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Bacterial membrane vesicles (BMVs) are crucial biological vehicles for facilitating interspecies and interkingdom interactions. However, the extent and mechanisms of BMV involvement in bacterial-algal communication remain elusive. This study provides evidence of BMVs delivering cargos to targeted microalgae. Membrane vesicles (MVs) from Chitinimonas prasina LY03 demonstrated an algicidal profile similar to strain LY03. Further investigation revealed Tambjamine LY2, an effective algicidal compound, selectively packaged into LY03-MVs. Microscopic imaging demonstrated efficient delivery of Tambjamine LY2 to microalgae Heterosigma akashiwo and Thalassiosira pseudonana through membrane fusion. In addition, the study demonstrated the versatile cargo delivery capabilities of BMVs to algae, including the transfer of MV-carried nucleic acids into algal cells and the revival of growth in iron-depleted microalgae by MVs. Collectively, our findings reveal a previously unknown mechanism by which algicidal bacteria store hydrophobic algicidal compounds in MVs to trigger target microalgae death and highlight BMV potency in understanding and engineering bacterial-algae cross-talk.
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Bacterias , Microalgas , Microalgas/metabolismo , Bacterias/metabolismo , Membrana Celular/metabolismo , Interacciones MicrobianasRESUMEN
The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.
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Currently, it is still challenging to develop a hydrogel electrolyte matrix that can successfully achieve a harmonious combination of mechanical strength, ionic conductivity, and interfacial adaptability. Herein, a multi-networked hydrogel electrolyte with a high entanglement effect based on gelatin/oxidized dextran/methacrylic anhydride, denoted as ODGelMA is constructed. Attribute to the Schiff base network formulation of âRCâNâ, oxidized dextran integrated gelatin chains induce a dense hydrophilic conformation group. Furthermore, addition of methacrylic anhydride through a grafting process, the entangled hydrogel achieves impressive mechanical features (6.8 MPa tensile strength) and high ionic conductivity (3.68 mS cm-1 at 20 °C). The ODGelMA electrolyte regulates the zinc electrode by circumventing dendrite growth, and showcases an adaptable framework reservoir to accelerate the Zn2+ desolvation process. Benefiting from the entanglement effect, the Zn anode achieves an outstanding average Coulombic efficiency (CE) of 99.8% over 500 cycles and cycling stability of 900 h at 5 mA cm-2 and 2.5 mAh cm-2. The Zn||I2 full cell yields an ultra-long cycling stability of 10 000 cycles with a capacity retention of 92.4% at 5 C. Furthermore, a 60 mAh single-layer pouch cell maintains a stable work of 350 cycles.
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OBJECTIVE: In B-cell acute lymphoblastic leukemia (B-ALL), current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50% of cases, underscoring the urgent need for new therapeutic regimens for this patient population. The present study aimed to determine whether HZX-02-059, a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) and tubulin, is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients. METHODS: Cell proliferation, vacuolization, apoptosis, cell cycle, and in-vivo tumor growth were evaluated. In addition, Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL. RESULTS: HZX-02-059 was found to inhibit cell proliferation, induce vacuolization, promote apoptosis, block the cell cycle, and reduce in-vivo tumor growth. Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations. CONCLUSION: Overall, these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Tubulina (Proteína) , Humanos , Proliferación Celular , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/uso terapéuticoRESUMEN
BACKGROUND: Astrogliosis and white matter lesions (WML) are key characteristics of vascular contributions to cognitive impairment and dementia (VCID). However, the molecular mechanisms underlying VCID remain poorly understood. Stimulation of Na-K-Cl cotransport 1 (NKCC1) and its upstream kinases WNK (with no lysine) and SPAK (the STE20/SPS1-related proline/alanine-rich kinase) play a role in astrocytic intracellular Na+ overload, hypertrophy, and swelling. Therefore, in this study, we assessed the effect of SPAK inhibitor ZT-1a on pathogenesis and cognitive function in a mouse model of VCID induced by bilateral carotid artery stenosis (BCAS). METHODS: Following sham or BCAS surgery, mice were randomly assigned to receive either vehicle (DMSO) or SPAK inhibitor ZT-1a treatment regimen (days 14-35 post-surgery). Mice were then evaluated for cognitive functions by Morris water maze, WML by ex vivo MRI-DTI analysis, and astrogliosis/demyelination by immunofluorescence and immunoblotting. RESULTS: Compared to sham control mice, BCAS-Veh mice exhibited chronic cerebral hypoperfusion and memory impairments, accompanied by significant MRI DTI-detected WML and oligodendrocyte (OL) death. Increased activation of WNK-SPAK-NKCC1-signaling proteins was detected in white matter tissues and in C3d+ GFAP+ cytotoxic astrocytes but not in S100A10+ GFAP+ homeostatic astrocytes in BCAS-Veh mice. In contrast, ZT-1a-treated BCAS mice displayed reduced expression and phosphorylation of NKCC1, decreased astrogliosis, OL death, and WML, along with improved memory functions. CONCLUSION: BCAS-induced upregulation of WNK-SPAK-NKCC1 signaling contributes to white matter-reactive astrogliosis, OL death, and memory impairment. Pharmacological inhibition of the SPAK activity has therapeutic potential for alleviating pathogenesis and memory impairment in VCID.
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Disfunción Cognitiva , Demencia Vascular , Animales , Ratones , Gliosis/tratamiento farmacológico , Modelos Animales de Enfermedad , Cognición , InflamaciónRESUMEN
Nickel-rich layered oxide cathodes promise ultrahigh energy density but is plagued by the mechanical failure of the secondary particle upon (de)lithiation. Existing approaches for alleviating the structural degradation could retard pulverization, yet fail to tune the stress distribution and root out the formation of cracks. Herein, we report a unique strategy to uniformize the stress distribution in secondary particle via Kirkendall effect to stabilize the core region during electrochemical cycling. Exotic metal/metalloid oxides (such as Al2O3 or SiO2) is introduced as the heterogeneous nucleation seeds for the preferential growth of the precursor. The calcination treatment afterwards generates a dopant-rich interior structure with central Kirkendall void, due to the different diffusivity between the exotic element and nickel atom. The resulting cathode material exhibits superior structural and electrochemical reversibility, thus contributing to a high specific energy density (based on cathode) of 660 Wh kg-1 after 500 cycles with a retention rate of 86%. This study suggests that uniformizing stress distribution represents a promising pathway to tackle the structural instability facing nickel-rich layered oxide cathodes.
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Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.
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Antimaláricos , Endopeptidasas , Malaria Falciparum , Plasmodium yoelii , Animales , Ratones , Plasmodium yoelii/genética , Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Antimaláricos/uso terapéutico , Resistencia a Múltiples Medicamentos/genética , Resistencia a Medicamentos/genéticaRESUMEN
In cells, wild-type RasGTP complexes exist in two distinct states: active State 2 and inactive State 1. These complexes regulate their functions by transitioning between the two states. However, the mechanisms underlying this state transition have not been clearly elucidated. To address this, we conducted a detailed simulation study to characterize the energetics of the stable states involved in the state transitions of the HRasGTP complex, specifically from State 2 to State 1. This was achieved by employing multiscale quantum mechanics/molecular mechanics and enhanced sampling molecular dynamics methods. Based on the simulation results, we constructed the two-dimensional free energy landscapes that provide crucial information about the conformational changes of the HRasGTP complex from State 2 to State 1. Furthermore, we also explored the conformational changes from the intermediate state to the product state during guanosine triphosphate hydrolysis. This study on the conformational changes involved in the HRas state transitions serves as a valuable reference for understanding the corresponding events of both KRas and NRas as well.
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Simulación de Dinámica Molecular , Proteínas ras , Proteínas ras/metabolismo , Guanosina Trifosfato/metabolismoRESUMEN
PRMT1 plays a vital role in breast tumorigenesis; however, the underlying molecular mechanisms remain incompletely understood. Herein, we show that PRMT1 plays a critical role in RNA alternative splicing, with a preference for exon inclusion. PRMT1 methylome profiling identifies that PRMT1 methylates the splicing factor SRSF1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and exon inclusion. In breast tumors, PRMT1 overexpression is associated with increased SRSF1 arginine methylation and aberrant exon inclusion, which are critical for breast cancer cell growth. In addition, we identify a selective PRMT1 inhibitor, iPRMT1, which potently inhibits PRMT1-mediated SRSF1 methylation, exon inclusion, and breast cancer cell growth. Combination treatment with iPRMT1 and inhibitors targeting SRSF1 phosphorylation exhibits an additive effect of suppressing breast cancer cell growth. In conclusion, our study dissects a mechanism underlying PRMT1-mediated RNA alternative splicing. Thus, PRMT1 has great potential as a therapeutic target in breast cancer treatment.
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Empalme Alternativo , Neoplasias de la Mama , Humanos , Femenino , Metilación , Empalme Alternativo/genética , Transformación Celular Neoplásica/genética , ARN/metabolismo , Neoplasias de la Mama/genética , Exones/genética , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
The step- and atom-efficient dimerization strategy is frequently used in nature to build structural complexity and diversity. We propose the rationale and structural features of the versatile monomers that are responsible for "diversity through dimerization". Using 5-FAM-maleimide combined with a UHPLC-MS/MS-FBMN workflow, we successfully identified a diverse set of dimeric natural products from fungus Panus rudis F01315, in which all four complex 4'5-ring scaffolds are derived from one monomeric epoxyquinol and endowed with functional diversity.
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Productos Biológicos , Espectrometría de Masas en Tándem , Productos Biológicos/química , Dimerización , HongosRESUMEN
There is an urgent need to discover new antibacterial drugs and provide new treatment options for clinical antimicrobial resistance (AMR) pathogen infections. Inspired by the structural insights from analyzing the co-crystal structure of lefamulin with the ribosomes of S. aureus, a series of novel pleuromutilin derivatives of phenylene sulfide incorporated with urea moiety were designed and synthesized. The structure-activity relationship (SAR) study revealed that derivatives with urea in the meta position of phenylene sulfide had optimal antibacterial activities in vitro. Among them, 21h was the most potent one against Methicillin-resistant Staphylococcus aureus (MRSA) and clinical AMR Gram-positive bacteria with minimum inhibitory concentrations (MICs) in the range of 0.00195-0.250 µg/mL. And it possessed low resistance frequency, prolonged Post-Antibiotic Effect and the capability to overcome lefamulin-induced resistance. Furthermore, 21h exhibited potent antibacterial activity in vivo in both the thigh infection model and trauma infection model, representing a promising lead for the development of new antibiotics against Gram-positive pathogens, especially for AMR bacteria.
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Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Antibacterianos/farmacología , Antibacterianos/química , Staphylococcus aureus , Relación Estructura-Actividad , Pruebas de Sensibilidad Microbiana , Sulfuros/farmacología , PleuromutilinasRESUMEN
Protein kinases have proven to be a very productive class of therapeutic targets, and over 90 inhibitors are currently in clinical use primarily for the treatment of cancer. Repurposing these inhibitors as antimalarials could provide an accelerated path to drug development. In this study, we identified BI-2536, a known potent human polo-like kinase 1 inhibitor, with low nanomolar antiplasmodial activity. Screening of additional PLK1 inhibitors revealed further antiplasmodial candidates despite the lack of an obvious orthologue of PLKs in Plasmodium. A subset of these inhibitors was profiled for their in vitro killing profile, and commonalities between the killing rate and inhibition of nuclear replication were noted. A kinase panel screen identified PfNEK3 as a shared target of these PLK1 inhibitors; however, phosphoproteome analysis confirmed distinct signaling pathways were disrupted by two structurally distinct inhibitors, suggesting PfNEK3 may not be the sole target. Genomic analysis of BI-2536-resistant parasites revealed mutations in genes associated with the starvation-induced stress response, suggesting BI-2536 may also inhibit an aminoacyl-tRNA synthetase.
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Antimaláricos , Humanos , Antimaláricos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinasa Tipo Polo 1RESUMEN
Rational design and fabrication of small interfering RNA (siRNA) delivery system with simple production scheme, specific targeting capability, responsiveness to endogenous stimuli and potential multi-functionalities remains technically challenging. Herein, we screen and design a virus-mimicking polysaccharide nanocomplex that shows specific gene delivery capability in a selective subset of leukocytes. A virus-inspired poly (alkyl methacrylate-co-methacrylic acid) fragment was conjugated on barley ß-glucans (EEPG) to endow the nanocomplex with pH-dependent endosomal membrane destabilization capabilities, as confirmed both biologically and computationally. siRNA loaded EEPG nanocomplex is feasibly fabricated in a single-step manner, which exhibit efficient gene silencing efficacy towards Dectin-1+ monocytes/macrophages. The inherent targeting affinity and feasible gene silencing potency of EEPG nanocomplex are investigated in three independent murine inflammation models, including myocardial infarction, lung fibrosis and acute liver damage. Significant enhanced accumulation level of EEPG nanocomplex is observed in cardiac lesion site, indicating its exclusive targeting capability for ischemic heart diseases. As a proof of concept, siTGF-ß based gene therapy is confirmed in murine model with heart fibrosis. Overall, our findings suggest the designed EEPG nanocomplex is favorable for siRNA delivery, which might have translational potential as a versatile platform in inflammation-related diseases.
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Silenciador del Gen , Técnicas de Transferencia de Gen , Ratones , Animales , ARN Interferente Pequeño/genética , Endosomas , Terapia GenéticaRESUMEN
BACKGROUND: Capillary malformation (CM) is the most common vascular malformation. Large scale studies on its incidence and risk factors are limited in China. OBJECTIVE: Our study aimed to investigate the incidence of CM in Chinese infants and to evaluate its potential risk factors. METHODS: A cross-sectional study, including 7299 infants (aged < 1 year) were collected by a self-administered questionnaire. Independent-samples T tests or χ2 tests and multivariable logistic models were used to examine the potential risk factors for CM. RESULTS: The incidences of salmon patches and port-wine stains (PWSs) were 9.10% and 0.80%, respectively. In analyses, male sex (OR: 1.32, 95% CI: 1.12-1.55) and birth hypoxia (OR: 5.61, 95% CI: 4.39-7.16) were risk factors for salmon patches. Birth hypoxia (OR: 12.58, 95% CI: 7.26-21.79) and pregnancy-induced hypertension syndrome (PIH; OR: 3.66, 95% CI: 1.49-8.99) were associated with a higher risk of PWSs. CONCLUSION: This epidemiological study had the largest sample size of infants with CM in the world thus far, which updated its incidence in Chinese infants and found the potential risk factors for CM.
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Mancha Vino de Oporto , Malformaciones Vasculares , Embarazo , Femenino , Humanos , Masculino , Lactante , Estudios Transversales , Estudios Epidemiológicos , China/epidemiología , HipoxiaRESUMEN
The growing prevalence of antimicrobial resistance poses a grave threat to human health. Among the most difficult bacterial infections to treat are those caused by multidrug-resistant (MDR) Gram-negative pathogens because few effective regimens are available. One approach to this problem is to find ways to increase the activity of old antimicrobials that had seen limited application. Bicyclomycin, an inhibitor of transcription termination, is an example in which the additional inhibition of protein or RNA synthesis increases bicyclomycin-mediated lethality against Gram-negative bacteria. To examine the potential of bicyclomycin for the treatment of MDR bacterial pathogens, we first measured the MICs of bicyclomycin and other widely used antimicrobials against more than 100 multidrug-resistant Gram-negative clinical isolates. Bicyclomycin showed good coverage of carbapenem-resistant Enterobacteriaceae (CRE) and Escherichia coli (MIC50/MIC90 of 25/50 µg/mL for both bacteria) and moderate activity against Klebsiella pneumoniae (MIC50/MIC90 of 50/200 µg/mL). Bicyclomycin also exhibited synergy (e.g., fractional inhibitory concentration [FIC] index of <0.5) with doxycycline for the inhibition of bacterial growth by a checkerboard assay. Although bicyclomycin exhibited very weak lethality by itself, it showed synthetic lethality with doxycycline against K. pneumoniae: the combination killed 100- to 1,000-fold more bacteria than either agent alone. In a murine model of infection, the bicyclomycin-doxycycline combination showed better efficacy than either agent alone, and the combination treatment largely eliminated histopathological manifestations caused by infection. Thus, bicyclomycin, which has largely been limited to the treatment of Gram-negative digestive tract infections, can now be considered for the combination treatment of systemic multidrug-resistant infections caused by CRE, E. coli, and K. pneumoniae. IMPORTANCE As antimicrobial resistance continues to increase, options for effectively treating multidrug-resistant (MDR) Gram-negative infections are declining. Finding ways to enhance the lethality of old agents that have unique molecular targets is important because developing new antimicrobials is becoming increasingly difficult. The present work showed that the old antibiotic bicyclomycin has good bacteriostatic activity against multiple clinical isolates of three significant types of MDR Gram-negative pathogens frequently encountered in hospital infections, as required for the consideration of expanded indications. More significant is the synergistic growth-inhibitory effect and the enhancement of killing by the additional presence of doxycycline since this increases the in vivo efficacy. These data demonstrate that bicyclomycin-containing regimens have potential as new treatment options for MDR Gram-negative infections such as those caused by CRE, E. coli, and K. pneumoniae.
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Antiinfecciosos , Enterobacteriaceae Resistentes a los Carbapenémicos , Humanos , Ratones , Animales , Escherichia coli , Doxiciclina , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinfecciosos/farmacología , Klebsiella pneumoniae , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Bacteriana MúltipleRESUMEN
SPAK inhibitor ZT-1a was previously shown to be neuroprotective in murine ischemic stroke models. In this study, we further examined the efficacy of four ZT-1a derivatives (ZT-1c, -1d, -1g and -1h) on reducing stroke-induced sensorimotor function impairment and brain lesions. Vehicle control (Veh) or ZT-1 derivatives were administered via osmotic pump to adult C57BL/6J mice during 3-21 h post-stroke. Neurological behavior of these mice was assessed at days 1, 3, 5, and 7 post-stroke and MRI T2WI and DTI analysis was subsequently conducted in ex vivo brains. Veh-treated stroke mice displayed sensorimotor function deficits compared to Sham mice. In contrast, mice receiving ZT-1a derivatives displayed significantly lower neurological deficits at days 3-7 post-stroke (p < 0.05), with ZT-1a, ZT-1c and ZT-1d showing greater impact than ZT-1h and ZT-1g. ZT-1a treatment was the most effective in reducing brain lesion volume on T2WI and in preserving NeuN + neurons (p < 0.01), followed by ZT-1d > -1c > -1g > -1h. The Veh-treated stroke mice displayed white matter tissue injury, reflected by reduced fractional anisotropy (FA) or axial diffusivity (AD) values in external capsule, internal capsule and hippocampus. In contrast, only ZT-1a-as well as ZT-1c-treated stroke mice exhibited significantly higher FA and AD values. These findings demonstrate that post-stroke administration of SPAK inhibitor ZT-1a and its derivatives (ZT-1c and ZT-1d) is effective in protecting gray and white matter tissues in ischemic brains, showing a potential for ischemic stroke therapy development.
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Lesiones Encefálicas , Accidente Cerebrovascular Isquémico , Enfermedades del Sistema Nervioso , Accidente Cerebrovascular , Sustancia Blanca , Ratones , Animales , Ratones Endogámicos C57BL , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/patología , Encéfalo , Enfermedades del Sistema Nervioso/patología , Sustancia Blanca/patología , Lesiones Encefálicas/patología , Accidente Cerebrovascular Isquémico/patologíaRESUMEN
Marine self-potential (SP) measurement is commonly conducted for seafloor sulfide detection and hydrothermal vent studies in deep water using instruments towed close to the seafloor. However, this method has the following shortcomings: (1) It relies on ships for deep towing, and the need for a dedicated ship time lowers its efficiency. (2) Owing to complex topography, most towed instruments are located far from the seafloor to ensure safety, resulting in large effective signal attenuation and low signal-to-noise ratio. (3) The measurement direction is generally a single axis, with only the electric field of the axial component observed, providing limited information. With the gradual maturity of autonomous underwater vehicle (AUV) technology, it has become possible to mount marine SP measurement tools on AUVs for detection. Compared with conventional methods, this method has significant advantages in terms of efficiency, signal-to-noise ratio, and multicomponent observation. The proposed tool is a lightweight underwater device having a compact design and low power consumption, making it suitable for AUVs. The overall volume of the tool is D50 mm × L350 mm, and the underwater weight is 0.6 kg. Chopper amplification technology ensures the low-noise measurement of electric field signals. In addition, the reformed electrodes enhance stability, thereby reducing the mechanical vibration noise. Laboratory test results show that the noise of the data logger is 7.8 nV/rt (Hz)@1 Hz. The marine test conducted in the southwest Indian Ocean verified the reliability of the proposed marine SP measurement tool. The maximum working depth was 4000 m. The test lasted â¼25 h, and the effective electric field data were collected for â¼17 h. This survey found a maximum SP anomaly of 0.55 mV/m in the Yuhuang hydrothermal field, which provided effective data support for the discovery of new seafloor sulfide anomalies.
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Five new indole diterpenoids named paspaline C-D (1-2) and paxilline B-D (3-5), as well as eleven known analogues (6-16), were identified from fungus Penicillium brefeldianum strain WZW-F-69, which was isolated from an abalone aquaculture base in Fujian province, China. Their structures were elucidated mainly through 1D- and 2D-NMR spectra analysis and ECD comparison. Compound 1 has a 6/5/5/6/6/8 hexacyclic ring system bearing 2,2-dimethyl-1,3-dioxocane, which is rare in natural products. Compound 2 has an unusual open F-ring structure. The cytotoxic activities against 10 cancer cell lines and antimicrobial activities against model bacteria and fungi of all compounds were assayed. No compound showed antimicrobial activity, but at a concentration of 1 µM, compounds 1 and 6 exhibited the highest inhibition rates of 71.2% and 83.4% against JeKo-1 cells and U2OS cells, respectively.
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Antiinfecciosos , Diterpenos , Penicillium , Penicillium/química , Indoles/química , Diterpenos/química , Hongos , Antiinfecciosos/metabolismo , Estructura MolecularRESUMEN
Aberrant activation of EGFR due to overexpression or mutation is associated with poor prognosis in many types of tumors. Here we show that blocking the sorting system that directs EGFR to plasma membrane is a potent strategy to treat EGFR-dependent tumors. We find that EGFR palmitoylation by DHHC13 is critical for its plasma membrane localization and identify ARF6 as a key factor in this process. N-myristoylated ARF6 recognizes palmitoylated EGFR via lipid-lipid interaction, recruits the exocyst complex to promote EGFR budding from Golgi, and facilitates EGFR transporting to plasma membrane in a GTP-bound form. To evaluate the therapeutic potential of this sorting system, we design a cell-permeable peptide, N-myristoylated GKVL-TAT, and find it effectively disrupts plasma membrane localization of EGFR and significantly inhibits progression of EGFR-dependent tumors. Our findings shed lights on the underlying mechanism of how palmitoylation directs protein sorting and provide an potential strategy to manage EGFR-dependent tumors.
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Factores de Ribosilacion-ADP , Neoplasias , Factores de Ribosilacion-ADP/metabolismo , Membrana Celular/metabolismo , Receptores ErbB/metabolismo , Guanosina Trifosfato/metabolismo , Humanos , Lípidos , Neoplasias/metabolismo , Transporte de ProteínasRESUMEN
The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.