RESUMO
The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.
Assuntos
Antimaníacos , Ácido Láctico , Carbonato de Lítio , Mitocôndrias , Neoplasias , Humanos , Linfócitos T CD8-Positivos , Ácido Láctico/metabolismo , Carbonato de Lítio/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Antimaníacos/farmacologiaRESUMO
Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.
Assuntos
Carcinoma Hepatocelular , Carnosina , Neoplasias Hepáticas , Humanos , Homeostase , Lisossomos , Hipóxia , Concentração de Íons de Hidrogênio , Microambiente TumoralRESUMO
Amino acid metabolism is essential for cell survival, while the byproduct ammonia is toxic and can injure cellular longevity. Here we show that CD8+ memory T (TM) cells mobilize the carbamoyl phosphate (CP) metabolic pathway to clear ammonia, thus promoting memory development. CD8+ TM cells use ß-hydroxybutyrylation to upregulate CP synthetase 1 and trigger the CP metabolic cascade to form arginine in the cytosol. This cytosolic arginine is then translocated into the mitochondria where it is split by arginase 2 to urea and ornithine. Cytosolic arginine is also converted to nitric oxide and citrulline by nitric oxide synthases. Thus, both the urea and citrulline cycles are employed by CD8+ T cells to clear ammonia and enable memory development. This ammonia clearance machinery might be targeted to improve T cell-based cancer immunotherapies.
Assuntos
Amônia , Citrulina , Citrulina/metabolismo , Amônia/metabolismo , Ureia/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Óxido Nítrico , Arginina/metabolismo , Arginase/metabolismoRESUMO
Tumor-derived factors are thought to regulate thrombocytosis and erythrocytopenia in individuals with cancer; however, such factors have not yet been identified. Here we show that tumor cell-released kynurenine (Kyn) biases megakaryocytic-erythroid progenitor cell (MEP) differentiation into megakaryocytes in individuals with cancer by activating the aryl hydrocarbon receptor-Runt-related transcription factor 1 (AhR-RUNX1) axis. During tumor growth, large amounts of Kyn from tumor cells are released into the periphery, where they are taken up by MEPs via the transporter SLC7A8. In the cytosol, Kyn binds to and activates AhR, leading to its translocation into the nucleus where AhR transactivates RUNX1, thus regulating MEP differentiation into megakaryocytes. In addition, activated AhR upregulates SLC7A8 in MEPs to induce positive feedback. Importantly, Kyn-AhR-RUNX1-regulated MEP differentiation was demonstrated in both humanized mice and individuals with cancer, providing potential strategies for the prevention of thrombocytosis and erythrocytopenia.
Assuntos
Neoplasias , Trombocitose , Animais , Camundongos , Cinurenina/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Megacariócitos/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células Precursoras Eritroides/metabolismo , Diferenciação Celular/fisiologia , Neoplasias/metabolismo , Trombocitose/metabolismo , ViésRESUMO
CD8+ T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8+ T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue to induce CD8+ T cell exhaustion within tumor microenvironments. We find that a continuously high level of IL-2 leads to the persistent activation of STAT5 in CD8+ T cells, which in turn induces strong expression of tryptophan hydroxylase 1, thus catalyzing the conversion to tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP subsequently activates AhR nuclear translocation, causing a coordinated upregulation of inhibitory receptors and downregulation of cytokine and effector-molecule production, thereby rendering T cells dysfunctional in the tumor microenvironment. This molecular pathway is not only present in mouse tumor models but is also observed in people with cancer, identifying IL-2 as a novel inducer of T cell exhaustion.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Interleucina-2/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Microambiente Tumoral , 5-Hidroxitriptofano/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Humanos , Interleucina-2/antagonistas & inibidores , Interleucina-2/genética , Células Jurkat , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Células MCF-7 , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células NIH 3T3 , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Triptofano Hidroxilase/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Metabolic reprogramming is an important feature of cancers that has been closely linked to post-translational protein modification (PTM). Lysine succinylation is a recently identified PTM involved in regulating protein functions, whereas its regulatory mechanism and possible roles in tumor progression remain unclear. Here, we show that OXCT1, an enzyme catalyzing ketone body oxidation, functions as a lysine succinyltransferase to contribute to tumor progression. Mechanistically, we find that OXCT1 functions as a succinyltransferase, with residue G424 essential for this activity. We also identified serine beta-lactamase-like protein (LACTB) as a main target of OXCT1-mediated succinylation. Extensive succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, ultimately leading to hepatocellular carcinoma (HCC) progression. In summary, this study establishes lysine succinyltransferase function of OXCT1 and highlights a link between HCC prognosis and LACTB K284 succinylation, suggesting a potentially valuable biomarker and therapeutic target for further development.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , beta-Lactamases , Humanos , beta-Lactamases/genética , beta-Lactamases/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Lisina/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Natural killer (NK) cells have crucial roles in tumor surveillance. We found that tumor-infiltrating NK cells in human liver cancers had small, fragmented mitochondria in their cytoplasm, whereas liver NK cells outside tumors, as well as peripheral NK cells, had normal large, tubular mitochondria. This fragmentation was correlated with reduced cytotoxicity and NK cell loss, resulting in tumor evasion of NK cell-mediated surveillance, which predicted poor survival in patients with liver cancer. The hypoxic tumor microenvironment drove the sustained activation of mechanistic target of rapamycin-GTPase dynamin-related protein 1 (mTOR-Drp1) in NK cells, resulting in excessive mitochondrial fission into fragments. Inhibition of mitochondrial fragmentation improved mitochondrial metabolism, survival and the antitumor capacity of NK cells. These data reveal a mechanism of immune escape that might be targetable and could invigorate NK cell-based cancer treatments.
Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Mitocôndrias/metabolismo , Idoso , Animais , Citotoxicidade Imunológica , Proteínas Quinases Associadas com Morte Celular/metabolismo , Feminino , Humanos , Vigilância Imunológica , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Masculino , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura , Dinâmica Mitocondrial , Análise de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Evasão TumoralRESUMO
Glycolysis facilitates the rapid recall response of CD8+ memory T (Tm) cells. However, it remains unclear whether Tm cells uptake exogenous glucose or mobilize endogenous sugar to fuel glycolysis. Here, we show that intracellular glycogen rather than extracellular glucose acts as the major carbon source for the early recall response. Following antigenic stimulation, Tm cells exhibit high glycogen phosphorylase (brain form, PYGB) activity, leading to glycogenolysis and release of glucose-6-phosphate (G6P). Elevated G6P mainly flows to glycolysis but is also partially channeled to the pentose phosphate pathway, which maintains the antioxidant capacity necessary for later recall stages. Mechanistically, TCR signaling directly induces phosphorylation of PYGB by LCK-ZAP70. Functionally, the glycogenolysis-fueled early recall response of CD8+ Tm cells accelerates the clearance of OVA-Listeria monocytogenes in an infected mouse model. Thus, we uncover a specific dependency on glycogen for the initial activation of memory T cells, which may have therapeutic implications for adaptive immunity.
Assuntos
Glicogenólise , Animais , Linfócitos T CD8-Positivos , Glucose/metabolismo , Glicogênio/metabolismo , Células T de Memória , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
Identification of mechanisms that program early effector T cells to either terminal effector T (Teff) or memory T (Tm) cells has important implications for protective immunity against infections and cancers. Here, we show that the cytosolic transcription factor aryl hydrocarbon receptor (AhR) is used by early Teff cells to program memory fate. Upon antigen engagement, AhR is rapidly up-regulated via reactive oxygen species signaling in early CD8+ Teff cells, which does not affect the effector response, but is required for memory formation. Mechanistically, activated CD8+ T cells up-regulate HIF-1α to compete with AhR for HIF-1ß, leading to the loss of AhR activity in HIF-1αhigh short-lived effector cells, but sustained in HIF-1αlow memory precursor effector cells (MPECs) with the help of autocrine IL-2. AhR then licenses CD8+ MPECs in a quiescent state for memory formation. These findings partially resolve the long-standing issue of how Teff cells are regulated to differentiate into memory cells.
Assuntos
Linfócitos T CD8-Positivos , Divisão Celular , Citosol , Espécies Reativas de OxigênioRESUMO
Phosphoglycerate dehydrogenase (PHGDH) is a key serine biosynthesis enzyme whose aberrant expression promotes various types of tumors. Recently, PHGDH has been found to have some non-canonical functions beyond serine biosynthesis, but its specific mechanisms in tumorigenesis remain unclear. Here, we show that PHGDH localizes to the inner mitochondrial membrane and promotes the translation of mitochondrial DNA (mtDNA)-encoded proteins in liver cancer cells. Mechanistically, we demonstrate that mitochondrial PHGDH directly interacts with adenine nucleotide translocase 2 (ANT2) and then recruits mitochondrial elongation factor G2 (mtEFG2) to promote mitochondrial ribosome recycling efficiency, thereby promoting mtDNA-encoded protein expression and subsequent mitochondrial respiration. Moreover, we show that treatment with a mitochondrial translation inhibitor or depletion of mtEFG2 diminishes PHGDH-mediated tumor growth. Collectively, our findings uncover a previously unappreciated function of PHGDH in tumorigenesis acting via promotion of mitochondrial translation and bioenergetics.
Assuntos
Neoplasias Hepáticas , Fosfoglicerato Desidrogenase , Humanos , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Desidrogenase/metabolismo , Linhagem Celular Tumoral , Serina , Neoplasias Hepáticas/genética , Carcinogênese , DNA MitocondrialRESUMO
Plant NAC transcription factors play a crucial role in enhancing cold stress tolerance, yet the precise molecular mechanisms underlying cold stress remain elusive. In this study, we identified and characterized CaNAC035, an NAC transcription factor isolated from pepper (Capsicum annuum) leaves. We observed that the expression of the CaNAC035 gene is induced by both cold and abscisic acid (ABA) treatments, and we elucidated its positive regulatory role in cold stress tolerance. Overexpression of CaNAC035 resulted in enhanced cold stress tolerance, while knockdown of CaNAC035 significantly reduced resistance to cold stress. Additionally, we discovered that CaSnRK2.4, a SnRK2 protein, plays an essential role in cold tolerance. In this study, we demonstrated that CaSnRK2.4 physically interacts with and phosphorylates CaNAC035 both in vitro and in vivo. Moreover, the expression of two ABA biosynthesis-related genes, CaAAO3 and CaNCED3, was significantly upregulated in the CaNAC035-overexpressing transgenic pepper lines. Yeast one-hybrid, Dual Luciferase, and electrophoretic mobility shift assays provided evidence that CaNAC035 binds to the promoter regions of both CaAAO3 and CaNCED3 in vivo and in vitro. Notably, treatment of transgenic pepper with 50 µm Fluridone (Flu) enhanced cold tolerance, while the exogenous application of ABA at a concentration of 10 µm noticeably reduced cold tolerance in the virus-induced gene silencing line. Overall, our findings highlight the involvement of CaNAC035 in the cold response of pepper and provide valuable insights into the molecular mechanisms underlying cold tolerance. These results offer promising prospects for molecular breeding strategies aimed at improving cold tolerance in pepper and other crops.
Assuntos
Ácido Abscísico , Capsicum , Ácido Abscísico/metabolismo , Resposta ao Choque Frio , Capsicum/fisiologia , Estresse Fisiológico/genética , Fosforilação , Folhas de Planta/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Plantas Geneticamente Modificadas/genéticaRESUMO
Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is an important cellular metabolite-sensing enzyme that can directly sense changes not only in ATP but also in metabolites associated with carbohydrates and fatty acids. However, less is known about whether and how AMPK senses variations in cellular amino acids. Here, we show that cysteine deficiency significantly triggers calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-mediated activation of AMPK. In addition, we found that CaMKK2 directly associates with cysteinyl-tRNA synthetase (CARS), which then binds to AMPKγ2 under cysteine deficiency to activate AMPK. Interestingly, we discovered that cysteine inhibits the binding of CARS to AMPKγ2, and thus, under cysteine deficiency conditions wherein the inhibitory effect of cysteine is abrogated, CARS mediates the binding of AMPK to CaMKK2, resulting in the phosphorylation and activation of AMPK by CaMKK2. Importantly, we demonstrate that blocking AMPK activation leads to cell death under cysteine-deficient conditions. In summary, our study is the first to show that CARS senses the absence of cysteine and activates AMPK through the cysteine-CARS-CaMKK2-AMPKγ2 axis, a novel adaptation strategy for cell survival under nutrient deprivation conditions.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Adaptação Fisiológica/genética , Aminoacil-tRNA Sintetases/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Cisteína/deficiência , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Trifosfato de Adenosina/metabolismo , Aminoacil-tRNA Sintetases/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Ligação Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteína Regulatória Associada a mTOR/genética , Proteína Regulatória Associada a mTOR/metabolismo , Transdução de SinaisRESUMO
Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker-based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133+ , ALDH+ , or side population CSCs, are able to form a tumor with only 100 cells in NOD-SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.
Assuntos
Carcinogênese/genética , Células-Tronco Neoplásicas/fisiologia , Antígeno AC133/genética , Aldeído Desidrogenase/genética , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Regulação para Cima/genética , Proteínas Wnt/genéticaRESUMO
Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.
Assuntos
Carcinogênese , Neoplasias Hepáticas , Humanos , Ácido Araquidônico , Linhagem Celular Tumoral , Proliferação de Células , Carcinogênese/genética , Transformação Celular Neoplásica , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Neoplasias Hepáticas/genética , Aspirina/farmacologia , Proteínas de Ligação a DNA/genética , Biomarcadores Tumorais , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.
RESUMO
OBJECTIVE: Clinically, it has been found that patients undergoing knee replacement have a high incidence of concomitant hallux valgus. In this study, we analyzed whether patients with osteoarthritis who underwent surgery and those patient who did not have surgery had an increased risk of hallux valgus by Mendelian randomization and performed reverse causal analysis. DESIGN: Genomewide association study (GWAS) data for osteoarthritis, categorized by knee arthritis with joint replacement, knee arthritis without joint replacement, hip arthritis with joint replacement, and hip arthritis without joint replacement.And acquired hallux valgus were downloaded for Mendelian randomized studies. MR analysis was performed using inverse variance-weighted (IVW), weighted median, and MR-Egger methods. MR-egger regression, MR pleiotropic residuals and outliers (MR-presso), and Cochran's Q statistical methods were used to evaluate heterogeneity and pleiotropy. RESULTS: The IVW results indicate that, compared to healthy individuals, patients who meet the criteria for knee osteoarthritis joint replacement surgery have a significantly higher risk of acquired hallux valgus. There were no significant causal relationships found for the remaining results. No significant heterogeneity or multiplicity was observed in all the Mr analyses. CONCLUSION: Our study supports the increased risk of acquired hallux valgus in patients eligible for knee replacement. There is necessary for clinicians to be concerned about the hallux valgus status of patients undergoing knee arthroplasty.
Assuntos
Artroplastia do Joelho , Estudo de Associação Genômica Ampla , Hallux Valgus , Análise da Randomização Mendeliana , Osteoartrite do Joelho , Humanos , Artroplastia do Joelho/efeitos adversos , Hallux Valgus/cirurgia , Hallux Valgus/genética , Hallux Valgus/epidemiologia , Osteoartrite do Joelho/cirurgia , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/epidemiologia , Fatores de Risco , Feminino , Masculino , Osteoartrite do Quadril/cirurgia , Osteoartrite do Quadril/genética , Osteoartrite do Quadril/epidemiologia , Pessoa de Meia-IdadeRESUMO
In order to improve the real-time performance of gesture recognition by a micro-Doppler map of mmWave radar, the point cloud based gesture recognition for mmWave radar is proposed in this paper. Two steps are carried out for mmWave radar-based gesture recognition. The first step is to estimate the point cloud of the gestures by 3D-FFT and the peak grouping. The second step is to train the TRANS-CNN model by combining the multi-head self-attention and the 1D-convolutional network so as to extract the features in the point cloud data at a deeper level to categorize the gestures. In the experiments, TI mmWave radar sensor IWR1642 is used as a benchmark to evaluate the feasibility of the proposed approach. The results show that the accuracy of the gesture recognition reaches 98.5%. In order to prove the effectiveness of our approach, a simply 2Tx2Rx radar sensor is developed in our lab, and the accuracy of recognition reaches 97.1%. The results show that our proposed gesture recognition approach achieves the best performance in real time with limited training data in comparison with the existing methods.
RESUMO
Steroid-induced femoral head necrosis (SIFHN) is a serious clinical complication that is caused by prolonged or excessive use of glucocorticoids (GCs). Osteoblast apoptosis and osteogenic differentiation dysfunction caused by GC-induced oxidative stress and mitochondrial impairment are strongly implicated in SIFHN. Apocynin (APO) is a kind of acetophenone extracted from an herb. In recent years, APO has received much attention for its antiapoptotic and antioxidant properties. This study aimed to investigate whether APO could protect against SIFHN and explore the mechanism. In our study, low-dose APO had no toxic effects on osteoblasts and restored dexamethasone (Dex)-treated osteoblasts by improving survival, inhibiting OS and restoring mitochondrial dysfunction. Mechanistically, APO alleviated Dex-induced osteoblast injury by activating the Nrf2 pathway, and the use of ML385 to block Nrf2 significantly eliminated the protective effect of APO. In addition, APO could reduce the formation of empty lacunae, restore bone mass and promote the expression of Nrf2 in SIFHN rats. In conclusion, APO protects osteoblasts from Dex-induced oxidative stress and mitochondrial dysfunction through activation of the Nrf2 pathway and may be a beneficial drug for the treatment of SIFHN.
Assuntos
Dexametasona , Doenças Mitocondriais , Ratos , Animais , Dexametasona/farmacologia , Dexametasona/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Osteogênese , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Estresse Oxidativo , Acetofenonas/farmacologia , Apoptose , Osteoblastos/metabolismo , Doenças Mitocondriais/metabolismoRESUMO
The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m6 A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m6 A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m6 A controls the translation of MRG mRNA via the specific m6 A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m6 A modifications in selected MRG transcripts promotes cancer progression.