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Maturation of neuronal circuits requires selective elimination of synaptic connections. Although neuron-intrinsic mechanisms are important in this process, it is increasingly recognized that glial cells also play a critical role. Without proper functioning of these cells, the number, morphology, and function of synaptic contacts are profoundly altered, resulting in abnormal connectivity and behavioral abnormalities. In addition to their role in synaptic refinement, glial cells have also been implicated in pathological synapse loss and dysfunction following injury or nervous system degeneration in adults. Although mechanisms regulating glia-mediated synaptic elimination are still being uncovered, it is clear this complex process involves many cues that promote and inhibit the removal of specific synaptic connections. Gaining a greater understanding of these signals and the contribution of different cell types will not only provide insight into this critical biological event but also be instrumental in advancing knowledge of brain development and neural disease.
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Sistema Nervoso Central/embriologia , Degeneração Neural/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Neuroglia/fisiologia , Neurônios/fisiologia , Sistema Nervoso Periférico/embriologia , Sinapses/fisiologia , Animais , Astrócitos/fisiologia , Evolução Biológica , Sistema Nervoso Central/crescimento & desenvolvimento , Sinais (Psicologia) , Exossomos/fisiologia , Humanos , Invertebrados/embriologia , Microglia/fisiologia , Morfogênese , Bainha de Mielina/fisiologia , Junção Neuromuscular/embriologia , Sistema Nervoso Periférico/crescimento & desenvolvimento , Sinapses/patologiaRESUMO
The transient receptor potential melastatin (TRPM) tetrameric cation channels are involved in a wide range of biological functions, from temperature sensing and taste transduction to regulation of cardiac function, inflammatory pain, and insulin secretion. The structurally conserved TRPM cytoplasmic domains make up >70 % of the total protein. To investigate the mechanism by which the TRPM cytoplasmic domains contribute to gating, we employed electrophysiology and cryo-EM to study TRPM5-a channel that primarily relies on activation via intracellular Ca2+. Here, we show that activation of mammalian TRPM5 channels is strongly altered by Ca2+-dependent desensitization. Structures of rat TRPM5 identify a series of conformational transitions triggered by Ca2+ binding, whereby formation and dissolution of cytoplasmic interprotomer interfaces appear to control activation and desensitization of the channel. This study shows the importance of the cytoplasmic assembly in TRPM5 channel function and sets the stage for future investigations of other members of the TRPM family.
Assuntos
Cálcio , Ativação do Canal Iônico , Canais de Cátion TRPM , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPM/química , Animais , Ativação do Canal Iônico/fisiologia , Ratos , Cálcio/metabolismo , Humanos , Microscopia Crioeletrônica , Células HEK293 , Citosol/metabolismo , Domínios Proteicos , Conformação ProteicaRESUMO
Circular RNAs (circRNAs) are covalently closed single-stranded RNAs. Four subclasses of circRNAs have been identified in animal cells, and they have unique features in their biogenesis, degradation, and transport. CircRNAs have diverse molecular functions in sponging miRNAs, regulating transcription, modulating RNA-binding proteins, and even encoding proteins. Some circRNAs are important regulators of various physiological processes to maintain homeostasis. Dysregulation of circRNAs is associated with human disorders, and individual circRNAs are crucial factors that contribute to major diseases including non-immunological diseases such as cancers, neurological disorders, cardiovascular disease, and metabolic disease. Debates on circRNAs have also been raised in recent years, and further studies would help to resolve these disputes and potentially lead to biomedical applications of circRNAs.
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Doenças Cardiovasculares , MicroRNAs , Neoplasias , RNA Circular , Animais , Doenças Cardiovasculares/genética , Humanos , Doenças Metabólicas/genética , MicroRNAs/genética , Neoplasias/genética , Doenças do Sistema Nervoso/genética , Splicing de RNA , RNA Circular/genéticaRESUMO
Environmental stressors caused by climate change are fundamental barriers to agricultural sustainability. Enhancing the stress resilience of crops is a key strategy in achieving global food security. Plants perceive adverse environmental conditions and initiate signaling pathways to activate precise responses that contribute to their survival. WRKY transcription factors (TFs) are essential players in several signaling cascades and regulatory networks that have crucial implications for defense responses in plants. This review summarizes advances in research concerning how WRKY TFs mediate various signaling cascades and metabolic adjustments as well as how epigenetic modifications involved in environmental stress responses in plants can modulate WRKYs and/or their downstream genes. Emerging research shows that clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)-mediated genome editing of WRKYs could be used to improve crop resilience.
Assuntos
Produtos Agrícolas , Fatores de Transcrição , Fatores de Transcrição/genética , Produtos Agrícolas/genética , Epigênese Genética , Edição de Genes , Transdução de Sinais/genéticaRESUMO
Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog [D-Phe6, ß-Ala11, Phe13, Nle14] Bn (6-14), in complex with Gq heterotrimers. These structures revealed the molecular mechanisms for the ligand binding, receptor activation, and Gq proteins signaling of GRPR, which are expected to accelerate the structure-based design of GRPR antagonists and agonists for the treatments of cancer and pruritus.
Assuntos
Neoplasias , Receptores da Bombesina , Masculino , Humanos , Camundongos , Animais , Receptores da Bombesina/agonistas , Receptores da Bombesina/metabolismo , Microscopia Crioeletrônica , Bombesina/farmacologia , Peptídeo Liberador de Gastrina/metabolismo , Prurido/metabolismoRESUMO
The enzymatic decarboxylation of fatty acids (FAs) represents an advance toward the development of biological routes to produce drop-in hydrocarbons. The current mechanism for the P450-catalyzed decarboxylation has been largely established from the bacterial cytochrome P450 OleTJE. Herein, we describe OleTPRN, a poly-unsaturated alkene-producing decarboxylase that outrivals the functional properties of the model enzyme and exploits a distinct molecular mechanism for substrate binding and chemoselectivity. In addition to the high conversion rates into alkenes from a broad range of saturated FAs without dependence on high salt concentrations, OleTPRN can also efficiently produce alkenes from unsaturated (oleic and linoleic) acids, the most abundant FAs found in nature. OleTPRN performs carbon-carbon cleavage by a catalytic itinerary that involves hydrogen-atom transfer by the heme-ferryl intermediate Compound I and features a hydrophobic cradle at the distal region of the substrate-binding pocket, not found in OleTJE, which is proposed to play a role in the productive binding of long-chain FAs and favors the rapid release of products from the metabolism of short-chain FAs. Moreover, it is shown that the dimeric configuration of OleTPRN is involved in the stabilization of the A-A' helical motif, a second-coordination sphere of the substrate, which contributes to the proper accommodation of the aliphatic tail in the distal and medial active-site pocket. These findings provide an alternative molecular mechanism for alkene production by P450 peroxygenases, creating new opportunities for biological production of renewable hydrocarbons.
Assuntos
Alcenos , Ácidos Graxos , Ácidos Graxos/metabolismo , Alcenos/química , Descarboxilação , Sistema Enzimático do Citocromo P-450/metabolismo , OxirreduçãoRESUMO
Do long noncoding RNAs (lncRNAs) contribute little or substantively to human biology? To address how lncRNA loci and their transcripts, structures, interactions, and functions contribute to human traits and disease, we adopt a genome-wide perspective. We intend to provoke alternative interpretation of questionable evidence and thorough inquiry into unsubstantiated claims. We discuss pitfalls of lncRNA experimental and computational methods as well as opposing interpretations of their results. The majority of evidence, we argue, indicates that most lncRNA transcript models reflect transcriptional noise or provide minor regulatory roles, leaving relatively few human lncRNAs that contribute centrally to human development, physiology, or behavior. These important few tend to be spliced and better conserved but lack a simple syntax relating sequence to structure and mechanism, and so resist simple categorization. This genome-wide view should help investigators prioritize individual lncRNAs based on their likely contribution to human biology.
Assuntos
RNA Longo não Codificante , Genoma , Humanos , RNA Longo não Codificante/genéticaRESUMO
DEAD-box RNA helicases are implicated in most aspects of RNA biology, where these enzymes unwind short RNA duplexes in an ATP-dependent manner. During the central step of the unwinding cycle, the two domains of the helicase core form a distinct closed conformation that destabilizes the RNA duplex, which ultimately leads to duplex melting. Despite the importance of this step for the unwinding process no high-resolution structures of this state are available. Here, I used nuclear magnetic resonance spectroscopy and X-ray crystallography to determine structures of the DEAD-box helicase DbpA in the closed conformation, complexed with substrate duplexes and single-stranded unwinding product. These structures reveal that DbpA initiates duplex unwinding by interacting with up to three base-paired nucleotides and a 5' single-stranded RNA duplex overhang. These high-resolution snapshots, together with biochemical assays, rationalize the destabilization of the RNA duplex and are integrated into a conclusive model of the unwinding process.
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RNA Helicases DEAD-box , Trifosfato de Adenosina , RNA Helicases DEAD-box/química , DNA Helicases , RNA/química , Escherichia coli/enzimologia , Escherichia coli/metabolismoRESUMO
Colorectal cancer (CRC) is a highly prevalent malignancy affecting the digestive system on a global scale. This study aimed to explore the previously unexplored role of CHPF in the progression of CRC. Our results revealed a significant upregulation of CHPF expression in CRC tumour tissues compared to normal tissues, with its levels correlating with tumour malignancy. In vitro experiments using CRC cell lines demonstrated that inhibiting CHPF expression suppressed cell proliferation, colony formation and cell migration, while promoting apoptosis. Conversely, overexpressing CHPF had the opposite effect. Additionally, our xenograft models in mice confirmed the inhibitory impact of CHPF knockdown on CRC progression using various cell models. Mechanistic investigations unveiled that CHPF may enhance VEGFB expression through E2F1-mediated transcription. Functionally, suppressing VEGFB expression successfully mitigated the oncogenic effects induced by CHPF overexpression. Collectively, these findings suggest that CHPF may act as a tumour promoter in CRC, operating in a VEGFB-dependent manner and could be a potential target for therapeutic interventions in CRC treatment.
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Apoptose , Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Fator B de Crescimento do Endotélio Vascular , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Camundongos Nus , Transcrição Gênica , Fator B de Crescimento do Endotélio Vascular/metabolismo , Fator B de Crescimento do Endotélio Vascular/genéticaRESUMO
Clear cell renal cell carcinoma (ccRCC) is a commonly occurring and highly aggressive urological malignancy characterized by a significant mortality rate. Current therapeutic options for advanced ccRCC are limited, necessitating the discovery of novel biomarkers and therapeutic targets. Carboxypeptidase A4 (CPA4) is a zinc-containing metallocarboxypeptidase with implications in various cancer types, but its role in ccRCC remains unexplored. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized in order to investigate the differential expression patterns of CPA4. The expression of CPA4 in ccRCC patients was further verified using immunohistochemical (IHC) examination of 24 clinical specimens. A network of protein-protein interactions (PPI) was established, incorporating CPA4 and its genes that were expressed differentially. Functional enrichment analyses were conducted to anticipate the contribution of CPA4 in the development of ccRCC. To validate our earlier study, we conducted real-time PCR and cell functional tests on ccRCC cell lines. Our findings revealed that CPA4 is overexpressed in ccRCC, and the higher the expression of CPA4, the worse the clinical outcomes such as TNM stage, pathological stage, histological grade, etc. Moreover, patients with high CPA4 expression had worse overall survival, disease-specific survival and progress-free interval than patients with low expression. The PPI network analysis highlighted potential interactions contributing to ccRCC progression. Functional enrichment analysis indicated the involvement of CPA4 in the regulation of key pathways associated with ccRCC development. Additionally, immune infiltration analysis suggested a potential link between CPA4 expression and immune response in the tumour microenvironment. Finally, cell functional studies in ccRCC cell lines shed light on the molecular mechanisms underlying the role of CPA4 in promoting ccRCC formation. Overall, our study unveils CPA4 as a promising biomarker with prognostic potential in ccRCC. The identified interactions and pathways provide valuable insights into its implications in ccRCC development and offer a foundation for future research on targeted therapies. Further investigation of CPA4's involvement in immune responses may contribute to the development of immunotherapeutic strategies for ccRCC treatment.
Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Biomarcadores , Neoplasias Renais/genética , Proliferação de Células/genética , Microambiente Tumoral/genéticaRESUMO
Eukaryotic cells engage in autophagy, an internal process of self-degradation through lysosomes. Autophagy can be classified as selective or non-selective depending on the way it chooses to degrade substrates. During the process of selective autophagy, damaged and/or redundant organelles like mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes, and lipid droplets are selectively recycled. Specific cargo is delivered to autophagosomes by specific receptors, isolated and engulfed. Selective autophagy dysfunction is closely linked with cancers, neurodegenerative diseases, metabolic disorders, heart failure, etc. Through reviewing latest research, this review summarized molecular markers and important signaling pathways for selective autophagy, and its significant role in cancers. Moreover, we conducted a comprehensive analysis of small-molecule compounds targeting selective autophagy for their potential application in anti-tumor therapy, elucidating the underlying mechanisms involved. This review aims to supply important scientific references and development directions for the biological mechanisms and drug discovery of anti-tumor targeting selective autophagy in the future.
Assuntos
Autofagia , Neoplasias , Humanos , Autofagossomos , Núcleo Celular , Descoberta de DrogasRESUMO
BACKGROUND: Parkinson's disease (PD) patients exhibit an imbalance between neuronal activity and perfusion, referred to as abnormal neurovascular coupling (NVC). Nevertheless, the underlying molecular mechanism and how levodopa, the standard treatment in PD, regulates NVC is largely unknown. MATERIAL AND METHODS: A total of 52 drug-naïve PD patients and 49 normal controls (NCs) were enrolled. NVC was characterized in vivo by relating cerebral blood flow (CBF) and amplitude of low-frequency fluctuations (ALFF). Motor assessments and MRI scanning were conducted on drug-naïve patients before and after levodopa therapy (OFF/ON state). Regional NVC differences between patients and NCs were identified, followed by an assessment of the associated receptors/transporters. The influence of levodopa on NVC, CBF, and ALFF within these abnormal regions was analyzed. RESULTS: Compared to NCs, OFF-state patients showed NVC dysfunction in significantly lower NVC in left precentral, postcentral, superior parietal cortex, and precuneus, along with higher NVC in left anterior cingulate cortex, right olfactory cortex, thalamus, caudate, and putamen (P-value <0.0006). The distribution of NVC differences correlated with the density of dopaminergic, serotonin, MU-opioid, and cholinergic receptors/transporters. Additionally, levodopa ameliorated abnormal NVC in most of these regions, where there were primarily ALFF changes with limited CBF modifications. CONCLUSION: Patients exhibited NVC dysfunction primarily in the striato-thalamo-cortical circuit and motor control regions, which could be driven by dopaminergic and nondopaminergic systems, and levodopa therapy mainly restored abnormal NVC by modulating neuronal activity.
Assuntos
Acoplamento Neurovascular , Doença de Parkinson , Humanos , Levodopa/farmacologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Putamen , Circulação Cerebrovascular , DopaminaRESUMO
Iron is essential for many physiological processes, and the dysregulation of its metabolism is implicated in the pathogenesis of various diseases. Recent advances in iron metabolism research have revealed multiple complex pathways critical for maintaining iron homeostasis. Molecular imaging, an interdisciplinary imaging technique, has shown considerable promise in advancing research on iron metabolism. Here, we comprehensively review the multifaceted roles of iron at the cellular and systemic levels (along with the complex regulatory mechanisms of iron metabolism), elucidate appropriate imaging methods, and summarize their utility and fundamental principles in diagnosing and treating diseases related to iron metabolism. Utilizing molecular imaging technology to deeply understand the complexities of iron metabolism and its critical role in physiological and pathological processes offers new possibilities for early disease diagnosis, treatment monitoring, and the development of novel therapies. Despite technological limitations and the need to ensure the biological relevance and clinical applicability of imaging results, molecular imaging technology's potential to reveal the iron metabolic process is unparalleled, providing new insights into the link between iron metabolism abnormalities and various diseases.
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Plant secondary metabolites, including furanocoumarins, have attracted attention for decades as active molecules with therapeutic potential, especially those occurring in a limited number of species as evolutionarily specific and chemotaxonomically important. The most famous methoxyfuranocoumarins (MFCs), bergapten, xanthotoxin, isopimpinellin, phellopterin, byakangelicol, byakangelicin, isobergapten, pimpinellin, sphondin, as well as rare ones such as peucedanin and 8-methoxypeucedanin, apaensin, cnidilin, moellendorffiline and dahuribiethrins, have recently been investigated for their various biological activities. The α-glucosidase inhibitory activity and antioxidant potential of moellendorffiline, the antiproliferative and proapoptotic properties of non-UV-activated bergapten and xanthotoxin, the effect of MFC on the activity of tyrosinase, acetyl- and butylcholinesterase, and the role of these compounds as adjuvants in anticancer and antibacterial tests have been confirmed. The anticonvulsant effects of halfordin, the antidepressant effects of xanthotoxin, and the antiadipogenic, neuroprotective, anti-amyloid-ß, and anti-inflammatory (via increasing SIRT 1 protein expression) properties of phellopterin, as well as the activity of sphondin against hepatitis B virus, have also attracted interest. It is worth paying attention to the agonistic effect of xanthotoxin on bitter taste receptors (TAS2Rs) on cardiomyocytes, which may be important in the future treatment of tachycardia, as well as the significant anti-inflammatory activity of dahuribiethrins. It should be emphasized that MFCs, although in many cases isolated for the first time many years ago, are still of great interest as bioactive molecules. The aim of this review is to highlight key recent developments in the study of the diverse biological activities of MFCs and attempt to highlight promising directions for their further research. Where possible, descriptions of the mechanisms of action of MFC are provided, which is related to the constantly discovered therapeutic potential of these molecules. The review covers the results of experiments from the last ten years (2014-2023) conducted on isolated natural cMFCs and includes the activity of molecules that have not been activated by UV rays.
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Despite recent advances in tumor diagnosis and treatment technologies, the number of cancer cases and deaths worldwide continues to increase yearly, creating an urgent need to find new methods to prevent or treat cancer. Sulforaphane (SFN), as a member of the isothiocyanates (ITCs) family, which is the hydrolysis product of glucosinolates (GLs), has been shown to have significant preventive and therapeutic cancer effects in different human cancers. Early studies have shown that SFN scavenges oxygen radicals by increasing cellular defenses against oxidative damage, mainly through the induction of phase II detoxification enzymes by nuclear factor erythroid 2-related factor 2 (Nrf2). More and more studies have shown that the anticancer mechanism of SFN also includes induction of apoptotic pathway in tumor cells, inhibition of cell cycle progression, and suppression of tumor stem cells. Therefore, the application of SFN is expected to be a necessary new approach to treating cancer. In this paper, we review the multiple molecular mechanisms of SFN in cancer prevention and treatment in recent years, which can provide a new vision for cancer treatment.
Assuntos
Anticarcinógenos , Isotiocianatos , Neoplasias , Sulfóxidos , Isotiocianatos/farmacologia , Isotiocianatos/uso terapêutico , Sulfóxidos/farmacologia , Sulfóxidos/uso terapêutico , Humanos , Neoplasias/prevenção & controle , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismoRESUMO
The emergence of drug-resistant bacteria, facilitated by metallo-beta-lactamases (MBLs), presents a significant obstacle to the effective use of antibiotics in the management of clinical drug-resistant bacterial infections. AFM-1 is a MBL derived from Alcaligenes faecalis and shares 86% homology with the NDM-1 family. Both AFM-1 and NDM-1 demonstrate the ability to hydrolyze ampicillin and other ß-lactam antibiotics, however, their substrate affinities vary, and the specific reason for this variation remains unknown. We present the high-resolution structure of AFM-1. The active center of AFM-1 binds two zinc ions, and the conformation of the key amino acid residues in the active center is in accordance with that of NDM-1. However, the substrate-binding pocket of AFM-1 is considerably smaller than that of NDM-1. Additionally, the mutation of amino acid residues in the Loop3 region, as compared to NDM-1, results in the formation of a dense hydrophobic patch comprised of hydrophobic amino acid residues in this area, which facilitates substrate binding. Our findings lay the foundation for understanding the molecular mechanism of AFM-1 with a high affinity for substrates and provide a novel theoretical foundation for addressing the issue of drug resistance caused by B1 MBLs.
Assuntos
Modelos Moleculares , beta-Lactamases , beta-Lactamases/química , beta-Lactamases/metabolismo , beta-Lactamases/ultraestrutura , beta-Lactamases/genética , Alcaligenes faecalis/enzimologia , Alcaligenes faecalis/química , Conformação Proteica , Zinco/química , Zinco/metabolismo , Cristalografia por Raios X , Domínio Catalítico , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Sequência de Aminoácidos , Sítios de LigaçãoRESUMO
BACKGROUND: Postharvest quality deterioration poses a significant challenge to the commercial value of fresh lotus seeds. Low temperature storage is widely employed as the primary method for preserving postharvest lotus seeds during storage and transportation. RESULTS: This approach effectively extends the storage life of lotus seeds, resulting in distinct physiological changes compared to room temperature storage, including a notable reduction in starch, protein, H2O2, and MDA content. Here, we conducted RNA-sequencing to generate global transcriptome profiles of postharvest lotus seeds stored under room or low temperature conditions. Principal component analysis (PCA) revealed that gene expression in postharvest lotus seeds demonstrated less variability during low temperature storage in comparison to room temperature storage. A total of 14,547 differentially expressed genes (DEGs) associated with various biological processes such as starch and sucrose metabolism, energy metabolism, and plant hormone signaling response were identified. Notably, the expression levels of DEGs involved in ABA signaling were significantly suppressed in contrast to room temperature storage. Additionally, nine weighted gene co-expression network analysis (WGCNA)-based gene molecular modules were identified, providing insights into the co-expression relationship of genes during postharvest storage. CONCLUSION: Our findings illuminate transcriptional differences in postharvest lotus seeds between room and low temperature storage, offering crucial insights into the molecular mechanisms of low temperature preservation in lotus seeds.
Assuntos
Temperatura Baixa , Sementes , Transcriptoma , Sementes/genética , Lotus/genética , Lotus/fisiologia , Lotus/metabolismo , Regulação da Expressão Gênica de Plantas , Perfilação da Expressão GênicaRESUMO
BACKGROUND: Wheat, a crucial food crop in China, is highly vulnerable to drought stress throughout its growth and development. WRKY transcription factors (TFs), being one of the largest families of TFs, play a vital role in responding to various abiotic stresses in plants. RESULTS: Here, we cloned and characterized the TF TaWRKY31 isolated from wheat. This TF, belonging to the WRKY II family, contains a WRKYGQK amino acid sequence and a C2H2-type zinc finger structure. TaWRKY31 exhibits tissue-specific expression and demonstrates responsiveness to abiotic stresses in wheat. TaWRKY31 protein is localized in the nucleus and can function as a TF with transcription activating activity at the N-terminus. Results showed that the wheat plants with silenced strains (BSMV:TaWRKY31-1as and BSMV:TaWRKY31-2as) exhibited poor growth status and low relative water content when subjected to drought treatment. Moreover, the levels of O2·-, H2O2, and malondialdehyde (MDA) in the BSMV:TaWRKY31-induced wheat plants increased, while the activities of antioxidant enzymes (superoxide dismutase, peroxidase, and catalase) decreased. Compared to control plants, BSMV:TaWRKY31-induced wheat plants exhibited lower expression levels of TaSOD (Fe), TaPOD, TaCAT, TaDREB1, TaP5CS, TaNCED1, TaSnRK2, TaPP2C, and TaPYL5.Under stress or drought treatment conditions, the overexpression of TaWRKY31 in Arabidopsis resulted in decreased levels of H2O2 and MDA, as well as reduced stomatal opening and water loss. Furthermore, an increase in resistance oxidase activity, germination rate, and root length in the TaWRKY31 transgenic Arabidopsis was observed. Lastly, overexpression of TaWRKY31 in Arabidopsis resulted in higher the expression levels of AtNCED3, AtABA2, AtSnRK2.2, AtABI1, AtABF3, AtP5CS1, AtSOD (Cu/Zn), AtPOD, AtCAT, AtRD29A, AtRD29B, and AtDREB2A than in control plants. CONCLUSIONS: Our findings indicate that TaWRKY31 enhances drought resistance in plants by promoting the scavenging of reactive oxygen species, reducing stomatal opening, and increasing the expression levels of stress-related genes.
Assuntos
Arabidopsis , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Secas , Arabidopsis/metabolismo , Triticum/genética , Triticum/metabolismo , Resistência à Seca , Peróxido de Hidrogênio/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Regulação da Expressão Gênica de Plantas , Estresse Fisiológico/genética , Água/metabolismoRESUMO
Varicella-zoster virus (VZV), a common pathogen with humans as the sole host, causes primary infection and undergoes a latent period in sensory ganglia. The recurrence of VZV is often accompanied by severe neuralgia in skin tissue, which has a serious impact on the life of patients. During the acute infection of VZV, there are few related studies on the pathophysiological mechanism of skin tissue. In this study, transcriptome sequencing data from the acute response period within 2 days of VZV antigen stimulation of the skin were used to explore a model of the trajectory of skin tissue changes during VZV infection. It was found that early VZV antigen stimulation caused activation of mainly natural immune-related signaling pathways, while in the late phase activation of mainly active immune-related signaling pathways. JAK-STAT, NFκB, and TNFα signaling pathways are gradually activated with the progression of infection, while Hypoxia is progressively inhibited. In addition, we found that dendritic cell-mediated immune responses play a dominant role in the lesion damage caused by VZV antigen stimulation of the skin. This study provides a theoretical basis for the study of the molecular mechanisms of skin lesions during acute VZV infection.
Assuntos
Herpesvirus Humano 3 , Transdução de Sinais , Pele , Infecção pelo Vírus da Varicela-Zoster , Herpesvirus Humano 3/genética , Pele/patologia , Pele/virologia , Pele/imunologia , Animais , Infecção pelo Vírus da Varicela-Zoster/virologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Infecção pelo Vírus da Varicela-Zoster/genética , Infecção pelo Vírus da Varicela-Zoster/patologia , Humanos , Camundongos , Células Dendríticas/imunologia , Herpes Zoster/virologia , Herpes Zoster/patologia , Herpes Zoster/genética , Herpes Zoster/imunologia , Transcriptoma , Modelos Animais de Doenças , Antígenos Virais/imunologia , Antígenos Virais/genética , NF-kappa B/metabolismo , NF-kappa B/genéticaRESUMO
Ovarian cancer is a major cause of death among cancer patients. Recent research has shown that the transmembrane emp24 domain (TMED) protein family plays a role in the progression of various types of cancer. In this study, we investigated the expression of TMED3 in ovarian cancer tumors compared to nontumor tissues using immunohistochemical staining. We found that TMED3 was overexpressed in ovarian cancer tumors, and its high expression was associated with poor disease-free and overall survival. To understand the functional implications of TMED3 overexpression in ovarian cancer, we conducted experiments to knockdown TMED3 using short hairpin RNA (shRNA). We observed that TMED3 knockdown resulted in reduced cell viability and migration, as well as increased cell apoptosis. Additionally, in subcutaneous xenograft models in BALB-c nude mice, TMED3 knockdown inhibited tumor growth. Further investigation revealed that SMAD family member 2 (SMAD2) was a downstream target of TMED3, driving ovarian cancer progression. TMED3 stabilized SMAD2 by inhibiting the E3 ligase NEDD4-mediated ubiquitination of SMAD2. To confirm the importance of SMAD2 in TMED3-mediated ovarian cancer, we performed functional rescue experiments and found that SMAD2 played a critical role in this process. Moreover, we discovered that the PI3K-AKT pathway was involved in the promoting effects of TMED3 overexpression on ovarian cancer cells. Overall, our study identifies TMED3 as a prognostic indicator and tumor promoter in ovarian cancer. Its function is likely mediated through the regulation of the SMAD2 and PI3K-AKT signaling pathway. These findings contribute to our understanding of the molecular mechanisms underlying ovarian cancer progression and provide potential targets for therapeutic intervention.