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , FN-kappa B/genética , Transducción de Señal/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Remodelación Ventricular/genéticaRESUMEN
SCOPE: Akkermansia muciniphila (A. muciniphila) is an intestinal commensal with anti-inflammatory properties both in the intestine and other organs. The aim is to investigate the effects of oral administration of A. muciniphila on lipid metabolism, immunity, and cuff-induced neointima formation in hyperlipidemic APOE*3-Leiden (E3L).CETP mice. METHODS AND RESULTS: Hyperlipidemic male E3L.CETP mice are daily treated with 2 × 108 CFU A. muciniphila by oral gavage for 4 weeks and the effects are determined on plasma lipid levels, immune parameters, and cuff-induced neointima formation and composition. A. muciniphila administration lowers body weight and plasma total cholesterol and triglycerides levels. A. muciniphila influences the immune cell composition in mesenteric lymph nodes, as evident from an increased total B cell population, while reducing the total T cell and neutrophil populations. Importantly, A. muciniphila reduces the expression of the activation markers MHCII on dendritic cells and CD86 on B cells. A. muciniphila also increases whole blood ex vivo lipopolysaccharide-stimulated IL-10 release. Finally, although treatment with A. muciniphila improves lipid metabolism and immunity, it does not affect neointima formation or composition. CONCLUSIONS: Four weeks of treatment with A. muciniphila exerts lipid-lowering and immunomodulatory effects, which are insufficient to inhibit neointima formation in hyperlipidemic E3L.CETP mice.
Asunto(s)
Hiperlipidemias/terapia , Factores Inmunológicos/farmacología , Lípidos/sangre , Probióticos/administración & dosificación , Administración Oral , Akkermansia/inmunología , Akkermansia/fisiología , Animales , Apolipoproteína E3/genética , Modelos Animales de Enfermedad , Hipercolesterolemia/inmunología , Hipercolesterolemia/metabolismo , Hipercolesterolemia/terapia , Hiperlipidemias/inmunología , Hiperlipidemias/metabolismo , Metabolismo de los Lípidos , Lipopolisacáridos/sangre , Ganglios Linfáticos/inmunología , Masculino , Ratones Mutantes , Neointima/etiología , Neointima/prevención & controlRESUMEN
BACKGROUND: The instructions of manufacturers of methodologies for anti-HIV-1/2 antibodies screening tests re-commend avoiding analyzing blood samples with hemolysis or lipemia, but they do not mention references about scientific studies evaluating their interference. The increased need for an opportune detection of HIV infection to avoid its spread has led to public health institutions including routine HIV screening even in internal medicine and emergency rooms. Nevertheless, these blood samples are usually associated with the presence of lipemia and/ or hemolysis, leaving doubt for probable misinterpretations. This fact highlights the need for applying verification techniques, established under the internal methodological conditions of each laboratory, in order to increase the coverage of HIV screening and to ensure the reliability of their results. METHODS: Following the ethics committee approval and patient's informed consent, a confirmed anti-HIV-1 positive human serum (undetectable viral load and p24 antigen, and stable total lymphocytes > 30%) was obtained. This work describes techniques for the semiquantitative analysis of anti-HIV antibodies of three commercial HIV-screening methodologies (immunochromatography, enzyme-immunoassay and chemiluminescence) and to deter-mine the detection limit of these screening tests, as well as evaluating the maximum concentration of total lipids and of free hemoglobin that do not interfere in the detection limits. RESULTS: The highest analyzed concentration of total lipid (870 mg/dL) did not interfere with the detection limits of anti-HIV-1 antibodies in any of the evaluated methodologies. Free hemoglobin presented interference at different concentrations depending on the methodology: immunochromatography (0.57 g/dL)), enzyme-immunoassay (8.6 g/dL), and chemiluminescence (11.5 g/dL)). CONCLUSIONS: Concentrations of lipemia above postprandial levels or hemolysis induced by experimental manipulation might not interfere with HIV-serological screening. Determining the maximum permissible limits of lipemia and hemolysis by each manufacturer or laboratory based on an internal evaluation of their serological methodology would increase the reliability of HIV-diagnosis in internal medicine and emergency rooms and in patients with dyslipidemia or physiological hemolysis.
Asunto(s)
Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/diagnóstico , Seropositividad para VIH/diagnóstico , VIH-1/inmunología , Serodiagnóstico del SIDA/métodos , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/sangre , Infecciones por VIH/virología , Seropositividad para VIH/sangre , Seropositividad para VIH/virología , VIH-1/fisiología , Hemoglobinas/inmunología , Hemoglobinas/metabolismo , Hemólisis/inmunología , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/inmunología , Límite de Detección , Lípidos/sangre , Lípidos/inmunología , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Primary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological treatments. The unmet need of strategies to efficiently target tumor "stressness" represents a strong clinical motivation to better understand the underlying mechanisms of stress adaptation. Here, we have investigated how lipid loading may be involved in the paracrine crosstalk between cancer cells and the stromal compartment of the hypoxic tumor microenvironment. METHODS: Regions from patient GBM tumors with or without the lipid loaded phenotype were isolated by laser capture microdissection and subjected to comparative gene expression analysis in parallel with cultured GBM cells with or without lipid loading. The potential involvement of extracellular lipids in the paracrine crosstalk with stromal cells was studied by immunoprofiling of the secretome and functional studies in vitro as well as in various orthotopic GBM mouse models, including hyperlipidemic ApoE-/- mice. Statistical analyses of quantitative experimental methodologies were performed using unpaired Student's T test. For survival analyses of mouse experiments, log-rank test was used, whereas Kaplan-Meier was performed to analyze patient survival. RESULTS: We show that the lipid loaded niche of GBM patient tumors exhibits an amplified hypoxic response and that the acquisition of extracellular lipids by GBM cells can reinforce paracrine activation of stromal cells and immune cells. At the functional level, we show that lipid loading augments the secretion of e.g. VEGF and HGF, and may potentiate the cross-activation of endothelial cells and macrophages. In line with these data, in vivo studies suggest that combined local tumor lipid loading and systemic hyperlipidemia of ApoE-/- mice receiving a high fat diet induces tumor vascularization and macrophage recruitment, and was shown to significantly decrease animal survival. CONCLUSIONS: Together, these data identify extracellular lipid loading as a potentially targetable modulator of the paracrine adaptive response in the hypoxic tumor niche and suggest the contribution of the distinct lipid loaded phenotype in shaping the glioma microenvironment.
Asunto(s)
Glioma/inmunología , Glioma/metabolismo , Hipoxia/metabolismo , Metabolismo de los Lípidos , Macrófagos/inmunología , Neovascularización Patológica/inmunología , Neovascularización Patológica/metabolismo , Comunicación Paracrina , Animales , Biomarcadores , Línea Celular Tumoral , Modelos Animales de Enfermedad , Espacio Extracelular/metabolismo , Glioma/patología , Xenoinjertos , Humanos , Hiperlipidemias/inmunología , Hiperlipidemias/metabolismo , Hipoxia/inmunología , Macrófagos/patología , Ratones , Microambiente Tumoral/inmunologíaRESUMEN
Vascular smooth muscle cells (VSMCs) constitute the major cells in the media layer of arteries, and are critical to maintain the integrity of the arterial wall. They participate in arterial wall remodeling, and play important roles in atherosclerosis throughout all stages of the disease. Studies demonstrate that VSMCs can adopt numerous phenotypes depending on inputs from endothelial cells (ECs) of the intima, resident cells of the adventitia, circulating immune cells, hormones, and plasma lipoproteins. This plasticity allows them to perform multiple tasks in physiology and disease. In this minireview, we focus on a previously underappreciated activity of VSMCs, i.e., their impact on atherosclerosis immunity via formation of artery tertiary lymphoid organs (ATLOs).
Asunto(s)
Aterosclerosis/etiología , Aterosclerosis/metabolismo , Susceptibilidad a Enfermedades , Inmunidad , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Adventicia/inmunología , Envejecimiento/inmunología , Envejecimiento/metabolismo , Animales , Aterosclerosis/patología , Biomarcadores , Plasticidad de la Célula/inmunología , Citocinas/metabolismo , Susceptibilidad a Enfermedades/inmunología , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/complicaciones , Hiperlipidemias/inmunología , Hiperlipidemias/metabolismo , Mediadores de Inflamación/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Ratones , Músculo Liso Vascular/citología , Músculo Liso Vascular/inmunología , Miocitos del Músculo Liso/inmunología , Placa Aterosclerótica/etiología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologíaRESUMEN
This study first investigates how the intake level of glycated fish protein (GP), enriched with Amadori products, affects gut health by modifying the fermentation of gut microbiota and accumulation of advanced glycation end products (AGEs) in rats fed a high-fat diet. Hyperlipidemic rats were fed a fish protein (FP) control diet, 6% low-level GP (L-GP) diet, and 12% high-level GP (H-GP) diet for four weeks. Compared to the FP diet, the GP diet greatly changed the pattern of protein fermentation and reduced inflammation markers and blood lipids, but increased the AGE plasma accumulation and fecal excretion. Furthermore, the GP supplementation significantly decreased Ruminiclostridium_6 and Desulfovibrio (p < 0.05), and the L-GP diet showed more effects on the increase of butyrate-producing Ruminococcus_1 and Roseburia, while the H-GP diet considerably decreased Helicobacter and Lachnospiraceae_NK4A136_group. Correlation-type principal-component analysis (PCA) clearly indicated that these biological effects of intake of GP were related to the modulation of gut microbiota composition and fermentation metabolite profiles. Overall, the low intake level of glycated fish protein may have a more beneficial effect on gut health.
Asunto(s)
Proteínas de Peces/química , Proteínas de Peces/metabolismo , Microbioma Gastrointestinal , Tracto Gastrointestinal/inmunología , Productos Finales de Glicación Avanzada/metabolismo , Hiperlipidemias/dietoterapia , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Dieta Alta en Grasa/efectos adversos , Femenino , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/microbiología , Productos Finales de Glicación Avanzada/química , Humanos , Hiperlipidemias/etiología , Hiperlipidemias/inmunología , Hiperlipidemias/microbiología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Vascular grafts often exhibit low patency rates in clinical settings due to the pathological environment within the patients requiring the surgery. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have attracted increasing attention. These sEVs contain many potent signaling molecules that play important roles in tissue regeneration, such as microRNA and cytokines. In this study, a sEVs-functionalized vascular graft was developed, and in vivo performance was systematically evaluated in a rat model of hyperlipidemia. Electrospun poly (ε-caprolactone) (PCL) vascular grafts were first modified with heparin, to enhance the anti-thrombogenicity. MSC-derived sEVs were loaded onto the heparinized PCL grafts to obtain functional vascular grafts. As-prepared vascular grafts were implanted to replace a segment of rat abdominal artery (1â¯cm) for up to 3 months. Results showed that the incorporation of MSC-derived sEVs effectively inhibited thrombosis and calcification, thus enhancing the patency of vascular grafts. Furthermore, regeneration of the endothelium and vascular smooth muscle was markedly enhanced, as attributed to the bioactive molecules within the sEVs, including vascular endothelial growth factor (VEGF), miRNA126, and miRNA145. More importantly, MSC-derived sEVs demonstrated a robust immunomodulatory effect, that is, they induced the transition of macrophages from a pro-inflammatory and atherogenic (M1) phenotype to an anti-inflammatory and anti-osteogenic (M2c) phenotype. This phenotypic switch was confirmed in both in vitro and in vivo analyses. Taken together, these results suggest that fabrication of vascular grafts with immunomodulatory function can provide an effective approach to improve vascular performance and functionality, with translational implication in cardiovascular regenerative medicine.