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The myosin heavy chain 9 (MYH9) gene, located on human chromosome 22, encodes non-muscle myosin heavy chain IIA (NM IIA). This protein is essential to various cellular events, such as generating intracellular chemomechanical force and facilitating the movement of the actin cytoskeleton. Mutations associated with thrombocytopenia in autosomal dominant diseases first highlighted the significance of the MYH9 gene. In recent years, numerous studies have demonstrated the pivotal roles of MYH9 in various cancers. However, its effects on cancer are intricate and not fully comprehended. Furthermore, the elevated expression of MYH9 in certain malignancies suggests its potential as a target for tumor therapy. Nonetheless, there is a paucity of literature summarizing MYH9's role in tumors and the therapeutic strategies centered on it, necessitating a systematic analysis. This paper comprehensively reviews and analyzes the pertinent literature in this domain, elucidating the fundamental structural characteristics, biological functions, and the nexus between MYH9 and tumors. The mechanisms through which MYH9 contributes to tumor development and its multifaceted roles in the tumorigenic process are also explored. Additionally, we discuss the relationship between MYH9-related diseases (MYH9-RD) and tumors and also summarize tumor therapeutic approaches targeting MYH9. The potential clinical applications of studying the MYH9 gene include improving early diagnosis, clinical staging, and prognosis of tumors. This paper is anticipated to provide novel insights for tumor therapy.
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Background: Despite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD. Methods: A genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane's Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction. Results: Our thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy. Conclusion: This study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.
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Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Análise da Randomização Mendeliana , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Feminino , Masculino , Creatinina/sangue , Polimorfismo de Nucleotídeo Único , Biomarcadores/sangue , Estudos de Coortes , Rim/metabolismo , Pessoa de Meia-IdadeRESUMO
The human gut microbiome (GM) impacts various physiological processes and can lead to pathological conditions and even carcinogenesis if homeostasis is disrupted. Recent studies have indicated a connection between the GM and prostatic disease. However, the underlying mechanisms are still unclear. This review aims to provide a summary of the existing information regarding the connection between the GM and various prostatic conditions such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Furthermore, the review aims to identify possible pathogenic mechanisms and suggest potential ways of targeting GM to prevent and treat prostatic disease. Due to the complexity of the mechanism between GM and prostatic diseases, additional research is required to comprehend the association between the two. This will lead to more effective treatment options for prostatic disease.
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Microbioma Gastrointestinal , Humanos , Masculino , Doenças Prostáticas/microbiologia , Doenças Prostáticas/prevenção & controle , Neoplasias da Próstata/microbiologia , Prostatite/microbiologia , Hiperplasia Prostática/microbiologia , AnimaisRESUMO
Macrophages are widely distributed throughout various tissues of the body, and mounting evidence suggests their involvement in regulating the tissue microenvironment, thereby influencing disease onset and progression through direct or indirect actions. In chronic kidney disease (CKD), disturbances in renal functional homeostasis lead to inflammatory cell infiltration, tubular expansion, glomerular atrophy, and subsequent renal fibrosis. Macrophages play a pivotal role in this pathological process. Therefore, understanding their role is imperative for investigating CKD progression, mitigating its advancement, and offering novel research perspectives for fibrosis treatment from an immunological standpoint. This review primarily delves into the intrinsic characteristics of macrophages, their origins, diverse subtypes, and their associations with renal fibrosis. Particular emphasis is placed on the transition between M1 and M2 phenotypes. In late-stage CKD, there is a shift from the M1 to the M2 phenotype, accompanied by an increased prevalence of M2 macrophages. This transition is governed by the activation of the TGF-ß1/SMAD3 and JAK/STAT pathways, which facilitate macrophage-to-myofibroblast transition (MMT). The tyrosine kinase Src is involved in both signaling cascades. By thoroughly elucidating macrophage functions and comprehending the modes and molecular mechanisms of macrophage-fibroblast interaction in the kidney, novel, tailored therapeutic strategies for preventing or attenuating the progression of CKD can be developed.
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Fibrose , Macrófagos , Insuficiência Renal Crônica , Humanos , Macrófagos/patologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/metabolismo , Animais , Transdução de Sinais , Rim/patologia , Rim/metabolismo , Progressão da Doença , FenótipoRESUMO
BACKGROUND: The impacts of maternal depression during mid-to-late pregnancy on fetal growth have been extensively investigated. However, the association between maternal depression during early pregnancy and fetal intrauterine growth are less clear. METHODS: A prospective study comprised 23,465 eligible pregnant women and their offspring was conducted at a hospital-based center in Shanghai. Prenatal depression was assessed used using Patient Health Questionnaire (PHQ-9) before 14 gestational weeks. Differences in fetal growth trajectory of different maternal depressive statuses during three periods (16-23, 24-31, and 32-41 gestational weeks) were compared using a multilevel model with fractional polynomials. RESULTS: Women with depressive symptoms during early pregnancy had higher longitudinal fetal trajectories, with an estimated increase in fetal weight (ß = 0.33; 95 % CI, 0.06-0.61), compared to those without depressive symptoms. Increases in fetal abdominal circumference among women with depressive symptoms were observed before 23 gestational weeks. Offspring born to mothers with early pregnancy depression had a significantly higher birth weight of 14.13 g (95 % CI, 1.33-27.81 g) and an increased risk of severe large size for gestational age (adjusted odds ratio [aOR], 1.64; 95 % CI, 1.32-2.04) and macrosomia (aOR, 1.21; 95 % CI, 1.02-1.43). LIMITATIONS: Self-rated scale was used to assess depressive symptoms rather than clinical diagnosis. And Long-term effects of early pregnancy depression on offspring were not explored. CONCLUSIONS: The study revealed an association between maternal depression during early pregnancy and increased fetal biometrics, higher birth weight, and an elevated risk of severe large size for gestational age and macrosomia.
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Depressão , Desenvolvimento Fetal , Complicações na Gravidez , Humanos , Feminino , Gravidez , Adulto , Desenvolvimento Fetal/fisiologia , Estudos Prospectivos , Complicações na Gravidez/psicologia , Depressão/psicologia , Depressão/epidemiologia , China/epidemiologia , Idade Gestacional , Peso ao Nascer , Estudos Longitudinais , Macrossomia Fetal/epidemiologia , Adulto Jovem , Recém-NascidoRESUMO
Objectives: The relationship between cathepsins and prostate cancer (PCa) has been reported. However, there is a lack of research on cathepsins and benign prostate diseases (BPDs). This study investigated the potential genetic link between cathepsins and BPDs through the utilization of Mendelian randomization (MR) analysis to determine if a causal relationship exists. Methods: Publicly accessible summary statistics on BPDs were obtained from FinnGen Biobank. The data comprised 149,363 individuals, with 30,066 cases and 119,297 controls for BPH, and 123,057 individuals, with 3,760 cases and 119,297 controls for prostatitis. The IEU OpenGWAS provided the Genome-wide association data on ten cathepsins. To evaluate the causal relationship between BPDs and cathepsins, five distinct MR analyses were employed, with the primary method being the inverse variance weighted (IVW) approach. Additionally, sensitivity analyses were conducted to examine the horizontal pleiotropy and heterogeneity of the findings. Results: The examination of IVW MR findings showed that cathepsin O had a beneficial effect on BPH (IVW OR=0.94, 95% CI 0.89-0.98, P=0.0055), while cathepsin X posed a threat to prostatitis (IVW OR=1.08, 95% CI 1.00-1.16, P=0.047). Through reverse MR analysis, it was revealed that prostatitis had an adverse impact on cathepsin V (IVW OR=0.89, 95% CI 0.80-0.99, P=0.035), while no favorable association was observed between BPH and cathepsins. The results obtained from MR-Egger, weighted median, simple mode, and weighted mode methods were consistent with the findings of the IVW approach. Based on sensitivity analyses, heterogeneity, and horizontal pleiotropy are unlikely to distort the results. Conclusion: This study offers the initial evidence of a genetic causal link between cathepsins and BPDs. Our findings revealed that cathepsin O was beneficial in preventing BPH, whereas cathepsin X posed a potential threat to prostatitis. Additionally, prostatitis negatively affected cathepsin V level. These three cathepsins could be targets of diagnosis and treatment for BPDs, which need further research.
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Catepsinas , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Hiperplasia Prostática , Humanos , Masculino , Catepsinas/genética , Hiperplasia Prostática/genética , Hiperplasia Prostática/epidemiologia , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Predisposição Genética para Doença , Neoplasias da Próstata/genética , Neoplasias da Próstata/epidemiologia , Prostatite/genética , Prostatite/epidemiologia , Doenças Prostáticas/genética , Doenças Prostáticas/epidemiologiaRESUMO
Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim of this research was to clarify the role and mechanism of LKB1 in restraining telomerase activity in lung adenocarcinoma. The results showed that LKB1 induced cellular senescence and apoptosis either in vitro or in vivo. Overexpression of LKB1 in LKB1-deficient A549 cells led to the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. As a transcription factor, Sp1 mediated TERT inhibition after LKB1 overexpression. LKB1 induced lactate production and inhibited histone H4 (Lys8) and H4 (Lys16) lactylation, which further altered Sp1-related transcriptional activity. The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments.
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Quinases Proteína-Quinases Ativadas por AMP , Adenocarcinoma de Pulmão , Senescência Celular , Histonas , Neoplasias Pulmonares , Proteínas Serina-Treonina Quinases , Fator de Transcrição Sp1 , Telomerase , Animais , Humanos , Camundongos , Células A549 , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Quinases Proteína-Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Nus , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Telomerase/metabolismo , Telomerase/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We theoretically propose and demonstrate topological parabolic umbilic beams (PUBs) with high-dimensional caustic by mapping catastrophe theory into optics. The PUBs are first experimentally observed via dimensionality reduction. Due to the high-dimensionality, such light beams exhibit rich caustic structures characterized by optical singularities where the high-intensity gradient appears. Further, we propose an improved caustic approach to artificially tailored structured beams which exhibit significant intensity gradient and phase gradient. The properties can trap and drive particles to move along the predesigned trajectory, respectively. The advantages for structured caustic beams likely enable new applications in flexible particle manipulation, light-sheet microscopy, and micromachining.
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Maintaining the structural integrity of genomic chromosomal DNA is an essential role of cellular life and requires two important biological mechanisms: the DNA damage response (DDR) mechanism and telomere protection mechanism at chromosome ends. Because abnormalities in telomeres and cellular DDR regulation are strongly associated with human aging and cancer, there is a reciprocal regulation of telomeres and cellular DDR. Moreover, several drug treatments for DDR are currently available. This paper reviews the progress in research on the interaction between telomeres and cellular DNA damage repair pathways. The research on the crosstalk between telomere damage and DDR is important for improving the efficacy of tumor treatment. However, further studies are required to confirm this hypothesis.
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Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph+) leukemia. However, a series of issues, including drug resistance, relapse and intolerance, are still an unmet medical need. Here, we report the targeted siRNA-based lipid nanoparticles in Ph+ leukemic cell lines for gene therapy of Ph+ leukemia, which specifically targets a recently identified NEDD8 E3 ligase RAPSYN in Ph+ leukemic cells to disrupt the neddylation of oncogenic BCR-ABL. To achieve the specificity for Ph+ leukemia therapy, a single-chain fragment variable region (scFv) of anti-CD79B monoclonal antibody was covalently conjugated on the surface of OA2-siRAPSYN lipid nanoparticles to generate the targeted lipid nanoparticles (scFv-OA2-siRAPSYN). Through effectively silencing RAPSYN gene in leukemic cell lines by the nanoparticles, BCR-ABL was remarkably degraded accompanied by the inhibition of proliferation and the promotion of apoptosis. The specific targeting, therapeutic effects and systemic safety were further evaluated and demonstrated in cell line-derived mouse models. The present study has not only addressed the clinical need of Ph+ leukemia, but also enabled gene therapy against a less druggable target.
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Proteínas de Fusão bcr-abl , Nanopartículas , Animais , Humanos , Camundongos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Inativação Gênica , Terapia Genética/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Camundongos Endogâmicos BALB C , Nanopartículas/química , Proteína NEDD8/metabolismo , Proteína NEDD8/genética , RNA Interferente Pequeno , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas Musculares/metabolismoRESUMO
Accumulated alterations in metabolic control provide energy and anabolic demands for enhanced cancer cell proliferation. Exemplified by the Warburg effect, changes in glucose metabolism during cancer progression are widely recognized as a characteristic of metabolic disorders. Since telomerases are a vital factor in maintaining DNA integrity and stability, any damage threatening telomerases could have a severe impact on DNA and, subsequently, whole-cell homeostasis. However, it remains unclear whether the regulation of glucose metabolism in cancer is connected to the regulation of telomerase. In this review, we present the latest insights into the crosstalk between telomerase function and glucose metabolism in cancer cells. However, at this moment this subject is not well investigated that the association is mostly indirectly regulations and few explicit regulating pathways were identified between telomerase and glucose metabolism. Therefore, the information presented in this review can provide a scientific basis for further research on the detail mechanism and the clinical application of cancer therapy, which could be valuable in improving the effectiveness of chemotherapy.
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Glucose , Neoplasias , Telomerase , Humanos , Telomerase/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Glucose/metabolismo , AnimaisRESUMO
This paper examines fixed-time synchronization (FxTS) for two-dimensional coupled reaction-diffusion complex networks (CRDCNs) with impulses and delay. Utilizing the Lyapunov method, a FxTS criterion is established for impulsive delayed CRDCNs. Herein, impulses encompass both synchronizing and desynchronizing variants. Subsequently, by employing a Lyapunov-Krasovskii functional, two FxTS boundary controllers are formulated for CRDCNs with Neumann and mixed boundary condition, respectively. It is observed that vanishing Dirichlet boundary contributes to the synchronization of the CRDCNs. Furthermore, this study calculates the optimal constant for the Poincaré inequality in the square domain, which is instrumental in analyzing FxTS conditions for boundary controllers. Conclusive numerical examples underscore the efficacy of the proposed theoretical findings.
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Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.
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Carcinoma de Células Renais , Aprendizado Profundo , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Células Endoteliais , Algoritmos , Análise de Célula Única , Antimetabólitos , Metilases de Modificação do DNA , Descoberta de Drogas , Neoplasias Renais/tratamento farmacológico , DNA , Microambiente TumoralRESUMO
Renal fibrosis, specifically tubulointerstitial fibrosis, represents the predominant pathological consequence observed in the context of progressive chronic kidney conditions. The pathogenesis of renal fibrosis encompasses a multifaceted interplay of mechanisms, including but not limited to interstitial fibroblast proliferation, activation, augmented production of extracellular matrix (ECM) components, and impaired ECM degradation. Notably, mitochondria, the intracellular organelles responsible for orchestrating biological oxidation processes in mammalian cells, assume a pivotal role within this intricate milieu. Mitochondrial dysfunction, when manifest, can incite a cascade of events, including inflammatory responses, perturbed mitochondrial autophagy, and associated processes, ultimately culminating in the genesis of renal fibrosis. This comprehensive review endeavors to furnish an exegesis of mitochondrial pathophysiology and biogenesis, elucidating the precise mechanisms through which mitochondrial aberrations contribute to the onset and progression of renal fibrosis. We explored how mitochondrial dysfunction, mitochondrial cytopathy and mitochondrial autophagy mediate ECM deposition and renal fibrosis from a multicellular perspective of mesangial cells, endothelial cells, podocytes, macrophages and fibroblasts. Furthermore, it succinctly encapsulates the most recent advancements in the realm of mitochondrial-targeted therapeutic strategies aimed at mitigating renal fibrosis.
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Fibrose , Mitocôndrias , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Animais , Rim/patologia , Rim/metabolismo , Nefropatias/patologia , Nefropatias/metabolismo , Nefropatias/etiologia , Nefropatias/terapia , Autofagia/fisiologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologiaRESUMO
OBJECTIVES: The objective of this study was to investigate the glycolytic activity of adenomyosis, which is characterized by malignant biological behaviors including abnormal cell proliferation, migration, invasion, cell regulation, and epithelial-mesenchymal transition. METHODS: From January 2021 to August 2022, a total of 15 patients who underwent total hysterectomy for adenomyosis and 14 patients who had non-endometrial diseases, specifically with cervical squamous intraepithelial neoplasia and uterine myoma, were included in this study. Myometrium with ectopic endometrium from patients with adenomyosis while normal myometrium from patients in the control group were collected. All samples were confirmed by a histopathological examination. The samples were analyzed by liquid chromatography-mass spectrometry (LC-MS), real-time quantitative PCR, NAD+/NADH assay kit as well as the glucose and lactate assay kits. RESULTS: Endometrial stroma and glands could be observed within the myometrium of patients in the adenomyosis group. We found that the mRNA expressions of HK1, PFKFB3, glyceraldehyde-3-phospate dehydrogenase (GAPDH), PKM2, and PDHA as well as the protein expressions of PFKFB3 were elevated in ectopic endometrial tissues of the adenomyosis group as compared to normal myometrium of the control group. The level of fructose 1,6-diphosphate was increased while NAD + and NAD+/NADH ratio were decreased compared with the control group. Besides, increased glucose consumption and lactate production were observed in myometrium with ectopic endometrium. CONCLUSIONS: We concluded that altered glycolytic phenotype of the myometrium with ectopic endometrium in women with adenomyosis may contribute the development of adenomyosis.
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Adenomiose , Humanos , Feminino , Adenomiose/patologia , Miométrio/metabolismo , NAD/metabolismo , Endométrio/metabolismo , Glucose/metabolismo , Lactatos/metabolismoRESUMO
BACKGROUND: Fibrin(ogen) deposition in the central nervous system (CNS) contributes to neuropathological injury; however, its role in ischemic stroke is unknown. In this study, we identified fibrinogen as a novel proinflammatory regulator of post-stroke neuroinflammation and revealed the neuro-protection effect of fibrin-derived γ377-395peptide in stroke. METHODS: Fibrinogen depletion and fibrinogen-derived γ377-395peptide treatment were performed 2 h after establishing a permanent middle cerebral artery occlusion (pMCAO) model. The infarction volume, neurological score, fibrin(ogen) deposition, and inflammatory response were evaluated 24 h after occlusion. Both in vivo and in vitro studies were conducted to assess the therapeutic potential of the γ377-395peptide in blocking the interactions between fibrin(ogen) and neutrophils. RESULTS: Fibrin(ogen) deposited in the infarct core promoted post-stroke inflammation and exacerbated neurological deficits in the acute phase after stroke onset. Reducing fibrinogen deposition resulted in a decrease in infarction volume, improved neurological scores, and reduced inflammation in the brain. Additionally, the presence of neutrophil accumulation near fibrin(ogen) deposits was observed in ischemic lesions, and the engagement of fibrin(ogen) by integrin receptor αMß2 promoted neutrophil activation and post-stroke inflammation. Finally, inhibiting fibrin(ogen)-mediated neutrophil activation using a fibrinogen-derived γ377-395peptide significantly attenuated neurological deficits. CONCLUSIONS: Fibrin(ogen) is a crucial regulator of post-stroke inflammation and contributes to secondary brain injury. The inflammation induced by fibrin(ogen) is primarily driven by neutrophils during acute ischemic stroke and can be ameliorated using the fibrin-derived γ377-395peptide. Targeting the fibrin(ogen)-mediated neuropathological process represents a promising approach for neuroprotective therapy after stroke while preserving its beneficial coagulation function.
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AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Doenças Neuroinflamatórias , Inflamação/tratamento farmacológico , Inflamação/patologia , Fibrinogênio , Peptídeos , Fibrina , Acidente Vascular Cerebral/tratamento farmacológico , InfartoRESUMO
High-risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. Here, we report that HPV16 E6E7 promotes cervical cancer cell proliferation by activating the pentose phosphate pathway (PPP). We found that HPV16 E6 activates the PPP primarily by increasing glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. Mechanistically, HPV16 E6 promoted G6PD dimer formation by inhibiting its lactylation. Importantly, we suggest that G6PD K45 was lactylated during G6PD-mediated antioxidant stress. In primary human keratinocytes and an HPV-negative cervical cancer C33A cells line ectopically expressing HPV16 E6, the transduction of G6PD K45A (unable to be lactylated) increased GSH and NADPH levels and, correspondingly, decreasing ROS levels. Conversely, the re-expression of G6PD K45T (mimicking constitutive lactylation) in HPV16-positive SiHa cells line inhibited cell proliferation. In vivo, the inhibition of G6PD enzyme activity with 6-aminonicotinamide (6-An) or the re-expression of G6PD K45T inhibited tumor proliferation. In conclusion, we have revealed a novel mechanism of HPV oncoprotein-mediated malignant transformation. These findings might provide effective strategies for treating cervical and HPV-associated cancers.
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Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo do Útero/metabolismo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Via de Pentose Fosfato , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proliferação de CélulasRESUMO
Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid ß-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.
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Acil-CoA Oxidase , Transplante de Rim , Rim , Doenças Metabólicas , Animais , Ratos , Acil-CoA Oxidase/metabolismo , Aloenxertos , Fibrose , Rim/patologia , LipídeosRESUMO
BACKGROUND: The development of atopic dermatitis (AD) drugs is challenged by many disease phenotypes and trial design options, which are hard to explore experimentally. OBJECTIVE: We aimed to optimize AD trial design using simulations. METHODS: We constructed a quantitative systems pharmacology model of AD and standard of care (SoC) treatments and generated a phenotypically diverse virtual population whose parameter distribution was derived from known relationships between AD biomarkers and disease severity and calibrated using disease severity evolution under SoC regimens. RESULTS: We applied this workflow to the immunomodulator OM-85, currently being investigated for its potential use in AD, and calibrated the investigational treatment model with the efficacy profile of an existing trial (thereby enriching it with plausible marker levels and dynamics). We assessed the sensitivity of trial outcomes to trial protocol and found that for this particular example the choice of end point is more important than the choice of dosing regimen and patient selection by model-based responder enrichment could increase the expected effect size. A global sensitivity analysis revealed that only a limited subset of baseline biomarkers is needed to predict the drug response of the full virtual population. CONCLUSIONS: This AD quantitative systems pharmacology workflow built around knowledge of marker-severity relationships as well as SoC efficacy can be tailored to specific development cases to optimize several trial protocol parameters and biomarker stratification and therefore has promise to become a powerful model-informed AD drug development and personalized medicine tool.