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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.
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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
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.
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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
BACKGROUND: T cells are central to the immune responses contributing to hypertension. LGMN (legumain) is highly expressed in T cells; however, its role in the pathogenesis of hypertension remains unclear. METHODS: Peripheral blood samples were collected from patients with hypertension, and cluster of differentiation (CD)4+ T cells were sorted for gene expression and Western blotting analysis. TLGMNKO (T cell-specific LGMN-knockout) mice (Lgmnf/f/CD4Cre), regulatory T cell (Treg)-specific LGMN-knockout mice (Lgmnf/f/Foxp3YFP Cre), and RR-11a (LGMN inhibitor)-treated C57BL/6 mice were infused with Ang II (angiotensin II) or deoxycorticosterone acetate/salt to establish hypertensive animal models. Flow cytometry, 4-dimensional label-free proteomics, coimmunoprecipitation, Treg suppression, and in vivo Treg depletion or adoptive transfer were used to delineate the functional importance of T-cell LGMN in hypertension development. RESULTS: LGMN mRNA expression was increased in CD4+ T cells isolated from hypertensive patients and mice, was positively correlated with both systolic and diastolic blood pressure, and was negatively correlated with serum IL (interleukin)-10 levels. TLGMNKO mice exhibited reduced Ang II-induced or deoxycorticosterone acetate/salt-induced hypertension and target organ damage relative to wild-type (WT) mice. Genetic and pharmacological inhibition of LGMN blocked Ang II-induced or deoxycorticosterone acetate/salt-induced immunoinhibitory Treg reduction in the kidneys and blood. Anti-CD25 antibody depletion of Tregs abolished the protective effects against Ang II-induced hypertension in TLGMNKO mice, and LGMN deletion in Tregs prevented Ang II-induced hypertension in mice. Mechanistically, endogenous LGMN impaired Treg differentiation and function by directly interacting with and facilitating the degradation of TRAF6 (tumor necrosis factor receptor-associated factor 6) via chaperone-mediated autophagy, thereby inhibiting NF-κB (nuclear factor kappa B) activation. Adoptive transfer of LGMN-deficient Tregs reversed Ang II-induced hypertension, whereas depletion of TRAF6 in LGMN-deficient Tregs blocked the protective effects. CONCLUSIONS: LGMN deficiency in T cells prevents hypertension and its complications by promoting Treg differentiation and function. Specifically targeting LGMN in Tregs may be an innovative approach for hypertension treatment.
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Hipertensão , Fator 6 Associado a Receptor de TNF , Animais , Humanos , Camundongos , Acetatos/efeitos adversos , Acetatos/metabolismo , Angiotensina II/toxicidade , Angiotensina II/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Desoxicorticosterona/efeitos adversos , Desoxicorticosterona/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores , Fator 6 Associado a Receptor de TNF/metabolismoRESUMO
Senile osteoporosis increases fracture risks. Bone marrow stromal cells (BMSCs) are sensitive to aging. Deep insights into BMSCs aging are vital to elucidate the mechanisms underlying age-related bone loss. Recent advances showed that osteoporosis is associated with aberrant DNA methylation of many susceptible genes. Galectin-1 (Gal-1) has been proposed as a mediator of BMSCs functions. In our previous study, we showed that Gal-1 was downregulated in aged BMSCs and global deletion of Gal-1 in mice caused bone loss via impaired osteogenesis potential of BMSCs. Gal-1 promoter is featured by CpG islands. However, there are no reports concerning the DNA methylation status in Gal-1 promoter during osteoporosis. In the current study, we sought to investigate the role of DNA methylation in Gal-1 downregulation in aged BMSCs. The potential for anti-bone loss therapy based on modulating DNA methylation is explored. Our results showed that Dnmt3b-mediated Gal-1 promoter DNA hypermethylation plays an important role in Gal-1 downregulation in aged BMSCs, which inhibited ß-catenin binding on Gal-1 promoter. Bone loss of aged mice was alleviated in response to in vivo deletion of Dnmt3b from BMSCs. Finally, when bone marrow of young wild-type (WT) mice or young Dnmt3bPrx1-Cre mice was transplanted into aged WT mice, Gal-1 level in serum and trabecular bone mass were elevated in recipient aged WT mice. Our study will benefit for deeper insights into the regulation mechanisms of Gal-1 expression in BMSCs during osteoporosis development, and for the discovery of new therapeutic targets for osteoporosis via modulating DNA methylation status.NEW & NOTEWORTHY There is Dnmt3b-mediated DNA methylation in Gal-1 promoter in aged bone marrow stromal cell (BMSC). DNA methylation causes Gal-1 downregulation and osteogenesis attenuation of aged BMSC. DNA methylation blocks ß-catenin binding on Gal-1 promoter. Bone loss of aged mice is alleviated by in vivo deletion of Dnmt3b from BMSC.
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Benzamidas , Células-Tronco Mesenquimais , Osteoporose , Tirosina/análogos & derivados , Animais , Camundongos , Metilação de DNA/genética , beta Catenina/metabolismo , Galectina 1/genética , Galectina 1/metabolismo , Osteogênese/genética , Osteoporose/genética , Osteoporose/metabolismo , Células-Tronco Mesenquimais/metabolismo , Regiões Promotoras Genéticas/genética , Diferenciação Celular , Células da Medula Óssea/metabolismoRESUMO
BACKGROUND: Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration. METHODS: The SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM. RESULTS: The SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01). CONCLUSION: The SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.
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Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste , Neoplasias Pulmonares , Camundongos Nus , Podofilotoxina , Carcinoma de Pequenas Células do Pulmão , Animais , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Camundongos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Podofilotoxina/farmacologia , Podofilotoxina/análogos & derivados , Podofilotoxina/uso terapêutico , Linhagem Celular Tumoral , Carcinomatose Meníngea/tratamento farmacológico , Carcinomatose Meníngea/secundário , Ensaios Antitumorais Modelo de Xenoenxerto , Proteólise/efeitos dos fármacosRESUMO
BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N-terminal propeptide of collagen type 3 (PRO-C3) is a biomarker of advanced fibrosis in MAFLD and PRO-C3 may be involved in renal fibrosis. We aimed to use PRO-C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD-CKD). METHODS: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy-confirmed MAFLD were included. Serum PRO-C3 concentration was measured and regression analyses were performed to examine associations with MAFLD-CKD. A derivative algorithm for MAFLD-CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. RESULTS: The study included two Asian cohorts (n = 180 with MAFLD-CKD; mean-eGFR: 94.93 mL/min/1.73 m2; median-urinary albumin-to-creatinine ratio: 6.58 mg/mmol). PRO-C3 was associated with the severity of MAFLD-CKD and independently associated with MAFLD-CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08-1.23, p < .001). A new non-invasive score (termed PERIOD) including PRO-C3 efficiently predicted MAFLD-CKD (AUROC = .842, 95% CI: .805-.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691-.893) with similar results in all patient subgroups. In the MAFLD-CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO-C3-based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836-.964). CONCLUSIONS: The PERIOD score is helpful for accurately predicting the risk of MAFLD-CKD. PRO-C3 can also be used to assess liver fibrosis in people with MAFLD-CKD.
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Complemento C3 , Hepatopatia Gordurosa não Alcoólica , Insuficiência Renal Crônica , Humanos , Complemento C3/análise , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco , Povo AsiáticoRESUMO
An electrochemical oxidative cross-coupling strategy for the synthesis of N-sulfenylsulfoximines from sulfoximines and thiols was accomplished, giving diverse N-sulfenylsulfoximines in moderate to good yields. Moreover, this strategy can be extended to construct the N-P bond of N-phosphinylated sulfoximines. With electrons as reagents, the oxidative dehydrogenation cross-coupling reaction proceeds smoothly in the absence of traditional redox reagents.
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Electrochromic devices built with ionogel electrolytes are seen as a pivotal step toward the future of quasi-solid electrochromic devices, due to their striking properties like exceptional safety and high ionic conductivity. Yet, the poor mechanical strength of electrolyte of these devices remains a constraint that hampers their advancement. As a resolution, this research explores the use of a robust, transparent ionogel electrolyte, which is designed using an in situ microphase separation strategy. The ionogels are highly transparent and robust and exhibit excellent physicochemical stability, including a wide electrochemical window and high temperature tolerance. Benefitting from these properties, a high-performance electrochromic device is fabricated through in situ polymerization with the ionogels, PPRODOT as the electrochromic layer, and PEDOT: PSS as the ion storage layer, achieving high transmittance contrast (43.1%), fast response (1/1.7 s), high coloring efficiency (1296.4 cm2 C-1), and excellent cycling endurance (>99.9% retention after 2000 cycles). In addition, using ITO-poly(ethylene terephthalate) as flexible substrates, a deformable electrochromic device displaying high stability is realized, highlighting the potential use in functional wearables.
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Eletrólitos , Géis , Polimerização , Eletrólitos/química , Géis/química , Técnicas Eletroquímicas , Polímeros/química , Condutividade ElétricaRESUMO
In response to the urgent need for highly precise and efficient stitching measurements of large-aperture-angle non-holonomic spherical surfaces, a differential confocal interference automatic stitching measurement system for large-aperture-angle non-holonomic spherical surfaces was developed. The system realizes precise positioning of the confocal position through differential confocal precise focusing technology. Through the stitching model, coordinate transformation and error compensation were performed on subaperture data, and the stitching measurement of the spherical surface shape was realized. The positions and postures of the tested samples were adjusted automatically using an automatic adjustment workbench. The stitching measurement accuracy of this measurement system can attain 0.0013λ, relative error can attain 1.36%, and measurement time for eight subaperture stitching is 6 min. This system achieves automatic and rapid adjustment of large-aperture-angle spherical elements and high-precision, nondestructive, fast, and automatic measurement of surface stitching.
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OBJECTIVE: This study seeks to explore the impact of fast track surgery (FTS) with three-port in patients treated with laparoscopic radical cystectomy and ileal conduit on postoperative recovery, hospital stay and the complications. METHODS: This retrospective study analyzed 230 patients with invasive bladder cancer who underwent laparoscopic radical cystectomy at the Second Hospital of Anhui Medical University between December 2011 to January 2023. 50 patients received conventional surgery (CS) and 180 patients received FTS with three-port. Patients were assessed for time to normal diet consumption, time to passing first flatus, number of postoperative recovery days and complications. Trends of serum C-reactive protein levels were monitored preoperatively and on postoperative days 1, 3 and 7. RESULTS: Patients who underwent FTS with three-port had a shorter duration to first flatus (P < 0.05). And number of postoperative hospital days and the length of hospital stay were notably shorter in contrast to the CS group (P < 0.05). Serum CRP levels on postoperative day 7 were markedly reduced in those of the FTS group compared to the CS group (P < 0.05). Those of the CS group experienced more frequent rates of complications compared to those of the FTS with three-port group (P < 0.05). CONCLUSION: Our findings demonstrate that the FTS with three-port program hastens postoperative recovery and reduces duration of hospital stay. It is safer and more effective than the CS program in the Chinese population undergoing laparoscopic radical cystectomy.
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Cistectomia , Laparoscopia , Tempo de Internação , Complicações Pós-Operatórias , Neoplasias da Bexiga Urinária , Derivação Urinária , Humanos , Cistectomia/métodos , Cistectomia/efeitos adversos , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Masculino , Laparoscopia/métodos , Laparoscopia/efeitos adversos , Feminino , Estudos Retrospectivos , Derivação Urinária/métodos , Pessoa de Meia-Idade , Tempo de Internação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Idoso , Seguimentos , Prognóstico , Assistência Perioperatória/métodos , China/epidemiologiaRESUMO
Piezocatalysis, a heterogeneous catalytic technique, leverages the periodic electric field changes generated by piezoelectric materials under external forces to drive carriers for the advanced oxidation of organic pollutants. Antibiotics, as emerging trace organic pollutants in water sources, pose a potential threat to animals and drinking water safety. Thus, piezoelectric catalysis can be used to degrade trace organic pollutants in water. In this work, BaTiO3 and La-doped BaTiO3 were synthesized using an improved sol-gel-hydrothermal method and used as piezocatalytic materials to degrade sulfadiazine (SDZ) with ultrasound activation. High-crystallinity products with nano cubic and spherical morphologies were successfully synthesized. An initial concentration of SDZ ranging from 1 to 10 mg/L, a catalysis dosage range from 1 to 2.5 mg/mL, pH, and the background ions in the water were considered as influencing factors and tested. The reaction rate constant was 0.0378 min-1 under the optimum working conditions, and the degradation efficiency achieved was 89.06% in 60 min. La-doped BaTiO3 had a better degradation efficiency, at 14.98% on average, compared to undoped BaTiO3. Further investigations into scavengers revealed a partially piezocatalytic process for the degradation of SDZ. In summary, our work provides an idea for green environmental protection in dealing with new types of environmental pollution.
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Burns are a common type of trauma that seriously affect not only the physical health, but also the mental health and quality of life of the patient. Extracorporeal shock wave therapy (ESWT) is an emerging treatment that has been used in clinical treatment. It has many advantages, including safety, non-invasiveness, efficiency, short treatment duration, fewer complications, and relatively low prices. In clinical settings, ESWT has played an important role in the healing process of burns and the prevention of sequelae. This article reviews the history of ESWT, the mechanism of ESWT to promote burn healing, and the application of ESWT in burns. Current status of ESWT treatment for burns as well as future perspectives for research have been summarized and proposed. However, patients with burns cannot be considered recovered when the wounds have healed, we need some new technology to adjust to the challenges of the future.
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Queimaduras , Tratamento por Ondas de Choque Extracorpóreas , Humanos , Qualidade de Vida , Cicatrização , Queimaduras/complicações , Queimaduras/terapia , Fatores de Tempo , Resultado do TratamentoRESUMO
Temperate japonica/geng (GJ) rice yield has significantly improved due to intensive breeding efforts, dramatically enhancing global food security. However, little is known about the underlying genomic structural variations (SVs) responsible for this improvement. We compared 58 long-read assemblies comprising cultivated and wild rice species in the present study, revealing 156 319 SVs. The phylogenomic analysis based on the SV dataset detected the putatively selected region of GJ sub-populations. A significant portion of the detected SVs overlapped with genic regions were found to influence the expression of involved genes inside GJ assemblies. Integrating the SVs and causal genetic variants underlying agronomic traits into the analysis enables the precise identification of breeding signatures resulting from complex breeding histories aimed at stress tolerance, yield potential and quality improvement. Further, the results demonstrated genomic and genetic evidence that the SV in the promoter of LTG1 is accounting for chilling sensitivity, and the increased copy numbers of GNP1 were associated with positive effects on grain number. In summary, the current study provides genomic resources for retracing the properties of SVs-shaped agronomic traits during previous breeding procedures, which will assist future genetic, genomic and breeding research on rice.
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Oryza , Oryza/genética , Melhoramento Vegetal , Genômica/métodos , Fenótipo , Grão ComestívelRESUMO
In response to increasing global warming, extreme heat stress significantly alters photosynthetic production. While numerous studies have investigated the temperature effects on photosynthesis, factors like vapour pressure deficit (VPD), leaf nitrogen, and feedback of sink limitation during and after extreme heat stress remain underexplored. This study assessed photosynthesis calculations in seven rice growth models using observed maximum photosynthetic rate (Pmax ) during and after short-term extreme heat stress in multi-year environment-controlled experiments. Biochemical models (FvCB-type) outperformed light response curve-based models (LRC-type) when incorporating observed leaf nitrogen, photosynthetically active radiation, temperatures, and intercellular CO2 concentration (Ci ) as inputs. Prediction uncertainty during heat stress treatment primarily resulted from variation in temperatures and Ci . Improving FVPD (the slope for the linear effect of VPD on Ci /Ca ) to be temperature-dependent, rather than constant as in original models, significantly improved Ci prediction accuracy under heat stress. Leaf nitrogen response functions led to model variation in leaf photosynthesis predictions after heat stress, which was mitigated by calibrated nitrogen response functions based on active photosynthetic nitrogen. Additionally, accounting for observed differences in carbohydrate accumulation between panicles and stems during grain filling improved the feedback of sink limitation, reducing Ci overestimation under heat stress treatments.
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Aquecimento Global , Resposta ao Choque Térmico , Nitrogênio , Oryza , Fotossíntese , Folhas de Planta , Dióxido de Carbono/fisiologia , Grão Comestível , Resposta ao Choque Térmico/fisiologia , Temperatura Alta/efeitos adversos , Modelos Biológicos , Nitrogênio/fisiologia , Oryza/fisiologia , Fotossíntese/fisiologia , Folhas de Planta/fisiologia , Fenômenos Fisiológicos Vegetais , TemperaturaRESUMO
Bone formation is dependent on the osteoblasts which are differentiated from bone marrow stromal cells (BMSCs). In addition to potent proliferation, self-renewal, and pluripotent differentiation, BMSCs have been extensively studied due to their low immunogenicity and immunomodulatory effects. Recently, galectin-1 (Gal-1) has been proposed as a potent mediator of immunomodulatory properties of BMSCs. Previous study demonstrated that Gal-1 showed age-related decline in mice serum and serum Gal-1 was positively associated with bone mass in mice. The current study makes attempts to elucidate the functional role of Gal-1 in skeletal system by investigating the regulation of Gal-1 expression during BMSCs osteogenic differentiation and the molecular mechanisms underlying the effects of Gal-1 on BMSCs osteogenic differentiation. In Gal-1 null (-/-) mice, bone loss was observed due to bone formation attenuation. In in vitro experiments, Gal-1 supported the osteogenic differentiation of BMSCs by binding to CD146 to activate Lrp5 expression and Wnt/ß-catenin signaling pathway. Meanwhile, there was positive feedback regulation via Wnt/ß-catenin signaling to maintain Gal-1 high-level expression during osteogenic differentiation of BMSCs. More importantly, Gal-1 down-regulation in BMSCs and attenuation of osteogenic differentiation potential of BMSCs were observed in aged mice compared with young mice. Gal-1 over-expression could enhance osteogenic differentiation potential of aged BMSCs. Our study will benefit not only for deeper insights into the functional role of Gal-1 but also for finding new targets to modulate BMSCs osteogenic differentiation.
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Doenças Ósseas Metabólicas/metabolismo , Galectina 1/genética , Células-Tronco Mesenquimais , Animais , Doenças Ósseas Metabólicas/genética , Células da Medula Óssea/metabolismo , Diferenciação Celular , Células Cultivadas , Galectina 1/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteogênese , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Laccase domain-containing 1 (LACC1) protein is an enzyme highly expressed in inflammatory macrophages, and studies have shown that it has a key role in diseases such as inflammatory bowel disease, arthritis, and microbial infections. Therefore, in this review, we focus on LACC1-mediated catalysis. In detail, LACC1 converts l-CITrulline (l-CIT) to l-ORNithine (l-ORN) and isocyanic acid in mice and humans and acts as a bridge between proinflammatory nitric oxide synthase (NOS2) and polyamine immunometabolism, thus exerting anti-inflammatory and antibacterial effects. Considering the actions of LACC1, targeting LACC1 may be a potent therapeutic avenue for inflammation-related diseases and microbial infection diseases.
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Artrite , Doenças Inflamatórias Intestinais , Humanos , Camundongos , Animais , Lacase/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Artrite/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Óxido Nítrico/metabolismoRESUMO
INTRODUCTION: Moderate exercise benefits bone health, but excessive loading leads to bone fatigue and a decline in mechanical properties. Low-intensity pulsed ultrasound (LIPUS) can stimulate bone formation. The purpose of this study was to explore whether LIPUS could augment the skeletal benefits of high-intensity exercise. MATERIALS AND METHODS: MC3T3-E1 osteoblasts were treated with LIPUS at 80 mW/cm2 or 30 mW/cm2 for 20 min/day. Forty rats were divided into sham treatment normal control (Sham-NC), sham treatment high-intensity exercise (Sham-HIE), 80 mW/cm2 LIPUS (LIPUS80), and high-intensity exercise combined with 80 mW/cm2 LIPUS (LIPUS80-HIE). The rats in HIE group were subjected to 30 m/min slope treadmill exercise for 90 min/day, 6 days/week for 12 weeks. The LIPUS80-HIE rats were irradiated with LIPUS (1 MHz, 80 mW/cm2) for 20 min/day at bilateral hind limb after exercise. RESULTS: LIPUS significantly accelerated the proliferation, differentiation, mineralization, and migration of MC3T3-E1 cells. Compared to 30 mW/cm2 LIPUS, 80 mW/cm2 LIPUS got better promotion effect. 12 weeks of high-intensity exercise significantly reduced the muscle force, which was significantly reversed by LIPUS. Compared with the Sham-NC group, Sham-HIE group significantly optimized bone microstructure and enhanced mechanical properties of femur, and LIPUS80-HIE further enhanced the improvement effect on bone. The mechanisms may be related to activate Wnt/ß-catenin signal pathway and then up-regulate the protein expression of Runx2 and VEGF, the key factors of osteogenesis and angiogenesis. CONCLUSION: LIPUS could augment the skeletal benefits of high-intensity exercise through Wnt/ß-catenin signal pathway.
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Ondas Ultrassônicas , beta Catenina , Ratos , Animais , Diferenciação Celular , Músculos , Via de Sinalização WntRESUMO
BACKGROUND: Emerging evidence has shown the crucial roles of pleomorphic adenoma gene (PLAG) family genes in multiple cancers. However, their functions and mechanisms in pancreatic adenocarcinoma (PAAD) remain poorly understood. METHODS: We analyzed the expression levels of PLAG family genes in both The Cancer Genome Atlas (TCGA) database and a Gene Expression Omnibus (GEO) database, and confirmed the results in our three independent cohorts of 382 PAAD tissues and 362 adjacent nontumor pancreatic tissues. Integrated analyses were carried out to explore the function, mechanism and prognostic value of the selected PLAG family gene in PAAD patients. RESULTS: By analyzing the TCGA and GEO databases, PLAGL1 was identified to be downregulated in PAAD tissues, and its decreasing levels of both mRNA and protein were verified in our three independent PAAD cohorts. PLAGL1 expression was inversely correlated with clinicopathological factors including the Ki67+ cell rate and pathologic stage. Further GSEA of the TCGA-PAAD cohort demonstrated that multiple signaling pathways implicated in cell proliferation were enriched in the lower PLAGL1 expressing PAAD group. Moreover, we demonstrated that PLAGL1 expression was obviously negatively associated with patients' overall survival outcome in both the TCGA-PAAD cohort and our verification cohorts. Additionally, through MTS and BrdU assays, we further demonstrated in vitro that PLAGL1 had the impact of preventing the proliferation of pancreatic cancer cells. CONCLUSIONS: Our present study suggested that downregulated PLAGL1 might act as a biomarker in predicts poor prognosis and one of important factors in increasing cell proliferation in PAAD. This study provides us with a novel prognostic marker and therapeutic strategy for PAAD, which deserves further study.
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Adenocarcinoma , Neoplasias Pancreáticas , Fatores de Transcrição , Proteínas Supressoras de Tumor , Humanos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Neoplasias PancreáticasRESUMO
Previous studies have reported the immunotoxicity of per- and polyfluoroalkyl substances (PFASs), but it remains a significant challenge to assess over 10,000 distinct PFASs registered in the distributed structure-searchable toxicity (DSSTox) database. We aim to reveal the mechanisms of immunotoxicity of different PFASs and hypothesize that PFAS immunotoxicity is dependent on the carbon chain length. Perfluorobutanesulfonic acid (PFBA), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) representing different carbon chain lengths (4-9) at environmentally relevant levels strongly reduced the host's antibacterial ability during the zebrafish's early-life stage. Innate and adaptive immunities were both suppressed after PFAS exposures, exhibiting a significant induction of macrophages and neutrophils and expression of immune-related genes and indicators. Interestingly, the PFAS-induced immunotoxic responses were positively correlated to the carbon chain length. Moreover, PFASs activated downstream genes of the toll-like receptor (TLR), uncovering a seminal role of TLR in PFAS immunomodulatory effects. Myeloid differentiation factor 88 (MyD88) morpholino knock-down experiments and MyD88 inhibitors alleviated the immunotoxicity of PFASs. Overall, the comparative results demonstrate differences in the immunotoxic responses of PFASs due to carbon chain length in zebrafish, providing new insights into the prediction and classification of PFASs mode of toxic action based on carbon chain length.
Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Poluentes Químicos da Água , Animais , Peixe-Zebra , Carbono , Fator 88 de Diferenciação Mieloide , Fluorocarbonos/toxicidadeRESUMO
Biocompatible materials and biocarriers have attracted great attention in biological wastewater treatment owing to their excellent performance in improving pollutant removal. Graphene-based material, a biocarrier candidate, with excellent adsorbability and conductivity was increasingly applied in anaerobic digestion due to its exceptional potential in the adsorption and electron transfer process. Nevertheless, the green approach for the formation of bio-graphene complexes and their mechanism in dye removal is limited. The aim of this study is to investigate and assess the performance of biological graphene hydrogel (BGH) formed by Shewanella putrefaciens CN32 on the removal of methyl orange (MO) and methylene blue (MB). The results showed that the formation of BGH is determined by the physicochemical characteristics of graphene oxide, including sheet size, oxidation degree, and interlayer distance. BGHs significantly increased the removal efficiency of dyes in comparison to non-graphene samples, with a 24-h removal rate of MO and MB reaching 92.9% and 91%, respectively. The synergetic mechanism of BGH on the enhanced removal rate of organic dye can be ascribed to GO's ability in accelerating extracellular electron transfer and stimulating biodegradation pathways relating to c-type cytochromes, including MtrA and MtrC. These findings provided an understanding of the relationship between graphene-based nanomaterials and Shewanella, which facilitated their future application in environmental biotechnology.