RESUMEN
Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.
Asunto(s)
Proteínas de la Membrana , Membranas Mitocondriales , Proteínas Mitocondriales , Mitofagia , Proteína Fosfatasa 2C , Proteolisis , Animales , Ratones , Proteínas de la Membrana/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/metabolismo , Mitofagia/genética , Proteína Fosfatasa 2C/metabolismoRESUMEN
Hexokinase (HK) catalyzes the first irreversible rate-limiting step in glycolysis that converts glucose to glucose-6-phosphate. HK1 is ubiquitously expressed in the brain, erythrocytes, and other tissues where glycolysis serves as the major source of ATP production. Spermatogenic cell-specific type 1 hexokinase (HK1S) is expressed in sperm but its physiological role in male mice is still unknown. In this study, we generate Hk1s knockout mice using the CRISPR/Cas9 system to study the gene function in vivo. Hk1s mRNA is exclusively expressed in testes starting from postnatal day 18 and continuing to adulthood. HK1S protein is specifically localized in the outer surface of the sperm fibrous sheath (FS). Depletion of Hk1s leads to infertility in male mice and reduces sperm glycolytic pathway activity, yet they have normal motile parameters and ATP levels. In addition, by using in vitro fertilization (IVF), Hk1s deficient sperms are unable to fertilize cumulus-intact or cumulus-free oocytes, but can normally fertilize zona pellucida-free oocytes. Moreover, Hk1s deficiency impairs sperm migration into the oviduct, reduces acrosome reaction, and prevents capacitation-associated increases in tyrosine phosphorylation, which are probable causes of infertility. Taken together, our results reveal that HK1S plays a critical role in sperm function and male fertility in mice.
Asunto(s)
Fertilidad , Hexoquinasa , Infertilidad Masculina , Ratones Noqueados , Capacitación Espermática , Espermatozoides , Tirosina , Animales , Hexoquinasa/genética , Hexoquinasa/metabolismo , Masculino , Ratones , Fosforilación , Espermatozoides/metabolismo , Capacitación Espermática/genética , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Fertilidad/genética , Tirosina/metabolismo , Femenino , Testículo/metabolismo , Motilidad Espermática/genética , Glucólisis , Espermatogénesis/genéticaRESUMEN
BACKGROUND: Calcification of the aortic valve leads to increased leaflet stiffness and consequently results in the development of calcific aortic valve disease (CAVD). However, the underlying molecular and cellular mechanisms of calcification remain unclear. Here, we identified a novel aortic valve calcification-associated PIWI-interacting RNA (piRNA; AVCAPIR) that increases valvular calcification and promotes CAVD progression. METHODS: Using piRNA sequencing, we identified piRNAs contributing to the pathogenesis of CAVD that we termed AVCAPIRs. High-cholesterol diet-fed ApoE-/- mice with AVCAPIR knockout were used to examine the role of AVCAPIR in aortic valve calcification (AVC). Gain- and loss-of-function assays were conducted to determine the role of AVCAPIR in the induced osteogenic differentiation of human valvular interstitial cells. To dissect the mechanisms underlying AVCAPIR-elicited procalcific effects, we performed various analyses, including an RNA pulldown assay followed by liquid chromatography-tandem mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing. RNA pulldown and RNA immunoprecipitation assays were used to study piRNA interactions with proteins. RESULTS: We found that AVCAPIR was significantly upregulated during AVC and exhibited potential diagnostic value for CAVD. AVCAPIR deletion markedly ameliorated AVC in high-cholesterol diet-fed ApoE-/- mice, as shown by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity and mean transvalvular pressure gradient, as well as increased aortic valve area), and diminished levels of osteogenic markers (Runx2 and Osterix) in aortic valves. These results were confirmed in osteogenic medium-induced human valvular interstitial cells. Using unbiased protein-RNA screening and molecular validation, we found that AVCAPIR directly interacts with FTO (fat mass and obesity-associated protein), subsequently blocking its N6-methyladenosine demethylase activity. Further transcriptomic and N6-methyladenosine modification epitranscriptomic screening followed by molecular validation confirmed that AVCAPIR hindered FTO-mediated demethylation of CD36 mRNA transcripts, thus enhancing CD36 mRNA stability through the N6-methyladenosine reader IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1). In turn, the AVCAPIR-dependent increase in CD36 stabilizes its binding partner PCSK9 (proprotein convertase subtilisin/kexin type 9), a procalcific gene, at the protein level, which accelerates the progression of AVC. CONCLUSIONS: We identified a novel piRNA that induced AVC through an RNA epigenetic mechanism and provide novel insights into piRNA-directed theranostics in CAVD.
Asunto(s)
Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , ARN Interferente Pequeño , Animales , Calcinosis/metabolismo , Calcinosis/genética , Calcinosis/patología , Válvula Aórtica/metabolismo , Válvula Aórtica/patología , Válvula Aórtica/anomalías , Humanos , Ratones , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/patología , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Masculino , Osteogénesis , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales de Enfermedad , Enfermedad de la Válvula Aórtica/metabolismo , Enfermedad de la Válvula Aórtica/genética , Enfermedad de la Válvula Aórtica/patología , ARN de Interacción con PiwiRESUMEN
The strength-ductility trade-off has long been a Gordian knot in conventional metallic structural materials and it is no exception in multi-principal element alloys. In particular, at ultrahigh yield strengths, plastic instability, that is, necking, happens prematurely, because of which ductility almost entirely disappears. This is due to the growing difficulty in the production and accumulation of dislocations from the very beginning of tensile deformation that renders the conventional dislocation hardening insufficient. Here we propose that premature necking can be harnessed for work hardening in a VCoNi multi-principal element alloy. Lüders banding as an initial tensile response induces the ongoing localized necking at the band front to produce both triaxial stress and strain gradient, which enables the rapid multiplication of dislocations. This leads to forest dislocation hardening, plus extra work hardening due to the interaction of dislocations with the local-chemical-order regions. The dual work hardening combines to restrain and stabilize the premature necking in reverse as well as to facilitate uniform deformation. Consequently, a superior strength-and-ductility synergy is achieved with a ductility of ~20% and yield strength of 2 GPa during room-temperature and cryogenic deformation. These findings offer an instability-control paradigm for synergistic work hardening to conquer the strength-ductility paradox at ultrahigh yield strengths.
RESUMEN
Multiple isozymes are encoded in the Caenorhabditis elegans genome for the various sphingolipid biosynthesis reactions, but the contributions of individual isozymes are characterized only in part. We developed a simple but effective reversed-phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS) method that enables simultaneous identification and quantification of ceramides (Cer), glucosylceramides (GlcCer), and sphingomyelins (SM) from the same MS run. Validating this sphingolipid profiling method, we show that nearly all 47 quantifiable sphingolipid species found in young adult worms were reduced upon RNA interference (RNAi) of sptl-1 or elo-5, which are both required for synthesis of the id17:1 sphingoid base. We also confirm that HYL-1 and HYL-2, but not LAGR-1, constitute the major ceramide synthase activity with different preference for fatty acid substrates, and that CGT-3, but not CGT-1 and CGT-2, plays a major role in producing GlcCers. Deletion of sms-5 hardly affected SM levels. RNAi of sms-1, sms-2, and sms-3 all lowered the abundance of certain SMs with an odd-numbered N-acyl chains (mostly C21 and C23, with or without hydroxylation). Unexpectedly, sms-2 RNAi and sms-3 RNAi elevated a subset of SM species containing even-numbered N-acyls. This suggests that sphingolipids containing even-numbered N-acyls could be regulated separately, sometimes in opposite directions, from those containing odd-numbered N-acyls, which are presumably monomethyl branched chain fatty acyls. We also find that ceramide levels are kept in balance with those of GlcCers and SMs. These findings underscore the effectiveness of this RPLC-MS/MS method in studies of C. elegans sphingolipid biology.
Asunto(s)
Caenorhabditis elegans , Isoenzimas , Esfingolípidos , Animales , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/enzimología , Esfingolípidos/biosíntesis , Esfingolípidos/metabolismo , Isoenzimas/metabolismo , Isoenzimas/genética , Espectrometría de Masas en Tándem , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Ceramidas/metabolismo , Ceramidas/biosíntesis , Interferencia de ARN , Cromatografía LiquidaRESUMEN
Unraveling the mechanism of chirality transfer across length scales is crucial to the rational development of functional materials with hierarchical chirality. The key obstacle is the lack of structural information, especially at the mesoscopic level. We report herein the structural identification of helical covalent organic frameworks (heliCOFs) with hierarchical chirality, which integrate molecular chirality, channel chirality, and morphology chirality into one crystalline entity. Specifically, benefiting from the highly ordered structure of heliCOFs, the existence of chiral channels at the mesoscopic level has been confirmed by electron crystallography, and the handedness of these chiral channels has been directly determined through the stereopair imaging technique. Accordingly, the chirality transfer in heliCOFs from microscopic to macroscopic levels could be rationalized with a layer-rotating model that has been supported by both crystal structure analysis and theoretical calculations. Observation of chiral channels in heliCOFs not only provides unprecedented data for the understanding of the chirality transfer process but also sheds new light on the rational construction of highly ordered polymeric materials with hierarchical chirality.
RESUMEN
PURPOSE: The objective of this study was to identify potential predictors of immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitor therapy among serum indexes, case data, and liquid biopsy results. METHODS: We retrospectively analyzed 418 patients treated with anti-programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) inhibitors from January 2018 to May 2022 in our cancer center. We identified factors that correlated with the occurrence of irAEs and evaluated associations between irAEs and anti-PD-1/PD-L1 inhibitor responses. RESULTS: The incidence of irAEs was 42.1%, and pneumonitis (9.1%), thyroid toxicity (9.1%), cardiotoxicity (8.1%), and dermatologic toxicity (6.9%) were the four most common irAEs. Multivariate logistic analysis identified female sex, antibiotic use, higher post-treatment neutrophil-to-lymphocyte ratio (NLR), and higher baseline circulating tumor cell (CTC) level, as predictive biomarkers for the occurrence of irAEs. A lower baseline prognostic nutritional index (PNI), body mass index (BMI) ≥ 25 kg/m2, and higher post-treatment lactate dehydrogenase (LDH) level were predictive factors for more severe irAEs (higher severity grade). Patients without irAEs had better overall survival than those with irAEs. Specifically, pneumonitis and cardiotoxicity were found to be significant predictors of poor prognosis in the irAE subgroup with different organ-related irAEs. Low-dose steroid (dexamethasone 10 mg) treatment had no significant effect on outcomes. CONCLUSIONS: Gender, antibiotic use, post-treatment NLR, and baseline CTC level are potential predictive biomarkers of irAEs, while baseline PNI, BMI, and post-treatment LDH may predict the severity of irAEs. The predictive effect of irAE occurrence on survival benefit may depend on the type of irAE.
Asunto(s)
Neoplasias , Neumonía , Humanos , Femenino , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Cardiotoxicidad , Receptor de Muerte Celular Programada 1 , Estudios Retrospectivos , Antibacterianos , Biomarcadores , Neoplasias/tratamiento farmacológicoRESUMEN
Adjuvants play a critical role in the induction of effective immune responses by vaccines. Here, a self-assembling nanovaccine platform that integrates adjuvant functions into the delivery vehicle is prepared. Cationic Lentinan (CLNT) is mixed with ovalbumin (OVA) to obtain a self-assembling nanovaccine (CLNTO nanovaccine), which induces the uptake and maturation of bone marrow dendritic cells (BMDCs) via the toll-like receptors 2/4 (TLR2/4) to produce effective antigen cross-presentation. CLNTO nanovaccines target lymph nodes (LNs) and induce a robust OVA-specific immune response via TLR and tumor necrosis factor (TNF) signaling pathways, retinoic acid-inducible gene I (RIG-I) receptor, and cytokine-cytokine receptor interactions. In addition, CLNTO nanovaccines are found that promote the activation of follicular helper T (Tfh) cells and induce the differentiation of germinal center (GC) B cells into memory B cells and plasma cells, thereby enhancing the immune response. Vaccination with CLNTO nanovaccine significantly inhibits the growth of ovalbumin (OVA)-expressing B16 melanoma cell (B16-OVA) tumors, indicating its great potential for cancer immunotherapy. Therefore, this study presents a simple, safe, and effective self-assembling nanovaccine that induces helper T cell 1 (Th1) and helper T cell (Th2) immune responses, making it an effective vaccine delivery system.
RESUMEN
BACKGROUND: Intravitreal injections of angiogenesis inhibitors have proved efficacious in the majority of patients with ocular angiogenesis. However, one-fourth of all treated patients fail to derive benefits from intravitreal injections. tRNA-derived small RNA (tsRNA) emerges as a crucial class of non-coding RNA molecules, orchestrating key roles in the progression of human diseases by modulating multiple targets. Through our prior sequencing analyses and bioinformatics predictions, tRNA-Cys-5-0007 has shown as a potential regulator of ocular angiogenesis. This study endeavors to elucidate the precise role of tRNA-Cys-5-0007 in the context of ocular angiogenesis. METHODS: Quantitative reverse transcription PCR (qRT-PCR) assays were employed to detect tRNA-Cys-5-0007expression. EdU assays, sprouting assays, transwell assays, and Matrigel assays were conducted to elucidate the involvement of tRNA-Cys-5-0007 in endothelial angiogenic effects. STZ-induced diabetic model, OIR model, and laser-induced CNV model were utilized to replicate the pivotal features of ocular vascular diseases and evaluate the influence of tRNA-Cys-5-0007 on ocular angiogenesis and inflammatory responses. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were employed to elucidate the anti-angiogenic mechanism of tRNA-Cys-5-0007. Exosomal formulation was employed to enhance the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. RESULTS: tRNA-Cys-5-0007 expression was down-regulated under angiogenic conditions. Conversely, tRNA-Cys-5-0007 overexpression exhibited anti-angiogenic effects in retinal endothelial cells, as evidenced by reduced proliferation, sprouting, migration, and tube formation abilities. In diabetic, laser-induced CNV, and OIR models, tRNA-Cys-5-0007 overexpression led to decreased ocular vessel leakage, inhibited angiogenesis, and reduced ocular inflammation. Mechanistically, these effects were attributed to the targeting of vascular endothelial growth factor A (VEGFA) and TGF-ß1 by tRNA-Cys-5-0007. The utilization of an exosomal formulation further potentiated the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. CONCLUSIONS: Concurrent targeting of tRNA-Cys-5-0007 for anti-angiogenic and anti-inflammatory therapy holds promise for enhancing the effectiveness of current anti-angiogenic therapy.
Asunto(s)
Inhibidores de la Angiogénesis , Antiinflamatorios , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antiinflamatorios/farmacología , Humanos , ARN de Transferencia/metabolismo , ARN de Transferencia/genética , Ratones Endogámicos C57BL , Proliferación Celular/efectos de los fármacos , Neovascularización Coroidal/patología , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/metabolismo , Masculino , Oftalmopatías/tratamiento farmacológico , Oftalmopatías/patología , Oftalmopatías/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Neovascularización Patológica , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/patología , Retinopatía Diabética/metabolismo , Ratones , Células Endoteliales de la Vena Umbilical Humana/metabolismoRESUMEN
BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (m6A) is the frequent RNA modification and plays a critical role in MIRI. However, it is unclear whether lncRNA Snhg1 regulates MIRI progression and whether the lncRNA Snhg1 was modified by m6A methylation. METHODS: Mouse cardiomyocytes HL-1 cells were utilized to construct the hypoxia/reoxygenation (H/R) injury model. HL-1 cell viability was evaluated utilizing CCK-8 method. Cell apoptosis, mitochondrial reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were quantitated utilizing flow cytometry. RNA immunoprecipitation and dual-luciferase reporter assays were applied to measure the m6A methylation and the interactions between lncRNA Snhg1 and targeted miRNA or target miRNAs and its target gene. The I/R mouse model was constructed with adenovirus expressing lncRNA Snhg1. HE and TUNEL staining were used to evaluate myocardial tissue damage and apoptosis. RESULTS: LncRNA Snhg1 was down-regulated after H/R injury, and overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization. Besides, lncRNA Snhg1 could target miR-361-5p, and miR-361-5p targeted OPA1. Overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization though the miR-361-5p/OPA1 axis. Furthermore, WTAP induced lncRNA Snhg1 m6A modification in H/R-stimulated HL-1 cells. Moreover, enforced lncRNA Snhg1 repressed I/R-stimulated myocardial tissue damage and apoptosis and regulated the miR-361-5p and OPA1 levels. CONCLUSION: WTAP-mediated m6A modification of lncRNA Snhg1 regulated MIRI progression through modulating myocardial apoptosis, mitochondrial ROS production, and mitochondrial polarization via miR-361-5p/OPA1 axis, providing the evidence for lncRNA as the prospective target for alleviating MIRI progression.
Asunto(s)
Apoptosis , MicroARNs , Dinámicas Mitocondriales , Daño por Reperfusión Miocárdica , Miocitos Cardíacos , ARN Largo no Codificante , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/patología , Ratones , Apoptosis/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Línea Celular , Masculino , Ratones Endogámicos C57BL , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Especies Reactivas de Oxígeno/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Secuencia de Bases , Metilación , Potencial de la Membrana MitocondrialRESUMEN
We compute the total cross section and invariant mass distribution for heavy-quark pair production in e^{+}e^{-} annihilation at the next-to-next-to-next-to-leading order in QCD. The obtained results are expressed as piecewise functions defined by several deeply expanded power series, facilitating a rapid numerical evaluation. Utilizing top-pair production at a collision energy of 500 GeV as a benchmark, we observe a correction of approximately 0.1% for the total cross section and around 10% for the majority of the invariant mass distribution range. These results play a crucial role in significantly reducing theoretical uncertainty: the scale dependence has been diminished to 0.06% for the total cross section and to 5% for the invariant mass distribution. This reduction of uncertainty meets the stringent requirements of future lepton colliders.
RESUMEN
We present the results for the complete next-to-leading order electroweak corrections to ppâHH at the Large Hadron Collider, focusing on the dominant gluon-gluon fusion process. While the corrections at the total cross-section level are approximately -4%, those near the energy of HH production threshold exceed +15%, and corrections at the high-energy region are around -10%, leading to a shape distortion for the differential distributions. Our findings substantially diminish the theoretical uncertainties associated with this pivotal process, providing valuable input for understanding the shape of the Higgs boson potential upon comparison with experimental measurements.
RESUMEN
The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states.
Asunto(s)
Ácidos Dicarboxílicos , Hígado , Metabolómica , Animales , Humanos , Ratas , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Biomarcadores , Células HEK293 , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones OrgánicosRESUMEN
BACKGROUND: Alzheimer's disease (AD), affecting many elders worldwide, is characterized by A-beta and tau-related cognitive decline. Accumulating evidence suggests that brain iron accumulation is an important characteristic of AD. However, the function and mechanism of the iron-mediated gut-brain axis on AD is still unclear. METHODS: A Caenorhabditis elegans model with tau-overexpression and a high-Fe diet mouse model of cognitive impairment was used for probiotic function evaluation. With the use of qPCR, and immunoblotting, the probiotic regulated differential expression of AD markers and iron related transporting genes was determined. Colorimetric kits, IHC staining, and immunofluorescence have been performed to explore the probiotic mechanism on the development of gut-brain links and brain iron accumulation. RESULTS: In the present study, a high-Fe diet mouse model was used for evaluation in which cognitive impairment, higher A-beta, tau and phosphorylated (p)-tau expression, and dysfunctional phosphate distribution were observed. Considering the close crosstalk between intestine and brain, probiotics were then employed to delay the process of cognitive impairment in the HFe mouse model. Pediococcus acidilactici (PA), but not Bacillus subtilis (BN) administration in HFe-fed mice reduced brain iron accumulation, enhanced global alkaline phosphatase (AP) activity, accelerated dephosphorylation, lowered phosphate levels and increased brain urate production. In addition, because PA regulated cognitive behavior in HFe fed mice, we used the transgenic Caenorhabditis elegans with over-expressed human p-tau for model, and then PA fed worms became more active and longer lived than E.coli fed worms, as well as p-tau was down-regulated. These results suggest that brain iron accumulation influences AD risk proteins and various metabolites. Furthermore, PA was shown to reverse tau-induced pathogenesis via iron transporters and AP-urate interaction. CONCLUSIONS: PA administration studies demonstrate that PA is an important mediator of tau protein reduction, p-tau expression and neurodegenerative behavior both in Caenorhabditis elegans and iron-overload mice. Finally, our results provide candidates for AP modulation strategies as preventive tools for promoting brain health. Video Abstract.
Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Pediococcus acidilactici , Ratones , Animales , Humanos , Anciano , Pediococcus acidilactici/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Caenorhabditis elegans/metabolismo , Ácido Úrico , Ratones Transgénicos , Enfermedad de Alzheimer/metabolismo , Hierro , FosfatosRESUMEN
Cytoplasmic male sterility (CMS) is a very important factor to produce hybrid seeds, and the restoration of fertility involves the expression of many fertility-related genes. Our previous study showed that the expression of CaPIPLC5 was significantly up-regulated in pepper restorer accessions and minimally expressed in sterile accessions, speculating that CaPIPLC5 is related to the restoration of fertility. In this study, we further validated the function of CaPIPLC5 in the restoration of fertility. The results showed that CaPIPLC5 was specifically expressed in the anthers of the restorer accessions with the subcellular localization in the cytoplasm. Furthermore, the expression of CaPIPLC5 was significantly higher in restorer lines and restorer combinations than that in CMS lines and their maintainer lines. Silencing CaPIPLC5 led to the number of pollen decreased, pollen grains wrinkled, and the ratio of pollen germination reduced. In addition, the joint analysis of Yeast One-Hybrid (Y1H) and Dual-Luciferase (dual-LUC) assays suggested that transcription factors such as CaARF5, CabZIP24 and CaMYB-like1, interacted with the promoter regions of CaPIPLC5, which regulated the expression of CaPIPLC5. The present results provide new insights into the study of CaPIPLC5 involved in the restoration of fertility in pepper.
Asunto(s)
Capsicum , Regulación de la Expresión Génica de las Plantas , Infertilidad Vegetal , Proteínas de Plantas , Polen , Capsicum/genética , Capsicum/fisiología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Infertilidad Vegetal/genética , Polen/genética , Polen/fisiología , Fertilidad/genética , Regiones Promotoras Genéticas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The Friedel-Crafts alkylation of arenes is an important part of electrophilic aromatic substitution reactions. However, the reactivity of arenes is weakened by electron-withdrawing substituents, leading to limited substrate scopes and applications. Herein, we developed an efficient HOTf-promoted Friedel-Crafts alkylation reaction of broad arenes with α-aryl-α-diazoesters under metal-free and solvent-free conditions.
RESUMEN
ß-Ga2O3has been widely investigated for its stability and thermochemical properties. However, the preparation ofß-Ga2O3thin films requires complex growth techniques and high growth temperatures, and this has hindered the application ofß-Ga2O3thin films. In this study,ß-Ga2O3thin films with good crystalline quality were prepared using a green method, and an ultraviolet (UV) detector based onß-Ga2O3with a photocurrent of 2.54 × 10-6A and a dark current of 1.19 × 10-8A has been developed. Two-dimensional materials have become premium materials for applications in optoelectronic devices due to their high conductivity. Here, we use the suitable energy band structure between Nb2C and Ga2O3to create a high carrier migration barrier, which reduces the dark current of the device by an order of magnitude. In addition, the device exhibits solar-blind detection, high responsiveness (28 A W-1) and good stability. Thus, the Nb2C/ß-Ga2O3heterojunction is expected to be one of the promising devices in the field of UV photoelectric detection.
RESUMEN
Oncolytic peptides represented potential novel candidates for anticancer treatments especially drug-resistant cancer cell lines. One of the most promising and extensively studied is LTX-315, which is considered as the first in class oncolytic peptide and has entered phase I/II clinical trials. Nevertheless, the shortcomings including poor proteolytic stability, moderate anticancer durability and high synthesis costs may hinder the widespread clinical applications of LTX-315. In order to reduce the synthesis costs, as well as develop derivatives possessing both high protease-stability and durable anticancer efficiency, twenty LTX-315-based derived-peptides were designed and efficiently synthesized. Especially, through solid-phase S-alkylation, as well as the optimized peptide cleavage condition, the derived peptides could be prepared with drastically reduced synthesis cost. The in vitro anticancer efficiency, serum stability, anticancer durability, anti-migration activity, and hemolysis effect were systematically investigated. It was found that derived peptide MS-13 exhibited comparable anticancer efficiency and durability to those of LTX-315. Strikingly, the D-type peptide MS-20, which is the enantiomer of MS-13, was demonstrated to possess significantly high proteolytic stability and sustained anticancer durability. In general, the cost-effective synthesis and stability-guided structural optimizations were conducted on LTX-315, affording the highly hydrolysis resistant MS-20 which possessed durable anticancer activity. Meanwhile, this study also provided a reliable reference for the future optimization of anticancer peptides through the solid-phase S-alkylation and L-type to D-type amino acid substitutions.
Asunto(s)
Antineoplásicos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Movimiento Celular/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/síntesis química , Hemólisis/efectos de los fármacos , OligopéptidosRESUMEN
INTRODUCTION: Primary central nervous system lymphoma (PCNSL) is a rare subtype of aggressive extranodal non-Hodgkin lymphoma. Currently, there is no standard of care for the treatment of refractory or relapsed PCNSL (r/r PCNSL). We conducted a prospective single-arm phase II study to evaluate zanubrutinib plus cytarabine for r/r PCNSL. METHODS: Using Simon's two-stage design, we analyzed 34 patients who received high-dose cytarabine (3.0 g/m2 once daily) for 2 days and zanubrutinib (160 mg twice daily) for 21 days each cycle for up to 6 cycles. The study was registered at www.chictr.org.cn as #ChiCTR2000039229. RESULTS: The median follow-up was 19 months. The overall response rate was 64.7% (95% confidence interval (CI), 47.9% to 78.5%) with a complete remission or unconfirmed complete remission rate of 47.1% (16/34) and a partial remission rate of 17.6% (6/34). The median progression-free survival was 4.5 months (95% CI, 1.5 to 9.4) and the median OS was 18 months (95%CI, 9.5 to not estimable). The median duration of the response was 9 months (95%CI, 3.2 to not estimable). The most common treatment-emergent adverse events were thrombocytopenia (55.9%). No treatment-related death occurred. CONCLUSION: Zanubrutinib and cytarabine showed efficacy in r/r PCNSL with an acceptable safety profile.
RESUMEN
Motivated by the clinical success of combining tyrosine kinase inhibitors with microtubule-targeted drugs in antitumor treatment, this paper presents a novel combi-targeting design for dual-target inhibitors, featuring arylformylurea-coupled quinazoline backbones. A series of target compounds (10a-10r) were designed, synthesized, and characterized. Biological assessments demonstrated that 10c notably potentiated ten tumor cell lines in vitro, with IC50 values ranging from 1.04 µM to 7.66 µM. Importantly, 10c (IC50 = 10.66 nM) exhibited superior inhibitory activity against EGFR kinases compared to the reference drug Gefitinib (25.42 nM) and reduced phosphorylated levels of EGFR, AKT, and ERK. Moreover, 10c significantly impeded tubulin polymerization, disrupted the intracellular microtubule network in A549 cells, induced apoptosis, led to S-phase cell cycle arrest, and hindered cell migration. In anticancer evaluation tests using A549 cancer-bearing nude mice models, 10c showed a therapeutic effect similar to Gefitinib, but required only half the dosage (15 mg/kg). These findings indicate that compound 10c is a promising dual-target candidate for anticancer therapy.