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1.
STAR Protoc ; 3(2): 101412, 2022 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-35620076

RESUMO

This protocol provides a pipeline for simultaneous recording of breathing and neural activities in awake, behaving mice. Breathing is recorded with thermistor probes implanted in the nasal cavity, which can be easily integrated with neural activity monitoring approaches such as fiber photometry. Here, we detail the procedures of the thermistor probe assembly, surgery, recording system setup, and data analysis. This protocol can be applied to investigate respiratory physiology and breathing changes during natural behaviors. For complete details on the use and execution of this protocol, please refer to Liu et al. (2022).


Assuntos
Respiração , Vigília , Animais , Camundongos , Fotometria
2.
PLoS One ; 17(1): e0261986, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35020750

RESUMO

INTRODUCTION: After stage 3 CKD, the risk of adverse cardiovascular events increased significantly. Therefore, we performed a meta-analysis to investigate the cardiovascular protective effect of SGLT2 inhibitors in patients with stage 3/4 CKD with different baseline kidney function or underlying diseases. METHOD: To identify eligible trials, we systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021. The primary cardiovascular outcome was defined as a combination of cardiovascular mortality and hospitalization due to heart failure. Baseline kidney functions (stage 3a CKD: eGFR45-59mL/min per 1.73m2, stage 3b CKD: eGFR30-44mL/min per 1.73m2, stage 4 CKD: eGFR<30mL/min per 1.73m2) and underlying diseases (Type 2 diabetes, heart failure (Preserved ejection fraction or reduced ejection fraction), atherosclerotic cardiovascular disease) were used to stratify efficacy and safety outcomes. The results were subjected to a sensitivity analysis to ensure that they were reliable. RESULTS: In the present study, a total of eleven trials were included that involved a total of 27,823 patients with stage 3/4 CKD. The treatment and control groups contained 14,451 and 13,372 patients, respectively. In individuals with stage 3/4 CKD, SGLT2 inhibitors reduced the risk of primary cardiovascular outcomes by 26% (HR 0.74, [95% CI 0.69-0.80], I2 = 0.00%), by 30% in patients with stage 3a CKD (HR 0.70, [95% CI 0.59-0.84], I2 = 18.70%), by 23% in patients with stage 3b CKD (HR 0.77, [95% CI 0.66-0.90], I2 = 2.12%), and by 29% in patients with stage 4 CKD (HR 0.71, [95% CI 0.53-0.96], I2 = 0.00%). The risk of primary outcomes was reduced by 29% (HR 0.71, [95% CI 0.63-0.80], I2 = 0.00%) in patients with type 2 diabetes, by 28% (HR 0.72, [95% CI 0.56-0.93], I2 = 37.23%) in patients with heart failure with preserved ejection fraction, by 21% (HR 0.79, [95% CI 0.70-0.89], I2 = 0.00%) in patients with heart failure with reduced ejection fraction, and by 25% (HR 0.75, [95% CI 0.64-0.88], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease. CONCLUSIONS: For stage 3/4 CKD, SGLT2 inhibitors significantly decreased the risk of primary cardiovascular outcomes, and these benefits were consistent throughout the spectrum of different kidney functions, even in stage 4 CKD. There was no evidence of increased adverse outcomes across different baseline clinical complications, such as type 2 diabetes, heart failure, or atherosclerotic cardiovascular disease.


Assuntos
Aterosclerose , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Hospitalização , Humanos , Masculino , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/mortalidade , Fatores de Risco
3.
Plant Biotechnol J ; 20(3): 437-453, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34655511

RESUMO

Starch accounts for over 80% of the total dry weight in cereal endosperm and determines the kernel texture and nutritional quality. Amyloplasts, terminally differentiated plastids, are responsible for starch biosynthesis and storage. We screened a series of rice mutants with floury endosperm to clarify the mechanism underlying amyloplast development and starch synthesis. We identified the floury endosperm19 (flo19) mutant which shows opaque of the interior endosperm. Abnormal compound starch grains (SGs) were present in the endosperm cells of the mutant. Molecular cloning revealed that the FLO19 allele encodes a plastid-localized pyruvate dehydrogenase complex E1 component subunit α1 (ptPDC-E1-α1) that is expressed in all rice tissues. In vivo enzyme assays demonstrated that the flo19 mutant showed decreased activity of the plastidic pyruvate dehydrogenase complex. In addition, the amounts of monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG) were much lower in the developing flo19 mutant endosperm, suggesting that FLO19 participates in fatty acid supply for galactolipid biosynthesis in amyloplasts. FLO19 overexpression significantly increased seed size and weight, but did not affect other important agronomic traits, such as panicle length, tiller number and seed setting rate. An analysis of single nucleotide polymorphism data from a panel of rice accessions identified that the pFLO19L haplotype was positively associated with grain length, implying a potential application in rice breeding. In summary, our study demonstrates that FLO19 is involved in galactolipid biosynthesis which is essential for amyloplast development and starch biosynthesis in rice.


Assuntos
Oryza , Grão Comestível , Endosperma/metabolismo , Galactolipídeos , Regulação da Expressão Gênica de Plantas , Mutação/genética , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plastídeos/metabolismo , Complexo Piruvato Desidrogenase , Amido/metabolismo
4.
Med Image Anal ; 76: 102313, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34911012

RESUMO

In recent years, deep learning technology has shown superior performance in different fields of medical image analysis. Some deep learning architectures have been proposed and used for computational pathology classification, segmentation, and detection tasks. Due to their simple, modular structure, most downstream applications still use ResNet and its variants as the backbone network. This paper proposes a modular group attention block that can capture feature dependencies in medical images in two independent dimensions: channel and space. By stacking these group attention blocks in ResNet-style, we obtain a new ResNet variant called ResGANet. The stacked ResGANet architecture has 1.51-3.47 times fewer parameters than the original ResNet and can be directly used for downstream medical image segmentation tasks. Many experiments show that the proposed ResGANet is superior to state-of-the-art backbone models in medical image classification tasks. Applying it to different segmentation networks can improve the baseline model in medical image segmentation tasks without changing the network architecture. We hope that this work provides a promising method for enhancing the feature representation of convolutional neural networks (CNNs) in the future.


Assuntos
Processamento de Imagem Assistida por Computador , Redes Neurais de Computação , Progressão da Doença , Humanos , Processamento de Imagem Assistida por Computador/métodos , Coluna Vertebral
5.
Neuron ; 110(5): 857-873.e9, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-34921781

RESUMO

Breathing can be heavily influenced by pain or internal emotional states, but the neural circuitry underlying this tight coordination is unknown. Here we report that Oprm1 (µ-opioid receptor)-expressing neurons in the lateral parabrachial nucleus (PBL) are crucial for coordinating breathing with affective pain in mice. Individual PBLOprm1 neuronal activity synchronizes with breathing rhythm and responds to noxious stimuli. Manipulating PBLOprm1 activity directly changes breathing rate, affective pain perception, and anxiety. Furthermore, PBLOprm1 neurons constitute two distinct subpopulations in a "core-shell" configuration that divergently projects to the forebrain and hindbrain. Through non-overlapping projections to the central amygdala and pre-Bötzinger complex, these two subpopulations differentially regulate breathing, affective pain, and negative emotions. Moreover, these subsets form recurrent excitatory networks through reciprocal glutamatergic projections. Together, our data define the divergent parabrachial opioidergic circuits as a common neural substrate that coordinates breathing with various sensations and behaviors such as pain and emotional processing.


Assuntos
Núcleo Central da Amígdala , Núcleos Parabraquiais , Animais , Tronco Encefálico , Emoções , Camundongos , Vias Neurais/fisiologia , Dor/metabolismo , Núcleos Parabraquiais/metabolismo
6.
J Transl Med ; 19(1): 500, 2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34876179

RESUMO

BACKGROUND: Diagnosing seronegative rheumatoid arthritis (RA) can be challenging due to complex diagnostic criteria. We sought to discover diagnostic biomarkers for seronegative RA cases by studying metabolomic and lipidomic changes in RA patient serum. METHODS: We performed comprehensive metabolomic and lipidomic profiling in serum of 225 RA patients and 100 normal controls. These samples were divided into a discovery set (n = 243) and a validation set (n = 82). A machine-learning-based multivariate classification model was constructed using distinctive metabolites and lipids signals. RESULTS: Twenty-six metabolites and lipids were identified from the discovery cohort to construct a RA diagnosis model. The model was subsequently tested on a validation set and achieved accuracy of 90.2%, with sensitivity of 89.7% and specificity of 90.6%. Both seropositive and seronegative patients were identified using this model. A co-occurrence network using serum omics profiles was built and parsed into six modules, showing significant association between the inflammation and immune activity markers and aberrant metabolism of energy metabolism, lipids metabolism and amino acid metabolism. Acyl carnitines (20:3), aspartyl-phenylalanine, pipecolic acid, phosphatidylethanolamine PE (18:1) and lysophosphatidylethanolamine LPE (20:3) were positively correlated with the RA disease activity, while histidine and phosphatidic acid PA (28:0) were negatively correlated with the RA disease activity. CONCLUSIONS: A panel of 26 serum markers were selected from omics profiles to build a machine-learning-based prediction model that could aid in diagnosing seronegative RA patients. Potential markers were also identified in stratifying RA cases based on disease activity.


Assuntos
Artrite Reumatoide , Lipidômica , Biomarcadores , Humanos , Metabolômica , Soro
7.
Front Endocrinol (Lausanne) ; 12: 781417, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956093

RESUMO

In diabetes mellitus (DM), disorders of glucose and lipid metabolism are significant causes of the onset and progression of diabetic nephropathy (DN). However, the exact roles of specific lipid molecules in the pathogenesis of DN remain unclear. This study recruited 577 participants, including healthy controls (HCs), type-2 DM (2-DM) patients, and DN patients, from the clinic. Serum samples were collected under fasting conditions. Liquid chromatography-mass spectrometry-based lipidomics methods were used to explore the lipid changes in the serum and identify potential lipid biomarkers for the diagnosis of DN. Lipidomics revealed that the combination of lysophosphatidylethanolamine (LPE) (16:0) and triacylglycerol (TAG) 54:2-FA18:1 was a biomarker panel for predicting DN. The receiver operating characteristic analysis showed that the panel had a sensitivity of 89.1% and 73.4% with a specificity of 88.1% and 76.7% for discriminating patients with DN from HCs and 2-DM patients. Then, we divided the DN patients in the validation cohort into microalbuminuria (diabetic nephropathy at an early stage, DNE) and macroalbuminuria (diabetic nephropathy at an advanced stage, DNA) groups and found that LPE(16:0), phosphatidylethanolamine (PE) (16:0/20:2), and TAG54:2-FA18:1 were tightly associated with the stages of DN. The sensitivity of the biomarker panel to distinguish between patients with DNE and 2-DM, DNA, and DNE patients was 65.6% and 85.9%, and the specificity was 76.7% and 75.0%, respectively. Our experiment showed that the combination of LPE(16:0), PE(16:0/20:2), and TAG54:2-FA18:1 exhibits excellent performance in the diagnosis of DN.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/diagnóstico , Lipidômica/métodos , Lipídeos/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Nat Commun ; 12(1): 6540, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34764263

RESUMO

Bony fusion caused by pathological new bone formation manifests the clinical feature of ankylosing spondylitis (AS). However, the underlying mechanism remains elusive. Here we discovered spontaneous kyphosis, arthritis and bony fusion in mature CD4-Cre;Ptpn11f/f mice, which present the pathophysiological features of AS. A population of CD4-Cre-expressing proliferating chondrocytes was SHP2 deficient, which could differentiate into pre-hypertrophic and hypertrophic chondrocytes. Functionally, SHP2 deficiency in chondrocytes impeded the fusion of epiphyseal plate and promoted chondrogenesis in joint cavity and enthesis. Mechanistically, aberrant chondrocytes promoted ectopic new bone formation through BMP6/pSmad1/5 signaling. It is worth emphasizing that such pathological thickness of growth plates was evident in adolescent humans with enthesitis-related arthritis, which could progress to AS in adulthood. Targeting dysfunctional chondrogenesis with Smo inhibitor sonidegib significantly alleviated the AS-like bone disease in mice. These findings suggest that blockade of chondrogenesis by sonidegib would be a drug repurposing strategy for AS treatment.


Assuntos
Condrócitos/metabolismo , Osteoblastos/metabolismo , Espondilite Anquilosante/metabolismo , Animais , Proliferação de Células/fisiologia , Condrogênese/genética , Condrogênese/fisiologia , Feminino , Inflamação/metabolismo , Camundongos , Camundongos Knockout
9.
Gut Microbes ; 13(1): 1987779, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34806521

RESUMO

Patients with ulcerative colitis (UC) have a high prevalence of mental disorders, such as depression and anxiety. Gut microbiota imbalance and disturbed metabolism have been suggested to play an important role in either UC or mental disorders. However, little is known about their detailed multi-omics characteristics in patients with UC and depression/anxiety. In this prospective observational study, 240 Chinese patients were enrolled, including 129 patients with active UC (69 in Phase 1 and 60 in Phase 2; divided into depression/non-depression or anxiety/non-anxiety groups), 49 patients with depression and anxiety (non-UC), and 62 healthy people. The gut microbiota of all subjects was analyzed using 16S rRNA sequencing. The serum metabolome and proteome of patients with UC in Phase 2 were analyzed using liquid chromatography/mass spectrometry. Associations between multi-omics were evaluated by correlation analysis. The prophylactic effect of candidate metabolites on the depressive-like behavior of mice with colitis was investigated. In total, 58% of patients with active UC had depression, while 50% had anxiety. Compared to patients with UC without depression/anxiety, patients with UC and depression/anxiety had lower fecal microbial community richness and diversity, with more Lactobacillales, Sellimonas, Streptococcus, and Enterococcus but less Prevotella_9 and Lachnospira. Most metabolites (e.g., glycochenodeoxycholate) were increased in the serum, while few metabolites, including 2'-deoxy-D-ribose and L-pipecolic acid, were decreased, accompanied by a general reduction in immunoglobulin proteins. These related bacteria, metabolites, and proteins were highly connected. A prophylactic administration of 2'-deoxy-D-ribose and L-pipecolic acid significantly reduced the depressive-like behaviors in mice with colitis and alleviated the inflammatory cytokine levels in their colon, blood and brain. This study has identified a comprehensive multi-omics network related to depression and anxiety in active UC. It is composed of a certain set of gut microbiota, metabolites, and proteins, which are potential targets for clinical intervention for patients with UC and depression/anxiety.


Assuntos
Ansiedade/microbiologia , Colite Ulcerativa/microbiologia , Depressão/microbiologia , Microbioma Gastrointestinal , Adolescente , Adulto , Idoso , Animais , Ansiedade/sangue , Ansiedade/complicações , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Depressão/sangue , Depressão/complicações , Fezes/microbiologia , Humanos , Metabolômica , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Proteômica , Adulto Jovem
10.
Mol Metab ; 54: 101367, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34737094

RESUMO

OBJECTIVE: Diabetic kidney disease (DKD) is the most common microvascular complication of type 2 diabetes mellitus (2-DM). Currently, urine and kidney biopsy specimens are the major clinical resources for DKD diagnosis. Our study proposes to evaluate the diagnostic value of blood in monitoring the onset of DKD and distinguishing its status in the clinic. METHODS: This study recruited 1,513 participants including healthy adults and patients diagnosed with 2-DM, early-stage DKD (DKD-E), and advanced-stage DKD (DKD-A) from 4 independent medical centers. One discovery and four testing cohorts were established. Sera were collected and subjected to training proteomics and large-scale metabolomics. RESULTS: Deep profiling of serum proteomes and metabolomes revealed several insights. First, the training proteomics revealed that the combination of α2-macroglobulin, cathepsin D, and CD324 could serve as a surrogate protein biomarker for monitoring DKD progression. Second, metabolomics demonstrated that galactose metabolism and glycerolipid metabolism are the major disturbed metabolic pathways in DKD, and serum metabolite glycerol-3-galactoside could be used as an independent marker to predict DKD. Third, integrating proteomics and metabolomics increased the diagnostic and predictive stability and accuracy for distinguishing DKD status. CONCLUSIONS: Serum integrative omics provide stable and accurate biomarkers for early warning and diagnosis of DKD. Our study provides a rich and open-access data resource for optimizing DKD management.


Assuntos
Nefropatias Diabéticas/sangue , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos de Coortes , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/metabolismo , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Proteômica
11.
Front Med (Lausanne) ; 8: 728089, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790672

RESUMO

Introduction: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on renal outcomes in patients with chronic kidney disease (CKD) were initially demonstrated in recent trials. However, the magnitude of renal benefits for CKD patients with different baseline features and underlying diseases remains unclear. Method: We systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021 to identify eligible trials. The primary outcome was a composite of worsening kidney function, end-stage kidney disease (ESKD), or renal death. Efficacy and safety outcomes were stratified by baseline features, such as type 2 diabetes, heart failure, atherosclerotic cardiovascular disease, proteinuria, and renal function. Results: A total of nine studies were included. These studies included 25,749 patients with estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 and 12,863 patients with urine albumin-to-creatinine ratio (UACR) >300 mg/g. SGLT2 inhibitors reduced the risk of the primary renal outcome by 30% in patients with eGFR<60 mL/min/1.73 m2 (HR 0.70, [95% CI 0.58-0.83], I2 = 0.00%) and by 43% in patients with UACR > 300 mg/g (HR 0.57, [95% CI 0.48-0.67], I2 = 16.59%). A similar benefit was observed in CKD patients with type 2 diabetes. SGLT2 inhibitors had no clear effects on renal outcomes in patients with eGFR<60 mL/min/1.73 m2 combined with atherosclerotic cardiovascular disease (HR 0.74, [95% CI 0.51-1.06], I2 = 0.00%). However, they reduced the risk of major renal outcomes by 46% (HR 0.54, [95% CI 0.38-0.76], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease and macroalbuminuria (defined as UACR > 300 mg/g). SGLT2 inhibitors did not significantly reduce the risk of major renal outcomes in CKD patients with heart failure (eGFR<60 mL/min/1.73 m2: HR 0.81, [95% CI 0.47-1.38], I2 = 0.00%; UACR > 300 mg/g: HR 0.66, [95% CI 0.41-1.07], I2 = 0.00%). SGLT2 inhibitors showed consistent renal benefits across different levels of eGFR (P interaction = 0.48). Conclusion: SGLT2 inhibitors significantly reduced the risk of the primary outcome in CKD patients. However, for patients with different features and underlying diseases, there exists differences in the renal protective effect.

12.
Artigo em Inglês | MEDLINE | ID: mdl-34599805

RESUMO

OBJECTIVES: This study aimed to characterize the systemic lipid profile of patients with asymptomatic hyperuricemia (HUA) and gout using lipidomics, and find potential underlying pathological mechanisms therefrom. METHODS: Sera were collected from Affiliated Hospital of Nanjing University of Chinese Medicine as center 1 (discovery and internal validation sets) and Suzhou Hospital of Traditional Chinese Medicine as center 2 (external validation set) including 88 normal subjects, 157 HUA and 183 gout patients. Lipidomics was performed by UHPLC-Q Exactive MS. Differential metabolites were identifed by both variable importance in the projection ≥ 1 in orthogonal partial least-squares discriminant analysis mode and false discovery rate adjusted p ≤ 0.05. Biomarkers were found by logistic regression and receiver operating characteristic (ROC) analysis. RESULTS: In the discovery set, a total of 245 and 150 metabolites respectively were found for normal subjects vs HUA and normal subjects vs gout. The disturbed metabolites included DAG, TAG, PC, PE, PI, etc. We also found 116 differential metabolites for HUA vs gout. Among them, the biomarker panel of TAG 18:1-20:0-22:1 and TAG 14:0-16:0-16:1 could differentiate well between HUA and gout. The area under ROC curve was 0.8288, the sensitivity was 82%, the specificity was 78% at a 95% confidence interval from 0.747-0.9106. In internal validation set, the predictive accuracy of TAG 18:1-20:0-22:1 and TAG 14:0-16:0-16:1 panel for differentiation of HUA and gout reached 74.38%, while 84.03% in external validation set. CONCLUSION: We identified serum biomarkers panel that have the potential to predict and diagnose HUA and gout patients.

13.
Clin Exp Rheumatol ; 39 Suppl 133(6): 23-29, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34251320

RESUMO

OBJECTIVES: At present, the pathogenesis of Sjögren's syndrome (SS) remains unclear. This research aimed to identify differential metabolites that contribute to SS diagnosis and discover the disturbed metabolic pathways. METHODS: Recent advances in mass spectrometry have allowed the identification of hundreds of unique metabolic signatures and the exploration of altered metabolite profiles in disease. In this study, 505 candidates including healthy controls (HCs) and SS patients were recruited and the serum samples were collected. A non-targeted gas chromatography-mass spectrometry (GC-MS) serum metabolomics method was used to explore the changes in serum metabolites. RESULTS: We found SS patients and HCs can be distinguished by 21 significant metabolites. The levels of alanine, tryptophan, glycolic acid, pelargonic acid, cis-1-2-dihydro-1-2-naphthalenediol, diglycerol, capric acid, turanose, behenic acid, dehydroabietic acid, stearic acid, linoleic acid, heptadecanoic acid, valine, and lactic acid were increased in serum samples from SS patients, whereas levels of catechol, anabasine, 3-6-anhydro-D-galactose, beta-gentiobiose, 2-ketoisocaproic acid and ethanolamine were decreased. The significantly changed pathways included the following: Linoleic acid metabolism; unsaturated fatty acid biosynthesis; aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; glycerolipid metabolism; selenocompound metabolism; galactose metabolism; alanine, aspartate and glutamate metabolism; glyoxylate and dicarboxylate metabolism; glycerophospholipid metabolism; and valine, leucine and isoleucine degradation. CONCLUSIONS: These findings enhance the informative capacity of biochemical analyses through the identification of serum biomarkers and the analysis of metabolic pathways and contribute to an improved understanding of the pathogenesis of SS.


Assuntos
Síndrome de Sjogren , Biomarcadores , Humanos , Metabolômica , Síndrome de Sjogren/diagnóstico
14.
Clin Exp Rheumatol ; 2021 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-34251324

RESUMO

OBJECTIVES: To identify potential lipid biomarkers by studying changes in the blood lipid profile of patients with systemic lupus erythematosus (SLE) using lipidomics. METHODS: Serum samples were collected from 115 SLE patients and 115 age- and sex-matched healthy controls (HCs). Lipid profiles were assessed using ultrahigh-performance liquid chromatography coupled with Q Exactive spectrometry, and possible lipid biomarkers were screened and evaluated by univariate and multivariate analyses. RESULTS: Metabolic phenotypes related to SLE disease activity index (SLEDAI) scores were detected in the serum of SLE patients, and these phenotypes indicated the activity of the disease. Alterations in energy metabolism, fatty acid metabolism and other pathways were observed in patients with SLE. Phosphatidylethanolamine (16:0/18:2), lysophosphatidylethanolamine (18:0), and acylcarnitine (11:0) can be used as biomarkers for the clinical diagnosis of SLE, and receiver operating characteristic (ROC) analysis indicated their effectiveness in diagnosing this disease. CONCLUSIONS: Our study identified serum biomarkers related to disease activity in patients with SLE, providing a basis for its clinical diagnosis.

15.
J Microbiol Biotechnol ; 31(9): 1272-1280, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34261853

RESUMO

With changes in human dietary patterns, the proportion of high-fat and high-cholesterol foods in the daily diet has increased. As a result, the incidence rate of cholelithiasis is increasing rapidly. Many studies have reported on the crucial role that the intestinal microflora plays in the progression of gallstones. Although the whole herb of Lysimachia christinae, a traditional Chinese medicine, has long been extensively used as a remedy for cholelithiasis in China, its effects on the intestinal microflora remain unknown. Hence, in this study, we investigated the ability of the aqueous extract of L. christinae (LAE) to prevent cholesterol gallstones (CGSs) in model animals by affecting the intestinal microflora. The effects of LAE on body weight, serum lipid profile, visceral organ indexes, and histomorphology were studied in male C57BL/6J mice, which were induced by a lithogenic diet. After the 8-week study, CGSs formation was greatly reduced after LAE treatment. LAE also reduced body weight gain and hyperlipidemia and restored the histomorphological changes. Moreover, the intestinal microflora exhibited significant variation. In the model group fed the lithogenic diet, the abundances of the genera unclassified Porphyromonadaceae, Lactobacillus and Alloprevotella decreased, but in contrast, Akkermansia dramatically increased compared with the control check group, which was fed a normal diet; the administration of LAE reversed these changes. These results imply that L. christinae can be considered an efficient therapy for eliminating CGSs induced by a high-fat and high-cholesterol diet, which may be achieved by influencing the intestinal microflora.


Assuntos
Colesterol/metabolismo , Cálculos Biliares/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Primulaceae/química , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Dieta/efeitos adversos , Modelos Animais de Doenças , Cálculos Biliares/etiologia , Cálculos Biliares/metabolismo , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/administração & dosagem , Ganho de Peso/efeitos dos fármacos
16.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34074761

RESUMO

Opioid-induced respiratory depression (OIRD) causes death following an opioid overdose, yet the neurobiological mechanisms of this process are not well understood. Here, we show that neurons within the lateral parabrachial nucleus that express the µ-opioid receptor (PBL Oprm1 neurons) are involved in OIRD pathogenesis. PBL Oprm1 neuronal activity is tightly correlated with respiratory rate, and this correlation is abolished following morphine injection. Chemogenetic inactivation of PBL Oprm1 neurons mimics OIRD in mice, whereas their chemogenetic activation following morphine injection rescues respiratory rhythms to baseline levels. We identified several excitatory G protein-coupled receptors expressed by PBL Oprm1 neurons and show that agonists for these receptors restore breathing rates in mice experiencing OIRD. Thus, PBL Oprm1 neurons are critical for OIRD pathogenesis, providing a promising therapeutic target for treating OIRD in patients.


Assuntos
Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Neurônios/metabolismo , Receptores Opioides mu/metabolismo , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/metabolismo , Analgésicos Opioides/farmacologia , Animais , Camundongos , Camundongos Transgênicos , Morfina/administração & dosagem , Morfina/farmacologia , Neurônios/patologia , Receptores Opioides mu/genética , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia
17.
Anal Chim Acta ; 1160: 338447, 2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-33894967

RESUMO

Drug-induced kidney injury causes structural or functional abnormalities of kidney, seriously affecting clinical practice and drug discovery. However, rapid and effective identification of nephrotoxic drug mechanisms is yet a challenging task arising from the complexity and diversity of various nephrotoxic mechanisms. Herein, we have constructed a polydopamine-polyethyleneimine/quantum dots sensor to instantaneously read out the nephrotoxic drugs mechanisms based on the disparate cell surface phenotypes. Cell surface components induced by multiple nephrotoxic drugs can change the fluorescence emission of multicolor quantum dots, generating their corresponding fluorescent fingerprints. The fluorescence response signatures induced by different nephrotoxic agents are gained with 84% accuracy via linear discriminant analysis. Furthermore, taking the time-toxicity relationship into consideration, dynamic fluorescent fingerprint is obtained through continuous monitoring the progress of renal cell damage, achieving 100% precise classification for nephrotoxic mechanisms of four types of antibiotics. Notably, the fluorescent fingerprint-based high-throughput sensor has been demonstrated by successfully distinguishing nephrotoxic drugs in seconds, employing a promising protocol to discriminate the specific mechanism of nephrotoxic drugs, as well as drug safety evaluation.


Assuntos
Preparações Farmacêuticas , Pontos Quânticos , Antibacterianos , Fluorescência , Polietilenoimina , Pontos Quânticos/toxicidade , Espectrometria de Fluorescência
18.
Theor Appl Genet ; 134(5): 1531-1543, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33688983

RESUMO

KEY MESSAGE: we identified a functional chromogen gene C from wild rice, providing a new insight of anthocyanin biosynthesis pathway in indica and japonica. Accumulation of anthocyanin is a desirable trait to be selected in rice domestication, but the molecular mechanism of anthocyanin biosynthesis in rice remains largely unknown. In this study, a novel allele of chromogen gene C, OrC1, from Oryza rufipongon was cloned and identified as a determinant regulator of anthocyanin biosynthesis. Although OrC1 functions in purple apiculus, leaf sheath and stigma in indica background, it only promotes purple apiculus in japonica. Transcriptome analysis revealed that OrC1 regulates flavonoid biosynthesis pathway and activates a few bHLH and WD40 genes of ternary MYB-bHLH-WD40 complex in indica. Differentially expressed genes and metabolites were found in the indica and japonica backgrounds, indicating that OrC1 activated the anthocyanin biosynthetic genes OsCHI, OsF3H and OsANS and produced six metabolites independently. Artificial selection and domestication of C1 gene in rice occurred on the coding region in the two subspecies independently. Our results reveal the regulatory system and domestication of C1, provide new insights into MYB transcript factor involved in anthocyanin biosynthesis, and show the potential of engineering anthocyanin biosynthesis in rice.


Assuntos
Antocianinas/biossíntese , Regulação da Expressão Gênica de Plantas , Metaboloma , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Compostos Cromogênicos/metabolismo , Perfilação da Expressão Gênica , Oryza/classificação , Oryza/genética , Oryza/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/metabolismo
19.
Rice (N Y) ; 14(1): 29, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33689034

RESUMO

BACKGROUND: The sequences of several important mitochondrion-encoded genes involved in respiration in higher plants are interrupted by introns. Many nuclear-encoded factors are involved in splicing these introns, but the mechanisms underlying this splicing remain unknown. RESULTS: We isolated and characterized a rice mutant named floury shrunken endosperm 5 (fse5). In addition to having floury shrunken endosperm, the fse5 seeds either failed to germinate or produced seedlings which grew slowly and died ultimately. Fse5 encodes a putative plant organelle RNA recognition (PORR) protein targeted to mitochondria. Mutation of Fse5 hindered the splicing of the first intron of nad4, which encodes an essential subunit of mitochondrial NADH dehydrogenase complex I. The assembly and NADH dehydrogenase activity of complex I were subsequently disrupted by this mutation, and the structure of the mitochondria was abnormal in the fse5 mutant. The FSE5 protein was shown to interact with mitochondrial intron splicing factor 68 (MISF68), which is also a splicing factor for nad4 intron 1 identified previously via yeast two-hybrid (Y2H) assays. CONCLUSION: Fse5 which encodes a PORR domain-containing protein, is essential for the splicing of nad4 intron 1, and loss of Fse5 function affects seed development and seedling growth.

20.
J Ethnopharmacol ; 274: 113997, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-33705918

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng is a valuable medicinal herb used in China for the prevention and treatment of cancer, diabetes, cardiovascular diseases and other diseases. As the main active ingredient of ginseng, ginsenoside has a wide range of pharmacological effects. Ginsenoside Rh2, a protopanaxadiol saponin from ginseng, exhibits anti-inflammatory and anticancer effects. AIM OF THE STUDY: The potential biological mechanism of Rh2 in the treatment of ulcerative colitis (UC) has not been clarified clearly. In our research, we aimed to explore the therapeutic effects of Rh2 on dextran sodium sulfate (DSS)-induced colitis and elucidate the mechanism of Rh2 in treating UC. METHODS: DSS-induced UC mice were established and randomly divided into the following four groups: control group, DSS group, Rh2 (50 mg/kg) group and sulfasalazine (SASP, 200 mg/kg) group. Except for the control group, 3% DSS drinking water was given to each group for 7 days, and the other two groups were intragastrically administered with Rh2 and SASP for 10 days. At the end of the experiment, colon samples were collected, and phenotypic and pathological analyses were performed in UC mice. Then, Western blot, immunohistochemistry and quantitative real-time PCR analyses were performed to determine the expression of signaling pathway-related factors. RESULTS: Rh2 markedly alleviated DSS-induced body weight loss, intestinal damage, colon length shortening and disease activity index (DAI) scores. Furthermore, proinflammatory cytokines, such as TNF-α, IL-6 and IL-1ß, were reduced by Rh2. Additionally, STAT3/miR-214 activation was also suppressed by Rh2 administration. In vitro, we demonstrated that Rh2 effectively inhibited IL-6-induced STAT3 phosphorylation and miR-214 expression in cultured normal colonic epithelial cells. CONCLUSION: Our results suggested that Rh2 exhibits potential application value in the treatment of UC, and its mechanism is related to the downregulation of STAT3/miR-214 levels, which is expected to be applicable in the treatment of clinical UC.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Ginsenosídeos/farmacologia , MicroRNAs/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Citocinas/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ginsenosídeos/química , Ginsenosídeos/uso terapêutico , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico
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