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With an electron-deficient rigid planar structure and excellent π-π stacking ability, hexaazatriphenylene (HAT) and its derivatives are widely used as basic building blocks for constructing covalent organic frameworks (COFs), components of organic light-emitting diodes and solar cells, and electrode materials for lithium-ion batteries (LIBs). Here, a HAT derivative, hexaazatriphenylenehexacarbonitrile, is explored as an anode material for LIBs. The HAT anode exhibited high initial reversible capacities of 672 mA h g-1 at 100 mA g-1 and 550 mA h g-1 at 400 mA g-1 and stable cycling with a capacity of 503 mA h g-1 after 1000 cycles at 400 mA g-1 corresponding to a capacity retention of 91.5%. Furthermore, the lithium storage mechanism and the cause of the first irreversible capacity loss of the HAT anode were investigated by X-ray photoelectron spectroscopy (XPS) analysis and density functional theory (DFT) calculations. We have carried out a series of analyses on the mechanism of initial capacity loss. This study provides new insight on initial capacity loss and provides valuable insights into the molecular design and the electrochemical properties of HAT-based anode materials.
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Mechanisms underlying the cardiovascular-kidney-metabolic (CKM) syndrome are unknown, although key small molecule metabolites may be involved. Bulk and spatial metabolomics identified adenine to be upregulated and specifically enriched in coronary blood vessels in hearts from patients with diabetes and left ventricular hypertrophy. Single nucleus gene expression studies revealed that endothelial methylthioadenosine phosphorylase (MTAP) was increased in human hearts with hypertrophic cardiomyopathy. The urine adenine/creatinine ratio in patients was predictive of incident heart failure with preserved ejection fraction. Heart adenine and MTAP gene expression was increased in a 2-hit mouse model of hypertrophic heart disease and in a model of diastolic dysfunction with diabetes. Inhibition of MTAP blocked adenine accumulation in the heart, restored heart dysfunction in mice with type 2 diabetes and prevented ischemic heart damage in a rat model of myocardial infarction. Mechanistically, adenine-induced impaired mitophagy was reversed by reduction of mTOR. These studies indicate that endogenous adenine is in a causal pathway for heart failure and ischemic heart disease in the context of CKM syndrome.
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AIM: Among multi-ethnic Asians, type 2 diabetes (T2D) clustered in three subtypes; mild obesity-related diabetes (MOD), mild age-related diabetes with insulin insufficiency (MARD-II) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII) had differential cardio-renal complication risk. We assessed the proteomic profiles to identify subtype specific biomarkers and its association with diabetes complications. METHODS: 1448 plasma proteins at baseline were measured and compared across the T2D subtypes. Multivariable cox regression was used to assess associations between significant proteomics features and cardio-renal complications. RESULTS: Among 645 T2D participants (SIRD-RII [19%], MOD [45%], MARD-II [36%]), 295 proteins expression differed significantly across the groups. These proteins were enriched in cell adhesion, neurogenesis and inflammatory response processes. In SIRD-RII group, ADH4, ACY1, THOP1, IGFBP2, NEFL, ENTPD2, CALB1, HAO1, CTSV, ITGAV, SCLY, EDA2R, ERBB2 proteins significantly associated with progressive CKD and LILRA5 protein with incident heart failure (HF). In MOD group, TAFA5, RSPO3, EDA2R proteins significantly associated with incident HF. In MARD-II group, FABP4 protein significantly associated with progressive CKD and PTPRN2 protein with major adverse cardiovascular events. Genetically determined NEFL and CALB1 were associated with kidney function decline. CONCLUSIONS: Each T2D subtype has unique proteomics signature and association with clinical outcomes and underlying mechanisms.
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Povo Asiático , Diabetes Mellitus Tipo 2 , Proteômica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Biomarcadores/sangue , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologiaRESUMO
Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.
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Compostos de Espiro , Estereoisomerismo , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Cobre/química , Alcaloides/síntese química , Alcaloides/químicaRESUMO
BACKGROUND: Diabetic kidney disease is an established risk factor for heart failure. However, the impact of incident heart failure on the subsequent risk of renal failure has not been systematically assessed in diabetic population. We sought to study the risk of progression to end stage kidney disease (ESKD) after incident heart failure in Asian patients with type 2 diabetes. METHODS: In this prospective cohort study, 1985 outpatients with type 2 diabetes from a regional hospital and a primary care facility in Singapore were followed for a median of 8.6 (interquartile range 6.2-9.6) years. ESKD was defined as a composite of progression to sustained eGFR below 15 ml/min/1.73m2, maintenance dialysis or renal death, whichever occurred first. RESULTS: 180 incident heart failure events and 181 incident ESKD events were identified during follow-up. Of 181 ESKD events, 38 (21%) occurred after incident heart failure. Compared to those did not progress to ESKD after incident heart failure (n = 142), participants who progressed to ESKD after heart failure occurrence were younger, had higher HbA1c and higher urine albumin-to-creatinine ratio at baseline. The excess risk of ESKD manifested immediately after heart failure occurrence, persisted for two years and was moderated thereafter. Cox regression suggested that, compared to counterparts with no heart failure event, participants with heart failure occurrence had 9.6 (95% CI 5.0- 18.3) fold increased risk for incident ESKD after adjustment for baseline cardio-renal risk factors including eGFR and albuminuria. It appeared that heart failure with preserved ejection fraction had a higher risk for ESKD as compared to those with reduced ejection fraction (adjusted HR 13.7 [6.3-29.5] versus 6.5 [2.3-18.6]). CONCLUSION: Incident heart failure impinges a high risk for progression to ESKD in individuals with type 2 diabetes. Our data highlight the need for intensive surveillance of kidney function after incident heart failure, especially within the first two years after heart failure diagnosis.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Progressão da Doença , Taxa de Filtração Glomerular , Insuficiência Cardíaca , Falência Renal Crônica , Rim , Humanos , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Idoso , Estudos Prospectivos , Incidência , Fatores de Tempo , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/fisiopatologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/fisiopatologia , Medição de Risco , Singapura/epidemiologia , Rim/fisiopatologia , Prognóstico , Biomarcadores/sangueRESUMO
CONTEXT: The CERT1 (Cardiovascular Event Risk Test) score derived from plasma ceramides has been applied clinically for cardiovascular risk assessment. OBJECTIVE: To study whether plasma ceramides predict risk of mortality in patients with type 2 diabetes. DESIGN, SETTING AND PARTICIPANTS: A prospective study which included 1903 outpatients with type 2 diabetes in a regional hospital and a primary care facility in Singapore. EXPOSURE AND OUTCOME: Plasma ceramides (d18:1/16:0, d18:1/18:0, d18:1/24:0, d18:1/24:1) were measured by mass spectrometry and CERT1 score was calculated accordingly. Main outcomes were all-cause and cause-specific mortality. RESULTS: 252 death events were identified during median of 9.3 years of follow-up. Compared to those with low score (≤ 2), participants with a high CERT1 score (≥ 7) had 1.86 (95% CI 1.30-3.65) fold increased risk for all-cause death after adjustment for cardio-renal risk factors including eGFR and albuminuria. As continuous variable, one- unit increment in CERT1 was associated with 8% increased risk for all-cause death (adjusted HR 1.08 [1.04-1.13]). Adding CERT1 onto RECODe (Risk Equations for Complications Of type 2 Diabetes) mortality risk engine significantly improved prediction of 10- year risk of all-cause death (AUC 0.810 to 0.823, delta 0.013 [0.005-0.022]). The association between CERT1 and non-cardiovascular death remained significant (adjusted HR 2.12 [1.32-3.42]), whereas its association with cardiovascular death became non-significant after adjustment for kidney measurements (adjusted HR 1.41 [0.78-2.56]). CONCLUSION: CERT1 score predicts mortality risk independent of clinical cardio-renal risk factors. Further studies are warranted to elucidate the mechanistic linkage between ceramide and mortality, especially non-cardiovascular mortality.
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Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Glicólise , Ácido Láctico , Humanos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Animais , Camundongos , Ácido Láctico/metabolismo , Ácido Láctico/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/complicações , Mitocôndrias/metabolismo , Adulto , Taxa de Filtração Glomerular , Idoso , Túbulos Renais Proximais/metabolismo , Glucose/metabolismo , Fosforilação Oxidativa , Biomarcadores/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/genética , Inibidores do Transportador 2 de Sódio-Glicose/farmacologiaRESUMO
Chlorophenols (CPs) are a group of pollutants that pose a great threat to the environment, they are widely used in industrial and agricultural wastes, pesticides, herbicides, textiles, pharmaceuticals and plastics. Among CPs, pentachlorophenol was listed as one of the persistent organic pollutants (POPs) by the Stockholm convention. This study aims to identify the UDP-glucosyltransferase (UGT) isoforms involved in the metabolic elimination of CPs. CPs' mono-glucuronide was detected in the human liver microsomes (HLMs) incubation mixture with co-factor uridine-diphosphate glucuronic acid (UDPGA). HLMs-catalyzed glucuronidation metabolism reaction equations followed Michaelis-Menten or substrate inhibition type. Recombinant enzymes and chemical reagents inhibition experiments were utilized to phenotype the main UGT isoforms involved in the glucuronidation of CPs. UGT1A6 might be the major enzyme in the glucuronidation of mono-chlorophenol isomer. UGT1A1, UGT1A6, UGT1A9, UGT2B4 and UGT2B7 were the most important five UGT isoforms for metabolizing the di-chlorophenol and tri-chlorophenol isomers. UGT1A1 and UGT1A3 were the most important UGT isoforms in the catalysis of tetra-chlorophenol and pentachlorophenol isomers. Species differences were investigated using rat liver microsomes (RLMs), pig liver microsomes (PLMs), dog liver microsomes (DLMs), and monkey liver microsomes (MyLMs). All these results were helpful for elucidating the metabolic elimination and toxicity of CPs.
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Clorofenóis , Glucuronosiltransferase , Microssomos Hepáticos , Glucuronosiltransferase/metabolismo , Clorofenóis/metabolismo , Animais , Microssomos Hepáticos/metabolismo , Humanos , Ratos , Poluentes Ambientais/metabolismo , Isoenzimas/metabolismo , Glucuronídeos/metabolismoRESUMO
Circulating ceramide levels are dysregulated in kidney disease. However, their associations with rapid decline in kidney function (RDKF) and end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) are unknown. In this prospective study of 1746 T2D participants, we examined the association of plasma ceramide Cer16:0, Cer18:0, Cer24:0, and Cer24:1 with RDKF, defined as an estimated glomerular filtration rate (eGFR) decline of 5 ml/min/1.73 m2 per year or greater, and ESKD defined as eGFR <15/min/1.73 m2 for at least 3 months, on dialysis or renal death at follow-up. During a median follow-up period of 7.7 years, 197 patients experienced RDKF. Ceramide Cer24:0 (odds ratio [OR] = 0.71, 95% CI 0.56-0.90) and ratios Cer16:0/Cer24:0 (OR = 3.54 [1.70-7.35]), Cer18:0/Cer24:0 (OR = 1.89 [1.10-3.25]), and Cer24:1/Cer24:0 (OR = 4.01 [1.93-8.31]) significantly associated with RDKF in multivariable analysis; 124 patients developed ESKD. The ratios Cer16:0/Cer24:0 (hazard ratio [HR] = 3.10 [1.44-6.64]) and Cer24:1/Cer24:0 (HR = 4.66 [1.93-11.24]) significantly associated with a higher risk of ESKD. The Cer24:1/Cer24:0 ratio improved risk discrimination for ESKD beyond traditional risk factors by small but statistically significant margin (Harrell C-index difference: 0.01; P = 0.022). A high ceramide risk score also associated with RDKF (OR = 2.28 [1.26-4.13]) compared to lower risk score. In conclusion, specific ceramide levels and their ratios are associated with RDKF and conferred an increased risk of ESKD, independently of traditional risk factors, including baseline renal functions in patients with T2D.
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Ceramidas , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Ceramidas/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Taxa de Filtração Glomerular , Estudos Prospectivos , Rim/fisiopatologia , Falência Renal Crônica/sangueRESUMO
Resonant exchange of the chiral Majorana fermions (MFs) that is coupled to two parallel Majorana zero modes (MZMs) or two parallel quantum dots (QDs) is investigated. We find that, in the two QDs coupling case, the resonant exchange for the chiral MFs is analogous to that in the MZM coupling case. We further propose a circuit based on topological superconductor, which is formed by the proximity coupling of a quantum anomalous Hall insulator and a s-wave superconductor, to observe the resonant exchange of chiral MFs pairs. The numerical calculations show that the resonant transmission of the chiral MFs can be adjusted by varying the coupling parameters at superconductor phase differenceΔφ=π. It is particularly noteworthy that, by only modulating the coupling strength between the two QDs, the resonant exchange may be switched on or off. By adding another MZM, the non-Abelian braiding like operation can be realized. Therefore, our design scheme may provide another way for non-Abelian braiding operation of MFs and the findings may have potential application value in the realization of topological quantum computers.
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This study aimed to investigate the role of macrophage polarization in the treatment of liver fibrosis by Fuzheng Huayu Tablets(FZHY) through single-cell, transcriptome sequencing and in vitro and in vivo experiments. Liver fibrosis-related datasets, transcriptomic datasets, and single-cell sequencing datasets were obtained from the Gene Expression Omnibus(GEO) database to screen differential genes. Liver fibrosis-related genes were obtained from GeneCards, DisGeNET, NCBI, PharmgKB, TTD and OMIM databases. Macrophage polarization-related genes were obtained from the GeneCards database. The above three gene sets were intersected to construct a protein-protein interaction(PPI) network. Cytoscape software was used to screen core proteins, and the expression pattern of core proteins was visualized by single-cell sequencing. A mouse model of liver fibrosis was constructed using carbon tetrachloride(CCl_4). Hematoxylin-eosin(HE) staining and Masson staining were used to observe the pathological morphology of liver tissues. The expressions of α-smooth muscle actin(α-SMA) and transforming growth factor-ß1(TGF-ß1) were detected by immunohistochemistry. The levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were detected by colorimetry. The le-vels of inflammatory factors in serum were detected by the enzyme-linked immunosorbent assay(ELISA). Furthermore, the expressions of α-SMA, TGF-ß1, cluster of differentiation 86(CD86) and thrombospondin 1(THBS1) in liver tissues were detected by Western blot(WB). Lipopolysaccharide(LPS) was used to stimulate RAW264.7 cells to construct the M1 macrophage polarization model. The cell counting kit-8(CCK-8) method was used to detect cell viability. WB was used to detect the protein expressions of CD86 and THBS1 in cells, and the messenger ribonucleic acid(mRNA) expression levels of tumor necrosis factor-α(TNF-α) and interleukin(IL)-1ß by real-time fluorescent quantitative reverse transcription polymerase chain reaction(RT-qPCR). The results showed that a total of 26 potential genes related to the polarization of liver fibrosis macrophages were obtained, and 10 core proteins related to the polarization of liver fibrosis macrophages such as THBS1, lumican(LUM) and fibulin-5(FBLN5) were screened. Single-cell data analysis indicated that THBS1, ranking highest, may be expressed by M1 macrophages. Animal experiments demonstrated that FZHY reduced inflammatory cell infiltration and collagen deposition in CCl_4-induced mouse liver, relieved liver injury and inflammation levels, and inhibited the expressions of α-SMA, TGF-ß1, CD86, and THBS1 proteins. Cell experiments revealed that FZHY significantly reduced intracellular expression of CD86 and THBS1 proteins and mRNA levels of TNF-α and IL-1ß. In conclusion, FZHY may ameliorate liver fibrosis by inhibiting THBS1 protein expression, suppressing M1 macrophage polarization, and reducing inflammation.
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Medicamentos de Ervas Chinesas , Cirrose Hepática , Transcriptoma , Animais , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Transcriptoma/efeitos dos fármacos , Masculino , Análise de Célula Única , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Chondrocytes are unique resident cells in the articular cartilage, and the pathological changes of them can lead to the occurrence of osteoarthritis(OA). Ligusticum cycloprolactam(LIGc) are derivatives of Z-ligustilide(LIG), a pharmacodynamic marker of Angelica sinensis, which has various biological functions such as anti-inflammation and inhibition of cell apoptosis. However, its protective effect on chondrocytes in the case of OA and the underlying mechanism remain unclear. This study conducted in vitro experiments to explore the molecular mechanism of LIGc in protecting chondrocytes from OA. The inflammation model of rat OA chondrocyte model was established by using interleukin-1ß(IL-1ß) to induce. LIGc alone and combined with glycyrrhizic acid(GA), a blocker of the high mobility group box-1 protein(HMGB1)/Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signaling pathway, were used to intervene in the model, and the therapeutic effects were systematically evaluated. The viability of chondrocytes treated with different concentrations of LIGc was measured by the cell counting kit-8(CCK-8), and the optimal LIGc concentration was screened out. Annexin V-FITC/PI apoptosis detection kit was employed to examine the apoptosis of chondrocytes in each group. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the expression of cyclooxygenase-2(COX-2), prostaglandin-2(PGE2), and tumor necrosis factor-alpha(TNF-α) in the supernatant of chondrocytes in each group. Western blot was employed to determine the protein levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, HMGB1, TLR4, and NF-κB p65. The mRNA levels of HMGB1, TLR4, NF-κB p65, and myeloid differentiation factor 88(MyD88) in chondrocytes were determined by real-time fluorescent quantitative PCR(RT-qPCR). The safe concentration range of LIGc on chondrocytes was determined by CCK-8, and then the optimal concentration of LIGc for exerting the effect was clarified. Under the intervention of IL-1ß, the rat chondrocyte model of OA was successfully established. The modeled chondrocytes showed increased apoptosis rate, promoted expression of COX-2, PGE2, and TNF-α, up-regulated protein levels of Bax, caspase-3, HMGB1, TLR4, and NF-κB p65 and mRNA levels of HMGB1, TLR4, NF-κB p65, and MyD88, and down-regulated protein level of Bcl-2. However, LIGc reversed the IL-1ß-induced changes of the above factors. Moreover, LIGc combined with GA showed more significant reversal effect than LIGc alone. These fin-dings indicate that LIGc extracted and derived from the traditional Chinese medicine A. sinensis can inhibit the inflammatory response of chondrocytes and reduce the apoptosis of chondrocytes, and this effect may be related to the HMGB1/TLR4/NF-κB signaling pathway. The pharmacological effect of LIGc on protecting chondrocytes has potential value in delaying the progression of OA and improving the clinical symptoms of patients, and deserves further study.
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Proteína HMGB1 , Ligusticum , Osteoartrite , Humanos , Ratos , Animais , NF-kappa B/genética , NF-kappa B/metabolismo , Condrócitos , Caspase 3/metabolismo , Proteína X Associada a bcl-2/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Proteína HMGB1/farmacologia , Dinoprostona , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transdução de Sinais , Inflamação/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Apoptose , RNA Mensageiro/metabolismoRESUMO
CONTEXT: Patients with younger onset of type 2 diabetes (YT2D) have increased risk for kidney failure compared to those with late onset. However, the mechanism of diabetic kidney disease (DKD) progression in this high-risk group is poorly understood. OBJECTIVES: To identify novel biomarkers and potential causal proteins associated with DKD progression in patients with YT2D. DESIGN AND PARTICIPANTS: Among YT2D (T2D onset age ≤ 40 years), 144 DKD progressors (cases) were matched for T2D onset age, sex, and ethnicity with 292 non-progressors (controls) and divided into discovery and validation sets. DKD progression was defined as decline of estimated glomerular filtration rate (eGFR) of 3ml/min/1.73m2 or greater or 40% decline in eGFR from baseline. 1472 plasma proteins were measured through a multiplex immunoassay that uses a proximity extension assay technology. Multivariable logistic regression was used to identify proteins associated with DKD progression. Mendelian randomization (MR) was used to evaluate causal relationship between plasma proteins and DKD progression. RESULTS: 42 plasma proteins were associated with DKD progression, independent of traditional cardio-renal risk factors, baseline eGFR and urine albumin-to-creatinine ratio (uACR). The proteins identified were related to inflammatory and remodelling biological processes. Our findings suggested angiogenin as one of the top signals (odds ratio =5.29, 95% CI 2.39-11.73, P = 4.03 × 10-5). Furthermore, genetically determined plasma angiogenin level was associated with increased odds of DKD progression. CONCLUSION: Large-scale proteomic analysis identified novel proteomic biomarkers for DKD progression in YT2D. Genetic evidence suggest a causal role of plasma angiogenin in DKD progression.
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CONTEXT: Metabolites in tricarboxylic acid (TCA) pathway have pleiotropic functions. OBJECTIVE: To study the association between urine TCA cycle metabolites and the risk for chronic kidney disease (CKD) progression in individuals with type 2 diabetes. DESIGN, SETTING AND PARTICIPANTS: A prospective study in a discovery (n = 1826) and a validation (n = 1235) cohort of type 2 diabetes in a regional hospital and a primary care facility. EXPOSURE AND OUTCOME: Urine lactate, pyruvate, citrate, alpha-ketoglutarate, succinate, fumarate and malate were measured by mass spectrometry. CKD progression was defined as a composite of sustained eGFR below 15â ml/min/1.73â m2â , dialysis, renal death or doubling of serum creatinine. RESULTS: During a median of 9.2 (IQR 8.1-9.7) and 4.0 (3.2-5.1) years of follow-up, 213 and 107 renal events were identified. Cox regression suggested that urine lactate, fumarate and malate were associated with an increased risk (adjusted hazard ratio, aHR [95% CI] 1.63 [1.16-2.28], 1.82 [1.17-2.82] and 1.49 [1.05-2.11], per SD), while citrate was associated with a low risk (aHR 0.83 [0.72-0.96] per SD) for the renal outcome after adjustment for cardio-renal risk factors. These findings were reproducible in the validation cohort. Noteworthy, fumarate and citrate were independently associated with the renal outcome after additional adjustment for other metabolites. CONCLUSION: Urine fumarate and citrate predict the risk for progression to ESKD independent of clinical risk factors and other urine metabolites. These two metabolites in TCA cycle pathway may play important roles in the pathophysiological network underpinning progressive loss of kidney function in patients with type 2 diabetes.
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BACKGROUND: A 32-year-old male patient was diagnosed with a 30% left pneumothorax on November 5, 2020, during which chest imaging indicated abnormalities. Despite this, pulmonary tuberculosis (TB) was not diagnosed or treated at that time due to a negative result in the MGIT960 culture. The patient experienced symptoms of cough and expectoration on April 24, 2022. Upon repeating the chest imaging, the condition had worsened, confirming the presence of pulmonary TB, leading to the patient's hospitalization. On September 1, 2022, the 11-year-old daughter of the patient was diagnosed with pulmonary tuberculosis accompanied by bronchial tuberculosis and tuberculous pleurisy. METHODS: The diagnosis of pulmonary tuberculosis was confirmed through sputum smears and Gene Xpert MTB/RIF testing, for the patient and his 11-year-old daughter in 2022. The patient underwent a 6-month combination therapy (2HRZE/4HR) comprising isoniazid, rifampicin, pyrazinamide, and ethambutol. His daughter with pulmonary tuberculosis accompanied by bronchial tuberculosis and tuberculous pleurisy underwent a 12-month combination therapy. RESULTS: Late diagnosis and treatment delays contribute to tuberculosis infections within families. Fortunately, after more than 3 months of antituberculosis treatment, the patient experienced relief from cough and sputum secretion, and there was improvement observed in the chest CT scan. Six months later, the patient was successfully cured of TB. 12 months later, his daughter also was successfully cured of TB. CONCLUSION SUBSECTIONS: Early diagnosis and treatment of tuberculosis (TB) is vital to reduce transmission, morbidity, and mortality.
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Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose Pleural , Tuberculose Pulmonar , Adulto , Criança , Humanos , Masculino , Tosse/etiologia , Diagnóstico Tardio , Mycobacterium tuberculosis/genética , Rifampina/uso terapêutico , Sensibilidade e Especificidade , Escarro , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , FemininoRESUMO
BACKGROUND: The prevalence of chronic kidney disease (CKD) is high. Identification of cases with CKD or at high risk of developing it is important to tailor early interventions. The objective of this study was to identify blood metabolites associated with prevalent and incident severe CKD, and to quantify the corresponding improvement in CKD detection and prediction. METHODS: Data from four cohorts were analyzed: Singapore Epidemiology of Eye Diseases (SEED) (n = 8802), Copenhagen Chronic Kidney Disease (CPH) (n = 916), Singapore Diabetic Nephropathy (n = 714), and UK Biobank (UKBB) (n = 103,051). Prevalent CKD (stages 3-5) was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2; incident severe CKD as CKD-related mortality or kidney failure occurring within 10 years. We used multivariable regressions to identify, among 146 blood metabolites, those associated with CKD, and quantify the corresponding increase in performance. RESULTS: Chronic kidney disease prevalence (stages 3-5) and severe incidence were 11.4% and 2.2% in SEED, and 2.3% and 0.2% in UKBB. Firstly, phenylalanine (Odds Ratio [OR] 1-SD increase = 1.83 [1.73, 1.93]), tyrosine (OR = 0.75 [0.71, 0.79]), docosahexaenoic acid (OR = 0.90 [0.85, 0.95]), citrate (OR = 1.41 [1.34, 1.47]) and triglycerides in medium high density lipoprotein (OR = 1.07 [1.02, 1.13]) were associated with prevalent stages 3-5 CKD. Mendelian randomization analyses suggested causal relationships. Adding these metabolites beyond traditional risk factors increased the area under the curve (AUC) by 3% and the sensitivity by 7%. Secondly, lactate (HR = 1.33 [1.08, 1.64]) and tyrosine (HR = 0.74 [0.58, 0.95]) were associated with incident severe CKD among individuals with eGFR < 90 mL/min/1.73 m2 at baseline. These metabolites increased the c-index by 2% and sensitivity by 5% when added to traditional risk factors. CONCLUSION: The performance improvements of CKD detection and prediction achieved by adding metabolites to traditional risk factors are modest and further research is necessary to fully understand the clinical implications of these findings.
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Biomarcadores , Taxa de Filtração Glomerular , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Prevalência , Biomarcadores/sangue , Idoso , Incidência , Singapura/epidemiologia , Índice de Gravidade de Doença , Valor Preditivo dos Testes , Adulto , Fatores de Risco , Medição de RiscoRESUMO
BACKGROUND: Angiogenin, an enzyme belonging to the ribonucleases A superfamily, plays an important role in vascular biology. Here, we sought to study the association of plasma angiogenin and major adverse cardiovascular events (MACEs) in patients with type 2 diabetes (T2D). METHODS: This prospective study included 1083 T2D individuals recruited from a secondary hospital and a primary care facility. The primary outcome was a composite of four-point MACE (nonfatal myocardial infarction, stroke, unstable angina pectoris leading to hospitalization and cardiovascular death). Circulating angiogenin was measured by a proximity extension assay. Cox regression models were used to evaluate the association of baseline plasma angiogenin with the risk of MACE. RESULTS: During a median follow-up of 9.3 years, 109 (10%) MACE were identified. Plasma angiogenin was significantly higher in participants with MACE than in those without MACE (P < 0.001). Doubling of plasma angiogenin concentration was associated with a 3.10-fold (95% CI 1.84-5.22) increased risk for MACE. The association was only moderately attenuated after adjustment for demographic and cardiometabolic risk factors (adjusted HR 2.38, 95% CI 1.34-4.23) and remained statistically significant after additional adjustment for estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (uACR) (adjusted HR 1.90, 95% CI 1.02-3.53). A consistent outcome was obtained when plasma angiogenin was analysed as a categorical variable in tertiles. CONCLUSIONS: Plasma angiogenin was associated with the risk of future cardiovascular events in patients with T2D and may be a promising novel biomarker for identifying high-risk T2D patients for early management.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Infarto do Miocárdio/complicações , Estudos Prospectivos , Ribonuclease Pancreático , Fatores de RiscoRESUMO
BACKGROUND: Lung cancer causes a huge disease burden, and early detection of positive pulmonary nodules (PPNs) as an early sign of lung cancer is extremely important for effective intervention. It is necessary to develop PPNs risk recognizer based on machine learning algorithm combined with central carbon metabolomics. METHODS: The study included 2248 participants at high risk for lung cancer from the Ma'anshan Community Lung Cancer Screening cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) was used to screen 18 central carbon-related metabolites in plasma, recursive feature elimination (RFE) was used to select all 42 features, followed by five machine learning algorithms for model development. The performance of the model was evaluated using area under the receiver operator characteristic curve (AUC), accuracy, precision, recall, and F1 scores. In addition, SHapley Additive exPlanations (SHAP) was performed to assess the interpretability of the final selected model and to gain insight into the impact of features on the predicted results. RESULTS: Finally, the two prediction models based on the random forest (RF) algorithm performed best, with AUC values of 0.87 and 0.83, respectively, better than other models. We found that homogentisic acid, fumaric acid, maleic acid, hippuric acid, gluconic acid, and succinic acid played a significant role in both PPNs prediction model and NPNs vs PPNs model, while 2-oxadipic acid only played a role in the former model and phosphopyruvate only played a role in the NPNs vs PPNs model. This model demonstrates the potential of central carbon metabolism for PPNs risk prediction and identification. CONCLUSION: We developed a series of predictive models for PPNs, which can help in the early detection of PPNs and thus reduce the risk of lung cancer.
Assuntos
Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Humanos , Neoplasias Pulmonares/diagnóstico , Detecção Precoce de Câncer , Algoritmos , Carbono , Aprendizado de MáquinaRESUMO
Inorganic-organic hybrid materials are a kind of multiduty materials with high crystallinity and definite structures, built from functional inorganic and organic components with highly tunable photochemical properties. Perylenediimides (PDIs) are a kind of strong visible light-absorbing organic dyes with π-electron-deficient planes and photochemical properties depending on their micro-environment, which provides a platform for designing tunable and efficient hybrid photocatalytic materials. Herein, four radical-doped PDI-based crystalline hybrid materials, Cl4-PDIâ SiW12O40 (1), Cl4-PDIâ SiMo12O40 (2), Cl4-PDIâ PW12O40 (3), and Cl4-PDIâ PMo12O40 (4), were attained by slow diffusion of polyoxometalates (POMs) into acidified Cl4-PDI solutions. The obtained PDI-based crystalline hybrid materials not only exhibited prominent photochromism, but also possessed reactive organic radicals under ambient conditions. Furthermore, all hybrid materials could be easily photoreduced to their radical anions (Cl4-PDIâ -), and then underwent a second photoexcitation to form energetic excited state radical anions (Cl4-PDIâ -*). However, experiments and theoretical calculations demonstrated that the formed energetic Cl4-PDIâ -* showed unusual POM-dependent photocatalytic efficiencies toward the oxidative coupling of amines and the iodoperfluoroalkylation of alkenes; higher photocatalytic efficiencies were found for hybrid materials 1 (anion: SiW12O40 4-) and 2 (anion: SiMo12O40 4-) compared to 3 (anion: PW12O40 3-) and 4 (anion: PMo12O40 3-). The photocatalytic efficiencies of these hybrid materials are mainly controlled by the energy differences between the SOMO-2 level of Cl4-PDIâ -* and the LUMO level of the POMs. The structure-photocatalytic activity relationships established in present work provide new research directions to both the photocatalysis and hybrid material fields, and will promote the integration of these areas to explore new materials with interesting properties.
RESUMO
CONTEXT: Genetic variants in melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) genes are strongly associated with childhood obesity. OBJECTIVE: This study aims to identify and functionally characterize MC3R and MC4R variants in an Asian cohort of children with severe early-onset obesity. METHODS: Whole-exome sequencing was performed to screen for MC3R and MC4R coding variants in 488 Asian children with severe early-onset obesity (body mass index for age ≥97th percentile). Functionality of the identified variants were determined via measurement of intracellular cyclic adenosine monophosphate (cAMP) concentrations and luciferase activity. RESULTS: Four MC3R and 2 MC4R heterozygous nonsynonymous rare variants were detected. There were 3 novel variants: MC3R c.151G > C (p.Val51Leu), MC4R c.127C > A (p.Gln43Lys), and MC4R c.272T > G (p.Met91Arg), and 3 previously reported variants: MC3R c.127G > A (p.Glu43Lys), MC3R c.97G > A (p.Ala33Thr), and MC3R c.437T > A (p.Ile146Asn). Both MC3R c.127G > A (p.Glu43Lys) and MC4R c.272T > G (p.Met91Arg) variants demonstrated defective downstream cAMP signaling activity. The MC4R c.127C > A (p.Gln43Lys) variant showed reduced cAMP signaling activity at low substrate concentration but the signaling activity was restored at high substrate concentration. The MC3R c.151G > C (p.Val51Leu) variant did not show a significant reduction in cAMP signaling activity compared to wild-type (WT) MC3R. Coexpression studies of the WT and variant MC3R/MC4R showed that the heterozygous variants did not exhibit dominant negative effect. CONCLUSION: Our functional assays demonstrated that MC3R c.127G > A (p.Glu43Lys) and MC4R c.272T > G (p.Met91Arg) variants might predispose individuals to early-onset obesity, and further studies are needed to establish the causative effect of these variants in the pathogenesis of obesity.