ABSTRACT
Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.
Subject(s)
Depression, Postpartum , Neurons , Obesity , TRPC Cation Channels , Animals , Female , Mice , Obesity/metabolism , Obesity/genetics , Male , Humans , TRPC Cation Channels/metabolism , TRPC Cation Channels/genetics , Depression, Postpartum/metabolism , Neurons/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Mice, Inbred C57BL , Oxytocin/metabolism , Maternal BehaviorABSTRACT
Plant immunity is activated upon pathogen perception and often affects growth and yield when it is constitutively active. How plants fine-tune immune homeostasis in their natural habitats remains elusive. Here, we discover a conserved immune suppression network in cereals that orchestrates immune homeostasis, centering on a Ca2+-sensor, RESISTANCE OF RICE TO DISEASES1 (ROD1). ROD1 promotes reactive oxygen species (ROS) scavenging by stimulating catalase activity, and its protein stability is regulated by ubiquitination. ROD1 disruption confers resistance to multiple pathogens, whereas a natural ROD1 allele prevalent in indica rice with agroecology-specific distribution enhances resistance without yield penalty. The fungal effector AvrPiz-t structurally mimics ROD1 and activates the same ROS-scavenging cascade to suppress host immunity and promote virulence. We thus reveal a molecular framework adopted by both host and pathogen that integrates Ca2+ sensing and ROS homeostasis to suppress plant immunity, suggesting a principle for breeding disease-resistant, high-yield crops.
Subject(s)
Calcium/metabolism , Free Radical Scavengers/metabolism , Fungal Proteins/metabolism , Oryza/immunology , Plant Immunity , Plant Proteins/metabolism , Reactive Oxygen Species/metabolism , CRISPR-Cas Systems/genetics , Cell Membrane/metabolism , Disease Resistance/genetics , Models, Biological , Oryza/genetics , Plant Diseases/immunology , Plant Proteins/genetics , Protein Binding , Protein Stability , Reproduction , Species Specificity , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Zea mays/immunologyABSTRACT
Translational reprogramming allows organisms to adapt to changing conditions. Upstream start codons (uAUGs), which are prevalently present in mRNAs, have crucial roles in regulating translation by providing alternative translation start sites1-4. However, what determines this selective initiation of translation between conditions remains unclear. Here, by integrating transcriptome-wide translational and structural analyses during pattern-triggered immunity in Arabidopsis, we found that transcripts with immune-induced translation are enriched with upstream open reading frames (uORFs). Without infection, these uORFs are selectively translated owing to hairpins immediately downstream of uAUGs, presumably by slowing and engaging the scanning preinitiation complex. Modelling using deep learning provides unbiased support for these recognizable double-stranded RNA structures downstream of uAUGs (which we term uAUG-ds) being responsible for the selective translation of uAUGs, and allows the prediction and rational design of translating uAUG-ds. We found that uAUG-ds-mediated regulation can be generalized to human cells. Moreover, uAUG-ds-mediated start-codon selection is dynamically regulated. After immune challenge in plants, induced RNA helicases that are homologous to Ded1p in yeast and DDX3X in humans resolve these structures, allowing ribosomes to bypass uAUGs to translate downstream defence proteins. This study shows that mRNA structures dynamically regulate start-codon selection. The prevalence of this RNA structural feature and the conservation of RNA helicases across kingdoms suggest that mRNA structural remodelling is a general feature of translational reprogramming.
Subject(s)
Codon, Initiator , Nucleic Acid Conformation , RNA, Double-Stranded , RNA, Messenger , Humans , Arabidopsis/genetics , Arabidopsis/immunology , Codon, Initiator/genetics , Innate Immunity Recognition , Open Reading Frames/genetics , Protein Biosynthesis/genetics , Protein Biosynthesis/immunology , Ribosomes/metabolism , RNA, Double-Stranded/chemistry , RNA, Double-Stranded/genetics , RNA, Double-Stranded/metabolism , RNA, Messenger/genetics , Transcriptome , DEAD-box RNA Helicases/chemistry , DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , Deep LearningABSTRACT
Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases1-5. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear6. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.
Subject(s)
Eating , Feeding Behavior , Obesity , Phenylalanine , Physical Conditioning, Animal , Adiposity/drug effects , Animals , Body Weight/drug effects , Diabetes Mellitus, Type 2 , Disease Models, Animal , Eating/physiology , Energy Metabolism , Feeding Behavior/physiology , Glucose/metabolism , Lactic Acid/metabolism , Mice , Obesity/metabolism , Obesity/prevention & control , Phenylalanine/administration & dosage , Phenylalanine/analogs & derivatives , Phenylalanine/metabolism , Phenylalanine/pharmacology , Physical Conditioning, Animal/physiologyABSTRACT
Transcription factor ELONGATED HYPOCOTYL5 (HY5) is the central hub for seedling photomorphogenesis. E3 ubiquitin (Ub) ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) inhibits HY5 protein accumulation through ubiquitination. However, the process of HY5 deubiquitination, which antagonizes E3 ligase-mediated ubiquitination to maintain HY5 homeostasis has never been studied. Here, we identified that Arabidopsis thaliana deubiquitinating enzyme, Ub-SPECIFIC PROTEASE 14 (UBP14) physically interacts with HY5 and enhances its protein stability by deubiquitination. The da3-1 mutant lacking UBP14 function exhibited a long hypocotyl phenotype, and UBP14 deficiency led to the failure of rapid accumulation of HY5 during dark to light. In addition, UBP14 preferred to stabilize nonphosphorylated form of HY5 which is more readily bound to downstream target genes. HY5 promoted the expression and protein accumulation of UBP14 for positive feedback to facilitate photomorphogenesis. Our findings thus established a mechanism by which UBP14 stabilizes HY5 protein by deubiquitination to promote photomorphogenesis in A. thaliana.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Basic-Leucine Zipper Transcription Factors , Gene Expression Regulation, Plant , Ubiquitination , Arabidopsis/metabolism , Arabidopsis/growth & development , Arabidopsis/genetics , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , Ubiquitin-Specific Proteases/metabolism , Ubiquitin-Specific Proteases/genetics , Protein Stability/radiation effects , Light , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Hypocotyl/growth & development , Hypocotyl/metabolism , Hypocotyl/geneticsABSTRACT
Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHbâ5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.
Subject(s)
Feeding Behavior , Habenula , Light , Animals , Male , Mice , Habenula/physiology , Feeding Behavior/physiology , Dorsal Raphe Nucleus/physiology , Humans , Mice, Inbred C57BL , Eating/physiology , Neural Pathways/physiology , Rats , Serotonergic Neurons/physiology , Nerve Net/physiology , DarknessABSTRACT
A widely used psychotherapeutic treatment for post-traumatic stress disorder (PTSD) involves performing bilateral eye movement (EM) during trauma memory retrieval. However, how this treatment-described as eye movement desensitization and reprocessing (EMDR)-alleviates trauma-related symptoms is unclear. While conventional theories suggest that bilateral EM interferes with concurrently retrieved trauma memories by taxing the limited working memory resources, here, we propose that bilateral EM actually facilitates information processing. In two EEG experiments, we replicated the bilateral EM procedure of EMDR, having participants engaging in continuous bilateral EM or receiving bilateral sensory stimulation (BS) as a control while retrieving short- or long-term memory. During EM or BS, we presented bystander images or memory cues to probe neural representations of perceptual and memory information. Multivariate pattern analysis of the EEG signals revealed that bilateral EM enhanced neural representations of simultaneously processed perceptual and memory information. This enhancement was accompanied by heightened visual responses and increased neural excitability in the occipital region. Furthermore, bilateral EM increased information transmission from the occipital to the frontoparietal region, indicating facilitated information transition from low-level perceptual representation to high-level memory representation. These findings argue for theories that emphasize information facilitation rather than disruption in the EMDR treatment.
Subject(s)
Electroencephalography , Eye Movement Desensitization Reprocessing , Humans , Female , Male , Young Adult , Adult , Eye Movement Desensitization Reprocessing/methods , Eye Movements/physiology , Stress Disorders, Post-Traumatic/physiopathology , Stress Disorders, Post-Traumatic/therapy , Stress Disorders, Post-Traumatic/psychology , Visual Perception/physiology , Memory/physiology , Brain/physiology , Photic Stimulation/methods , Memory, Short-Term/physiologyABSTRACT
SignificanceMany crystallization processes occurring in nature produce highly ordered hierarchical architectures. Their formation cannot be explained using classical models of monomer-by-monomer growth. One of the possible pathways involves crystallization through the attachment of oriented nanocrystals. Thus, it requires detailed understanding of the mechanism of particle dynamics that leads to their precise crystallographic alignment along specific faces. In this study, we discover a particle-morphology-independent oriented attachment mechanism for hematite nanocrystals. Independent of crystal morphology, particles always align along the [001] direction driven by aligning interactions between (001) faces and repulsive interactions between other pairs of hematite faces. These results highlight that strong face specificity along one crystallographic direction can render oriented attachment to be independent of initial particle morphology.
ABSTRACT
To gain a deeper understanding of the metabolic differences within and outside the body, as well as changes in transcription levels following estrus in yaks, we conducted transcriptome and metabolome analyses on female yaks in both estrus and non-estrus states. The metabolome analysis identified 114, 13, and 91 distinct metabolites in urine, blood, and follicular fluid, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted an enrichment of pathways related to amino acid and lipid metabolism across all three body fluids. Our transcriptome analysis revealed 122 differentially expressed genes within microRNA (miRNA) and 640 within long non-coding RNA (lncRNA). Functional enrichment analysis of lncRNA and miRNA indicated their involvement in cell signaling, disease resistance, and immunity pathways. We constructed a regulatory network composed of 10 lncRNAs, 4 miRNAs, and 30 mRNAs, based on the targeted regulation relationships of the differentially expressed genes. In conclusion, the accumulation of metabolites such as amino acids, steroids, and organic acids, along with the expression changes of key genes like miR-129 during yak estrus, provide initial insights into the estrus mechanism in yaks.
Subject(s)
MicroRNAs , RNA, Long Noncoding , Animals , Female , Cattle , Follicular Fluid , RNA, Long Noncoding/genetics , Gene Expression Profiling , MicroRNAs/genetics , MicroRNAs/metabolism , Transcriptome , Estrus/genetics , Gene Regulatory NetworksABSTRACT
Silicon (Si) is a promising anode material for high-energy-density lithium-ion batteries, but the significant volume change of Si particles during alloying/dealloying with lithium (Li) undermines the mechanical integrity of Si anode, causing electrode fracture, delamination and rapid capacity decay. Herein, a robust triple crosslinked network (TCN) binder with high ionic conductivity and hierarchical stress dissipation is reported for Si anodes, which is prepared by in situ chemical crosslinking polyacrylic acid (PAA) and melamine (MA). The triple interactions of hydrogen bonds, electrostatic interactions, and covalent amide bonds enhance the adhesion of binder to Si and synergistically promote stress dissipation within Si anodes, thus strengthening the dynamic structural stability of Si anodes during cycling. Moreover, the rapid coupling/decoupling of Li+ with the TCN binder enables an impressive Li+ transference number of 0.63 and high ionic conductivity of 1.2 × 10-4 S cm-1. Consequently, the Si-TCN anode delivers specific capacity of 2268 mAh g-1 with a high mass loading of 2 mg cm-2, high-rate performance of 1673 mAh g-1 at 5 A g-1, and stable cycling for 250 cycles at 1 A g-1, thus showing great prospects for high-energy-density Si-based batteries.
ABSTRACT
Mimicking efficient biocatalytic cascades using nanozymes has gained enormous attention in catalytic chemistry, but it remains challenging to develop a nanozyme-based cascade system to sequentially perform the desired reactions. Particularly, the integration of sequential hydrolysis and oxidation reactions into nanozyme-based cascade systems has not yet been achieved, despite their significant roles in various domains. Herein, a self-cascade Ce-MOF-818 nanozyme for sequential hydrolysis and oxidation reactions is developed. Ce-MOF-818 is the first Ce(IV)-based heterometallic metal-organic framework constructed through the coordination of Ce and Cu to distinct groups. It is successfully synthesized using an improved solvothermal method, overcoming the challenge posed by the significant difference in the binding speeds of Ce and Cu to ligands. With excellent organophosphate hydrolase-like (Km = 42.3 µM, Kcat = 0.0208 min-1 ) and catechol oxidase-like (Km = 2589 µM, Kcat = 1.25 s-1 ) activities attributed to its bimetallic active centers, Ce-MOF-818 serves as a promising self-cascade platform for sequential hydrolysis and oxidation. Notably, its catalytic efficiency surpasses that of physically mixed nanozymes by approximately fourfold, owning to the close integration of active sites. The developed hydrolysis-oxidation self-cascade nanozyme has promising potential applications in catalytic chemistry and provides valuable insights into the rational design of nanozyme-based cascade systems.
Subject(s)
Metal-Organic Frameworks , Hydrolysis , Oxidation-Reduction , Metal-Organic Frameworks/chemistry , Catalysis , BiocatalysisABSTRACT
Investigating the structural evolution and phase transformation of iron oxides is crucial for gaining a deeper understanding of geological changes on diverse planets and preparing oxide materials suitable for industrial applications. In this study, in-situ heating techniques are employed in conjunction with transmission electron microscopy (TEM) observations and ex-situ characterization to thoroughly analyze the thermal solid-phase transformation of akaganéite 1D nanostructures with varying diameters. These findings offer compelling evidence for a size-dependent morphology evolution in akaganéite 1D nanostructures, which can be attributed to the transformation from akaganéite to maghemite (γ-Fe2O3) and subsequent crystal growth. Specifically, it is observed that akaganéite nanorods with a diameter of â¼50 nm transformed into hollow polycrystalline maghemite nanorods, which demonstrated remarkable stability without arresting crystal growth under continuous heating. In contrast, smaller akaganéite nanoneedles or nanowires with a diameter ranging from 20 to 8 nm displayed a propensity for forming single-crystal nanoneedles or nanowires through phase transformation and densification. By manipulating the size of the precursors, a straightforward method is developed for the synthesis of single-crystal and polycrystalline maghemite nanowires through solid-phase transformation. These significant findings provide new insights into the size-dependent structural evolution and phase transformation of iron oxides at the nanoscale.
ABSTRACT
OBJECTIVE: In recent years, a series of clinical guidelines on neonatal hypoglycemia have been developed in different countries and regions. This systematic review was aimed at providing evidence for clinical decision-making and providing ideas for future research by comparatively analyzing the contents of various guidelines. METHODS: A multilateral approach was used, including comprehensive literature searches and online research. The retrieved studies were screened by two independent reviewers according to our inclusion criteria. The two reviewers independently extracted the descriptive data. Four appraisers assessed the guidelines using the AGREE-II instrument. RESULTS: Ten clinical guidelines on neonatal hypoglycemia were included, with a mean score of 45.28%-83.45% in six domains. The guidelines are relatively consistent in their recommendations on clinical symptoms of neonatal hypoglycemia, but different in risk factors, preventive measures, thresholds for clinical management of hypoglycemia, target glucose ranges for its control, and pharmacotherapy. CONCLUSION: By summarising the recommendations in the guidelines on neonatal hypoglycemia, we found that blood glucose values were not the only observational indicator, and other indicators (e.g., ketone bodies, lactate) related to glucose metabolism should also be considered for a comprehensive assessment. There is still a lack of consensus on thresholds for the clinical management of hypoglycemia and target glucose ranges for its control, and the recommendations on its pharmacotherapy are rather simple and sketchy. In the future, more high-quality studies are required to further improve the early identification of neonatal hypoglycemia and intervention strategies against it.
Subject(s)
Hypoglycemia , Infant, Newborn, Diseases , Infant, Newborn , Humans , Hypoglycemia/diagnosis , Hypoglycemia/prevention & control , Risk Assessment , Clinical Decision-Making , GlucoseABSTRACT
Acute pancreatitis (AP) is a rare adverse event of pembrolizumab with unclear clinical features. This study investigated the clinical features of pembrolizumab-induced AP to provide a reference for prevention and treatment. Case reports, case series and clinical studies of pembrolizumab-induced AP were collected by searching Chinese and English databases up to January 31, 2024. Thirty-one patients were included, with a median age of 59 years (range 39, 82). The median time from administration to onset of AP was 5.05 months (range 0.5, 16) and the median cycle was 7 cycles (range 1, 35). Twenty-two (71.0%) patients had elevated pancreatic amylase with a median value of 860 IU/L (range 105-12562), and 16 (51.6%) patients had elevated lipase with a median value of 282 IU/L (range 153-1034). Pancreatic biopsy showed neutrophil infiltration (9.7%) and lymphocyte infiltration (6.5%). Immunohistochemical staining showed CD8 dominated inflammatory infiltration (6.5%). The computed tomography showed diffuse enlargement (51.6%) and focal enlargement (51.6%) of the pancreas. Endoscopic ultrasound showed enlarged hypoechoic pancreas(16.1%). PET/CT showed increased FDG uptake (16.1%). The magnetic resonance cholangial pancreatography showed narrowing of main pancreatic duct (12.9%). AP symptoms and pancreatic enzymes improved after discontinuation of pembrolizumab and administration of steroids and infliximab. Clinicians should be aware that AP is a rare adverse reaction to pembrolizumab. Pembrolizumab induced AP can be initiated with steroids for control, and infliximab can be initiated with steroid-refractory AP.
Subject(s)
Antibodies, Monoclonal, Humanized , Pancreatitis , Humans , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Pancreatitis/chemically induced , Pancreatitis/diagnostic imaging , Middle Aged , Aged , Male , Female , Aged, 80 and over , Adult , Antineoplastic Agents, Immunological/adverse effects , Acute Disease , Treatment OutcomeABSTRACT
Nivolumab can cause fatal myocarditis. We aimed to analyze the clinical characteristics of nivolumab-induced myocarditis and provide evidence for clinical diagnosis, treatment, and prevention. Studies involving nivolumab-induced myocarditis were identified in electronic databases from 2000 to 2023 for retrospective analysis. A total of 66 patients were included, with a median age of 68 years. The median onset time of myocarditis is 11.5 days. The main organs affected in persons presented with myocarditis are heart (100.0%) and skeletal muscle (22.7%). The main clinical manifestations are dyspnea (49.2%), fatigue (47.6%), and myalgias (25.4%). The levels of troponin, troponin T, troponin I, creatine kinase, creatine kinase myocardial band, creatine phosphokinase, C-reactive protein, brain natriuretic peptide, and N-terminal brain natriuretic peptide precursor were significantly increased. Histopathology often shows lymphocyte infiltration, myocardial necrosis, and fibrosis. Myocardial immunological parameters usually present positive. Cardiac imaging often suggests complete heart block, intraventricular conduction delay, arrhythmia, myocardial infarction, edema, left ventricular ejection fractions reduction, ventricular dysfunction, and other symptoms of myocarditis. Forty-two (63.6%) patients achieved remission within a median time of 8 days after discontinuation of nivolumab and treatment with systemic corticosteroids, immunoglobulins, plasmapheresis, and immunosuppressant. Thirty-five patients eventually died attributed to myocarditis (68.6%), cancer (20.0%), respiratory failure (5.7%), and other reasons (5.7%). Nivolumab-induced myocarditis should be comprehensively diagnosed based on clinical symptoms, histopathological manifestations, immunological parameters, and cardiac function imaging examinations. Nivolumab should be discontinued immediately, plasmapheresis and systemic corticosteroids combined with immunoglobulins or immunosuppressants may be an effective treatment.
Subject(s)
Antineoplastic Agents, Immunological , Myocarditis , Humans , Aged , Nivolumab/adverse effects , Myocarditis/chemically induced , Myocarditis/diagnosis , Myocarditis/therapy , Antineoplastic Agents, Immunological/adverse effects , Retrospective Studies , Natriuretic Peptide, Brain/adverse effects , Immunosuppressive Agents/therapeutic use , Adrenal Cortex Hormones/adverse effects , Creatine KinaseABSTRACT
TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.
Subject(s)
Membrane Proteins , Nerve Tissue Proteins , Tauopathies , Animals , Humans , Mice , Disease Models, Animal , Membrane Proteins/genetics , Mice, Knockout , Mice, Transgenic , Mutation , Nerve Tissue Proteins/genetics , Paralysis/genetics , Polymorphism, Single Nucleotide , tau Proteins/genetics , tau Proteins/metabolism , Tauopathies/pathologyABSTRACT
Myocardial ischemia/reperfusion (MI/R) injury contributes to severe injury for cardiomyocytes. In this study, we aimed to explore the underlying mechanism of TFAP2C on cell autophagy in MI/R injury. MTT assay measured cell viability. The cells injury was evaluated by commercial kits. IF detected the level of LC3B. Dual luciferase reporter gene assay, ChIP or RIP assay were performed to verify the interactions between crucial molecules. We found that TFAP2C and SFRP5 expression were decreased while miR-23a-5p and Wnt5a increased in AC16 cells in response to H/R condition. H/R induction led to cell injury and induced autophagy, which were reversed by TFAP2C overexpression or 3-MA treatment (an autophagy inhibitor). Mechanistically, TFAP2C suppressed miR-23a expression through binding to miR-23a promoter, and SFRP5 was a target gene of miR-23a-5p. Moreover, miR-23a-5p overexpression or rapamycin reversed the protective impacts of TFAP2C overexpression on cells injury and autophagy upon H/R condition. In conclusion, TFAP2C inhibited autophagy to improve H/R-induced cells injury by mediating miR-23a-5p/SFRP5/Wnt5a axis.
Subject(s)
MicroRNAs , Myocardial Reperfusion Injury , Humans , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/metabolism , MicroRNAs/metabolism , Myocytes, Cardiac/metabolism , Autophagy/genetics , Apoptosis , Wnt-5a Protein/genetics , Wnt-5a Protein/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Transcription Factor AP-2/genetics , Transcription Factor AP-2/metabolismABSTRACT
OBJECTIVE: To investigate Life's Essential 8 (LE8), a measure of cardiovascular health (CVH), associations with mortality outcomes in cancer survivors. METHODS: A prospective cohort study included 1818 cancer survivors aged ≥20 years (weighted population: 13,204,583) from National Health and Nutrition Examination Survey (NHANES) 2005-2018. Linked to mortality data through 2019, LE8 data were gathered through self-reports and lab tests. An LE8 score of 80-100 is considered high CVH, 60-79 is moderate CVH, and 0-59 is low CVH. Multivariable Cox proportional hazards regression models were employed to evaluate the associations between LE8 and all-cause, cancer-specific and non-cancer mortality. Subsequently, subgroup analyses were conducted to assess the relationship between LE8 and mortality rates across various subgroups. RESULTS: At baseline, there were 1818 cancer survivors. In a 15-year follow-up, 2548 deaths occurred: 601 from cancer, 647 from heart disease, and 1300 from other causes. Multivariable models showed high CVH associated with lower hazard ratios for all-cause, cancer-specific and non-cancer mortality vs. low CVH. Cumulative mortality rates increased during follow-up, more so in the low CVH group. Subgroup analysis revealed significant LE8 interactions with age or Poverty Income Ratio (PIR) for all-cause mortality. Additionally, significant interactions between LE8 and PIR were identified for cancer-specific and non-cancer mortality risks (P for interaction <0.05). CONCLUSION: Among U.S. cancer survivors, higher CVH is independently linked to lower all-cause, cancer-specific, and non-cancer mortality risks. The new CVH definition shows promise as a primary prevention strategy to reduce mortality rates in U.S. cancer survivors.
Subject(s)
Cancer Survivors , Cardiovascular Diseases , Neoplasms , Humans , United States/epidemiology , Nutrition Surveys , Prospective Studies , Retrospective Studies , Risk FactorsABSTRACT
OBJECTIVES: To investigate the expression and function of WNT16, a member of the WNT family protein, in the context of systemic lupus erythematosus (SLE). METHODS: WNT16 expression was assessed in peripheral blood mononuclear cells (PBMCs) from 35 SLE patients and 25 healthy individuals using quantitative polymerase chain reaction. Additionally, serum WNT16 protein levels were quantified via enzyme-linked immunosorbent assay in 162 SLE patients, 96 healthy controls (HC), and disease controls comprised 154 individuals with rheumatoid arthritis (RA) and Sjögren's syndrome (SS). We investigated the associations between WNT16 protein levels and clinical manifestations, laboratory indices, and disease activity in SLE patients. Receiver operating characteristic (ROC) curve analysis was employed to evaluate the diagnostic potential of serum WNT16 for SLE. Furthermore, we performed a knockdown assay on Jeko-1 cells and assessed cell proliferation and apoptosis using Cell Counting Kit-8 and flow cytometry. RESULTS: WNT16 mRNA in SLE patients' PBMCs were significantly lower than those in HC. Furthermore, serum WNT16 in SLE patients were markedly reduced compared to HC, RA, and SS cohorts. ROC curve analysis indicated that plasma WNT16 levels could serve as a potential biomarker for SLE identification (AUC=0.809, SLE vs. HC; AUC=0.760, SLE vs. RA; AUC=0.710, SLE vs. SS). Notably, a weak positive correlation was observed between WNT16 protein and both alkaline phosphatase and lymphocyte percentages. Conversely, a weak negative correlation existed between WNT16 and low-density lipoprotein, neutrophil percentage, and the incidence of pleurisy and disease activity. Additionally, our study confirmed that WNT16 knockdown impairs cell proliferation and enhances apoptosis. CONCLUSIONS: Serum WNT16 levels effectively differentiate SLE patients from healthy controls and individuals with other autoimmune disorders. WNT16 serves as a potential biomarker with high sensitivity. The diminished expression of WNT16 in SLE may have a significant role in its pathogenesis through the regulation of cell proliferation and apoptosis.