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Autophagy Jul 2024Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation....
Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.
PubMed: 38953310
DOI: 10.1080/15548627.2024.2374692 -
International Journal of Particle... Jun 2024It is known that radiation to dentofacial structures during childhood can lead to developmental disturbances. However, this appears to be a relatively subordinated... (Review)
Review
PURPOSE
It is known that radiation to dentofacial structures during childhood can lead to developmental disturbances. However, this appears to be a relatively subordinated research subject. For this reason, this review aims to establish the current evidence base on the effect of PBT on dentofacial development in paediatric patients treated for cancer in the head and neck region.
MATERIALS AND METHODS
A comprehensive search was undertaken to identify both published and unpublished studies or reports. A single reviewer completed initial screening of abstracts; 2 independent reviewers completed secondary screening and data extraction. A narrative synthesis was then conducted.
RESULTS
82 records were screened in total, resulting in 11 included articles. These articles varied in terms of study design and reporting quality. Owing to both poor study reporting and limited patient numbers, it is not possible to determine the effect of cancer diagnosis, chronological age at treatment, radiation dose or treatment modality on the incidence of facial deformation or dental development anomalies.
CONCLUSION
Disturbances in dentofacial development are an under-reported toxicity in paediatric cancer survivors treated with PBT to the head and neck. There is a need for more research on dentofacial toxicity reporting, focused on the impact of treatment age, radiation dose, concurrent therapies, and the subsequent impact on quality of life.
PubMed: 38952615
DOI: 10.1016/j.ijpt.2024.100107 -
Molecular Imaging 2024To investigate the performance of diffusion-tensor imaging (DTI) and hydrogen proton magnetic resonance spectroscopy (H-MRS) parameters in predicting the...
OBJECTIVE
To investigate the performance of diffusion-tensor imaging (DTI) and hydrogen proton magnetic resonance spectroscopy (H-MRS) parameters in predicting the immunohistochemistry (IHC) biomarkers of glioma.
METHODS
Patients with glioma confirmed by pathology from March 2015 to September 2019 were analyzed, the preoperative DTI and H-MRS images were collected, apparent diffusion coefficient (ADC) and fractional anisotropy (FA), in the lesion area were measured, the relative values relative ADC (rADC) and relative FA (rFA) were obtained by the ratio of them in the lesion area to the contralateral normal area. The peak of each metabolite in the lesion area of H-MRS image: N-acetylaspartate (NAA), choline (Cho), and creatine (Cr), and metabolite ratio: NAA/Cho, NAA/(Cho + Cr) were selected and calculated. The preoperative IHC data were collected including CD34, Ki-67, p53, S-100, syn, vimentin, NeuN, Nestin, and glial fibrillary acidic protein.
RESULTS
One predicting parameter of DTI was screened, the rADC of the Ki-67 positive group was lower than that of the negative group. Two parameters of H-MRS were found to have significant reference values for glioma grades, the NAA and Cr decreased as the grade of glioma increased, moreover, Ki-67 Li was negatively correlated with NAA and Cr.
CONCLUSION
NAA and Cr have potential application value in predicting glioma grades and tumor proliferation activity. Only rADC has predictive value for Ki-67 expression among DTI parameters.
Topics: Humans; Glioma; Male; Female; Middle Aged; Adult; Immunohistochemistry; Brain Neoplasms; Diffusion Tensor Imaging; Magnetic Resonance Imaging; Aged; Proton Magnetic Resonance Spectroscopy; Young Adult
PubMed: 38952400
DOI: 10.1177/15353508241261583 -
Journal of Leukocyte Biology Jul 2024The absolute lymphocyte count (ALC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) offer convenient means to assess systemic inflammation...
The absolute lymphocyte count (ALC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) offer convenient means to assess systemic inflammation post-cancer treatment, which influences treatment outcomes. Understanding these biomarker variations and leukocyte subpopulation interplay is crucial for optimizing radiotherapy. Herein, leukocyte subpopulations (T-CD4+, T-CD8+, B-cells, NK-cells, neutrophils, monocytes) during and after brain irradiation (using X-rays or Protons) in tumor-free mice were used to compute ALC, LMR, and NLR, on which radiation parameter influence was assessed by principal component analysis (PCA). NLR kinetics were further examined using modeling. Leukocyte subpopulations interplays and their response to radiation parameters were examined using PCA and correlation analysis. Under X-rays, ALC and LMR decreased, with ALC recovered to baseline after irradiation, but not LMR. Both X-rays and protons increased the NLR during irradiation, recovering in protons but not X-rays. Both irradiation volume and dose rate had a pronounced effect on the NLR. Leukocyte subpopulation interplay was observed under X-rays and protons, normalizing in the proton group by day 28. Lymphopenia was observed in all lymphocyte subpopulations under X-ray irradiation but not protons. The recovery patterns varied among the subpopulations. Neutrophil counts increased during irradiation, with the recovery of protons, but not X-rays, by day 28. Interplays between NK-cells and myeloid subpopulations were evident under X-rays but not protons. Importantly, no interplay was detected between myeloid cells and T/B-cells, indicating that LMR and NLR variations were primarily due to independent responses to brain irradiation. A tumor-free experimental mouse model was used to study the effects of brain radiotherapy on systemic immunity. When administering fractionated irradiation with a total dose of 20 Gy using a vertical beam to either the whole brain or hemi-brain, proton irradiation had fewer adverse impacts on the immune system compared to X-rays in tumor-free rodents.
PubMed: 38952292
DOI: 10.1093/jleuko/qiae156 -
The Journal of Organic Chemistry Jul 2024We have successfully synthesized a series of bidentate ligands by utilizing 2-(trimethylsilyl)phenyl trifluorosulfonate as a precursor for the benzyl group. This method...
We have successfully synthesized a series of bidentate ligands by utilizing 2-(trimethylsilyl)phenyl trifluorosulfonate as a precursor for the benzyl group. This method proceeded by inserting a polythiourea into the C═S π-bond, intramolecular ring proton migration, and ring opening. Salient features of this strategy are mild reaction conditions, a novel product structure, excellent stereochemistry, and a good functional group tolerance. Furthermore, a series of density functional theory calculations were performed to gain insights into the transfer mechanism.
PubMed: 38951997
DOI: 10.1021/acs.joc.4c00894 -
Biotechnology and Applied Biochemistry Jul 2024A violet pigment (violacein) bacterial isolate AMA-5 was isolated from soil samples collected from Achanakmar Biosphere Reserve, Mungeli district, Chhattisgarh, India....
A violet pigment (violacein) bacterial isolate AMA-5 was isolated from soil samples collected from Achanakmar Biosphere Reserve, Mungeli district, Chhattisgarh, India. The yield of biocolor from this isolate was screened in minimal medium after 48 h of incubation at 37°C ± 2°C temperature. The violet pigment was extracted in ethanol. It was also observed that ammonium chloride (2.5 g/1000 mL) as a nitrogen source is the best to enhance AMA-5 pigment production among other nitrogen sources (ammonium sulfate, tryptophan, ammonium iron sulfate, and peptone). The Sanger sequencing of 16S rDNA of strain AMA-5 showed similarity with Chromobacterium piscinae. From the available literature and research articles, it was assumed that this violet color pigment is violacein. It was further verified by conducting high-performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance (H-NMR) analysis. The violet biocolor that extracted was used in cotton and polyester fabric dyeing. After the fabrics treated with sodium chloride as a mordant were completely dried, it was identified that the color was solidifying. Overall study showed that C. piscinae AMA-5 has good potential for production of violacein, which is the most important industrial natural dye used to add color to textile products.
PubMed: 38951986
DOI: 10.1002/bab.2629 -
Journal of Nanobiotechnology Jul 2024Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently,...
BACKGROUND
Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear.
RESULTS
Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs.
CONCLUSIONS
These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.
Topics: Animals; Extracellular Vesicles; Mice; Myocardial Reperfusion Injury; Myocytes, Cardiac; Male; Mice, Inbred C57BL; Mitochondrial Proton-Translocating ATPases; Mitochondria; Myocardium; Reactive Oxygen Species; Ferroptosis; Disease Models, Animal
PubMed: 38951822
DOI: 10.1186/s12951-024-02618-x -
Nature Materials Jul 2024The voltage penalty driving water dissociation (WD) at high current density is a major obstacle in the commercialization of bipolar membrane (BPM) technology for energy...
The voltage penalty driving water dissociation (WD) at high current density is a major obstacle in the commercialization of bipolar membrane (BPM) technology for energy devices. Here we show that three materials descriptors, that is, electrical conductivity, microscopic surface area and (nominal) surface-hydroxyl coverage, effectively control the kinetics of WD in BPMs. Using these descriptors and optimizing mass loading, we design new earth-abundant WD catalysts based on nanoparticle SnO synthesized at low temperature with high conductivity and hydroxyl coverage. These catalysts exhibit exceptional performance in a BPM electrolyser with low WD overvoltage (η) of 100 ± 20 mV at 1.0 A cm. The new catalyst works equivalently well with hydrocarbon proton-exchange layers as it does with fluorocarbon-based Nafion, thus providing pathways to commercializing advanced BPMs for a broad array of electrolysis, fuel-cell and electrodialysis applications.
PubMed: 38951650
DOI: 10.1038/s41563-024-01943-8 -
Communications Biology Jun 2024Light is a significant factor for living organisms with photosystems, like microbial rhodopsin-a retinal protein that functions as an ion pump, channel, and sensory...
Light is a significant factor for living organisms with photosystems, like microbial rhodopsin-a retinal protein that functions as an ion pump, channel, and sensory transduction. Gloeobacter violaceus PCC7421, has a proton-pumping rhodopsin gene, the Gloeobacter rhodopsin (GR). The helix-turn-helix family of transcriptional regulators has various motifs, and they regulate gene expression in the presence of various metal ions. Here, we report that active proton outward pumping rhodopsin interacted with the helix-turn-helix transcription regulator and regulated gene expression. This interaction is confirmed using ITC analysis (K of 8 μM) and determined the charged residues required. During in vitro experiments using fluorescent and luciferase reporter systems, ATP-binding cassette (ABC) transporters and the self-regulation of G. violaceus transcriptional regulator (GvTcR) are regulated by light, and gene regulation is observed in G. violaceus using the real-time polymerase chain reaction. These results expand our understanding of the natural potential and limitations of microbial rhodopsin function.
Topics: ATP-Binding Cassette Transporters; Light; Gene Expression Regulation, Bacterial; Transcription Factors; Cyanobacteria; Proton Pumps; Bacterial Proteins; Rhodopsins, Microbial; Rhodopsin
PubMed: 38951607
DOI: 10.1038/s42003-024-06471-4 -
Nature Nanotechnology Jul 2024
PubMed: 38951596
DOI: 10.1038/s41565-024-01699-x