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1.
Biomaterials ; 312: 122707, 2025 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39121729

RESUMO

Polypyrimidine tract-binding protein 1 (PTBP1) regulates numerous alternative splicing events during tumor progression and neurogenesis. Previously, PTBP1 downregulation was reported to convert astrocytes into functional neurons; however, how PTBP1 regulates astrocytic physiology remains unclear. In this study, we revealed that PTBP1 modulated glutamate uptake via ATP1a2, a member of Na+/K+-ATPases, and glutamate transporters in astrocytes. Ptbp1 knockdown altered mitochondrial function and energy metabolism, which involved PTBP1 regulating mitochondrial redox homeostasis via the succinate dehydrogenase (SDH)/Nrf2 pathway. The malfunction of glutamate transporters following Ptbp1 knockdown resulted in enhanced excitatory synaptic transmission in the cortex. Notably, we developed a biomimetic cationic triblock polypeptide system, i.e., polyethylene glycol44-polylysine30-polyleucine10 (PEG44-PLL30-PLLeu10) with astrocytic membrane coating to deliver Ptbp1 siRNA in vitro and in vivo, which approach allowed Ptbp1 siRNA to efficiently cross the blood-brain barrier and target astrocytes in the brain. Collectively, our findings suggest a framework whereby PTBP1 serves as a modulator in glutamate transport machinery, and indicate that biomimetic methodology is a promising route for in vivo siRNA delivery.


Assuntos
Astrócitos , Ácido Glutâmico , Ribonucleoproteínas Nucleares Heterogêneas , Homeostase , Fator 2 Relacionado a NF-E2 , Proteína de Ligação a Regiões Ricas em Polipirimidinas , RNA Interferente Pequeno , Animais , Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Camundongos , Transdução de Sinais , Membrana Celular/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Humanos , Mitocôndrias/metabolismo
2.
Mol Cell ; 84(17): 3169-3171, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39241750

RESUMO

In this issue of Molecular Cell, Xie et al.1 revealed that the proteasome is a constitutive component of plant stress granules (SGs), and that enhanced proteolytic activity is essential for efficient SG disassembly and plant survival during the stress response.


Assuntos
Grânulos Citoplasmáticos , Homeostase , Complexo de Endopeptidases do Proteassoma , Estresse Fisiológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Grânulos Citoplasmáticos/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/enzimologia , Proteólise
3.
Proc Natl Acad Sci U S A ; 121(38): e2321525121, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39250660

RESUMO

A major next step in hematopoietic stem cell (HSC) biology is to enhance our quantitative understanding of cellular and evolutionary dynamics involved in undisturbed hematopoiesis. Mathematical models have been and continue to be key in this respect, and are most powerful when parameterized experimentally and containing sufficient biological complexity. In this paper, we use data from label propagation experiments in mice to parameterize a mathematical model of hematopoiesis that includes homeostatic control mechanisms as well as clonal evolution. We find that nonlinear feedback control can drastically change the interpretation of kinetic estimates at homeostasis. This suggests that short-term HSC and multipotent progenitors can dynamically adjust to sustain themselves temporarily in the absence of long-term HSCs, even if they differentiate more often than they self-renew in undisturbed homeostasis. Additionally, the presence of feedback control in the model renders the system resilient against mutant invasion. Invasion barriers, however, can be overcome by a combination of age-related changes in stem cell differentiation and evolutionary niche construction dynamics based on a mutant-associated inflammatory environment. This helps us understand the evolution of e.g., TET2 or DNMT3A mutants, and how to potentially reduce mutant burden.


Assuntos
Diferenciação Celular , Hematopoese , Células-Tronco Hematopoéticas , Mutação , Animais , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Hematopoese/genética , Hematopoese/fisiologia , DNA Metiltransferase 3A/metabolismo , Homeostase , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Modelos Biológicos , Linhagem da Célula , Dioxigenases , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Evolução Clonal , Modelos Teóricos
4.
Semin Immunopathol ; 46(5): 15, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39240397

RESUMO

Over the last few decades, scientists have recognized the critical role that various components of the extracellular matrix (ECM) play in maintaining homeostatic immunity. Besides, dysregulation in the synthesis or degradation levels of these components directly impacts the mechanisms of immune response during tissue injury caused by tumor processes or the regeneration of the tissue itself in the event of damage. ECM is a complex network of protein compounds, proteoglycans and glycosaminoglycans (GAGs). Hyaluronic acid (HA) is one of the major GAGs of this network, whose metabolism is strictly physiologically regulated and quickly altered in injury processes, affecting the behavior of different cells, from stem cells to differentiated immune cells. In this revision we discuss how the native or chemically modified HA interacts with its specific receptors and modulates intra and intercellular communication of immune cells, focusing on cancer and tissue regeneration conditions.


Assuntos
Homeostase , Ácido Hialurônico , Neoplasias , Regeneração , Humanos , Ácido Hialurônico/metabolismo , Ácido Hialurônico/química , Neoplasias/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Animais , Matriz Extracelular/metabolismo , Imunidade
5.
Cell Mol Biol Lett ; 29(1): 116, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237893

RESUMO

Lysosomes are acidic organelles involved in crucial intracellular functions, including the degradation of organelles and protein, membrane repair, phagocytosis, endocytosis, and nutrient sensing. Given these key roles of lysosomes, maintaining their homeostasis is essential for cell viability. Thus, to preserve lysosome integrity and functionality, cells have developed a complex intracellular system, called lysosome quality control (LQC). Several stressors may affect the integrity of lysosomes, causing Lysosomal membrane permeabilization (LMP), in which membrane rupture results in the leakage of luminal hydrolase enzymes into the cytosol. After sensing the damage, LQC either activates lysosome repair, or induces the degradation of the ruptured lysosomes through autophagy. In addition, LQC stimulates the de novo biogenesis of functional lysosomes and lysosome exocytosis. Alterations in LQC give rise to deleterious consequences for cellular homeostasis. Specifically, the persistence of impaired lysosomes or the malfunctioning of lysosomal processes leads to cellular toxicity and death, thereby contributing to the pathogenesis of different disorders, including neurodegenerative diseases (NDs). Recently, several pieces of evidence have underlined the importance of the role of lysosomes in NDs. In this review, we describe the elements of the LQC system, how they cooperate to maintain lysosome homeostasis, and their implication in the pathogenesis of different NDs.


Assuntos
Lisossomos , Doenças Neurodegenerativas , Lisossomos/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo , Animais , Homeostase , Autofagia
6.
Front Immunol ; 15: 1443297, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224588

RESUMO

α -1 antitrypsin (A1AT) is a 52 kDa acute-phase glycoprotein belonging to the serine protease inhibitor superfamily (SERPIN). It is primarily synthesized by hepatocytes and to a lesser extent by monocytes, macrophages, intestinal epithelial cells, and bronchial epithelial cells. A1AT is encoded by SERPINA1 locus, also known as PI locus, highly polymorphic with at least 100 allelic variants described and responsible for different A1AT serum levels and function. A1AT inhibits a variety of serine proteinases, but its main target is represented by Neutrophil Elastase (NE). However, recent attention has been directed towards its immune-regulatory and homeostatic activities. A1AT exerts immune-regulatory effects on different cell types involved in innate and adaptive immunity. Additionally, it plays a role in metal and lipid metabolism, contributing to homeostasis. An adequate comprehension of these mechanisms could support the use of A1AT augmentation therapy in many disorders characterized by a chronic immune response. The aim of this review is to provide an up-to-date understanding of the molecular mechanisms and regulatory pathways responsible for immune-regulatory and homeostatic activities of A1AT. This knowledge aims to support the use of A1AT in therapeutic applications. Furthermore, the review summarizes the current state of knowledge regarding the application of A1AT in clinical and laboratory settings human and animal models.


Assuntos
Homeostase , alfa 1-Antitripsina , Humanos , alfa 1-Antitripsina/imunologia , alfa 1-Antitripsina/uso terapêutico , alfa 1-Antitripsina/metabolismo , Animais , Imunidade Inata , Imunidade Adaptativa
7.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 46(4): 592-602, 2024 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-39223024

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease with the main manifestations of progressive cognitive dysfunction,behavioral disorders,and gradual decline of living ability.The etiology of AD is complex,and the pathogenesis of this disease remains controversial.Calcium signaling plays an important role in regulating neuronal activities,including neurotransmitter release,synaptic plasticity,memory storage,and neuronal apoptosis.Increasing studies have shown that neuronal calcium dyshomeostasis is a major pathological factor in the occurrence and development of AD.This article reviews the role and research progress in intracellular calcium dyshomeostasis in AD,including the relationship between calcium homeostasis and amyloid ß,the role of calcium/calmodulin-dependent protein kinases in tau phosphorylation,calcium signaling pathways,the relationship between calcium homeostasis and mitochondrial function,autophagy,and neuroinflammation.


Assuntos
Doença de Alzheimer , Cálcio , Homeostase , Doença de Alzheimer/metabolismo , Humanos , Cálcio/metabolismo , Peptídeos beta-Amiloides/metabolismo , Sinalização do Cálcio/fisiologia , Mitocôndrias/metabolismo , Proteínas tau/metabolismo , Autofagia/fisiologia , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Neurônios/metabolismo , Fosforilação
8.
Drug Des Devel Ther ; 18: 3811-3824, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39219694

RESUMO

Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs. Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model. Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity. Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.


Assuntos
Homeostase , Isoindóis , Testes de Sensibilidade Microbiana , Compostos Organosselênicos , Oxirredução , Estreptomicina , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/química , Isoindóis/farmacologia , Animais , Camundongos , Homeostase/efeitos dos fármacos , Estreptomicina/farmacologia , Antituberculosos/farmacologia , Antituberculosos/química , Mycobacterium marinum/efeitos dos fármacos , Azóis/farmacologia , Azóis/química , Relação Dose-Resposta a Droga , Antibacterianos/farmacologia , Antibacterianos/química , Relação Estrutura-Atividade , Estrutura Molecular , Camundongos Endogâmicos BALB C
9.
Adv Anat Embryol Cell Biol ; 239: 57-90, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39283482

RESUMO

The existence of functionally diverse and plastic ß cells in islets of Langerhans has been reported since the 1980s. Recently, high-resolution technologies have advanced our understanding of ß-cell heterogeneity and plasticity. Here, we define plasticity broadly as dynamic changes in cellular phenotypes and heterogeneity as differences in cellular behaviors. Individual ß cells react differently to environmental challenges and act together to maintain ß-cell mass and glucose homeostasis within a narrow range of 70-140 mg/dL. During the progress of diabetes, this elaborate balance is disrupted, and a lack of ß-cell compensation leads to dysregulated blood glucose. In this chapter, we assess ß-cell stress that instigates increased ß-cell heterogeneity and adaptive ß-cell responses such as proliferation, dedifferentiation, maturity, and insulin secretion. We also discuss the maturity, electrical activity, and insulin secretion of well-characterized ß-cell subgroups. Finally, we touch upon the plasticity of other non-ß pancreatic cells and their cooperation with ß cells to maintain homeostasis.


Assuntos
Plasticidade Celular , Células Secretoras de Insulina , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Humanos , Animais , Secreção de Insulina , Insulina/metabolismo , Homeostase
10.
J Cell Mol Med ; 28(17): e70090, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39261902

RESUMO

Mitochondrial dysfunction is a pivotal event contributing to the development of ageing-related kidney disorders. Lon protease 1 (LONP1) has been reported to be responsible for ageing-related renal fibrosis; however, the underlying mechanism(s) of LONP1-driven kidney ageing with respect to mitochondrial disturbances remains to be further explored. The level of LONP1 was tested in the kidneys of aged humans and mice. Renal fibrosis and mitochondrial quality control were confirmed in the kidneys of aged mice. Effects of LONP1 silencing or overexpression on renal fibrosis and mitochondrial quality control were explored. In addition, N6-methyladenosine (m6A) modification and methyltransferase like 3 (METTL3) levels, the relationship between LONP1 and METTL3, and the impacts of METTL3 overexpression on mitochondrial functions were confirmed. Furthermore, the expression of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and the regulatory effects of IGF2BP2 on LONP1 were confirmed in vitro. LONP1 expression was reduced in the kidneys of aged humans and mice, accompanied by renal fibrosis and mitochondrial dysregulation. Overexpression of LONP1 alleviated renal fibrosis and maintained mitochondrial homeostasis, while silencing of LONP1 had the opposite effect. Impaired METTL3-m6A signalling contributed at least in part to ageing-induced LONP1 modification, reducing subsequent degradation in an IGF2BP2-dependent manner. Moreover, METTL3 overexpression alleviated proximal tubule cell injury, preserved mitochondrial stability, inhibited LONP1 degradation, and protected mitochondrial functions. LONP1 mediates mitochondrial function in kidney ageing and that targeting LONP1 may be a potential therapeutic strategy for improving ageing-related renal fibrosis.


Assuntos
Adenosina , Envelhecimento , Fibrose , Homeostase , Nefropatias , Rim , Metiltransferases , Mitocôndrias , Proteínas Mitocondriais , Proteínas de Ligação a RNA , Mitocôndrias/metabolismo , Animais , Metiltransferases/metabolismo , Metiltransferases/genética , Humanos , Envelhecimento/metabolismo , Camundongos , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Rim/patologia , Rim/metabolismo , Masculino , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/etiologia , Nefropatias/genética , Proteases Dependentes de ATP/metabolismo , Proteases Dependentes de ATP/genética , Transdução de Sinais , Camundongos Endogâmicos C57BL
11.
Biol Sex Differ ; 15(1): 72, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39278930

RESUMO

BACKGROUND: Sex differences exist in the prevalence and progression of major glomerular diseases. Podocytes are the essential cell-type in the kidney which maintain the physiological blood-urine barrier, and pathological changes in podocyte homeostasis are critical accelerators of impairment of kidney function. However, sex-specific molecular signatures of podocytes under physiological and stress conditions remain unknown. This work aimed at identifying sexual dimorphic molecular signatures of podocytes under physiological condition and pharmacologically challenged homeostasis with mechanistic target of rapamycin (mTOR) inhibition. mTOR is a crucial regulator involved in a variety of physiological and pathological stress responses in the kidney and inhibition of this pathway may therefore serve as a general stress challenger to get fundamental insights into sex differences in podocytes. METHODS: The genomic ROSAmT/mG-NPHS2 Cre mouse model was used which allows obtaining highly pure podocyte fractions for cell-specific molecular analyses, and vehicle or pharmacologic treatment with the mTOR inhibitor rapamycin was performed for 3 weeks. Subsequently, deep RNA sequencing and proteomics were performed of the isolated podocytes to identify intrinsic sex differences. Studies were supplemented with metabolomics from kidney cortex tissues. RESULTS: Although kidney function and morphology remained normal in all experimental groups, RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways. Interestingly, rapamycin abolished prominent sex-specific clustering of podocyte gene expression and induced major changes only in male transcriptome. Several sex-biased transcription factors could be identified as possible upstream regulators of these sexually dimorphic responses. Concordant to transcriptomics, metabolomic changes were more prominent in males. Remarkably, high number of previously reported kidney disease genes showed intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition. CONCLUSIONS: Our results highlight remarkable intrinsic sex-differences and sex-specific response patterns towards pharmacological challenged podocyte homeostasis which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. This work provides rationale and an in-depth database for novel targets to be tested in specific kidney disease models to advance with sex-specific treatment strategies.


The global burden of chronic kidney diseases is rapidly increasing and is projected to become the fifth most common cause of years of life lost worldwide by 2040. Sexual dimorphism in kidney diseases and transplantation is well known, yet sex-specific therapeutic strategies are still missing. One reason is the lack of knowledge due to the lack of inclusion of sex as a biological variable in study designs. This work aimed at identification of molecular signatures of male and female podocytes, gate-keepers of the glomerular filtration barrier. Like cardiomyocytes, podocytes are terminally differentiated cells which are highly susceptible towards pathological challenges. Podocytes are the decisive cell-type of the kidney to maintain the physiological blood-urine barrier, and disturbances of their homeostasis critically accelerate kidney function impairment. By help of a genomic mouse model, highly purified podocytes were obtained from male and female mice with and without pharmacological challenge of the mechanistic target of rapamycin (mTOR) signaling pathway which is known to be deregulated in major kidney diseases. Deep RNA sequencing, proteomics and metabolomics revealed strong intrinsic sex differences in the expression levels of mitochondrial, translation and structural transcripts, protein abundances and regulation of metabolic pathways which might fundamentally contribute to sex differences in kidney disease susceptibilities and progression. Remarkably, high number of previously reported kidney disease genes showed so far unknown intrinsic sexual dimorphism and/or different response patterns towards mTOR inhibition. Our work provides an in-depth database for novel targets to be tested in kidney disease models to advance with sex-specific treatment strategies.


Assuntos
Homeostase , Podócitos , Caracteres Sexuais , Sirolimo , Animais , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Masculino , Feminino , Sirolimo/farmacologia , Homeostase/efeitos dos fármacos , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Transcriptoma , Inibidores de MTOR/farmacologia
12.
J Cell Mol Med ; 28(17): e70050, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39223947

RESUMO

Cardiovascular disease remains one of the leading causes of death globally. Recent advancements in sequencing technologies have led to the identification of a unique population of macrophages within the heart, termed cardiac resident macrophages (CRMs), which exhibit self-renewal capabilities and play crucial roles in regulating cardiac homeostasis, inflammation, as well as injury and repair processes. This literature review aims to elucidate the origin and phenotypic characteristics of CRMs, comprehensively outline their contributions to cardiac homeostasis and further summarize their functional roles and molecular mechanisms implicated in the onset and progression of cardiovascular diseases. These insights are poised to pave the way for novel therapeutic strategies centred on targeted interventions based on the distinctive properties of resident macrophages.


Assuntos
Inflamação , Macrófagos , Humanos , Macrófagos/metabolismo , Animais , Inflamação/patologia , Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/citologia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/metabolismo , Homeostase
13.
Gut Microbes ; 16(1): 2393272, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224006

RESUMO

The intestine is the largest organ in terms of surface area in the human body. It is responsible not only for absorbing nutrients but also for protection against the external world. The gut microbiota is essential in maintaining a properly functioning intestinal barrier, primarily through producing its metabolites: short-chain fatty acids, bile acids, and tryptophan derivatives. Ethanol overconsumption poses a significant threat to intestinal health. Not only does it damage the intestinal epithelium, but, maybe foremostly, it changes the gut microbiome. Those ethanol-driven changes shift its metabolome, depriving the host of the protective effect the physiological gut microbiota has. This literature review discusses the impact of ethanol consumption on the gut, the gut microbiota, and its metabolome, providing a comprehensive overview of the mechanisms through which ethanol disrupts intestinal homeostasis and discussing potential avenues for new therapeutic intervention.


Assuntos
Etanol , Microbioma Gastrointestinal , Homeostase , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Etanol/metabolismo , Etanol/farmacologia , Animais , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestinos/microbiologia , Intestinos/efeitos dos fármacos
14.
Development ; 151(18)2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39222051

RESUMO

Male infertility can be caused by chromosomal abnormalities, mutations and epigenetic defects. Epigenetic modifiers pre-program hundreds of spermatogenic genes in spermatogonial stem cells (SSCs) for expression later in spermatids, but it remains mostly unclear whether and how those genes are involved in fertility. Here, we report that Wfdc15a, a WFDC family protease inhibitor pre-programmed by KMT2B, is essential for spermatogenesis. We found that Wfdc15a is a non-canonical bivalent gene carrying both H3K4me3 and facultative H3K9me3 in SSCs, but is later activated along with the loss of H3K9me3 and acquisition of H3K27ac during meiosis. We show that WFDC15A deficiency causes defective spermiogenesis at the beginning of spermatid elongation. Notably, depletion of WFDC15A causes substantial disturbance of the testicular protease-antiprotease network and leads to an orchitis-like inflammatory response associated with TNFα expression in round spermatids. Together, our results reveal a unique epigenetic program regulating innate immunity crucial for fertility.


Assuntos
Homeostase , Espermátides , Espermatogênese , Masculino , Animais , Espermatogênese/genética , Camundongos , Espermátides/metabolismo , Testículo/metabolismo , Histonas/metabolismo , Peptídeo Hidrolases/metabolismo , Peptídeo Hidrolases/genética , Epigênese Genética , Infertilidade Masculina/genética , Camundongos Endogâmicos C57BL , Meiose/genética , Células-Tronco Germinativas Adultas/metabolismo , Camundongos Knockout , Imunidade Inata/genética , Espermatogônias/metabolismo
15.
Cell Death Dis ; 15(9): 656, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39242581

RESUMO

Thyroid cancer is the most frequently observed endocrine-related malignancy among which anaplastic thyroid cancer (ATC) is the most fatal subtype. The synthesis of protein is active to satisfy the rapid growth of ATC tumor, but the mechanisms regulating protein synthesis are still unknown. Our research revealed that kinetochore protein NUF2 played an essential role in protein synthesis and drove the progression of ATC. The prognosis of patients with thyroid carcinoma was positively correlated with high NUF2 expression. Depletion of NUF2 in ATC cells notably inhibited the proliferation and induced apoptosis, while overexpression of NUF2 facilitated ATC cell viability and colony formation. Deletion of NUF2 significantly suppressed the growth and metastasis of ATC in vivo. Notably, knockdown of NUF2 epigenetically inhibited the expression of magnesium transporters through reducing the abundance of H3K4me3 at promoters, thereby reduced intracellular Mg2+ concentration. Furthermore, we found the deletion of NUF2 or magnesium transporters significantly inhibited the protein synthesis mediated by the PI3K/Akt/mTOR pathway. In conclusion, NUF2 functions as an emerging regulator for protein synthesis by maintaining the homeostasis of intracellular Mg2+, which finally drives ATC progression.


Assuntos
Progressão da Doença , Homeostase , Magnésio , Carcinoma Anaplásico da Tireoide , Animais , Feminino , Humanos , Camundongos , Apoptose , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Magnésio/metabolismo , Camundongos Nus , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Serina-Treonina Quinases TOR/metabolismo
16.
Mar Pollut Bull ; 207: 116926, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39244887

RESUMO

The heavy metal lead (Pb) pollution in marine environment has been widely concerned. The liver and intestine are important for the health of fish. In this study, the grouper were exposed to 1 µg/L Pb for 14 days, and the physiological homeostasis changes were explored via gut-liver axis. The results showed that Pb stress caused liver morphological changes, oxidative stress, and the accumulation and peroxidation of the lipids. The liver metabolism were disturbed, especially amino acid metabolism and the synthesis and degradation of ketone bodies. Pb stress also caused intestinal mucosal ablation, tight junction dysfunction and inflammatory response. Additionally, intestinal microbial diversity was decreased, and the community composition was altered especially several bacteria genera (Ruminococcus UCG-005, Ruminococcus UCG-014, Oscillibacter, and Streptococcus) were significantly correlated with the physiological indexes and metabolites of the liver. These results reveal that Pb stress negatively affect the physiological homeostasis of the grouper via gut-liver axis.


Assuntos
Microbioma Gastrointestinal , Homeostase , Chumbo , Fígado , Poluentes Químicos da Água , Animais , Chumbo/toxicidade , Fígado/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Estresse Oxidativo , Bass/fisiologia
17.
Sci Rep ; 14(1): 21398, 2024 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271793

RESUMO

Gestational diabetes mellitus (GDM) adversely affects offspring glucose homeostasis and risk of developing obesity. Here, we examined the association between glycemia in pregnant women with overweight or obesity without GDM and offspring metabolic health. Maternal fasting glucose concentrations and glucose 2-h after an oral glucose tolerance test (OGTT) were measured in 208 women with a pre-pregnancy body mass index (BMI) of 28-45 kg/m2 without GDM. Offspring outcomes were collected at birth, 3, and 5 years of age. Linear mixed models with time as fixed factor and subject ID as random effects were used for analysis. No associations were found between maternal fasting or 2-h glucose concentrations with offspring glucose and insulin concentrations from birth to 5 years of age. However, maternal fasting glucose in GW 28 and 36, and 2-h OGTT glucose in GW 28 were positively associated with C-peptide concentration at birth. Maternal fasting glucose concentrations in GW 28 and 36 were positively associated with weight-for-length, and maternal fasting glucose in GW 36 was associated with BMI z-score at birth. In summary, blood glucose in pregnant women with overweight or obesity is positively associated with offspring C-peptide concentration, weight-for-length, and BMI z-score at birth, even in the absence of GDM.


Assuntos
Glicemia , Índice de Massa Corporal , Teste de Tolerância a Glucose , Homeostase , Obesidade , Sobrepeso , Humanos , Feminino , Gravidez , Adulto , Glicemia/metabolismo , Obesidade/metabolismo , Obesidade/sangue , Sobrepeso/metabolismo , Sobrepeso/sangue , Diabetes Gestacional/metabolismo , Diabetes Gestacional/sangue , Recém-Nascido , Pré-Escolar , Insulina/sangue , Insulina/metabolismo , Peptídeo C/sangue , Jejum/sangue , Complicações na Gravidez/metabolismo , Complicações na Gravidez/sangue
18.
Sci Rep ; 14(1): 21375, 2024 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271951

RESUMO

Plant growth regulators are cost-effective and efficient methods for enhancing plant defenses under stress conditions. This study investigates the ability of two plant growth-regulating substances, thiourea (TU) and arginine (Arg), to mitigate salinity stress in wheat. The results show that both TU and Arg, particularly when used together, modify plant growth under salinity stress. Their application significantly increases the activities of antioxidant enzymes while decreasing the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and relative electrolyte leakage (REL) in wheat seedlings. Additionally, these treatments significantly reduce the concentrations of Na+ and Ca2+ and the Na+/K+ ratio, while significantly increasing K+ levels, thereby preserving ionic osmotic balance. Importantly, TU and Arg markedly enhance the chlorophyll content, net photosynthetic rate, and gas exchange rate in wheat seedlings under salinity stress. The use of TU and Arg, either individually or in combination, results in a 9.03-47.45% increase in dry matter accumulation, with the maximum increase observed when both are used together. Overall, this study highlights that maintaining redox homeostasis and ionic balance are crucial for enhancing plant tolerance to salinity stress. Furthermore, TU and Arg are recommended as potential plant growth regulators to boost wheat productivity under such conditions, especially when applied together.


Assuntos
Arginina , Homeostase , Oxirredução , Estresse Salino , Plântula , Tioureia , Triticum , Triticum/metabolismo , Triticum/efeitos dos fármacos , Triticum/crescimento & desenvolvimento , Tioureia/farmacologia , Tioureia/análogos & derivados , Arginina/metabolismo , Plântula/metabolismo , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Malondialdeído/metabolismo , Fotossíntese/efeitos dos fármacos , Clorofila/metabolismo , Reguladores de Crescimento de Plantas/metabolismo
19.
Int J Mol Sci ; 25(17)2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39273244

RESUMO

Redox homeostasis is the balance between oxidation and reduction reactions. Its maintenance depends on glutathione, including its reduced and oxidized form, GSH/GSSG, which is the main intracellular redox buffer, but also on the nicotinamide adenine dinucleotide phosphate, including its reduced and oxidized form, NADPH/NADP+. Under conditions that enable yeast cells to undergo fermentative metabolism, the main source of NADPH is the pentose phosphate pathway. The lack of enzymes responsible for the production of NADPH has a significant impact on yeast cells. However, cells may compensate in different ways for impairments in NADPH synthesis, and the choice of compensation strategy has several consequences for cell functioning. The present study of this issue was based on isogenic mutants: Δzwf1, Δgnd1, Δald6, and the wild strain, as well as a comprehensive panel of molecular analyses such as the level of gene expression, protein content, and enzyme activity. The obtained results indicate that yeast cells compensate for the lack of enzymes responsible for the production of cytosolic NADPH by changing the content of selected proteins and/or their enzymatic activity. In turn, the cellular strategy used to compensate for them may affect cellular efficiency, and thus, the ability to grow or sensitivity to environmental acidification.


Assuntos
Fermentação , Homeostase , NADP , Oxirredução , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , NADP/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Glutationa/metabolismo , Via de Pentose Fosfato
20.
Int J Mol Sci ; 25(17)2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39273346

RESUMO

Articular cartilage receives nutrients and oxygen from the synovial fluid to maintain homeostasis. However, compared to tissues with abundant blood flow, articular cartilage is exposed to a hypoxic environment (i.e., physioxia) and has an enhanced hypoxic stress response. Hypoxia-inducible factors (HIFs) play a pivotal role in this physioxic environment. In normoxic conditions, HIFs are downregulated, whereas in physioxic conditions, they are upregulated. The HIF-α family comprises three members: HIF-1α, HIF-2α, and HIF-3α. Each member has a distinct function in articular cartilage. In osteoarthritis, which is primarily caused by degeneration of articular cartilage, HIF-1α is upregulated in chondrocytes and is believed to protect articular cartilage by acting anabolically on it. Conversely, in contrast to HIF-1α, HIF-2α exerts a catabolic influence on articular cartilage. It may therefore be possible to develop a new treatment for OA by controlling the expression of HIF-1α and HIF-2α with drugs or by altering the oxygen environment in the joints.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Cartilagem Articular , Condrócitos , Homeostase , Subunidade alfa do Fator 1 Induzível por Hipóxia , Osteoartrite , Humanos , Cartilagem Articular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Osteoartrite/metabolismo , Condrócitos/metabolismo , Oxigênio/metabolismo , Hipóxia/metabolismo , Hipóxia/fisiopatologia
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