RÉSUMÉ
PURPOSE: Elevated bilirubin levels have been associated with major depressive disorder (MDD); however, the exact impact of bilirubin on MDD and the underlying molecular mechanisms remain unclear. Here, we explored the influence of bilirubin on MDD and sought to identify the mechanisms via which bilirubin induces depressive-like behavior. PATIENTS AND METHODS: Forty patients who were diagnosed with MDD and received treatment with selective serotonin reuptake inhibitors (SSRIs) were included, with 43 healthy volunteers serving as controls. Clinical symptoms were evaluated using Hamilton depression rating scale-24 (HAMD-24) and the Hamilton anxiety rating scale. Serum concentrations of total bilirubin (TBIL) and indirect bilirubin (IBIL) were measured at baseline and after treatment using an automated biochemical analyzer. The connection between clinical symptoms and TBIL or IBIL was examined using Pearson correlation. Chronic restraint stress (CRS) was employed to generate a rat model of depression. TBIL, IBIL in rat serum were measured by ELISA. Reactive oxygen species (ROS) contents in rat hippocampal tissues were quantified by flow cytometry. The levels of microglial markers and the extent of neuronal damage in the rat hippocampus were assessed by immunofluorescence and transmission electron microscopy, respectively. RESULTS: Serum TBIL and IBIL levels were higher in patients with MDD than in the healthy controls. After treatment with SSRIs, the serum levels of TBIL and IBIL in MDD patients were significantly reduced. The levels of TBIL and IBIL were associated with HAMD-24 in MDD patients. Compared with the controls, the serum levels of TBIL, IBIL and the hippocampal ROS contents were elevated in CRS-exposed rats. Fluoxetine lowered inflammatory factor levels, mitigated oxidative stress. CONCLUSION: Our findings indicate a possible correlation between elevated serum bilirubin and depressive symptoms. Increases in ROS levels, along with neuronal damage, may represent pathological mechanisms underlying MDD.
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Bilirubine , Trouble dépressif majeur , Modèles animaux de maladie humaine , Hippocampe , Inbiteurs sélectifs de la recapture de la sérotonine , Animaux , Bilirubine/sang , Mâle , Rats , Humains , Trouble dépressif majeur/sang , Trouble dépressif majeur/traitement médicamenteux , Femelle , Adulte , Hippocampe/métabolisme , Hippocampe/anatomopathologie , Adulte d'âge moyen , Inbiteurs sélectifs de la recapture de la sérotonine/pharmacologie , Inbiteurs sélectifs de la recapture de la sérotonine/usage thérapeutique , Espèces réactives de l'oxygène/métabolisme , Espèces réactives de l'oxygène/sang , Rat Sprague-Dawley , Stress oxydatif/physiologie , Stress oxydatif/effets des médicaments et des substances chimiquesRÉSUMÉ
OBJECTIVE: Accumulating evidence supports the idea that inflammation may contribute to the pathophysiology of major depressive disorder (MDD). Duloxetine, a serotonin-norepinephrine reuptake inhibitor, exhibits anti-inflammatory effects both in vitro and in vivo. In this study, we investigated the impact of duloxetine on changes in serum proinflammatory cytokine levels among individuals diagnosed with MDD. METHODS: A cohort of 23 drug-naïve individuals diagnosed with MDD and 23 healthy controls were included in this study. The severity of depressive symptoms was evaluated using the 24-item Hamilton Depression Scale (HAMD-24). A panel of 7 proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), were quantified using multiplex Luminex assays. The levels of serum cytokines in healthy controls and patients with MDD were compared at baseline. All patients received duloxetine at a dosage range of 40-60 mg/day for a duration of 4 weeks. The HAMD-24 scores and serum cytokine levels were compared before and after duloxetine treatment. RESULTS: Compared with healthy controls, patients with MDD had significantly greater levels of IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ (P < 0.05). Moreover, there was a significant decrease in HAMD-24 scores observed pre- and post-treatment (t = 13.161, P < 0.001). Furthermore, after 4 weeks of treatment, the serum levels of IL-8 (t = 3.605, P = 0.002), IL-12 (t = 2.559, P = 0.018), and IFN-γ (t = 3.567, P = 0.002) decreased significantly. However, there were no significant differences in other cytokines, including IL-1ß, IL-2, IL-6, and TNF-α, before and after treatment (P > 0.05). CONCLUSIONS: These findings present compelling evidence, potentially for the first time, indicating that duloxetine treatment may effectively reduce the serum concentrations of IL-8, IL-12, and IFN-γ in individuals diagnosed with MDD. However, the precise mechanisms underlying this effect remain unclear and warrant further investigation.
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Cytokines , Trouble dépressif majeur , Chlorhydrate de duloxétine , Humains , Chlorhydrate de duloxétine/usage thérapeutique , Trouble dépressif majeur/traitement médicamenteux , Trouble dépressif majeur/sang , Femelle , Mâle , Cytokines/sang , Adulte , Adulte d'âge moyen , Antidépresseurs/usage thérapeutique , Études cas-témoins , Inflammation/sang , Inflammation/traitement médicamenteuxRÉSUMÉ
Aristolochia contorta Bunge is an academically and medicinally important plant species. It belongs to the magnoliids, with an uncertain phylogenetic position, and is one of the few plant species lacking a whole-genome duplication (WGD) event after the angiosperm-wide WGD. A. contorta has been an important traditional Chinese medicine material. Since it contains aristolochic acids (AAs), chemical compounds with nephrotoxity and carcinogenicity, the utilization of this plant has attracted widespread attention. Great efforts are being made to increase its bioactive compounds and reduce or completely remove toxic compounds. MicroRNAs (miRNAs) and natural antisense transcripts (NATs) are two classes of regulators potentially involved in metabolism regulation. Here, we report the identification and characterization of 223 miRNAs and 363 miRNA targets. The identified miRNAs include 51 known miRNAs belonging to 20 families and 172 novel miRNAs belonging to 107 families. A negative correlation between the expression of miRNAs and their targets was observed. In addition, we identified 441 A. contorta NATs and 560 NAT-sense transcript (ST) pairs, of which 12 NATs were targets of 13 miRNAs, forming 18 miRNA-NAT-ST modules. Various miRNAs and NATs potentially regulated secondary metabolism through the modes of miRNA-target gene-enzyme genes, NAT-STs, and NAT-miRNA-target gene-enzyme genes, suggesting the complexity of gene regulatory networks in A. contorta. The results lay a solid foundation for further manipulating the production of its bioactive and toxic compounds.
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Aristolochia , Régulation de l'expression des gènes végétaux , Réseaux de régulation génique , microARN , Métabolisme secondaire , microARN/génétique , microARN/métabolisme , Aristolochia/génétique , Métabolisme secondaire/génétique , ARN antisens/génétique , Génome végétal , ARN des plantes/génétiqueRÉSUMÉ
Cardiovascular disease remains the leading cause of mortality on a global scale. Individuals who possess risk factors for cardiovascular disease, such as high blood pressure (BP) and obesity, face an elevated risk of experiencing organ-specific pathophysiological changes. This damage includes pathophysiological changes in the heart and peripheral vascular systems, such as ventricular hypertrophy, arterial stiffening, and vascular narrowing and stenosis. Consequently, these damages are associated with an increased risk of developing severe cardiovascular outcomes including stroke, myocardial infarction, heart failure, and coronary heart disease. Among all the risk factors associated with cardiovascular disease, high blood pressure emerges as the most prominent. However, conventional resting BP measurement methods such as auscultatory or oscillometric methods may fail to identify many individuals with asymptomatic high BP. Recently, exercise BP has emerged as a valuable diagnostic tool for identifying real (high) blood pressure levels and assessing underlying cardiovascular risk, in addition to resting BP measurements in adults. Furthermore, numerous established factors, such as low cardiorespiratory fitness and high body fatness, have been confirmed to contribute to exercise BP and the associated cardiovascular risk. Modifying these factors may help reduce high exercise BP and, consequently, alleviate the burden of cardiovascular disease. A significant body of evidence has demonstrated cardiovascular disease in later life have their origins in early life. Children and adolescents with these cardiovascular risk factors also possess a greater propensity to develop cardiovascular diseases later in life. Nevertheless, the majority of previous studies on the clinical utility of exercise BP have been conducted in middle-to-older aged populations, often with pre-existing clinical conditions. Therefore, there is a need to investigate further of the factors influencing exercise BP in adolescence and its association with cardiovascular risk in early life. Our previously published work showed that exercise BP is a potential useful method to detect adolescents with increased cardiovascular risk. Children and adolescents with cardiovascular risk factors are more likely to develop cardiovascular diseases later in life. However, previous studies on the clinical utility of exercise BP have largely focused on middle-to-older aged populations with pre-existing clinical conditions. Therefore, there is a need to investigate further the factors influencing exercise BP in adolescence and its association with future cardiovascular risk. Our previous studies, which focused on exercise BP measured at submaximal intensity, have shown that exercise BP is a potentially useful method for identifying adolescents at increased cardiovascular risk. Our previous findings suggest that improving cardio-respiratory fitness and reducing body fatness may help to reduce the risk of developing cardiovascular disease and improve overall cardiovascular health. These findings have important implications for the development of effective prevention and early detection strategies, which can contribute to improved public health outcomes.
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Pression sanguine , Capacité cardiorespiratoire , Maladies cardiovasculaires , Exercice physique , Humains , Enfant , Adolescent , Capacité cardiorespiratoire/physiologie , Pression sanguine/physiologie , Facteurs de risque , Mâle , Facteurs de risque de maladie cardiaque , FemelleRÉSUMÉ
BACKGROUND AND AIMS: The global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants noninvasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population. METHODS: Treatment-naive CHB patients with concurrent HS who underwent liver biopsy in 10 medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from SHAP (Shapley Additive exPlanations), were compared with Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index using the area under receiver-operating characteristic curve (AUROC) and decision curve analysis (DCA). RESULTS: Of 1,198 eligible patients, the random forest model achieved AUROCs of 0.778 (95% confidence interval [CI], 0.749-0.807) for diagnosing advanced fibrosis (random forest advanced fibrosis model) and 0.777 (95% CI, 0.748-0.806) for diagnosing cirrhosis (random forest cirrhosis model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the random forest advanced fibrosis model obtained an AUROC of 0.825 (95% CI, 0.787-0.862) in patients with hepatitis B virus DNA ≥105 IU/mL, and the random forest cirrhosis model had an AUROC of 0.828 (95% CI, 0.774-0.883) in female patients. The 2 models outperformed Fibrosis-4 Index, nonalcoholic fatty liver disease Fibrosis Score, and aspartate aminotransferase-to-platelet ratio index in the training cohort, and also performed well in the validation cohort. CONCLUSIONS: The random forest models provide reliable, noninvasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the comanagement of the 2 diseases. CLINICALTRIALS: gov, Number: NCT05766449.
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Prunella vulgaris is an important material for Chinese medicines with rosmarinic acid (RA) as its index component. Based on the chromosome-level genome assembly we obtained recently, 51 RA biosynthesis-related genes were identified. Sequence feature, gene expression pattern and phylogenetic relationship analyses showed that 17 of them could be involved in RA biosynthesis. In vitro enzymatic assay showed that PvRAS3 catalyzed the condensation of p-coumaroyl-CoA and caffeoyl-CoA with pHPL and DHPL. Its affinity toward p-coumaroyl-CoA was higher than caffeoyl-CoA. PvRAS4 catalyzed the condensation of p-coumaroyl-CoA with pHPL and DHPL. Its affinity toward p-coumaroyl-CoA was lower than PvRAS3. UPLC and LC-MS/MS analyses showed the existence of RA, 4-coumaroyl-3',4'-dihydroxyphenyllactic acid, 4-coumaroyl-4'-hydroxyphenyllactic acid and caffeoyl-4'-hydroxyphenyllactic acid in P. vulgaris. Generation and analysis of pvras3 homozygous mutants showed significant decrease of RA, 4-coumaroyl-3',4'-dihydroxyphenyllactic acid, 4-coumaroyl-4'-hydroxyphenyllactic acid and caffeoyl-4'-hydroxyphenyllactic acid and significant increase of DHPL and pHPL. It suggests that PvRAS3 is the main enzyme catalyzing the condensation of acyl donors and acceptors during RA biosynthesis. The role of PvRAS4 appears minor. The results provide significant information for quality control of P. vulgaris medicinal materials.
RÉSUMÉ
MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs in plants. They play critical functions in various biological processes during plant growth and development. Salvia miltiorrhiza is a well-known traditional Chinese medicinal plant with significant medicinal, economic, and academic values. In order to elucidate the role of miRNAs in S. miltiorrhiza, six small RNA libraries from mature roots, young roots, stems, mature leaves, young leaves and flowers of S. miltiorrhiza and one degradome library from mixed tissues were constructed. A total of 184 miRNA precursors, generating 137 known and 49 novel miRNAs, were genome-widely identified. The identified miRNAs were predicted to play diversified regulatory roles in plants through regulating 891 genes. qRT-PCR and 5' RLM-RACE assays validated the negative regulatory role of smi-miR159a in SmMYB62, SmMYB78, and SmMYB80. To elucidate the function of smi-miR159a in bioactive compound biosynthesis, smi-miR159a transgenic hairy roots were generated and analyzed. The results showed that overexpression of smi-miR159a caused a significant decrease in rosmarinic acid and salvianolic acid B contents. qRT-PCR analysis showed that the targets of smi-miR159a, including SmMYB62, SmMYB78, and SmMYB80, were significantly down-regulated, accompanied by the down-regulation of SmPAL1, SmC4H1, Sm4CL1, SmTAT1, SmTAT3, SmHPPR1, SmRAS, and SmCYP98A14 genes involved in phenolic acid biosynthesis. It suggests that smi-miR159a is a significant negative regulator of phenolic acid biosynthesis in S. miltiorrhiza.
Sujet(s)
Régulation de l'expression des gènes végétaux , Hydroxybenzoates , microARN , Salvia miltiorrhiza , Salvia miltiorrhiza/génétique , Salvia miltiorrhiza/métabolisme , microARN/génétique , Hydroxybenzoates/métabolisme , Racines de plante/génétique , Racines de plante/métabolisme , ARN des plantes/génétique , Génome végétalRÉSUMÉ
The impact of concurrent fatty liver (FL) on response to antiviral therapy in chronic hepatitis B (CHB) patients has not been well characterized. We aimed to systematically review and analyse antiviral treatment response in CHB patients with and without FL. We searched PubMed, Embase, Web of Science and the Cochrane Library databases from inception to 31 May 2023 for relevant studies. Biochemical response (BR), complete viral suppression (CVS) and hepatitis B e antigen (HBeAg) seroconversion in CHB patients with FL (CHB-FL) and without FL (non-FL CHB) were compared. In an initial pool of 2101 citations, a total of 10 studies involving 2108 patients were included. After 12 weeks of treatment, CHB-FL patients as compared with non-FL CHB patients had lower BR rate (48.37% [108/227] vs. 72.98% [126/174], p = .04) but similar trend for CVS (36.86% [80/227] vs. 68.81% [114/174], p = .05) and similar rates of HBeAg seroconversion (6.59% [7/103] vs. 7.40% [7/110], p = .89). However, at week 48, there were no statistically significant differences between CHB-FL and non-FL CHB patients in any of the outcomes, including BR (60.03% [213/471] vs. 69.37% [314/717], p = .67), CVS (65.63% [459/746] vs. 73.81% [743/1132], p = .27) and HBeAg seroconversion (10.01% [30/275] vs. 14.06% [65/453], p = .58) with similar findings for week 96. BR rate was lower in CHB-FL patients after 12 weeks of antiviral treatment. However, after a longer follow-up of either 48 or 96 weeks, no statistically significant differences were observed in BR, CVS or HBeAg seroconversion rates between CHB patients with and without FL.
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Antiviraux , Stéatose hépatique , Antigènes e du virus de l'hépatite virale B , Hépatite B chronique , Humains , Hépatite B chronique/traitement médicamenteux , Antiviraux/usage thérapeutique , Antigènes e du virus de l'hépatite virale B/sang , Résultat thérapeutique , Séroconversion , Virus de l'hépatite B/immunologie , Virus de l'hépatite B/effets des médicaments et des substances chimiques , ADN viral/sangRÉSUMÉ
Context: The coexistence of hypertension and elevated homocysteine (Hcy) levels has a mutually reinforcing impact on the susceptibility to cardio-cerebrovascular disease. Objective: The aim was to assess the prevalence, clinical correlation, and demographic characteristics of hyperhomocysteinemia (HHcy) within the Chinese urban population with hypertension. Methods: A cohort of 473 individuals with hypertension were selected from four communities in Shenzhen, China. Demographic attributes, clinical profiles, and lifestyle behaviors were gathered and compared between individuals with and without HHcy. A logistic regression model was employed to examine potential factors associated with the prevalence of HHcy. Correlation between Hcy levels and clinical characteristics was assessed through multiple linear regression analysis. Results: The prevalence of HHcy in the population with hypertension was 31.3%. In comparison to individuals without HHcy, those with HHcy exhibited a higher proportion of males, a higher prevalence of smoking and alcohol consumption, and a higher proportion of cases with the homozygous (TT) genotype at the MTHFR C677T polymorphism. Moreover, individuals with HHcy had lower levels of folic acid (FA), and lower fruit and vitamin B12 intake. Furthermore, the risk factors for HHcy were male (B = 1.430, OR = 4.179) and MTHFR (TT) (B = 1.086, OR = 2.961). In addition, the multiple linear regression analysis revealed a significant association between Hcy levels and gender (B = -2.784, P = 0.004), MTHFR genotypes (B = 1.410, P = 0.005), and FA levels (B = -0.136, P = 0.030). Conclusion: The high prevalence of HHcy among hypertensive patients in this Chinese urban population underscores the necessity for interventions targeting modifiable risk factors such as dietary choices and lifestyle practices.
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Hyperhomocystéinémie , Hypertension artérielle , Humains , Mâle , Femelle , Population urbaine , Hyperhomocystéinémie/complications , Hyperhomocystéinémie/épidémiologie , Prévalence , Hypertension artérielle/épidémiologie , Chine/épidémiologieRÉSUMÉ
OBJECTIVE: It is known that cytokines play a role in both depression and anxiety. This study aimed to compare the levels of multiple cytokines in patients with first-episode drug-naive major depressive disorder (MDD) with or without anxiety and analyze the correlation between the level of depression or anxiety and the serum cytokine levels. METHODS: The study involved 55 patients with first-episode drug-naive MDD. To assess anxiety symptoms, the 14-item HAMA was used. MDD patients were divided into two groups: 23 MDD patients without anxiety and 32 MDD patients with anxiety. The measurement of 37 cytokines was conducted. Serum cytokine levels between patients with MDD without anxiety and anxiety were compared. In multiple linear regression models, the relationship between the group and abnormal cytokines was explored. The receiver operating characteristic (ROC) curve analysis was performed to estimate diagnostic performance of serum cytokines in discriminating MDD patients with anxiety from MDD patients without anxiety. A correlation was evaluated between the scores of HAMD or HAMA and the serum cytokine levels. RESULTS: In MDD patients with anxiety, IL-17 C and CCL17 levels were significantly lower than in MDD patients without anxiety (all P < 0.05). Multiple measurements were corrected with Benjamini-Hochberger corrections, but none of these differences persisted (all P > 0.05). The results of multiple linear regression models revealed that after controlling for other independent variables, group was not a significant independent predictor of serum IL-17 C or CCL17 (all P > 0.05). The AUC values of IL-17 C and CCL17 were 0.643 and 0.637, respectively, in discriminating MDD patients with anxiety from MDD patients without anxiety. The results of partial correlation analyses showed the scores of HAMD were negatively correlated with the IL-17 C (r = -0.314, P = 0.021) levels with sex as a covariate. CONCLUSIONS: The findings suggest that there is a potential absence of disparity in the levels of circulating cytokines among individuals diagnosed with first-episode drug-naïve MDD, regardless of the presence or absence of comorbid anxiety.
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Trouble dépressif majeur , Humains , Trouble dépressif majeur/diagnostic , Interleukine-17 , Anxiété/complications , Troubles anxieux/complications , CytokinesRÉSUMÉ
Inflammation plays an important role in the pathogenesis of depression; however, the underlying mechanisms remain unclear. Apart from the disordered circadian rhythm in animal models and patients with depression, dysfunction of clock genes has been reported to be involved with the progress of inflammation. This study aimed to investigate the role of circadian clock genes, especially brain and muscle ARNT-like 1 (Bmal1), in the linkage between inflammation and depression. Lipopolysaccharide (LPS)-challenged rats and BV2 cells were used in the present study. Four intraperitoneal LPS injections of 0.5 mg/kg were administered once every other day to the rats, and BV2 cells were challenged with LPS for 24 h at the working concentration of 1 mg/L, with or without the suppression of Bmal1 via small interfering RNA. The results showed that LPS could successfully induce depression-like behaviors and an "inflammatory storm" in rats, as indicated by the increased immobility time in the forced swimming test and the decreased saccharin preference index in the saccharin preference test, together with hyperactivity of the hypothalamic-pituitary-adrenal axis, hyperactivation of astrocyte and microglia, and increased peripheral and central abundance of tumor necrosis factor-α, interleukin 6, and C-reactive protein. Moreover, the protein expression levels of brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, Copine6, and Synaptotagmin1 (Syt-1) decreased in the hippocampus and hypothalamus, whereas the expression of triggering receptor expressed on myeloid cells 2 increased. Interestingly, the fluctuation of temperature and serum concentration of melatonin and corticosterone was significantly different between the groups. Furthermore, protein expression levels of the circadian locomotor output cycles kaput, cryptochrome 2, and period 2 was significantly reduced in the hippocampus of LPS-challenged rats, whereas Bmal1 expression was significantly increased in the hippocampus but decreased in the hypothalamus, where it was co-located with neurons, microglia, and astrocytes. Consistently, apart from the reduced cell viability and increased phagocytic ability, LPS-challenged BV2 cells presented a similar trend with the changed protein expression in the hippocampus of the LPS model rats. However, the pathological changes in BV2 cells induced by LPS were reversed after the suppression of Bmal1. These results indicated that LPS could induce depression-like pathological changes, and the underlying mechanism might be partly associated with the imbalanced expression of Bmal1 and its regulated dysfunction of the circadian rhythm.
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Dépression , Lipopolysaccharides , Animaux , Rats , Dépression/induit chimiquement , Hippocampe , Axe hypothalamohypophysaire/métabolisme , Inflammation/induit chimiquement , Inflammation/métabolisme , Lipopolysaccharides/toxicité , Muscles/métabolisme , Axe hypophyso-surrénalien/métabolismeRÉSUMÉ
Ischemic stroke is a prominent contributor to global morbidity and mortality rates. The intricate and diverse mechanisms underlying ischemia-reperfusion injury remain poorly comprehended. RNA methylation, an emerging epigenetic modification, plays a crucial role in regulating numerous biological processes, including immunity, DNA damage response, tumorigenesis, metastasis, stem cell renewal, adipocyte differentiation, circadian rhythms, cellular development and differentiation, and cell division. Among the various RNA modifications, N6-methyladenosine (m6A) modification stands as the most prevalent in mammalian mRNA. Recent studies have demonstrated the crucial involvement of m6A modification in the pathophysiological progression of ischemic stroke. This review aims to elucidate the advancements in ischemic stroke-specific investigations pertaining to m6A modification, consolidate the underlying mechanisms implicated in the participation of m6A modification during the onset of ischemic stroke, and deliberate on the potential of m6A modification as a viable therapeutic target for ischemic stroke.
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Adénosine , Accident vasculaire cérébral ischémique , Humains , Animaux , Méthylation , Accident vasculaire cérébral ischémique/génétique , Accident vasculaire cérébral ischémique/métabolisme , Adénosine/analogues et dérivés , Adénosine/métabolisme , ARN/métabolisme , ARN/génétique ,RÉSUMÉ
Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.
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Insulinorésistance , Protéines G ral , Animaux , Humains , Mâle , Souris , Adipocytes blancs/métabolisme , Tissu adipeux/métabolisme , Obésité/étiologie , Obésité/métabolisme , Prise de poids , Protéines G ral/métabolismeRÉSUMÉ
Background: With increasingly prevalent coexistence of chronic hepatitis B (CHB) and hepatic steatosis (HS), simple, non-invasive diagnostic methods to accurately assess the severity of hepatic inflammation are needed. We aimed to build a machine learning (ML) based model to detect hepatic inflammation in patients with CHB and concurrent HS. Methods: We conducted a multicenter, retrospective cohort study in China. Treatment-naive CHB patients with biopsy-proven HS between April 2004 and September 2022 were included. The optimal features for model development were selected by SHapley Additive explanations, and an ML algorithm with the best accuracy to diagnose moderate to severe hepatic inflammation (Scheuer's system ≥ G3) was determined and assessed by decision curve analysis (DCA) and calibration curve. This study is registered with ClinicalTrials.gov (NCT05766449). Findings: From a pool of 1,787 treatment-naive patients with CHB and HS across eleven hospitals, 689 patients from nine of these hospitals were chosen for the development of the diagnostic model. The remaining two hospitals contributed to two independent external validation cohorts, comprising 509 patients in validation cohort 1 and 589 in validation cohort 2. Eleven features regarding inflammation, hepatic and metabolic functions were identified. The gradient boosting classifier (GBC) model showed the best performance in predicting moderate to severe hepatic inflammation, with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI 0.83-0.88) in the training cohort, and 0.89 (95% CI 0.86-0.92), 0.76 (95% CI 0.73-0.80) in the first and second external validation cohorts, respectively. A publicly accessible web tool was generated for the model. Interpretation: Using simple parameters, the GBC model predicted hepatic inflammation in CHB patients with concurrent HS. It holds promise for guiding clinical management and improving patient outcomes. Funding: This research was supported by the National Natural Science Foundation of China (No. 82170609, 81970545), Natural Science Foundation of Shandong Province (Major Project) (No. ZR2020KH006), Natural Science Foundation of Jiangsu Province (No.BK20231118), Tianjin Key Medical Discipline (Specialty), Construction Project, TJYXZDXK-059B, Tianjin Health Science and Technology Project key discipline special, TJWJ2022XK034, and Research project of Chinese traditional medicine and Chinese traditional medicine combined with Western medicine of Tianjin municipal health and Family Planning Commission (2021022).
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Rheumatoid arthritis (RA) is a multifaceted autoimmune disease characterized by systemic inflammation, affecting both articular and extra-articular structures. This condition results in inflammation of joints and synovial membranes, accompanied by the development of systemic comorbidities. Despite extensive research, the precise pathogenic mechanisms responsible for RA have yet to be completely understood. RNA methylation, a burgeoning epigenetic alteration, assumes a pivotal function in the regulation of a myriad of biological phenomena, encompassing immunity, DNA damage response, tumorigenesis, metastasis, stem cell renewal, adipocyte differentiation, circadian rhythms, cellular development and differentiation, and cell division. The N6-methyladenosine (m6A) modification is the most prevalent among the various RNA modifications found in mammalian mRNA. Recent studies have provided evidence of the significant role played by m6A modification in the pathophysiological progression of RA. This review aims to provide a comprehensive analysis of the progress made in research focused on m6A modification in the context of RA, consolidate the underlying mechanisms involved in m6A modification during the initiation of RA and discuss the potential of targeting m6A modification as a viable therapeutic approach for RA.
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Polyarthrite rhumatoïde , Maladies auto-immunes , Animaux , Polyarthrite rhumatoïde/génétique , Inflammation , , MammifèresRÉSUMÉ
BACKGROUND: Alcohol dependence (AD) results in several medical problems including vitamin D deficiency and thyroid dysfunction. However, the relationship between these two complications remains unclear. The aim of the present study was to explore the relationship between serum vitamin D and thyroid hormone profiles in male patients with AD. METHODS: A total of 117 male patients with AD were enrolled. Vitamin D deficiency was defined as serum concentrations of the main circulating vitamin D, 25-hydroxy vitamin D [25(OH)D], below 50 nmol/L. The AD patients were divided into two groups accordingly: 46 patients with normal vitamin D levels (normal group) and 71 patients with vitamin D deficiency (deficiency group). The levels of thyroid hormone profiles including total triiodothyronine 3 (TT3), total thyroxine 4 (TT4), thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) between the two groups were compared. Correlation between the serum levels of 25(OH)D and thyroid hormone profiles was evaluated using simple correlation (Pearson's correlation) and multivariable analysis using linear regression models. RESULTS: The prevalence of vitamin D deficiency in male patients with AD is 60.7% (71/117; 95% confidence interval: 51.6-69.1%). Moreover, the serum levels of TT3 (t = -2.682, p = 0.009), TT4 (t = -2.033, p = 0.044), fT3 (t = -2.986, p = 0.003), and fT4 (t = -2.558, p = 0.012) in deficiency group were significantly higher than those in normal group. Post hoc power analyses showed that the power for fT3 was sufficient (power > 0.80). Furthermore, univariate analysis showed that the serum vitamin D levels were negatively correlated with the TT3 (r = -0.189, p = 0.044), fT3 (r = -0.350, p < 0.001), and fT4 (r = -0.198, p = 0.033) levels, while multivariate analysis indicated that only fT3 was independently related to the serum levels of vitamin D in male patients with AD. CONCLUSIONS: These results suggested that the serum vitamin D levels may be associated with fT3 in male patients with AD.
Sujet(s)
Alcoolisme , Carence en vitamine D , Humains , Mâle , Tri-iodothyronine , Thyroxine , Alcoolisme/complications , Hormones thyroïdiennes , Thyréostimuline , Vitamine D , Vitamines , Carence en vitamine D/complicationsRÉSUMÉ
OBJECTIVES: To evaluate the efficacy and safety of molnupiravir for intra-household post-exposure prophylaxis (PEP) of COVID-19. METHODS: MOVe-AHEAD was a randomized, controlled, double-blind, phase 3 trial comparing molnupiravir (800 mg twice daily for 5 days) with placebo. Eligible participants were adult, unvaccinated, asymptomatic household contacts of patients with laboratory-confirmed COVID-19. The primary efficacy endpoint was the incidence of COVID-19 through day 14 in modified intention-to-treat (MITT) participants (those who received ≥1 dose of study intervention) without detectable SARS-CoV-2 at baseline, termed the MITT-VN population. Superiority of molnupiravir was prespecified as a stratified one-sided p-value of <0.0249 for the treatment difference in this endpoint. RESULTS: The MITT population comprised 763 participants randomized to molnupiravir and 764 to placebo; 83.6% had anti-SARS-CoV-2 antibodies at baseline. In the MITT-VN population, COVID-19 rates through day 14 were 6.5% with molnupiravir and 8.5% with placebo (one-sided p-value: 0.0848). In the molnupiravir arm, 25/35 of confirmed COVID-19 events (71.4%) occurred after completion of treatment (versus 17/49 [34.7%] for placebo). Adverse event rates were low and similar between molnupiravir and placebo. CONCLUSIONS: Molnupiravir was well-tolerated but did not meet the prespecified superiority criterion, possibly influenced in part by the high pre-existing immunity in the trial population.
RÉSUMÉ
Depression is a common mental disease with disastrous effect on the health and wealth globally. Focusing on the role for inflammation and immune activation in the pathogenesis of depression, many tries have been taken into effect targeting at the blockage of inflammatory cytokines, among which interleukin- 6 (IL-6) and its receptor antagonist tocilizumab attracts more attention, with inconsistent findings. Moderate to severe depressive disorder (MSDD) patients were enrolled and the serum concentrations of IL-6 and tumor necrosis factor-α (TNF-α) measured, their correlation with the Hamilton Depression Rating Scale-24 (HAMD-24) scores was analyzed, and their role in discriminating MSDD patients from the health controls were evaluated. Meanwhile, a depression rat model was established by intraperitoneal injection of LPS, and tocilizumab was administrated doing 50 mg/kg via intravenous injection. The behavioral performance was observed, the serum concentration of IL-6, TNF-α, and C-reactive protein (CRP) was measured, and the protein expression of IL-6 and TNF-α in the hippocampus were also detected. The activity of the Hypothalamic-pituitary-adrenal (HPA) axis was observed, and the protein expression levels in the hippocampus were detected via western blot. Moreover, the immunofluorescence staining (IF) technique was used to investigate the co-location of IL-6 and neuron (MAP2), astrocyte (GFAP), or microglial (IBA-1). The results showed that the serum IL-6 level was significantly increased in the MSDD patients and lipopolysaccharide (LPS)-challenged rats, with a significant correlation with the HAMD-24 scores or struggling time in the FST and corticosterone (CORT) abundance. Results of ROC analysis showed a significant diagnosis value of IL-6 in discriminating MSDD patients or depression rats from the controls in the present study. Tocilizumab could relieve the depression-like behaviors induced by LPS, together with a normal abundance of serum CORT and hypothalamic CRH expression. Moreover, tocilizumab could alleviate the "inflammatory storm" and impaired hippocampal synaptic plasticity in LPS-challenged depression rats, inhibiting the hyperactivation of astrocyte and microglia, decreasing the peripheral and central abundance of IL-6, CRP, and TNF-α, and balancing the hippocampal expression levels of synaptic plasticity-associated proteins and key molecular in Wnt/ß-catenin signaling pathway. These results indicated a predictive role of IL-6 in discriminating depression from controls, and demonstrated an antidepressant effect of tocilizumab in LPS-challenged rats, targeting at the inflammatory storm and the subsequent impairments of hippocampal synaptic plasticity.
Sujet(s)
Interleukine-6 , Lipopolysaccharides , Humains , Rats , Animaux , Interleukine-6/métabolisme , Lipopolysaccharides/pharmacologie , Facteur de nécrose tumorale alpha/métabolisme , Antidépresseurs/pharmacologie , Antidépresseurs/usage thérapeutique , Hippocampe , Marqueurs biologiques/métabolisme , Dépression/traitement médicamenteux , Dépression/métabolismeRÉSUMÉ
Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance, and fatty liver disease. Here we report that mitochondria undergo fragmentation and reduced oxidative capacity specifically in inguinal white adipose tissue after feeding mice high fat diet (HFD) by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes from mice fed HFD. Targeted deletion of Rala in white adipocytes prevents the obesity-induced fragmentation of mitochondria and produces mice resistant to HFD-induced weight gain via increased fatty acid oxidation. As a result, these mice also exhibit improved glucose tolerance and liver function. In vitro mechanistic studies revealed that RalA suppresses mitochondrial oxidative function in adipocytes by increasing fission through reversing the protein kinase A-catalyzed inhibitory Ser637phosphorylation of the mitochondrial fission protein Drp1. Active RalA recruits protein phosphatase 2A (PP2Aa) to specifically dephosphorylate this inhibitory site on Drp1, activating the protein, thus increasing mitochondrial fission. Adipose tissue expression of the human homolog of Drp1, DNML1, is positively correlated with obesity and insulin resistance in patients. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics towards excessive fission, contributing to weight gain and related metabolic dysfunction.