RESUMO
Type 2 diabetes (T2D) results from insulin secretory dysfunction arising in part from the loss of pancreatic islet ß-cells. Several factors contribute to ß-cell loss, including islet amyloid formation, which is observed in over 90% of individuals with T2D. The amyloid is comprised of human islet amyloid polypeptide (hIAPP). Here we provide evidence that early in aggregation, hIAPP forms toxic oligomers prior to formation of amyloid fibrils. The toxic oligomers contain α-sheet secondary structure, a nonstandard secondary structure associated with toxic oligomers in other amyloid diseases. De novo, synthetic α-sheet compounds designed to be nontoxic and complementary to the α-sheet structure in the toxic oligomers inhibit hIAPP aggregation and neutralize oligomer-mediated cytotoxicity in cell-based assays. In vivo administration of an α-sheet design to mice for 4 weeks revealed no evidence of toxicity nor did it elicit an immune response. Furthermore, the α-sheet designs reduced endogenous islet amyloid formation and mitigation of amyloid-associated ß-cell loss in cultured islets isolated from an hIAPP transgenic mouse model of islet amyloidosis. Characterization of the involvement of α-sheet in early aggregation of hIAPP and oligomer toxicity contributes to elucidation of the molecular mechanisms underlying amyloid-associated ß-cell loss.
Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Humanos , Camundongos , Animais , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Amiloide/química , Peptídeos beta-AmiloidesRESUMO
APOA1 and APOB are the structural proteins of high-density lipoprotein and APOB-containing lipoproteins, such as low-density lipoprotein and very low-density lipoprotein, respectively. The 4 smaller APOCs (APOC1, APOC2, APOC3, and APOC4) are exchangeable apolipoproteins; they are readily transferred among high-density lipoproteins and APOB-containing lipoproteins. The APOCs regulate plasma triglyceride and cholesterol levels by modulating substrate availability and activities of enzymes interacting with lipoproteins and by interfering with APOB-containing lipoprotein uptake through hepatic receptors. Of the 4 APOCs, APOC3 has been best studied in relation to diabetes. Elevated serum APOC3 levels predict incident cardiovascular disease and progression of kidney disease in people with type 1 diabetes. Insulin suppresses APOC3 levels, and accordingly, elevated APOC3 levels associate with insulin deficiency and insulin resistance. Mechanistic studies in a mouse model of type 1 diabetes have demonstrated that APOC3 acts in the causal pathway of diabetes-accelerated atherosclerosis. The mechanism is likely due to the ability of APOC3 to slow the clearance of triglyceride-rich lipoproteins and their remnants, thereby causing an increased accumulation of atherogenic lipoprotein remnants in lesions of atherosclerosis. Less is known about the roles of APOC1, APOC2, and APOC4 in diabetes.
Assuntos
Aterosclerose , Diabetes Mellitus Tipo 1 , Insulinas , Camundongos , Animais , Apolipoproteína C-II , Lipoproteínas , Triglicerídeos , Lipoproteínas HDL/metabolismo , Apolipoproteína C-III , Lipoproteínas LDL/metabolismo , Aterosclerose/metabolismo , Apolipoproteínas BRESUMO
Serum apolipoprotein C3 (APOC3) predicts incident cardiovascular events in people with type 1 diabetes, and silencing of APOC3 prevents both lesion initiation and advanced lesion necrotic core expansion in a mouse model of type 1 diabetes. APOC3 acts by slowing the clearance of triglyceride-rich lipoproteins, but lipid-free APOC3 has recently been reported to activate an inflammasome pathway in monocytes. We therefore investigated the contribution of hematopoietic inflammasome pathways to atherosclerosis in mouse models of type 1 diabetes. LDL receptor-deficient diabetes mouse models were transplanted with bone marrow from donors deficient in NOD, LRR and pyrin domain-containing protein 3 (NLRP3), absent in melanoma 2 (AIM2) or gasdermin D (GSDMD), an inflammasome-induced executor of pyroptotic cell death. Mice with diabetes exhibited inflammasome activation and consistently, increased plasma interleukin-1ß (IL-1ß) and IL-18. Hematopoietic deletions of NLRP3, AIM2, or GSDMD caused smaller atherosclerotic lesions in diabetic mice. The increased lesion necrotic core size in diabetic mice was independent of macrophage pyroptosis because hematopoietic GSDMD deficiency failed to prevent necrotic core expansion in advanced lesions. Our findings demonstrate that AIM2 and NLRP3 inflammasomes contribute to atherogenesis in diabetes and suggest that necrotic core expansion is independent of macrophage pyroptosis. ARTICLE HIGHLIGHTS: The contribution of hematopoietic cell inflammasome activation to atherosclerosis associated with type 1 diabetes is unknown. The goal of this study was to address whether hematopoietic NOD, LRR, and pyrin domain-containing protein 3 (NLRP3), absent in melanoma 2 (AIM2) inflammasomes, or the pyroptosis executioner gasdermin D (GSDMD) contributes to atherosclerosis in mouse models of type 1 diabetes. Diabetic mice exhibited increased inflammasome activation, with hematopoietic deletions of NLRP3, AIM2, or GSDMD causing smaller atherosclerotic lesions in diabetic mice, but the increased lesion necrotic core size in diabetic mice was independent of macrophage pyroptosis. Further studies on whether inflammasome activation contributes to cardiovascular complications in people with type 1 diabetes are warranted.
Assuntos
Aterosclerose , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Melanoma , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/fisiologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Experimental/complicações , Gasderminas , Camundongos Endogâmicos NOD , Necrose , Proteínas de TransporteRESUMO
BACKGROUND: Early identification of fungal sinusitis remains a challenge. Previously, we observed a high false negative rate of using A-mode ultrasound to diagnose maxillary fungal sinusitis. This study aims to assess the accuracy of the diagnosis of fungal maxillary sinusitis using sinus plain film and ultrasound. METHODS: The screening criteria is defined as the combination of a positive sinus plain film and a false negative sinus ultrasound. We retrospectively reviewed preoperative imaging of patients with fungal sinusitis and unilateral bacterial sinusitis of the maxillary sinus undergoing functional endoscopic sinus surgery from May 2013 to December 2019 in our hospital and evaluated the diagnostic performance of this screening method. RESULTS: Forty-eight patients were included. Twenty-two and 26 patients were diagnosed with fungal sinusitis and bacterial sinusitis, respectively. Sixteen patients (72.7%) with fungal sinusitis presented with a false negative sinus ultrasound and met our screening criteria for fungal sinusitis. The screening criteria reached significance in the receiver operating characteristic curve analysis (p < 0.001). The area under the curve was 0.829. The sensitivity, specificity, and accuracy are 72.7%, 93.2%, and 88.4%, respectively. CONCLUSION: A high false negative rate of sinus ultrasound in patients with fungal sinusitis was found. A positive sinus plain film combined with a false negative sinus ultrasound can potentially become an easy and cost-effective screening tool for diagnosing fungal maxillary sinusitis before consideration of computed tomography scanning.
Assuntos
Sinusite Maxilar , Sinusite , Humanos , Seio Maxilar/diagnóstico por imagem , Sinusite Maxilar/diagnóstico por imagem , Estudos Retrospectivos , Sinusite/diagnóstico por imagem , Sinusite/microbiologia , Ultrassonografia/métodosRESUMO
With the increasing prevalence of diabetes worldwide, vascular complications of diabetes are also on the rise. Diabetes results in an increased risk of macrovascular complications, with atherosclerotic cardiovascular disease (CVD) being the leading cause of death in adults with diabetes. The exact mechanisms for how diabetes promotes CVD risk are still unclear, although it is evident that monocytes and macrophages are key players in all stages of atherosclerosis both in the absence and presence of diabetes, and that phenotypes of these cells are altered by the diabetic environment. Evidence suggests that at least five pro-atherogenic mechanisms involving monocytes and macrophages contribute to the accelerated atherosclerotic lesion progression and hampered lesion regression associated with diabetes. These changes include (1) increased monocyte recruitment to lesions; (2) increased inflammatory activation; (3) altered macrophage lipid accumulation and metabolism; (4) increased macrophage cell death; and (5) reduced efferocytosis. Monocyte and macrophage phenotypes and mechanisms have been revealed mostly by different animal models of diabetes. The roles of specific changes in monocytes and macrophages in humans with diabetes remain largely unknown. There is an ongoing debate on whether the changes in monocytes and macrophages are caused by altered glucose levels, insulin deficiency or insulin resistance, lipid abnormalities, or combinations of these factors. Current research in humans and mouse models suggests that reduced clearance of triglyceride-rich lipoproteins and their remnants is one important mechanism whereby diabetes adversely affects macrophages and promotes atherosclerosis and CVD risk. Although monocytes and macrophages readily respond to the diabetic environment and can be seen as protagonists in diabetes-accelerated atherosclerosis, they are likely not instigators of the increased CVD risk.
RESUMO
Alzheimer's disease (AD) is characterized by the deposition of ß-sheet-rich, insoluble amyloid ß-peptide (Aß) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aß oligomers adopt a nonstandard secondary structure, termed "α-sheet." These oligomers form in the lag phase of aggregation, when Aß-associated cytotoxicity peaks, en route to forming nontoxic ß-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aß, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aß-induced paralysis in a transgenic Aß Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Estrutura Secundária de Proteína , Peptídeos beta-Amiloides/metabolismo , Animais , Anticorpos , Encéfalo/metabolismo , Encéfalo/patologia , Caenorhabditis elegans , Humanos , Immunoblotting , Camundongos , Agregados Proteicos , Agregação Patológica de ProteínasAssuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: The aim of this study was to evaluate the diagnostic efficacy of sinus ultrasound for acute and subacute maxillary sinusitis (ASMS) by investigating the agreement between different tools. We also proposed a confirmatory tool directed protocol for adult acute sinusitis, to enhance diagnostic accuracy. METHODS: This prospective cohort study enrolled patients who were older than 18 years, with a diagnosis of maxillary sinusitis. The duration of symptoms was confined to less than 12 weeks. Rigid nasal endoscopy, sinus ultrasound, and plain sinus film were performed for all patients on the same day to confirm the diagnosis. Kappa statistics were used to test interrater reliability. RESULTS: A total of 148 maxillary sinuses in 74 patients (38 men, 36 women) were evaluated. Sinus ultrasound and rigid nasal endoscopy disclosed the best agreement (agreement = 0.78, κ = 0.556). The agreement of rigid nasal endoscopy and plain sinus film was relatively poor (agreement = 0.72, κ = 0.446). Sinus ultrasound and plain sinus film had the poorest diagnostic consistency (agreement = 0.67, κ = 0.338). CONCLUSION: Sinus ultrasound is a quick, safe, cost effective, and relatively easy-to-use technique for clinicians to evaluate the maxillary sinus. Sinus ultrasound and rigid nasal endoscopy are complementary tests to confirm the diagnosis of ASMS.
Assuntos
Seio Maxilar/diagnóstico por imagem , Sinusite Maxilar/diagnóstico por imagem , Ultrassonografia/métodos , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
RATIONALE: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland carcinoma that histologically resembles in situ and invasive ductal carcinoma of the breast. We present the first case of advanced SDC of the minor salivary gland arising from the supraglottis and review the literature on the clinicopathologic characteristics and prognosis of SDC. PATIENT CONCERNS: A 59-year-old male patient with progressive difficulty in swallowing and a muffled voice for 2 months. DIAGNOSES: The patient was diagnosed with SDC arising from the supraglottis with extensive tumor invasion into the subsites of the larynx and pharynx. INTERVENTIONS: Due to impending airway obstruction, the patient underwent CO2 laser debulking surgery. In addition to local disease, lymph node and distant metastases were also noted at diagnosis and concurrent chemoradiation therapy was arranged. OUTCOMES: Laryngeal function was preserved and tracheostomy was avoided. The patient has survived for >1 year after the initial diagnosis. LESSONS: SDC is a rare and aggressive subtype of salivary gland carcinoma that histologically resembles in situ and invasive ductal carcinoma of the breast. Here we presented the first case of advanced SDC of the minor salivary gland arising from the supraglottis that was treated with CO2 laser debulking surgery followed by concurrent chemoradiation therapy. Due to their rarity, further studies are required to establish the most effective treatment protocol for advanced SDC.
Assuntos
Carcinoma , Quimiorradioterapia/métodos , Procedimentos Cirúrgicos de Citorredução , Laringe , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares , Glândulas Salivares Menores/patologia , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/cirurgia , Carcinoma/patologia , Carcinoma/fisiopatologia , Carcinoma/terapia , Procedimentos Cirúrgicos de Citorredução/instrumentação , Procedimentos Cirúrgicos de Citorredução/métodos , Humanos , Laringe/patologia , Laringe/fisiopatologia , Laringe/cirurgia , Lasers de Gás/uso terapêutico , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/fisiopatologia , Neoplasias das Glândulas Salivares/terapia , Resultado do TratamentoRESUMO
Betel quid (BQ) is a psychostimulant, an addictive substance, and a group 1 carcinogen that exhibits the potential to induce adverse health effects. Approximately, 600 million users chew a variety of BQ. Areca nut (AN) is a necessary ingredient in BQ products. Arecoline is the primary alkaloid in the AN and can be metabolized through the cytochrome P450 (CYP) superfamily by inducing reactive oxygen species (ROS) production. Full-length CYP26B1 is related to the development of oral pharyngeal cancers. We investigated whether a splice variant of CYP26B1 is associated with the occurrence of ROS related oral and pharyngeal cancer. Cytotoxicity assays were used to measure the effects of arecoline on cell viability in a dose-dependent manner. In vitro and in vivo studies were conducted to evaluate the expression of the CYP26B1 splice variant. The CYP26B1 splice variant exhibited lower expression than did full-length CYP26B1 in the human gingival fibroblast-1 and Ca9-22 cell models. Increased expression of the CYP26B1 splice variant was observed in human oral cancer tissue compared with adjacent normal tissue, and increased expression was observed in patients at a late tumor stage. Our results suggested that the CYP26B1 splice variant is associated with the occurrence of BQ-related oral cancer.