RESUMO
Pathogens compromise host defense responses by strategically secreting effector proteins. However, the molecular mechanisms by which effectors manipulate disease-resistance factors to evade host surveillance remain poorly understood. In this study, we characterized a Puccinia striiformis f. sp. tritici (Pst) effector Pst21674 with a signal peptide. Pst21674 was significantly upregulated during Pst infections in wheat (Triticum aestivum L.) and knocking down Pst21674 by host-induced gene silencing led to reduced Pst pathogenicity and restricted hyphal spread in wheat. Pst21674 interaction with the abscisic acid-, stress-, and ripening-induced protein TaASR3 was validated mainly in the nucleus. Size exclusion chromatography, bimolecular fluorescence complementation, and luciferase complementation imaging assays confirmed that TaASR3 could form a functional tetramer. Virus-induced gene silencing and overexpression demonstrated that TaASR3 contributes to wheat resistance to stripe rust by promoting accumulation of reactive oxygen species and cell death. Additionally, transcriptome analysis revealed that the expression of defense-related genes was regulated in transgenic wheat plants overexpressing TaASR3. Interaction between Pst21674 and TaASR3 interfered with the polymerization of TaASR3 and suppressed TaASR3-mediated transcriptional activation of defense-related genes. These results indicate that Pst21674 serves as an important virulence factor secreted into the host nucleus to impede wheat resistance to Pst, possibly by targeting and preventing polymerization of TaASR3.
Assuntos
Basidiomycota , Triticum , Triticum/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Basidiomycota/fisiologia , Inativação Gênica , Virulência/genética , Doenças das Plantas/genéticaRESUMO
The large yield of anaerobic digestates and the suboptimal efficacy of nutrient slow-release severely limit its practical application. To address these issues, a new biochar based fertilizer (MAP@BRC) was developed using biogas residue biochar (BRC) to recover nitrogen and phosphorus from biogas slurry. The nutrient release patterns of MAP@BRC and mechanisms for enhancing soil fertility were studied, and it demonstrated excellent performance, with 59% total nitrogen and 50% total phosphorus nutrient release rates within 28 days. This was attributed to the coupling of the mechanism involving the dissolution of struvite skeletons and the release of biochar pores. Pot experiments showed that crop yield and water productivity were doubled in the MAP@BRC group compared with unfertilized planting. The application of MAP@BRC also improved soil nutrient levels, reduced soil acidification, increased microbial populations, and decreased soil heavy metal pollution risk. The key factors that contributed to the improvement in soil fertility by MAP@BRC were an increase in available nitrogen and the optimization of pH levels in the soil. Overall, MAP@BRC is a safe, slow-release fertilizer that exhibits biochar-fertilizer interactions and synergistic effects. This slow-release fertilizer was prepared by treating a phosphorus-rich biogas slurry with a nitrogen-rich biogas slurry, and it simultaneously addresses problems associated with livestock waste treatment and provides a promising strategy to promote zero-waste agriculture.
Assuntos
Biocombustíveis , Carvão Vegetal , Fertilizantes , Nitrogênio , Fósforo , Solo , Fertilizantes/análise , Carvão Vegetal/química , Solo/química , Fósforo/análise , Nitrogênio/análise , Biocombustíveis/análise , Agricultura/métodosRESUMO
Folic acid (FA) is easily photodegraded to yield 6-formylpterin and pterin-6-carboxylic acid, which can generate reactive oxygen species and result in the formation of oxidized guanine derivatives such as 8-hydroxy-2'-deoxyguanosine and 8-hydroxy-guanosine. In this study, we developed a simple, rapid, and sensitive liquid chromatography-tandem mass spectrometry strategy for the simultaneous determination of FA photolysis products and oxidized guanine derivatives in plasma samples. Chromatographic separation was performed on a Waters HSS T3 column (2.1 × 100 mm, 5.0 µm) with gradient elution at a flow rate of 0.25 mL/min. Plasma samples were first pretreated with 1% formic acid, followed by protein precipitation with methanol. The developed method showed good linear relationships between 1 and 2000 ng/mL (r2 > 0.99). The intra- and inter-day precisions ranged from 2.6% to 7.5% and from 2.5% to 6.5%, respectively. Recoveries of the analytes were between 75.4% and 112.4% with the relative standard deviation < 9.1%. Finally, the method was applied to quantify FA photolysis products and oxidized guanine derivatives in rats with light and non-light conditions.
Assuntos
Ácido Fólico , Espectrometria de Massas em Tandem , Ratos , Animais , Espectrometria de Massas em Tandem/métodos , Ratos Sprague-Dawley , Fotólise , Cromatografia Líquida/métodos , Cromatografia Líquida de Alta Pressão/métodosRESUMO
Amplification of amino acids synthesis is reported to promote tumorigenesis. The serine/glycine biosynthesis pathway is a reversible conversion of serine and glycine catalyzed by cytoplasmic serine hydroxymethyltransferase (SHMT)1 and mitochondrial SHMT2; however, the role of SHTM1 in renal cell carcinoma (RCC) is still unclear. We found that low SHMT1 expression is correlated with poor survival of RCC patients. The in vitro study showed that overexpression of SHMT1 suppressed RCC proliferation and migration. In the mouse tumor model, SHMT1 significantly retarded RCC tumor growth. Furthermore, by gene network analysis, we found several SHMT1-related genes, among which homeobox D8 (HOXD8) was identified as the SHMT1 regulator. Knockdown of HOXD8 decreased SHMT1 expression, resulting in faster RCC growth, and rescued the SHMT1 overexpression-induced cell migration defects. Additionally, ChIP assay found the binding site of HOXD8 to SHMT1 promoter was at the -456~-254 bp region. Taken together, SHMT1 functions as a tumor suppressor in RCC. The transcription factor HOXD8 can promote SHMT1 expression and suppress RCC cell proliferation and migration, which provides new mechanisms of SHMT1 in RCC tumor growth and might be used as a potential therapeutic target candidate for clinical treatment.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Humanos , Camundongos , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Glicina , Glicina Hidroximetiltransferase/genética , Glicina Hidroximetiltransferase/química , Glicina Hidroximetiltransferase/metabolismo , Proteínas de Homeodomínio/genética , Neoplasias Renais/genética , Serina/metabolismo , Fatores de TranscriçãoRESUMO
Targeted imaging is playing an increasingly important role in the early detection and precise diagnosis of cancer. This need has motivated research into sensory nanomaterials that can be constructed into imaging agents to serve as biosensors. Graphene quantum dots (GQDs) as a valuable nanoprobe show great potential for use in two-photon biological imaging. However, most as-prepared GQDs exhibit a low two-photon absorption cross-section, narrow spectral coverage, and "one-to-one" signal conversion mode, which greatly hamper their wide application in sensitive early-stage cancer detection. Herein, a versatile strategy has been employed to fabricate an aptamer Sgc8c-functionalized hybrid as a proof-of-concept of the signal amplification strategy for targeted cancer imaging. In this study, GQDs with two-photon imaging performance, and silica nanoparticles (SiO2 NPs) as nanocarriers to provide amplified recognition events by high loading of GQD signal tags, were adopted to construct a two-photon hybrid-based signal amplification strategy. Thus, the obtained hybrid (denoted SiO2@GQDs) enabled extremely strong fluorescence with a quantum yield up to 0.49, excellent photostability and biocompatibility, and enhanced bright two-photon fluorescence up to 2.7 times that of bare GQDs (excitation at 760 nm; emission at 512 nm). Moreover, further modification with aptamer Sgc8c showed little disruption to the structure of the SiO2@GQDs-hybrid and the corresponding two-photon emission. Hence, SiO2@GQDs-Sgc8c showed specific responses to target cells. Moreover, it could be used as a signal-amplifying two-photon nanoprobe for targeted cancer imaging with high specificity and great efficiency, which exhibits a distinct green fluorescence compared to that of GQDs-Sgc8c or SiO2@GQDs. This signal amplification strategy holds great potential for the accurate early diagnosis of tumors and offers new tools for the detection a wide variety of analytes in clinical application.
Assuntos
Grafite , Nanopartículas , Neoplasias , Pontos Quânticos , Humanos , Pontos Quânticos/química , Grafite/química , Dióxido de Silício/química , Nanopartículas/química , Oligonucleotídeos , Neoplasias/diagnóstico por imagemRESUMO
Reactive Oxygen Species (ROS) play an important role in oxidative stress and are related to the lipid accumulation in microalgae. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase can oxidize O2 to O2- ultimately. However, the function of NADPH oxidase and its contribution to the production of the intracellular total ROS are still unclear. In this study, the function of NADPH oxidase in Chlorella pyrenoidosa (C. pyrenoidosa) was investigated by adding activators Ca2+ and NADPH and inhibitors EGTA, LaCl3, DPI and BAPTA of NADPH oxidase. The results show that the addition of activators of Ca2+ or NADPH significantly increased the intracellular concentrations of ROS molecules (H2O2, O2-, and OH·) in C. pyrenoidosa. Moreover, the intracellular ROS level was higher under the nitrogen-deficient and phosphorus-deficient conditions than in control condition, but the addition of the inhibitors (EGTA, LaCl3, DPI, and BAPTA) of NADPH oxidase significantly reduced the intracellular concentrations of H2O2, O2-, and OH·. The study shows that NADPH oxidase actively participated in the production of intracellular ROS in C. pyrenoidosa, demonstrating that NADPH oxidase was another important element in the production of intracellular ROS in addition to mitochondria, chloroplasts and lysozymes in microalgae.
Assuntos
Chlorella , Espécies Reativas de Oxigênio , Ácido Egtázico , Peróxido de Hidrogênio/farmacologia , NADP , NADPH OxidasesRESUMO
The past decade has witnessed tremendous progress achieved in taste research, while few studies focus on interactions among taste compounds. Indeed, sweeteners and acidulants are commonly used food additives, and sweet-sour mixtures always provide improved tastes. For example, sensory studies have shown that sourness suppresses sweetness. However, the degree of sweetness suppression by sourness is difficult to evaluate quantitatively and objectively. Therefore, we propose a biohybrid tongue that is constructed by integrating mammalian gustatory epithelium with a microelectrode array chip. The taste quality and intensity information is coded in time-frequency patterns of local field potential. Different response patterns evoked by sweet and sour stimuli are observed, and the response is dose-dependent. Then, interaction effects of sourness against sweetness are quantified. The results indicate that suppression of sweetness by sourness occurs by increasing sourness concentrations. In summary, this study provides a powerful new tool for quantitative evaluation of sweet, sour, and their binary taste interactions that mimic the mammalian taste system.
Assuntos
Edulcorantes , Paladar , Animais , Mamíferos , Paladar/fisiologia , LínguaRESUMO
Eriocitrin, a lemons flavanone, exhibits several biological properties, antiproliferative, and proapoptotic effects. However, its molecular mechanical action is not entirely clarified. Oxidative stress causes abnormal stimulation of signal transducer and activator of transcription 3 (STAT3) and c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs) signaling has been strongly connected with the ruling of cell survival and apoptosis of cancer cells. Herein, we investigated an antiproliferative and proapoptotic effect that Eriocitrin modulates STAT3/MAPKs signaling activation in MCF-7 cells. We noticed that Eriocitrin strongly enhances reactive oxygen species (ROS) generation, alteration of mitochondrial outer membrane potential, and enhances apoptotic morphological changes. Furthermore, Eriocitrin suppressed STAT3 phosphorylation via inhibiting an upstream molecule of JAK2 and Src kinase activation, thereby blocking STAT3 nuclear translocation. Similarly, Eriocitrin causes oxidative stress-mediated JNK/p38 MAPK signaling activation. We confirmed that Eriocitrin induced ROS-mediated apoptosis inhibited by the antioxidant substance of N-acetylcysteine. Eriocitrin induced apoptosis via suppression of STAT3 signaling regulated proteins, activating proapoptotic factors Bax, caspase 7, 8, 9 and suppressing Bcl-2, Bcl-x expression in MCF-7 cells. Overall, these results evidenced that Eriocitrin can affect multiple signaling events associated with tumorigenesis. From this evidence, Eriocitrin, a novel chemotherapeutic agent, can be used to treat breast cancer.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Flavanonas/farmacologia , Janus Quinase 2/metabolismo , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Feminino , Humanos , Janus Quinase 2/genética , MAP Quinase Quinase 4/genética , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Fator de Transcrição STAT3/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
BACKGROUND: Atractylodes lancea (Thunb.) DC, a medicinal herb belonging to the Asteraceae family, often faces severe drought stress during its growth. Until now, there has been no research on the effect of drought stress on the quality formation of A. lancea. Therefore, the present study aimed to study the effects of drought stress on A. lancea through physical and chemical analysis, and to reveal the related molecular mechanisms via transcriptome analysis. RESULTS: The photosynthesis was markedly inhibited under drought stress. There were alterations to photosynthetic parameters (Pn, Gs, Ci) and chlorophyll fluorescence (Fv/Fm, NPQ), and the chlorophyll content decreased. Twenty genes encoding important regulatory enzymes in light and dark reactions, including the Rubisco gene of the Calvin cycle, were significantly downregulated. After exposure to drought stress for more than 4 days, the activities of four antioxidative enzymes (SOD, POD CAT and APX) began to decrease and continued to decrease with longer stress exposure. Meanwhile, most of the genes encoding antioxidative enzymes were downregulated significantly. The downregulation of 21 genes related to the respiratory electron transport chain indicated that the blocked electron transfer accelerated excessive ROS. The MDA content was significantly elevated. The above data showed that 15 days of drought stress caused serious oxidative damage to A. lancea. Drought stress not only reduced the size and dry weight of A. lancea, but also lowered the amount of total volatile oil and the content of the main bioactive components. The total volatile oil and atractylodin content decreased slightly, whereas the content of atractylon and ß-eudesmol decreased significantly. Moreover, ten significantly downregulated genes encoding sesquiterpene synthase were mainly expressed in rhizomes. CONCLUSIONS: After exposed to drought stress, the process of assimilation was affected by the destruction of photosynthesis; stress tolerance was impaired because of the inhibition of the antioxidative enzyme system; and bioactive component biosynthesis was hindered by the downregulation of sesquiterpene synthase-related gene expression. All these had negative impacts on the quality formation of A. lancea under drought stress.
Assuntos
Antioxidantes/metabolismo , Atractylodes/fisiologia , Fotossíntese , Transcriptoma , Atractylodes/metabolismo , Desidratação , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Biotrophic pathogens are believed to strategically manipulate sugar transport in host cells to enhance their access to carbohydrates. However, mechanisms of sugar translocation from host cells to biotrophic fungi such as powdery mildew across the plant-haustorium interface remain poorly understood. To investigate this question, systematic subcellular localisation analysis was performed for all the 14 members of the monosaccharide sugar transporter protein (STP) family in Arabidopsis thaliana. The best candidate AtSTP8 was further characterised for its transport properties in Saccharomyces cerevisiae and potential role in powdery mildew infection by gene ablation and overexpression in Arabidopsis. Our results showed that AtSTP8 was mainly localised to the endoplasmic reticulum (ER) and appeared to be recruited to the host-derived extrahaustorial membrane (EHM) induced by powdery mildew. Functional complementation assays in S. cerevisiae suggested that AtSTP8 can transport a broad spectrum of hexose substrates. Moreover, transgenic Arabidopsis plants overexpressing AtSTP8 showed increased hexose concentration in leaf tissues and enhanced susceptibility to powdery mildew. Our data suggested that the ER-localised sugar transporter AtSTP8 may be recruited to the EHM where it may be involved in sugar acquisition by haustoria of powdery mildew from host cells in Arabidopsis.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Ascomicetos , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Retículo Endoplasmático , Interações Hospedeiro-Patógeno , Monossacarídeos , Doenças das Plantas , Saccharomyces cerevisiaeRESUMO
Odor masking is a prominent phenomenon in the biological olfactory perception system. It has been applied in industry and daily life to develop masking agents to reduce or even eliminate the adverse effects of unpleasant odors. However, it is challenging to assess the odor masking efficiency with traditional gas sensors. Here, we took advantage of the olfactory perception system of an animal to develop a system for the evaluation and quantification of odor masking based on an in vivo bioelectronic nose. The linear decomposition method was used to extract the features of the spatial response pattern of the mitral/tufted (M/T) cell population of the olfactory bulb of a rat to monomolecular odorants and their binary mixtures. Finally, the masking intensity was calculated to quantitatively measure the degree of interference of one odor to another in the biological olfactory system. Compared with the human sensory evaluation reported in a previous study, the trend of masking intensity obtained with this system positively correlated with the human olfactory system. The system could quantitatively analyze the masking efficiency of masking agents, as well as assist in the development of new masking agents or flavored food in odor or food companies.
Assuntos
Odorantes , Bulbo Olfatório , Animais , Ratos , Linfócitos TRESUMO
Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.
Assuntos
Potenciais de Ação , Encéfalo , Epilepsia , Proteínas de Membrana , Mutação de Sentido Incorreto , Rede Nervosa , Neurotransmissores/metabolismo , Potenciais Sinápticos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Rede Nervosa/patologiaRESUMO
Alzheimer's disease (AD) is a chronic central neurodegenerative disease. The pathological features of AD are the extracellular deposition of senile plaques formed by amyloid-ß oligomers (AßOs) and the intracellular accumulation of neurofibrillary tangles formed by hyperphosphorylated tau protein. In this paper, an in vitro pathological model of AD based on neuronal network chip and its real-time dynamic analysis were presented. The hippocampal neuronal network was cultured on the microelectrode array (MEA) chip and induced by AßOs as an AD model in vitro to simultaneously record two firing patterns from the interneurons and pyramidal neurons. The spatial firing patterns mapping and cross-correlation between channels were performed to validate the degeneration of neuronal network connectivity. This biosensor enabled the detection of the AßOs toxicity responses, and the identification of connectivity and interactions between neuronal networks, which can be a novel technique in the research of AD pathological model in vitro.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Humanos , Emaranhados Neurofibrilares , Proteínas tauRESUMO
Men who have sex with men (MSM) are at risk for contracting hu- man immunodeficiency virus (HIV) infection. The objective of this study was to explore the characteristics and factors influencing unprotected anal intercourse (UAI) among MSM in Fuyang, China in order to develop an intervention program to prevent the spread of HIV infection among MSM. We conducted this cross sectional study among 413 MSM in 2013. Participants completed an interviewer- administered questionnaire and were tested for HIV and syphilis infections. Three hundred fifty of 413 subjects reported sexual activity with a male partner during the previous 6 months; of these 27(7.7%) had unprotected sex. Forty-four subjects had sex with a female partner during the previous 6 months; of these 25 (58.1%) had unprotected sex. The frequency of having unprotected sex with a female was significantly greater than with a male (χ2 = 84.52, p < 0.001). Multivariate logistic analysis showed education level (OR = 0.45, p = 0.003), length of time of current residence (OR = 0.47, p = 0.014), knowledge about HIV infection (OR = 0.09, p = 0.022) and integrated interventions (OR = 0.32, p < 0.001) were all significantly associated with UAI. High-risk sex behavior was common among the study population. A targeted interventions needs to be developed urgently.
Assuntos
Bissexualidade , Preservativos/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Homossexualidade Masculina , Comportamento Sexual/estatística & dados numéricos , Sexo sem Proteção/estatística & dados numéricos , Adulto , China/epidemiologia , Estudos Transversais , Escolaridade , Infecções por HIV/epidemiologia , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Fatores de Risco , Parceiros Sexuais , Adulto JovemRESUMO
Background: The effects of chili intake on overweight and obesity have attracted significant interest in recent years. This study aimed to investigate the correlation between chili consumption frequency, body mass index (BMI), and obesity prevalence in the American population. Methods: Data from participants in National Health and Nutrition Examination Survey (NHANES) 2003-2006 were collected. We enrolled 6,138 participants with complete information on chili intake and BMI in this cross-sectional study. Multivariate logistic regression and sensitivity analyses were conducted to explore the relationship between chili intake frequency and BMI and obesity. Subgroup analyses and interaction tests were employed to assess the stability of the observed correlation. Results: Increased chili consumption frequency was linked to higher BMI values and a greater prevalence of obesity. Compared to the non-consumption group, the highest frequency group had a multivariate-adjusted ß of 0.71 (95% CI: 0.05, 1.38) for BMI and an OR of 1.55 (95% CI: 1.22, 1.97) for obesity in the fully adjusted model. This positive association between chili intake frequency and obesity was more pronounced in females and older adults (≥ 60 years old). Conclusion: Our findings suggest a positive association between chili intake frequency and BMI and obesity in United States adults, suggesting that controlling chili intake frequency could potentially contribute to improved weight management in the general population.
RESUMO
Paleolatitudes of volcanic rocks reveal that prominent changes in volcanic trend of the Hawaii-Emperor hotspot chain represent meridional migration of the magma source. However, models assuming latitudinal plume migration fail to explain the observed age distribution, rock composition, and erratic paleolatitude changes of the oldest Emperor seamounts. Here we use data-assimilation models to better reproduce the Hawaii-Emperor hotspot track by systematically considering plate reconstruction, plume-lithosphere interaction, and simplified melt generation and migration. Our results show that plate drag and plume-ridge interaction are both important in explaining the observed seamount ages. These shallow dynamic processes could account for 50% of the observed paleolatitude's secular reduction and erratic variations over time, where the necessary southward migration of the Hawaiian plume root is significantly less than previously thought. We conclude that plume-lithosphere interaction represents a common mechanism in affecting hotspot track, and has important implications in understanding mantle dynamics and plate reference frames.
RESUMO
Olfactory dysfunction (OD) is a highly prevalent symptom and an early sign of neurodegenerative diseases in humans. However, the roles of peripheral olfactory system in disease progression and the mechanisms behind neurodegeneration remain to be studied. Olfactory epithelium (OE) organoid is an ideal model to study pathophysiology in vitro, yet the reliance on 3D culture condition limits continual in situ monitoring of organoid development. Here, we combined impedance biosensors and live imaging for real-time spatiotemporal analysis of OE organoids morphological and physiological features during Alzheimer's disease (AD) progression. The impedance measurements showed that organoids generated from basal stem cells of APP/PS1 transgenic mice had lower proliferation rate than that from wild-type mice. In concert with the biosensor measurements, live imaging enabled to visualize the spatial and temporal dynamics of organoid morphology. Abnormal protein aggregation and accumulation, including amyloid plaques and neurofibrillary tangles, was found in AD organoids and increased as disease progressed. This multimodal in situ bioelectrical measurement and imaging provide a new platform for investigating onset mechanisms of OD, which would shed new light on early diagnosis and treatment of neurodegenerative disease.
Assuntos
Doença de Alzheimer , Técnicas Biossensoriais , Doenças Neurodegenerativas , Transtornos do Olfato , Humanos , Camundongos , Animais , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Células-Tronco/metabolismo , Organoides/metabolismo , Transtornos do Olfato/metabolismo , Peptídeos beta-Amiloides/metabolismoRESUMO
Osteoarthritis (OA) is one of the most common joint diseases, there are no effective disease-modifying drugs, and the pathological mechanisms of OA need further investigation. Here, we show that H3K36 methylations were decreased in senescent chondrocytes and age-related osteoarthritic cartilage. Prrx1-Cre inducible H3.3K36M transgenic mice showed articular cartilage destruction and osteophyte formation. Conditional knockout Nsd1Prrx1-Cre mice, but not Nsd2Prrx1-Cre or Setd2Prrx1-Cre mice, replicated the phenotype of K36M/+; Prrx1-Cre mice. Immunostaining results showed decreased anabolic and increased catabolic activities in Nsd1Prrx1-Cre mice, along with decreased chondrogenic differentiation. Transcriptome and ChIP-seq data revealed that Osr2 was a key factor affected by Nsd1. Intra-articular delivery of Osr2 adenovirus effectively improved the homeostasis of articular cartilage in Nsd1Prrx1-Cre mice. In human osteoarthritic cartilages, both mRNA and protein levels of NSD1 and OSR2 were decreased. Our results indicate that NSD1-induced H3K36 methylations and OSR2 expression play important roles in articular cartilage homeostasis and OA. Targeting H3K36 methylation and OSR2 would be a novel strategy for OA treatment.
Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Humanos , Animais , Condrócitos/metabolismo , Metiltransferases/metabolismo , Osteoartrite/patologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Camundongos Transgênicos , Homeostase , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismoRESUMO
Ginsenoside compound K (GCK) possesses a glucocorticoid (GC)-like structure and functions as an agonist of the glucocorticoid receptor (GR), thereby exerting anti-inflammatory effects through GR activation. However, it remains unclear whether GCK leads to hyperglycemia, which is a known adverse reaction associated with classical GCs. In this study, we have successfully demonstrated that GCK exerts its anti-inflammatory effects in a rat model of adjuvant arthritis without impacting gluconeogenesis and pentose phosphate pathways, thus avoiding any glucose metabolism disorders. By employing the GR mutant plasmid, we have identified the binding site between GCK and GR as GRM560T, which differs from the binding site shared by dexamethasone (DEX) and GR. Notably, compared to DEX, GCK induces distinct levels of phosphorylation at S211 on GR upon binding to activate steroid receptor coactivator 1 (SRC1)-a co-factor responsible for mediating anti-inflammatory effects-while not engaging peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-an associated coactivator involved in gluconeogenesis.
Assuntos
Anti-Inflamatórios , Artrite Experimental , Ginsenosídeos , Ratos Sprague-Dawley , Receptores de Glucocorticoides , Animais , Ginsenosídeos/farmacologia , Ratos , Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Masculino , Receptores de Glucocorticoides/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Humanos , Dexametasona/farmacologiaRESUMO
Background: The cardioprotective effect of remote ischemia preconditioning in clinical studies is inconsistent with experimental results. Adaptation to high-altitude hypoxia has been reported to be cardioprotective in animal experiments. However, the clinical significance of the cardioprotective effect of high-altitude adaptation has not been demonstrated. Methods: A retrospective cohort study with propensity score matching was designed to compare the outcomes of cardiac surgery between highlanders and lowlanders in a tertiary teaching hospital. The data of adult cardiac surgical patients from January 2013 to December 2022, were collected for analysis. Patients with cardiopulmonary bypass and cardioplegia were divided into a low-altitude group (<1,500â m) and a high-altitude group (≥1,500â m) based on the altitude of their place of residence. Results: Of 3,020 patients, the majority (87.5%) permanently lived in low-altitude regions [495 (435, 688)â m], and there were 379 patients (12.5%) in the high-altitude group [2,552 (1,862, 3,478)â m]. The 377 highlander patients were matched with lowlander patients at a ratio of 1:1. The high-altitude group exhibited a 44.5% reduction in the incidence of major adverse cardiovascular events (MACEs) compared with the low-altitude group (6.6% vs. 11.9%, P = 0.017). The patients in the moderate high-altitude subgroup (2,500-3,500â m) had the lowest incidence (5.6%) of MACEs among the subgroups. The level of creatinine kinase muscle-brain isoenzymes on the first postoperative morning was lower in the high-altitude group than in the low-altitude group (66.5 [47.9, 89.0]â U/L vs. 69.5 [49.3, 96.8]â U/L, P = 0.003). Conclusions: High-altitude adaptation exhibits clinically significant cardioprotection in cardiac surgical patients.