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1.
Arterioscler Thromb Vasc Biol ; 41(2): 714-730, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33327751

RESUMO

OBJECTIVE: Infiltrated macrophages actively promote perivascular adipose tissue remodeling and represent a dominant population in the perivascular adipose tissue microenvironment of hypertensive mice. However, the role of macrophages in initiating metabolic inflammation remains uncertain. SIRT3 (sirtuin-3), a NAD-dependent deacetylase, is sensitive to metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated metabolic shift in regulating NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome activation. Approach and Results: Here, we report that Ang II (angiotensin II) accelerates perivascular adipose tissue inflammation and fibrosis, accompanied by NLRP3 inflammasome activation and IL (interleukin)-1ß secretion in myeloid SIRT3 knockout (SIRT3-/-) mice. This effect is associated with adipose tissue mitochondrial dysfunction. In vitro studies indicate that the deletion of SIRT3 in bone marrow-derived macrophages induces IL-1ß production by shifting the metabolic phenotype from oxidative phosphorylation to glycolysis. Mechanistically, SIRT3 deacetylates and activates PDHA1 (pyruvate dehydrogenase E1 alpha) at lysine 83, and the loss of SIRT3 leads to PDH activity decrease and lactate accumulation. Knocking down LDHA (lactate dehydrogenase A) or using carnosine, a buffer against lactic acid, attenuates IL-1ß secretion. Furthermore, the blockade of IL-1ß from macrophages into brown adipocytes restores thermogenic markers and mitochondrial oxygen consumption. Moreover, NLRP3 knockout (NLRP3-/-) mice exhibited reduced IL-1ß production while rescuing the mitochondrial function of brown adipocytes and alleviating perivascular adipose tissue fibrosis. CONCLUSIONS: SIRT3 represents a potential therapeutic target to attenuate NLRP3-related inflammation. Pharmacological targeting of glycolytic metabolism may represent an effective therapeutic approach.


Assuntos
Tecido Adiposo Marrom/metabolismo , Plasticidade Celular , Metabolismo Energético , Hipertensão/enzimologia , Macrófagos/enzimologia , Paniculite/enzimologia , Sirtuína 3/metabolismo , Acetilação , Tecido Adiposo Marrom/patologia , Angiotensina II , Animais , Modelos Animais de Doenças , Fibrose , Células HEK293 , Humanos , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/patologia , Inflamassomos/genética , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Ácido Láctico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Paniculite/induzido quimicamente , Paniculite/genética , Paniculite/patologia , Fenótipo , Piruvato Desidrogenase (Lipoamida)/metabolismo , Transdução de Sinais , Sirtuína 3/genética
3.
Life Sci ; 260: 118424, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949586

RESUMO

AIMS: Cannabinoid receptor 2 (CB2R) is an important regulator of immunoinflammatory responses. Interestingly, studies have demonstrated that CB2R was expressed in metabolically active tissue, so we speculated that CB2R might have a crucial impact on energy balance. We thus examined the anti-inflammatory activities of CB2R and a CB2R agonist, JWH-133, in diet-induced obese in mice as well as in cultured macrophages. MATERIALS AND METHODS: We evaluated the in vivo effect of JWH-133 on diet-induced adipose tissue inflammation. We also assessed the in vitro effects of JWH-133 on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages, with a focus on the nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway. KEY FINDINGS: We found that JWH-133 reduced body weight gain, relieved glucose tolerance, and enhanced insulin sensitivity in a mouse model. It also down-regulated the expression of M1 macrophage biomarkers (tumor necrosis factor-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), IL-1ß, CC motif chemokine ligand 2, and C-X-C motif chemokine 10) in vivo and in vitro, but up-regulated levels of M2 macrophage biomarkers (IL-10 and arginase-1) in both mice and cultured macrophages. Furthermore, the underlying mechanisms were studied in an LPS-treated RAW264.7 cell line. We found a role for JWH-133 in controlling M1 macrophage polarization by activating the Nrf2/HO-1 pathway, while the effect of JWH-133 was diminished by a HO-1 inhibitor, Sn(IV) protoporphyrin IX dichloride. SIGNIFICANCE: JWH-133 showed anti-obesity effects that ameliorated pro-inflammatory M1 macrophage polarization through the Nrf2/HO-1 pathway. Therefore, our results provide a new proof for the potential use of the CB2R agonist, JWH-133, in the treatment of obesity.


Assuntos
Canabinoides/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Obesidade/etiologia , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Animais , Peso Corporal/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/etiologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/complicações , Obesidade/patologia , Paniculite/tratamento farmacológico , Paniculite/patologia , Células RAW 264.7 , Receptor CB2 de Canabinoide/agonistas
6.
Pediatr Blood Cancer ; 67(6): e28302, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32285995

RESUMO

This report offers novel clinical and diagnostic aspects of the association between germline mutations in HAVCR2 and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). The patient presented with panniculitis-like T-cell lymphoma involving mesenteric fatty tissue associated with hemophagocytic lymphohistiocytosis (HLH). Five years later, he developed a clonally unrelated SPTCL and underwent hematopoietic stem cell transplantation. Retrospectively, he was found to carry germline mutations in HAVCR2 associated with reduced T-cell immunoglobulin mucin-3 (TIM-3) expression. We show that mesenteric fatty tissue localization of SPTCL can be the presenting manifestation of TIM-3 deficiency, that this condition predisposes to recurrent lymphoma, and that flow cytometry is a possible screening tool.


Assuntos
Mutação em Linhagem Germinativa , Receptor Celular 2 do Vírus da Hepatite A/deficiência , Receptor Celular 2 do Vírus da Hepatite A/genética , Linfo-Histiocitose Hemofagocítica/patologia , Linfoma de Células T/patologia , Mesentério/patologia , Paniculite/patologia , Adolescente , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/metabolismo , Linfoma de Células T/complicações , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Masculino , Mesentério/metabolismo , Paniculite/complicações , Paniculite/genética , Paniculite/metabolismo , Prognóstico
7.
Metabolism ; 106: 154194, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135161

RESUMO

BACKGROUND: Low-grade inflammation and metabolic dysregulation are common comorbidities of obesity, both of which are associated with alterations in iRhom2-regulated pro-inflammatory cytokine and epidermal growth factor receptor (EGFR) ligand signaling. OBJECTIVE: Our objective was to determine the role of iRhom2 in the regulation of low-grade inflammation and metabolic dysregulation in a murine model of diet-induced obesity. METHODS: Wild type (WT) and iRhom2-deficient mice were fed normal chow (NC) or a high-fat diet (HFD) starting at 5 weeks of age for up to 33 weeks. Body composition, glucose and insulin tolerance, feeding behavior, and indirect calorimetry were measured at defined time points. Adipose tissue cytokine expression and inflammatory lesions known as crown-like structures (CLS) were analyzed at the end-point of the study. RESULTS: iRhom2-deficient mice show accelerated fat gain on a HFD, accompanied by insulin resistance. Indirect calorimetry did not demonstrate changes in energy expenditure or food intake, but locomotor activity was significantly reduced in HFD iRhom2-deficient mice. Interestingly, CLS, macrophage infiltration, and tumor necrosis factor (TNF) production were decreased in adipose tissue from HFD iRhom2-deficient mice, but circulating cytokines were unchanged. In inguinal and perigonadal fat, the EGFR ligand amphiregulin was markedly induced in HFD controls but completely prevented in iRhom2-deficient mice, suggesting a potentially dominant role of EGFR-dependent mechanisms over TNF in the modulation of insulin sensitivity. CONCLUSIONS: This study elucidates a novel role for iRhom2 as an immuno-metabolic regulator that affects adipose tissue inflammation independent of insulin resistance.


Assuntos
Tecido Adiposo/metabolismo , Proteínas de Transporte/fisiologia , Dieta Hiperlipídica , Inflamação/patologia , Resistência à Insulina/genética , Obesidade/etiologia , Ganho de Peso/genética , Tecido Adiposo/patologia , Animais , Proteínas de Transporte/genética , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Regulação para Baixo/genética , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Paniculite/genética , Paniculite/metabolismo , Paniculite/patologia
8.
J Vet Diagn Invest ; 32(2): 336-338, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32100641

RESUMO

A captive, adult female Brent goose (Branta bernicla) with a history of severe feather picking by its mate, was presented with 0.5-2.5 cm skin nodules on the head and neck. Histologic examination revealed a well-delineated dermal mass that surrounded an intact feather follicle and was composed of lakes of proteinaceous fluid and fibrin with scattered foamy macrophages and multinucleate giant cells. No bacteria or fungi were identified with histology, microbial culture, or PCR. Sterile panniculitis is an infrequent finding in animals and traumatic panniculitis is rarely sterile.


Assuntos
Doenças das Aves/diagnóstico , Gansos , Paniculite/veterinária , Animais , Animais de Zoológico , Doenças das Aves/etiologia , Doenças das Aves/patologia , Feminino , Humanos , Paniculite/diagnóstico , Paniculite/etiologia , Paniculite/patologia , Quebeque
9.
Clin Nucl Med ; 45(2): e69-e71, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31833924

RESUMO

A 30-year-old woman presented with persistent fever and elevated lactate dehydrogenase levels without skin rash. F-FDG PET/CT revealed FDG uptake in subcutaneous tissues in the forearm, buttocks, and lower limbs, whereas the trunk was unaffected. She was diagnosed with subcutaneous panniculitis-like T-cell lymphoma based on a PET/CT-guided subcutaneous tissue biopsy from the thigh. Although conventional cytotoxic agent-based chemotherapies failed to achieve disease remission, subsequent cyclosporine A treatment promptly resolved the fever and laboratory abnormalities. Remarkably, abnormal FDG uptake disappeared entirely on follow-up PET/CT, demonstrating its utility in the evaluations of responses to emerging cyclosporine A-based treatments in subcutaneous panniculitis-like T-cell lymphoma.


Assuntos
Ciclosporina/farmacologia , Fluordesoxiglucose F18 , Linfoma de Células T/diagnóstico por imagem , Linfoma de Células T/tratamento farmacológico , Paniculite/diagnóstico por imagem , Paniculite/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Ciclosporina/uso terapêutico , Feminino , Humanos , Linfoma de Células T/patologia , Paniculite/patologia , Resultado do Tratamento
11.
Am J Physiol Cell Physiol ; 318(1): C63-C72, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596606

RESUMO

Endocrine-disrupting chemicals interact with transcription factors essential for adipocyte differentiation. Exposure to endocrine-disrupting chemicals corresponds with elevated risks of obesity, but the effects of these compounds on human cells remain largely undefined. Widespread use of bisphenol AF (BPAF) as a bisphenol A (BPA) alternative in the plastics industry presents unknown health risks. To this end, we discovered that BPAF interferes with the metabolic function of mature human adipocytes. Although 4-day exposures to BPAF accelerated adipocyte differentiation, we observed no effect on mature fat cell marker genes. Additional gene and protein expression analysis showed that BPAF treatment during human adipocyte differentiation failed to suppress the proinflammatory transcription factor STAT1. Microscopy and respirometry experiments demonstrated that BPAF impaired mitochondrial function and structure. To test the hypothesis that BPAF fosters vulnerabilities to STAT1 activation, we treated mature adipocytes previously exposed to BPAF with interferon-γ (IFNγ). BPAF increased IFNγ activation of STAT1 and exposed mitochondrial vulnerabilities that disrupt adipocyte lipid and carbohydrate metabolism. Collectively, our data establish that BPAF activates inflammatory signaling pathways that degrade metabolic activity in human adipocytes. These findings suggest how the BPA alternative BPAF contributes to metabolic changes that correspond with obesity.


Assuntos
Adipócitos Brancos/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Metabolismo Energético/efeitos dos fármacos , Paniculite/induzido quimicamente , Fenóis/toxicidade , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Interferon gama/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , PPAR gama/genética , PPAR gama/metabolismo , Paniculite/metabolismo , Paniculite/patologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
15.
Rev Chilena Infectol ; 36(5): 670-673, 2019 Oct.
Artigo em Espanhol | MEDLINE | ID: mdl-31859811

RESUMO

Gnathostomiasis is an emerging disease in non-endemic countries. This zoonotic nematode requires aquatic freshwater environments to complete its life cycle where larvae get encrusted in fishes. Typically, the infection manifests as migratory subcutaneous lesion caused by the larvae trak, which produces an eosinophilic panniculitis. Here we describe a patient who presented a migratory lesion with no response to antimicrobial therapy, a careful travel and food history together with specific laboratory tests led to the correct diagnosis. Gnathostomiasis should be suspected in patients with migratory skin lesions who have consumed raw freshwater fish during travel to endemic countries in South America or Asia.


Assuntos
Gnatostomíase/patologia , Vulvite/patologia , Vulvite/parasitologia , Adulto , Animais , Diagnóstico Diferencial , Feminino , Gnathostoma , Gnatostomíase/parasitologia , Humanos , Paniculite/parasitologia , Paniculite/patologia , Doença Relacionada a Viagens , Vulvite/diagnóstico por imagem
16.
BMJ Case Rep ; 12(10)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594785

RESUMO

We report the case of an otherwise healthy 60-year-old man presenting with fever, leucocytosis and a painful swelling of the right calf. We initially performed cultural and cytological examination of the popliteal fossa mass, but the results were disappointingly inconclusive. The subsequent development of several erythematous subcutaneous nodules, rapidly evolving to broad ulcerative lesions, prompted us to reconsider the clinical setting as a whole, which included fever, marked leucocytosis and multiple subcutaneous nodules. A biopsy of the ulcerative lesions finally led to the diagnosis of neutrophilic panniculitis, which was sustained by a hybrid myelodysplastic/myeloproliferative disorder like BCR-ABL1-negative atypical chronic myeloid leukaemia. The patient was initially treated with high-dose intravenous corticosteroids, resulting in a dramatic improvement of the skin lesions and normalisation of blood tests. Azacytidine treatment was subsequently started, and the haematological disease remained stable.


Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Paniculite/patologia , Administração Intravenosa , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/uso terapêutico , Diagnóstico Diferencial , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Paniculite/etiologia , Neoplasias Cutâneas/patologia , Úlcera Cutânea/patologia , Resultado do Tratamento
18.
Rev. chil. infectol ; 36(5): 670-673, oct. 2019. graf
Artigo em Espanhol | LILACS | ID: biblio-1058095

RESUMO

Resumen La gnatostomiasis es una parasitosis emergente en países no endémicos. Este nematodo zoonótico requiere de agua dulce para su ciclo de vida, donde sus larvas se enquistan principalmente en peces. La migración subcutánea de las larvas produce habitualmente una paniculitis eosinofílica de rápido avance. Se describe un caso clínico de un paciente con una lesión migratoria, sin mejoría clínica con terapia antibacteriana. La búsqueda de factores de riesgo, sumado a la evolución y a los hallazgos de laboratorio hizo sospechar el diagnóstico. La gnatostomiasis debe ser sospechado en pacientes con lesiones de piel migratorias, que han consumido pescado crudo durante viajes a países endémicos en Sudamérica o Asia.


Gnathostomiasis is an emerging disease in non-endemic countries. This zoonotic nematode requires aquatic freshwater environments to complete its life cycle where larvae get encrusted in fishes. Typically, the infection manifests as migratory subcutaneous lesion caused by the larvae trak, which produces an eosinophilic panniculitis. Here we describe a patient who presented a migratory lesion with no response to antimicrobial therapy, a careful travel and food history together with specific laboratory tests led to the correct diagnosis. Gnathostomiasis should be suspected in patients with migratory skin lesions who have consumed raw freshwater fish during travel to endemic countries in South America or Asia.


Assuntos
Humanos , Animais , Feminino , Adulto , Vulvite/parasitologia , Vulvite/patologia , Gnatostomíase/patologia , Vulvite/diagnóstico , Paniculite/parasitologia , Paniculite/patologia , Diagnóstico Diferencial , Gnatostomíase/parasitologia , Doença Relacionada a Viagens , Gnathostoma
19.
Korean J Gastroenterol ; 74(3): 175-182, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554034

RESUMO

Pancreatitis, panniculitis, and polyarthritis (PPP) syndrome is a rare but critical disease with a high mortality rate. The diagnostic dilemma of PPP syndrome is the fact that symptoms occur unexpectedly. A 48-year-old man presented with fever and painful swelling of the left foot that was initially mistaken for cellulitis and gouty arthritis. The diagnosis of PPP syndrome was made based on the abdominal CT findings and elevated pancreatic enzyme levels, lobular panniculitis with ghost cells on a skin biopsy, and polyarthritis on a bone scan. The pancreatitis and panniculitis disappeared spontaneously over time, but the polyarthritis followed its own course despite the use of anti-inflammatory agents. In addition to this case, 30 cases of PPP syndrome in the English literature were reviewed. Most of the patients had initial symptoms other than abdominal pain, leading to misdiagnosis. About one-third of them were finally diagnosed with a pancreatic tumor, of which pancreatic acinar cell carcinoma was the most dominant. They showed a mortality rate of 32.3%, associated mainly with the pancreatic malignancy. Therefore, PPP syndrome should be considered when cutaneous or osteoarticular manifestations occur in patients with pancreatitis. Active investigation and continued observations are needed for patients suspected of PPP syndrome.


Assuntos
Artrite/diagnóstico , Pancreatite/diagnóstico , Paniculite/diagnóstico , Artrite/tratamento farmacológico , Artrite/patologia , Artrite Gotosa/diagnóstico , Osso e Ossos/diagnóstico por imagem , Celulite (Flegmão)/diagnóstico , Diagnóstico Diferencial , Eritema/diagnóstico , Eritema/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/uso terapêutico , Pancreatite/tratamento farmacológico , Pancreatite/patologia , Paniculite/tratamento farmacológico , Paniculite/patologia , Tomografia Computadorizada por Raios X
20.
J Nutr Biochem ; 72: 108173, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31499381

RESUMO

It is known that receptor for advanced glycation end products (RAGE) and its ligands accumulate in the fat tissues of obese individuals, and RAGE ligands induce M1 macrophage polarization, which in turn induces inflammation. We evaluated the effect of pyridoxamine on RAGE ligand accumulation and M1 polarization in the visceral, subcutaneous, and perivascular fat tissues of Sprague-Dawley rats fed a high fat diet (HFD). Pyridoxamine reduced HFD-induced weight gain, attenuated adipocyte size increases, RAGE ligand accumulations, RAGE-RAGE ligands binding, decreased macrophage M1 polarization and increased M2 polarization in visceral fat tissues, but not in subcutaneous tissues. Pyridoxamine induced glyoxalase 1 (Glo-1) expression in visceral fat in the HFD group, whereas pyridoxamine induced Glo-1 expression in perivascular fat tissues was no higher than that observed in the normal fat diet (NFD) controls. In vitro, pyridoxamine suppressed the release of RAGE ligands from AGE treated macrophages, but non-significantly attenuated RAGE ligands release in AGE treated adipocytes. Pyridoxamine was found to suppress weight increases and M1 polarization, and to increase Glo-1 expression through the RAGE pathway in perivascular and visceral fat tissues of HFD-induced obese rats. These findings suggest pyridoxamine is a candidate for the treatment of obesity or complications related to obesity-induced inflammation.


Assuntos
Adipócitos/efeitos dos fármacos , Paniculite/tratamento farmacológico , Piridoxamina/farmacologia , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Polaridade Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/patologia , Lactoilglutationa Liase/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Paniculite/patologia , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/patologia , Triglicerídeos/metabolismo , Ganho de Peso/efeitos dos fármacos
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