Abstract
Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the ...role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities.
Significance:
Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.
The age-dependent decline in remyelination potential of the central nervous system during ageing is associated with a declined differentiation capacity of oligodendrocyte progenitor cells (OPCs). The ...molecular players that can enhance OPC differentiation or rejuvenate OPCs are unclear. Here we show that, in mouse OPCs, nuclear entry of SIRT2 is impaired and NAD
levels are reduced during ageing. When we supplement β-nicotinamide mononucleotide (β-NMN), an NAD
precursor, nuclear entry of SIRT2 in OPCs, OPC differentiation, and remyelination were rescued in aged animals. We show that the effects on myelination are mediated via the NAD
-SIRT2-H3K18Ac-ID4 axis, and SIRT2 is required for rejuvenating OPCs. Our results show that SIRT2 and NAD
levels rescue the aged OPC differentiation potential to levels comparable to young age, providing potential targets to enhance remyelination during ageing.
Microglia activation induced by α-synuclein (α-syn) is one of the most important factors in Parkinson's disease (PD) pathogenesis. However, the molecular mechanisms by which α-syn exerts ...neuroinflammation and neurotoxicity remain largely elusive. Targeting metabotropic glutamate receptor 5 (mGluR5) has been an attractive strategy to mediate microglia activation for neuroprotection, which might be an essential regulator to modulate α-syn-induced neuroinflammation for the treatment of PD. Here, we showed that mGluR5 inhibited α-syn-induced microglia inflammation to protect from neurotoxicity in vitro and in vivo.
Co-immunoprecipitation assays were utilized to detect the interaction between mGluR5 and α-syn in microglia. Griess, ELISA, real-time PCR, western blotting, and immunofluorescence assays were used to detect the regulation of α-syn-induced inflammatory signaling, cytokine secretion, and lysosome-dependent degradation.
α-syn selectively interacted with mGluR5 but not mGluR3, and α-syn N terminal deletion region was essential for binding to mGluR5 in co-transfected HEK293T cells. The interaction between these two proteins was further detected in BV2 microglia, which was inhibited by the mGluR5 specific agonist CHPG without effect by its selective antagonist MTEP. Moreover, in both BV2 cells and primary microglia, activation of mGluR5 by CHPG partially inhibited α-syn-induced inflammatory signaling and cytokine secretion and also inhibited the microglia activation to protect from neurotoxicity. We further found that α-syn overexpression decreased mGluR5 expression via a lysosomal pathway, as evidenced by the lysosomal inhibitor, NH
Cl, by blocking mGluR5 degradation, which was not evident with the proteasome inhibitor, MG132. Additionally, co-localization of mGluR5 with α-syn was detected in lysosomes as merging with its marker, LAMP-1. Consistently, in vivo experiments with LPS- or AAV-α-syn-induced rat PD model also confirmed that α-syn accelerated lysosome-dependent degradation of mGluR5 involving a complex, to regulate neuroinflammation. Importantly, the binding is strengthened with LPS or α-syn overexpression but alleviated by urate, a potential clinical biomarker for PD.
These findings provided evidence for a novel mechanism by which the association of α-syn with mGluR5 was attributed to α-syn-induced microglia activation via modulation of mGluR5 degradation and its intracellular signaling. This may be a new molecular target for an effective therapeutic strategy for PD pathology.
Gas separation is a crucial process for the production of many highly valuable chemical feedstocks in the petrochemical industry. Traditional separation technologies, including cryogenic ...distillation, chemisorption, and solvent extraction, are energy-intensive or environmentally unfriendly. The development of new separation technologies with low energy consumption and high efficiency is of significant importance for adapting to the increasing industrial demands. Adsorptive gas separation based on solid porous adsorbents has made much progress over the past few decades, benefiting from low cost, high efficiency, and environment friendliness. In this regard, porous metal-organic frameworks (MOFs), as a novel class of crystalline porous materials featuring adjustable structures and finely tunable pore metrics, have shown great promise to address various gas separation challenges. Furthermore, the highly crystalline nature of MOFs endows this kind of material with a unique advantage, providing an in-depth understanding of the structure-property relationship, which is crucial and meaningful to guide the design of separating materials for gas separation. Herein, we summarize the main advancements achieved in the last five years of developing MOFs as physisorbents for various critical gas separations, including but not limited to the separation of light hydrocarbons, C
2
H
2
/CO
2
, and Xe/Kr, and CO
2
capture, and the separation mechanisms are also highlighted in each section. Finally, some challenges and perspectives in the design of MOFs for gas separation and industrial applications are outlined.
We herein not only provide a comprehensive overview of the most important advances in the development of MOFs as separating materials for gas separation over the last five years, but also provide an update of the current challenges in this active field.
Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an ...attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP‐qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR‐433, while dual luciferase assay was carried out to confirm the targeting relationship between miR‐433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo‐tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A‐miR‐433‐FXYD3‐PI3K‐AKT axis in the progression of HCC after loss‐ and gain‐function assays. KDM5A p‐p85 and p‐AKT were highly expressed but miR‐433 was down‐regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR‐433 by demethylating H3K4me3 on its promoterregion. miR‐433 negatively targeted FXYD3. Depleting miR‐433 or re‐expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down‐regulated miR‐433 and up‐regulated FXYD3‐PI3K‐AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3‐PI3K‐AKT axis to enhance angiogenesis in HCC by suppressing miR‐433.
Although many methods and new therapeutic drugs have been developed, the overall survival rate and long‐term survival rate of patients with gastric cancer (GC) are still not satisfactory. In this ...study, we investigated the effects of microRNA miR‐133a‐3p and transcription factor FOXP3 on proliferation and autophagy of GC cells and their interactions. Our results showed that knockdown of FOXP3 increased the proliferation and autophagy of GC cells. The relationship between FOXP3 and autophagy has not been reported previously. In addition, FOXP3 could directly bind the promoter region of TP53 and inhibit its expression. miR‐133a‐3p increased the proliferation and autophagy via decreasing the protein level of FOXP3 by targeting its 3′‐UTR. Our research provides new insights into the development of GC and provides new ideas and theoretical basis for the clinical treatment of GC and the development of new drug targets.
miR‐133a‐3p increased the proliferation and autophagy via decreasing the protein level of FOXP3 by targeting its 3′‐untranslated region. Our research provides new insights into the development of gastric cancer and provides new ideas and theoretical basis for the clinical treatment of gastric cancer and the development of new drug targets.
Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). ...Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame erlotinib resistance in non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative stress and altered multiple signaling pathways including the activation of JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic function of PGAM1 by allosteric regulation.
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•A PGAM1 allosteric inhibitor HKB99 is developed via structure-based optimization•HKB99 modulates PGAM1 both in its catalytic process and ACTA2 interaction•HKB99 suppresses NSCLC growth and metastasis through allosteric PGAM1 regulation•PGAM1 is a potential therapeutic target in NSCLC
PGAM1 plays a critical role in cancer cell metabolism. Huang et al. discovered a novel PGAM1 inhibitor HKB99, which allosterically blocks the structure of PGAM1, impacting both its catalytic activity and ACTA2 interaction. HKB99 significantly inhibits NSCLC tumor growth and metastasis in vivo by impacting both PGAM1’s metabolic activity and nonmetabolic function.
•The first study on Ba isotopes for UHP-HP eclogite-vein systems.•Ba isotopes can be considerably fractionated during metamorphic fluid processes.•Eclogite dehydration can release fluids with ...isotopically heavy Ba isotopes.•The fluids released from gneiss have different δ138/134Ba from the eclogite.•Ba isotopes can be used to distinguish various fluid sources in subduction zones.
Barium (Ba) and its stable isotopes are powerful geochemical tracers for the recycling of subducted materials into the convective mantle. However, this requires a good understanding of the behavior of Ba isotopes during subduction-zone fluid processes. Here we present the first integrated study on Ba isotopes for two eclogite-vein systems (Ganghe and Hualiangting) that formed at high-pressure (HP) and ultrahigh-pressure (UHP) metamorphic conditions from the Dabie orogen, central China. The Ganghe system displays constant δ138/134Ba (−0.01‰ to 0.03‰) in the UHP eclogites but relatively high δ138/134Ba (0.17‰) in the HP vein. In contrast, in the Hualiangting system, δ138/134Ba of the UHP eclogites vary from −0.14‰ to 0.05‰, while δ138/134Ba of the multiple HP veins and the retrograded amphibolites range from −0.17‰ to 0.34‰ and from −0.11‰ to 0.46‰, respectively.
The combined results suggest that Ba isotopes can be considerably fractionated during subduction-zone fluid processes. HP-UHP metamorphic dehydration of the eclogites during the early stages of exhumation can produce an isotopically heavy initial vein-forming fluid due to the preferential leaching of epidote enriched with heavy Ba isotopes from the host eclogites. However, such processes have limited effects on the bulk eclogites because the Ba-rich phengite exists as a residual phase. During vein formation, light Ba isotopes are preferentially enriched in minerals relative to the fluids, resulting in the residual fluids with high δ138/134Ba. In addition, the fluids released from the gneisses have negative δ138/134Ba which is different from the eclogites, indicating that Ba isotopes can be used to trace the source of the metasomatic fluids. This study demonstrates that the UHP metamorphic rocks and HP veins can record Ba isotope fractionation during subduction-zone metamorphism and fluid-rock interaction, and recycling of the metamorphic rocks could modify Ba isotopic composition of the mantle wedge and arc volcanics.
Propylene/propane (C
3
H
6
/C
3
H
8
) separation represents one of the most challenging and energy-intensive processes in the petrochemical industry due to their very similar sizes and physical ...properties. Most of the reported physisorbents still face the challenge of achieving simultaneously high C
3
H
6
uptake and selectivity with moderate adsorption enthalpy. Herein, we realize an efficient propylene nano-trap in a microporous MOF (ZJUT-2, Ni(pyz-SH)
2
SiF
6
) for highly efficient C
3
H
6
/C
3
H
8
separation. This MOF-based propylene nano-trap features a suitable pore cavity decorated with dual functionalities (-SH and SiF
6
2−
) to optimally interact with the C
3
H
6
molecule, affording both large C
3
H
6
capture capacity (123.5 cm
3
cm
−3
at 296 K and 0.5 bar) and high C
3
H
6
/C
3
H
8
selectivity of 17.2 achieved with moderate C
3
H
6
adsorption enthalpy (45 kJ mol
−1
). Theoretical calculations revealed that the appropriate pore cavity and dual functionalities synergistically construct an efficient nano-trap to match better with the C
3
H
6
molecule and thus provide stronger multipoint interactions with C
3
H
6
over C
3
H
8
. Actual breakthrough experiments demonstrated that this material can efficiently capture C
3
H
6
from C
3
H
6
/C
3
H
8
mixtures (50/50 and 10/90, v/v) under ambient conditions, affording both top-tier C
3
H
6
capture amount (2.6 mmol g
−1
) and dynamic selectivity of 10.
We have reported a dual functionalized single-molecule nano-trap MOF with both top-tier C
3
H
6
capture capacity and selectivity, affording both remarkably large C
3
H
6
uptake of 2.6 mmol g
−1
and high dynamic selectivity of 10 for C
3
H
6
/C
3
H
8
separation.
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