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1.
Circulation ; 150(6): 451-465, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-38682338

RESUMO

BACKGROUND: Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive. METHODS: We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)-expressing ECs in human umbilical vessels. To study the contribution of Abcg2-expressing ECs to vessel development and regeneration, we developed Abcg2CreErt2;ROSA TdTomato mice and performed lineage tracing during mouse development and during tissue regeneration after myocardial infarction injury. RNA sequencing and chromatin methylation chromatin immunoprecipitation followed by sequencing were conducted to study the gene regulation in Abcg2-expressing ECs. RESULTS: In human and mouse vessels, ECs with higher ABCG2 expression (ABCECs) possess higher clonal proliferative potential and in vivo vessel-forming potential compared with mature ECs. These cells could clonally contribute to vessel formation in primary and secondary recipients after transplantation. These features of ABCECs meet the criteria of CRECs. Results from lineage tracing experiments confirm that Abcg2-expressing CRECs (AbcCRECs) contribute to arteries, veins, and capillaries in cardiac tissue development and vascular tissue regeneration after myocardial infarction. Transcriptome and epigenetic analyses reveal that a gene expression signature involved in angiogenesis and vessel development is enriched in AbcCRECs. In addition, various angiogenic genes, such as Notch2 and Hey2, are bivalently modified by trimethylation at the 4th and 27th lysine residue of histone H3 (H3K4me3 and H3K27me3) in AbcCRECs. CONCLUSIONS: These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Humanos , Camundongos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/citologia , Neovascularização Fisiológica , Proliferação de Células , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/terapia , Regeneração , Células Endoteliais da Veia Umbilical Humana/metabolismo , Camundongos Transgênicos , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/citologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Linhagem da Célula
2.
Blood ; 142(6): 574-588, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37192295

RESUMO

Tyrosine kinase inhibitors (TKIs) are very effective in treating chronic myelogenous leukemia (CML), but primitive, quiescent leukemia stem cells persist as a barrier to the cure. We performed a comprehensive evaluation of metabolic adaptation to TKI treatment and its role in CML hematopoietic stem and progenitor cell persistence. Using a CML mouse model, we found that glycolysis, glutaminolysis, the tricarboxylic acid cycle, and oxidative phosphorylation (OXPHOS) were initially inhibited by TKI treatment in CML-committed progenitors but were restored with continued treatment, reflecting both selection and metabolic reprogramming of specific subpopulations. TKI treatment selectively enriched primitive CML stem cells with reduced metabolic gene expression. Persistent CML stem cells also showed metabolic adaptation to TKI treatment through altered substrate use and mitochondrial respiration maintenance. Evaluation of transcription factors underlying these changes helped detect increased HIF-1 protein levels and activity in TKI-treated stem cells. Treatment with an HIF-1 inhibitor in combination with TKI treatment depleted murine and human CML stem cells. HIF-1 inhibition increased mitochondrial activity and reactive oxygen species (ROS) levels, reduced quiescence, increased cycling, and reduced the self-renewal and regenerating potential of dormant CML stem cells. We, therefore, identified the HIF-1-mediated inhibition of OXPHOS and ROS and maintenance of CML stem cell dormancy and repopulating potential as a key mechanism of CML stem cell adaptation to TKI treatment. Our results identify a key metabolic dependency in CML stem cells persisting after TKI treatment that can be targeted to enhance their elimination.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas Tirosina Quinases , Camundongos , Humanos , Animais , Proteínas Tirosina Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Resistencia a Medicamentos Antineoplásicos
3.
Circ Res ; 132(1): e1-e21, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36448480

RESUMO

BACKGROUND: We examined components of systemic and intestinal renin-angiotensin system on gut barrier permeability, glucose homeostasis, systemic inflammation, and progression of diabetic retinopathy (DR) in human subjects and mice with type 1 diabetes (T1D). METHODS: T1D individual with (n=18) and without (n=20) DR and controls (n=34) were examined for changes in gut-regulated components of the immune system, gut leakage markers (FABP2 [fatty acid binding protein 2] and peptidoglycan), and Ang II (angiotensin II); Akita mice were orally administered a Lactobacillus paracasei (LP) probiotic expressing humanized ACE2 (angiotensin-converting enzyme 2) protein (LP-ACE2) as either a prevention or an intervention. Akita mice with genetic overexpression of humanAce2 by small intestine epithelial cells (Vil-Cre.hAce2KI-Akita) were similarly examined. After 9 months of T1D, circulatory, enteral, and ocular end points were assessed. RESULTS: T1D subjects exhibit elevations in gut-derived circulating immune cells (ILC1 cells) and higher gut leakage markers, which were positively correlated with plasma Ang II and DR severity. The LP-ACE2 prevention cohort and genetic overexpression of intestinal ACE2 preserved barrier integrity, reduced inflammatory response, improved hyperglycemia, and delayed development of DR. Improvements in glucose homeostasis were due to intestinal MasR activation, resulting in a GSK-3ß (glycogen synthase kinase-3 beta)/c-Myc (cellular myelocytomatosis oncogene)-mediated decrease in intestinal glucose transporter expression. In the LP-ACE2 intervention cohort, gut barrier integrity was improved and DR reversed, but no improvement in hyperglycemia was observed. These data support that the beneficial effects of LP-ACE2 on DR are due to the action of ACE2, not improved glucose homeostasis. CONCLUSIONS: Dysregulated systemic and intestinal renin-angiotensin system was associated with worsening gut barrier permeability, gut-derived immune cell activation, systemic inflammation, and progression of DR in human subjects. In Akita mice, maintaining intestinal ACE2 expression prevented and reversed DR, emphasizing the multifaceted role of the intestinal renin-angiotensin system in diabetes and DR.


Assuntos
Diabetes Mellitus Tipo 1 , Retinopatia Diabética , Hiperglicemia , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Retinopatia Diabética/prevenção & controle , Glucose/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Hiperglicemia/complicações , Inflamação/metabolismo , Intestino Delgado , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/genética , Sistema Renina-Angiotensina/fisiologia
4.
Am J Pathol ; 193(11): 1789-1808, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-36965774

RESUMO

This study investigated retinal changes in a Western diet (WD)-induced nonhuman primate model of type 2 diabetes. Rhesus nonhuman primates, aged 15 to 17 years, were fed a high-fat diet (n = 7) for >5 years reflective of the traditional WD. Age-matched controls (n = 6) were fed a standard laboratory primate diet. Retinal fundus photography, optical coherence tomography, autofluorescence imaging, and fluorescein angiography were performed before euthanasia. To assess diabetic retinopathy (DR), eyes were examined using trypsin digests, lipofuscin autofluorescence, and multimarker immunofluorescence on cross-sections and whole mounts. Retinal imaging showed venous engorgement and tortuosity, aneurysms, macular exudates, dot and blot hemorrhages, and a marked increase in fundus autofluorescence. Post-mortem changes included the following: decreased CD31 blood vessel density (P < 0.05); increased acellular capillaries (P < 0.05); increased density of ionized calcium-binding adaptor molecule expressing amoeboid microglia/macrophage; loss of regular distribution in stratum and spacing typical of ramified microglia; and increased immunoreactivity of aquaporin 4 and glial fibrillary acidic protein (P < 0.05). However, rhodopsin immunoreactivity (P < 0.05) in rods and neuronal nuclei antibody-positive neuronal density of 50% (P < 0.05) were decreased. This is the first report of a primate model of DR solely induced by a WD that replicates key features of human DR.


Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Animais , Humanos , Retinopatia Diabética/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Diabetes Mellitus Tipo 2/complicações , Dieta Ocidental , Vasos Retinianos/metabolismo , Primatas , Tomografia de Coerência Óptica/métodos
5.
Mol Ther ; 31(7): 2042-2055, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37016576

RESUMO

We reported previously that ß-site amyloid precursor protein cleaving enzyme (BACE1) is strongly expressed in the normal retina and that BACE1-/- mice develop pathological phenotypes associated with age-related macular degeneration (AMD). BACE1 expression is increased within the neural retina and retinal pigment epithelium (RPE) in AMD donor eyes suggesting that increased BACE1 is compensatory. We observed that AAV-mediated BACE1 overexpression in the RPE was maintained up to 6 months after AAV1-BACE1 administration. No significant changes in normal mouse visual function or retinal morphology were observed with low-dose vector while the high-dose vector demonstrated some early pathology which regressed with time. No increase in ß-amyloid was observed. BACE1 overexpression in the RPE of the superoxide dismutase 2 knockdown (SOD2 KD) mouse, which exhibits an AMD-like phenotype, prevented loss of retinal function and retinal pathology, and this was sustained out to 6 months. Furthermore, BACE1 overexpression was able to inhibit oxidative stress, microglial changes, and loss of RPE tight junction integrity (all features of AMD) in SOD2 KD mice. In conclusion, BACE1 plays a key role in retina/RPE homeostasis, and BACE1 overexpression offers a novel therapeutic target in the treatment of AMD.


Assuntos
Secretases da Proteína Precursora do Amiloide , Degeneração Macular , Animais , Camundongos , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Degeneração Macular/genética , Degeneração Macular/prevenção & controle , Retina/metabolismo , Epitélio Pigmentado da Retina/metabolismo
6.
Diabetologia ; 66(9): 1705-1718, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37311879

RESUMO

AIMS/HYPOTHESIS: Hyper-reflective crystalline deposits found in retinal lesions have been suggested to predict the progression of diabetic retinopathy, but the nature of these structures remains unknown. METHODS: Scanning electron microscopy and immunohistochemistry were used to identify cholesterol crystals (CCs) in human donor, pig and mouse tissue. The effects of CCs were analysed in bovine retinal endothelial cells in vitro and in db/db mice in vivo using quantitative RT-PCR, bulk RNA sequencing, and cell death and permeability assays. Cholesterol homeostasis was determined using 2H2O and 2H7-cholesterol. RESULTS: We identified hyper-reflective crystalline deposits in human diabetic retina as CCs. Similarly, CCs were found in the retina of a diabetic mouse model and a high-cholesterol diet-fed pig model. Cell culture studies demonstrated that treatment of retinal cells with CCs can recapitulate all major pathogenic mechanisms leading to diabetic retinopathy, including inflammation, cell death and breakdown of the blood-retinal barrier. Fibrates, statins and α-cyclodextrin effectively dissolved CCs present in in vitro models of diabetic retinopathy, and prevented CC-induced endothelial pathology. Treatment of a diabetic mouse model with α-cyclodextrin reduced cholesterol levels and CC formation in the retina, and prevented diabetic retinopathy. CONCLUSIONS/INTERPRETATION: We established that cholesterol accumulation and CC formation are a unifying pathogenic mechanism in the development of diabetic retinopathy.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , alfa-Ciclodextrinas , Animais , Bovinos , Camundongos , Humanos , Suínos , Retinopatia Diabética/metabolismo , alfa-Ciclodextrinas/efeitos adversos , alfa-Ciclodextrinas/metabolismo , Células Endoteliais/metabolismo , Diabetes Mellitus Experimental/metabolismo , Retina/metabolismo , Modelos Animais de Doenças , Colesterol/metabolismo
7.
Health Info Libr J ; 40(3): 231-232, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37621204

RESUMO

In the first of two special collections of COVID-19-related manuscripts, this issue focuses on how colleges and universities libraries and their users responded to the need for health information during the pandemic.


Assuntos
COVID-19 , Bibliotecas , Humanos , Pandemias , Universidades
8.
Health Info Libr J ; 40(4): 341-342, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37994580

RESUMO

In this second special collection of COVID-19-related manuscripts, our focus moves from health information within academia to health librarianship in the wider context. Although COVID-19 manuscripts may still occasionally appear in the Health Information and Libraries Journal, the World Health Organisation's declaration earlier this year of an end to the global health emergency marks an intentional editorial shift to adopting a broader perspective in publishing this type of work, a focus on public health information challenges and emergency preparedness, and a return to publishing a more familiar range of health library and information contexts and practice.


Assuntos
COVID-19 , Bibliotecas , Biblioteconomia , Humanos , Editoração , Saúde Global
9.
Health Info Libr J ; 40(2): 217, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37249090

RESUMO

Dissertations into Practice is changing. Details on how those new to health information, library and knowledge work can get involved coming shortly.


Assuntos
Conhecimento , Bibliotecários , Bibliotecas Médicas , Humanos
10.
Health Info Libr J ; 40(2): 123-124, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37431866

RESUMO

Searching for health information is a core activity for health library and knowledge workers, whether seeking to support health care workers in overcoming barriers to accessing drug information, exploring the potential of text mining in developing search filters, translating search filters for use on alternative databases, or the importance of updating search filters to ensure their ongoing utility.


Assuntos
Pessoal de Saúde , Comportamento de Busca de Informação , Bibliotecas , Humanos , Bases de Dados Factuais , Conhecimento , Mineração de Dados
11.
Health Info Libr J ; 40(1): 1-2, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36995251

RESUMO

The rigours of the past few years have demonstrated the importance of good health literacy levels with the imperative of being able to obtain and interpret information to maintain and improve one's health never more apparent. With this in mind, this issue is focused on consumer health information, the gender and population group differences that exist in information seeking behaviour, the challenges of understanding medical explanations and terminology, and existing criteria to assess and ultimately produce better consumer health information.


Assuntos
Informação de Saúde ao Consumidor , Letramento em Saúde , Humanos , Comportamento de Busca de Informação
12.
Diabetologia ; 65(4): 587-603, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35149880

RESUMO

The metabolically active retina obtains essential lipids by endogenous biosynthesis and from the systemic circulation. Clinical studies provide limited and sometimes conflicting evidence as to the relationships between circulating lipid levels and the development and progression of diabetic retinopathy in people with diabetes. Cardiovascular-system-focused clinical trials that also evaluated some retinal outcomes demonstrate the potential protective power of lipid-lowering therapies in diabetic retinopathy and some trials with ocular primary endpoints are in progress. Although triacylglycerol-lowering therapies with fibrates afforded some protection against diabetic retinopathy, the effect was independent of changes in traditional blood lipid classes. While systemic LDL-cholesterol lowering with statins did not afford protection against diabetic retinopathy in most clinical trials, and none of the trials focused on retinopathy as the main outcome, data from very large database studies suggest the possible effectiveness of statins. Potential challenges in these studies are discussed, including lipid-independent effects of fibrates and statins, modified lipoproteins and retinal-specific effects of lipid-lowering drugs. Dysregulation of retinal-specific cholesterol metabolism leading to retinal cholesterol accumulation and potential formation of cholesterol crystals are also addressed.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Inibidores de Hidroximetilglutaril-CoA Redutases , Colesterol , Diabetes Mellitus/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Ácidos Fíbricos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/química , Retina/fisiopatologia
13.
Gastroenterology ; 160(1): 39-46, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33130103

RESUMO

The role of angiotensin converting enzyme 2 has expanded from regulating the renin angiotensin system to regulating intestinal amino acid homeostasis and the gut microbiome. Recently, angiotensin converting enzyme 2 was identified as a primary receptor for severe acute respiratory syndrome coronaviruses 1 and 2 being expressed in multiple tissues including the luminal surface of the gut. In this brief perspective, we examine the role of angiotensin converting enzyme 2 as the receptor for severe acute respiratory syndrome coronavirus 2 and the impact of coronavirus disease 19 infection on the gut microbiome and on the gut epithelium.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/enzimologia , Gastroenterite/enzimologia , Microbioma Gastrointestinal , Mucosa Intestinal/enzimologia , Receptores Virais/metabolismo , SARS-CoV-2/patogenicidade , Enzima de Conversão de Angiotensina 2/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19/microbiologia , COVID-19/virologia , Fezes/microbiologia , Fezes/virologia , Gastroenterite/tratamento farmacológico , Gastroenterite/microbiologia , Gastroenterite/virologia , Microbioma Gastrointestinal/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/virologia , Sistema Renina-Angiotensina , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus , Tratamento Farmacológico da COVID-19
14.
Exp Eye Res ; 224: 109216, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36041509

RESUMO

Age-related macular degeneration (AMD) is a complex disease with increasing numbers of individuals being afflicted and treatment modalities limited. There are strong interactions between diet, age, the metabolome, and gut microbiota, and all of these have roles in the pathogenesis of AMD. Communication axes exist between the gut microbiota and the eye, therefore, knowing how the microbiota influences the host metabolism during aging could guide a better understanding of AMD pathogenesis. While considerable experimental evidence exists for a diet-gut-eye axis from murine models of human ocular diseases, human diet-microbiome-metabolome studies are needed to elucidate changes in the gut microbiome at the taxonomic and functional levels that are functionally related to ocular pathology. Such studies will reveal new ways to diminish risk for progression of- or incidence of- AMD. Current data suggest that consuming diets rich in dark fish, fruits, vegetables, and low in glycemic index are most retina-healthful during aging.


Assuntos
Microbioma Gastrointestinal , Degeneração Macular , Microbiota , Humanos , Camundongos , Animais , Metaboloma , Dieta , Degeneração Macular/metabolismo
15.
Circ Res ; 126(10): 1456-1474, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32264791

RESUMO

ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.


Assuntos
Betacoronavirus/fisiologia , Doenças Cardiovasculares , Infecções por Coronavirus , Pandemias , Peptidil Dipeptidase A/fisiologia , Pneumonia Viral , Sistema Renina-Angiotensina/fisiologia , Proteína ADAM17/fisiologia , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Humanos , Terapia de Alvo Molecular , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Receptores Virais/fisiologia , SARS-CoV-2 , Ligação Viral , Tratamento Farmacológico da COVID-19
16.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36012406

RESUMO

The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) complications. We aimed to investigate whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n = 146) and healthy individuals (n = 47) were collected during hospitalization and routine visits. Plasma microbiome was analyzed using 16S rRNA sequencing and gut permeability markers including fatty acid binding protein 2 (FABP2), peptidoglycan (PGN), and lipopolysaccharide (LPS) in both patient cohorts. Plasma samples of both cohorts contained predominately Proteobacteria, Firmicutes, Bacteroides, and Actinobacteria. COVID-19 subjects exhibit significant dysbiosis (p = 0.001) of the plasma microbiome with increased abundance of Actinobacteria spp. (p = 0.0332), decreased abundance of Bacteroides spp. (p = 0.0003), and an increased Firmicutes:Bacteroidetes ratio (p = 0.0003) compared to healthy subjects. The concentration of the plasma gut permeability marker FABP2 (p = 0.0013) and the gut microbial antigens PGN (p < 0.0001) and LPS (p = 0.0049) were significantly elevated in COVID-19 patients compared to healthy subjects. These findings support the notion that the intestine may represent a source for bacteremia and contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.


Assuntos
Actinobacteria , COVID-19 , Microbioma Gastrointestinal , Microbiota , Actinobacteria/genética , Bactérias/genética , Disbiose/microbiologia , Fezes/microbiologia , Firmicutes/genética , Microbioma Gastrointestinal/genética , Humanos , Lipopolissacarídeos , Peptidoglicano , RNA Ribossômico 16S/genética , SARS-CoV-2
17.
Health Info Libr J ; 39(4): 307-309, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36274262

RESUMO

To mark the CILIP Health Libraries Group celebrations of their 75th anniversary, this year's Virtual Issue brings together Health Information and Libraries Journal manuscripts that have been particularly influential or generated most interest in our readers, or represent a significant event in the journal's own history, while still having relevance to contemporary health library and knowledge service practice.


Assuntos
Bibliotecários , Bibliotecas Médicas , Bibliotecas , Humanos
18.
Diabetologia ; 64(11): 2575-2588, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34430981

RESUMO

AIMS/HYPOTHESIS: Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of the metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunological pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. METHODS: The present data show that leptin receptor-deficient (db/db) mice exhibit reduced hypothalamic SST neurons, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus delivery of diphtheria toxin subunit A (DTA) driven by an SST-cre system to deplete these neurons in Sstcre/gfp mice (SST-DTA). RESULTS: SST-DTA mice exhibit enhanced hypothalamic c-Fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed haematopoiesis, generating excess granulocyte-monocyte progenitors and increased proinflammatory (C-C chemokine receptor type 2; CCR2hi) monocytes. SST-DTA mice exhibited a 'diabetic retinopathy-like' phenotype: reduced visual function by optokinetic response (0.4 vs 0.25 cycles/degree; SST-DTA vs control mice); delayed electroretinogram oscillatory potentials; and increased percentages of retinal monocytes. Finally, mesenteric visceral adipose tissue from SST-DTA mice was resistant to catecholamine-induced lipolysis, displaying 50% reduction in isoprenaline (isoproterenol)-induced lipolysis compared with control littermates. Importantly, hyperglycaemia was not observed in SST-DTA mice. CONCLUSIONS/INTERPRETATION: The isolated reduction in hypothalamic SST neurons was able to recapitulate several hallmark features of type 2 diabetes in disease-relevant tissues.


Assuntos
Tecido Adiposo/metabolismo , Medula Óssea/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Retina/metabolismo , Somatostatina/metabolismo , Animais , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Toxina Diftérica/toxicidade , Eletrorretinografia , Citometria de Fluxo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase em Tempo Real
19.
Diabetologia ; 64(8): 1822-1833, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34003304

RESUMO

AIMS/HYPOTHESIS: The circadian clock influences both diabetes and immunity. Our goal in this study was to characterise more thoroughly the circadian patterns of immune cell populations and cytokines that are particularly relevant to the immune pathology of type 1 diabetes and thus fill in a current gap in our understanding of this disease. METHODS: Ten individuals with established type 1 diabetes (mean disease duration 11 years, age 18-40 years, six female) participated in a circadian sampling protocol, each providing six blood samples over a 24 h period. RESULTS: Daily ranges of population frequencies were sometimes large and possibly clinically significant. Several immune populations, such as dendritic cells, CD4 and CD8 T cells and their effector memory subpopulations, CD4 regulatory T cells, B cells and cytokine IL-6, exhibited statistically significant circadian rhythmicity. In a comparison with historical healthy control individuals, but using shipped samples, we observed that participants with type 1 diabetes had statistically significant phase shifts occurring in the time of peak occurrence of B cells (+4.8 h), CD4 and CD8 T cells (~ +5 h) and their naive and effector memory subsets (~ +3.3 to +4.5 h), and regulatory T cells (+4.1 h). An independent streptozotocin murine experiment confirmed the phase shifting of CD8 T cells and suggests that circadian dysrhythmia in type 1 diabetes might be an effect and not a cause of the disease. CONCLUSIONS/INTERPRETATION: Future efforts investigating this newly described aspect of type 1 diabetes in human participants are warranted. Peripheral immune populations should be measured near the same time of day in order to reduce circadian-related variation.


Assuntos
Transtornos Cronobiológicos/imunologia , Ritmo Circadiano/imunologia , Diabetes Mellitus Tipo 1/imunologia , Sistema Imunitário/fisiologia , Adolescente , Adulto , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Relógios Circadianos/genética , Células Dendríticas/imunologia , Feminino , Citometria de Fluxo , Humanos , Interleucina-6/sangue , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Adulto Jovem
20.
Diabetologia ; 64(7): 1674-1689, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33770194

RESUMO

AIMS/HYPOTHESIS: Homo sapiens evolved under conditions of intermittent food availability and prolonged fasting between meals. Periods of fasting are important for recovery from meal-induced oxidative and metabolic stress, and tissue repair. Constant high energy-density food availability in present-day society contributes to the pathogenesis of chronic diseases, including diabetes and its complications, with intermittent fasting (IF) and energy restriction shown to improve metabolic health. We have previously demonstrated that IF prevents the development of diabetic retinopathy in a mouse model of type 2 diabetes (db/db); however the mechanisms of fasting-induced health benefits and fasting-induced risks for individuals with diabetes remain largely unknown. Sirtuin 1 (SIRT1), a nutrient-sensing deacetylase, is downregulated in diabetes. In this study, the effect of SIRT1 stimulation by IF, fasting-mimicking cell culture conditions (FMC) or pharmacological treatment using SRT1720 was evaluated on systemic and retinal metabolism, systemic and retinal inflammation and vascular and bone marrow damage. METHODS: The effects of IF were modelled in vivo using db/db mice and in vitro using bovine retinal endothelial cells or rat retinal neuroglial/precursor R28 cell line serum starved for 24 h. mRNA expression was analysed by quantitative PCR (qPCR). SIRT1 activity was measured via histone deacetylase activity assay. NR1H3 (also known as liver X receptor alpha [LXRα]) acetylation was measured via western blot analysis. RESULTS: IF increased Sirt1 mRNA expression in mouse liver and retina when compared with non-fasted animals. IF also increased SIRT1 activity eightfold in mouse retina while FMC increased SIRT1 activity and expression in retinal endothelial cells when compared with control. Sirt1 expression was also increased twofold in neuronal retina progenitor cells (R28) after FMC treatment. Moreover, FMC led to SIRT1-mediated LXRα deacetylation and subsequent 2.4-fold increase in activity, as measured by increased mRNA expression of the genes encoding ATP-binding cassette transporter (Abca1 and Abcg1). These changes were reduced when retinal endothelial cells expressing a constitutively acetylated LXRα mutant were tested. Increased SIRT1/LXR/ABC-mediated cholesterol export resulted in decreased retinal endothelial cell cholesterol levels. Direct activation of SIRT1 by SRT1720 in db/db mice led to a twofold reduction of diabetes-induced inflammation in the retina and improved diabetes-induced visual function impairment, as measured by electroretinogram and optokinetic response. In the bone marrow, there was prevention of diabetes-induced myeloidosis and decreased inflammatory cytokine expression. CONCLUSIONS/INTERPRETATION: Taken together, activation of SIRT1 signalling by IF or through pharmacological activation represents an effective therapeutic strategy that provides a mechanistic link between the advantageous effects associated with fasting regimens and prevention of microvascular and bone marrow dysfunction in diabetes.


Assuntos
Angiopatias Diabéticas/prevenção & controle , Jejum/fisiologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Animais , Bovinos , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Células Cultivadas , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/terapia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/metabolismo , Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Hipoglicemiantes/farmacologia , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Retina/efeitos dos fármacos , Retina/patologia , Neurônios Retinianos/efeitos dos fármacos , Neurônios Retinianos/metabolismo , Neurônios Retinianos/patologia , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirtuína 1/efeitos dos fármacos , Sirtuína 1/genética , Sirtuína 1/metabolismo
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