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1.
Front Pharmacol ; 15: 1360932, 2024.
Article En | MEDLINE | ID: mdl-38881880

Background: Dl-3-n-Butylphthalide (NBP) has emerged as a potential therapeutic agent for cerebral hemorrhage, despite not being included in current guideline recommendations. Investigating the underlying physiological and pathological mechanisms of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment remains a critical area of research. Objective: This review aims to evaluate the efficacy of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment and elucidate its potential biological mechanisms, thereby providing evidence to support treatment optimization. Methods: A comprehensive search of seven electronic databases (PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP, and Wanfang Database) was conducted for studies published up to September 2023. Screening and data extraction were performed by a team of researchers. The Cochrane collaboration tool was utilized for risk bias assessment, and Revman 5.3 along with Stata 17.0 were employed for statistical analysis. Outcomes: We searched 254 literature, and 19 were included in this meta-analysis. The results showed that Dl-3-n-Butylphthalide improved the clinical efficacy rate (RR = 1.25, 95% CI 1.19-1.31; p = 0.00), quality of life (MD = 13.93, 95% CI: 11.88-15.98; p = 0.000), increased cerebral blood flow and velocity, reduced cerebral edema volume, Hcy concentration, and did not have obvious adverse reactions (RR = 0.68, 95% CI: 0.39-1.18; p = 0.10). Conclusion: This meta-analysis is the first to demonstrate the potential of Dl-3-n-Butylphthalide in treating cerebral hemorrhage. It suggests that Dl-3-n-Butylphthalide may alleviate clinical symptoms by modulating neurological function and improving hemodynamics. Our findings provide robust evidence for incorporating Dl-3-n-Butylphthalide into cerebral hemorrhage treatment strategies, potentially guiding future clinical practice and research. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID=355114, Identifier CRD42022355114.

3.
Cell Transplant ; 33: 9636897241262992, 2024.
Article En | MEDLINE | ID: mdl-38910431

Transplantation of mesenchymal stem cells (MSCs) is one of the hopeful treatments for spinal cord injury (SCI). Most current studies are in animals, and less in humans, and the optimal transplantation strategy for MSCs is still controversial. In this article, we explore the optimal transplantation strategy of MSCs through a network meta-analysis of the effects of MSCs on SCI in animal models. PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Service System (SinoMed) databases were searched by computer for randomized controlled studies on MSCs for SCI. Two investigators independently completed the literature screening and data extraction based on the inclusion and exclusion criteria. RevMan 5.4 software was used to assess the quality of the included literature. Stata 16.0 software was used for standard meta-analysis and network meta-analysis. Standardized mean difference (SMD) was used for continuous variables to combine the statistics and calculate 95% confidence interval (95% CI). P < 0.05 was considered a statistically significant difference. Cochrane's Q test and the I2 value were used to indicate the magnitude of heterogeneity. A random-effects model was used if I2 > 50% and P < 0.10 indicated significant heterogeneity between studies, and conversely, a fixed-effects model was used. Evidence network diagrams were drawn based on direct comparisons between various interventions. The surface under the cumulative ranking curve area (SUCRA) was used to predict the ranking of the treatment effects of each intervention. A total of 32 animal studies were included in this article for analysis. The results of the standard meta-analysis showed that MSCs improved motor ability after SCI. The network meta-analysis showed that the best treatment effect was achieved for adipose tissue-derived mesenchymal stromal cells (ADMSCs) in terms of cell source and intrathecal (IT) in terms of transplantation modality. For transplantation timing, the best treatment effect was achieved when transplantation was performed in the subacute phase. The available literature suggests that IT transplantation using ADMSCs in the subacute phase may be the best transplantation strategy to improve functional impairment after SCI. Future high-quality studies are still needed to further validate the results of this study to ensure the reliability of the results.


Disease Models, Animal , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Spinal Cord Injuries , Animals , Humans , Rats , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , Network Meta-Analysis , Spinal Cord Injuries/therapy
4.
Sci Rep ; 14(1): 14219, 2024 06 20.
Article En | MEDLINE | ID: mdl-38902308

A network meta-analysis of randomized controlled trials was conducted to compare and rank the effectiveness of various noninvasive brain stimulation (NIBS) for Parkinson's disease (PD). We searched PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Service System (SinoMed) databases from the date of database inception to April 30th, 2024. Two researchers independently screened studies of NIBS treatment in patients with PD based on inclusion and exclusion criteria. Two researchers independently performed data extraction of the included studies using an Excel spreadsheet and assessed the quality of the literature according to the Cochrane Risk of Bias Assessment Tool (RoB2). Network meta-analysis was performed in StataMP 17.0. A total of 28 studies involving 1628 PD patients were included. The results showed that HF-rTMS over the SMA (SMD = - 2.01; 95% CI [- 2.87, - 1.15]), HF-rTMS over the M1 and DLPFC (SMD = - 1.80; 95% CI [- 2.90, - 0.70]), HF-rTMS over the M1 (SMD = - 1.10; 95% CI [- 1.55, - 0.65]), a-tDCS over the DLPFC (SMD = - 1.08; 95% CI [- 1.90, - 0.27]), HF-rTMS over the M1 and PFC (SMD = - 0.92; 95% CI [- 1.71, - 0.14]), LF-rTMS over the M1 (SMD = - 0.72; 95% CI [- 1.17, - 0.28]), and HF-rTMS over the DLPFC (SMD = - 0.70; 95% CI [- 1.21, - 0.19]) were significantly improved motor function compared with sham stimulation. The SUCRA three highest ranked were HF-rTMS over the SMA (95.1%), HF-rTMS over the M1 and DLPFC (89.6%), and HF-rTMS over the M1 (73.0%). In terms of enhanced cognitive function, HF-rTMS over the DLPFC (SMD = 0.80; 95% CI [0.03,1.56]) was significantly better than sham stimulation. The SUCRA three most highly ranked were a-tDCS over the M1 (69.8%), c-tDCS over the DLPFC (66.9%), and iTBS over the DLPFC (65.3%). HF-rTMS over the M1 (SMD = - 1.43; 95% CI [- 2.26, - 0.61]) and HF-rTMS over the DLPFC (SMD = - 0.79; 95% CI [- 1.45, - 0.12)]) significantly improved depression. The SUCRA three highest ranked were HF-rTMS over the M1 (94.1%), LF-rTMS over the M1 (71.8%), and HF-rTMS over the DLPFC (69.0%). HF-rTMS over the SMA may be the best option for improving motor symptoms in PD patients. a-tDCS and HF-rTMS over the M1 may be the NIBS with the most significant effects on cognition and depression, separately.Trial registration: International Prospective Register of Systematic Review, PROSPERO (CRD42023456088).


Network Meta-Analysis , Parkinson Disease , Parkinson Disease/therapy , Parkinson Disease/physiopathology , Humans , Transcranial Magnetic Stimulation/methods , Randomized Controlled Trials as Topic , Treatment Outcome
6.
Sci Rep ; 14(1): 5894, 2024 Mar 11.
Article En | MEDLINE | ID: mdl-38467703

Global climate change associated with increased carbon emissions has become a global concern. Resource-based cities, by estimations, have emerged as major contributors to carbon emissions, accounting for approximately one-third of the national total. This underscores their pivotal role in the pursuit of carbon neutrality goals. Despite this, resource-based cities have long been neglected in current climate change mitigation policy discussions. Accordingly, using exploratory spatial data analysis and Geographical Weighted Regression method, this study investigates the determinants of carbon emissions and their spatial pattern in 113 resource-based cities in China. It can be concluded that: (1) The proportion of carbon emissions from resource-based cities in the national total has shown a marginal increase between 2003 and 2017, and the emissions from these cities have not yet reached their peak. (2) A relatively stable spatial pattern of "northeast high, southwest low" characterizes carbon emissions in resource-based cities, displaying significant spatial autocorrelation. (3) Population size, economic development level, carbon abatement technology, and the proportion of resource-based industries all contribute to the increase in carbon emissions in these cities, with carbon abatement technology playing a predominant role. (4) There is a spatial variation in the strength of the effects of the various influences.

7.
Front Mol Biosci ; 11: 1274850, 2024.
Article En | MEDLINE | ID: mdl-38523661

Mammalian cytosolic thioredoxin reductase (TrxR1) serves as an antioxidant protein by transferring electrons from NADPH to various substrates. The action of TrxR1 is achieved via reversible changes between NADPH-reduced and non-reduced forms, which involves C-terminal selenolthiol/selenenylsulfide exchanges. TrxR1 may be released into extracellular environment, where TrxR1 is present mainly in the non-reduced form with active-site disulfide and selenenylsulfide bonds. The relationships between extracellular TrxR1 and tumor metastasis or cellular signaling have been discovered, but there are few reports on small-molecule compounds in targeted the non-reduced form of TrxR1. Using eight types of small-molecule thiol-reactive reagents as electrophilic models, we report that the selenenylsulfide bond in the non-reduced form of TrxR1 functions as a selector for the thiol-reactive reagents at pH 7.5. The non-reduced form of TrxR1 is resistant to hydrogen peroxide/oxidized glutathione, but is sensitive to certain electrophilic reagents in different ways. With 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) and S-nitrosoglutathione (GSNO), the polarized selenenylsulfide bond breaks, and selenolate anion donates electron to the dynamic covalent bond in DTNB or GSNO, forming TNB-S-Se-TrxR1 complex or ON-Se-TrxR1 complex. The both complexes lose the ability to transfer electrons from NADPH to substrate. For diamide, the non-reduced TrxR1 actually prevents irreversible damage by this oxidant. This is consistent with the regained activity of TrxR1 through removal of diamide via dialysis. Diamide shows effective in the presence of human cytosolic thioredoxin (hTrx1), Cys residue(s) of which is/are preferentially affected by diamide to yield disulfide, hTrx1 dimer and the mixed disulfide between TrxR1-Cys497/Sec498 and hTrx1-Cys73. In human serum samples, the non-reduced form of TrxR1 exists as dithiothreitol-reducible polymer/complexes, which might protect the non-reduced TrxR1 from inactivation by certain electrophilic reagents under oxidative conditions, because cleavage of these disulfides can lead to regain the activity of TrxR1. The details of the selective response of the selenenylsulfide bond to electrophilic reagents may provide new information for designing novel small-molecule inhibitors (drugs) in targeted extracellular/non-reduced TrxR1.

8.
Phys Chem Chem Phys ; 26(11): 8784-8793, 2024 Mar 13.
Article En | MEDLINE | ID: mdl-38420852

The homogeneous condensation of water vapor at ambient temperature is studied using molecular dynamics simulation. We reveal that there is a droplet size at the nanoscale where water droplets can be stabilized in the condensation process. Our simulations show that the growth of water droplets is dominated by collision and coagulation between small water droplets after nucleation. This process is found to be accompanied by exceptionally fast evaporation such that droplet growth is balanced by evaporation when water droplets grow to a critical size, approximately 12.5 Å in radius, reaching a stable size distribution. The extremely high evaporation rate is attributed to the curvature dependence of surface tension. Surface tension shows a significant decrease with decreasing droplet size below 20 Å, which causes the total free energy of nanoscaled water droplets to rise after collision and coagulation. Consequently, water droplets have to shrink via fast evaporation. The curvature dependence of surface tension is related to the dielectric ordering of water molecules near the surface of water droplets. Owing to fast evaporation, secondary condensation occurs, and many small water clusters form, ultimately exhibiting a bimodal distribution of water-droplet size.

9.
Case Rep Oncol ; 17(1): 361-369, 2024.
Article En | MEDLINE | ID: mdl-38415271

Introduction: Cadonilimab (AK104) is an innovative human programmed cell death-1 (PD-1)/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody. Compared with the combination therapy of PD-1 and CTLA-4 blockers, less cellular toxicity of cadonilimab was significantly manifested. As one of the characteristic adverse effects of cadonilimab, infusion-related reactions (IRRs) represent fever, chills, rash, decreased blood pressure, and other symptoms. Case Presentation: Here, we documented seven cases of IRRs after the administration of cadonilimab. The symptoms of IRRs were relieved after the discontinuation of cadonilimab and the administration of diphenhydramine, dexamethasone, and cimetidine. Notably, 3 patients were able to tolerate the subsequent cadonilimab therapy under the pretreatment. Conclusion: In this study, we discovered that cadonilimab-related IRRs might be lessened or prevented by administering medication and the proper pretreatment and lowering the infusion rate.

10.
Cell ; 187(1): 184-203.e28, 2024 01 04.
Article En | MEDLINE | ID: mdl-38181741

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the cGAS-STING pathway. Multi-omics clustering identified four subtypes with subtype-specific therapeutic vulnerabilities. Cell line and patient-derived xenograft-based drug tests validated the specific therapeutic responses predicted by multi-omics subtyping. This study provides a valuable resource as well as insights to better understand SCLC biology and improve clinical practice.


Lung Neoplasms , Proteogenomics , Small Cell Lung Carcinoma , Humans , Cell Line , Lung Neoplasms/chemistry , Lung Neoplasms/genetics , Small Cell Lung Carcinoma/chemistry , Small Cell Lung Carcinoma/genetics , Heterografts , Biomarkers, Tumor/analysis
11.
Small ; 20(15): e2306237, 2024 Apr.
Article En | MEDLINE | ID: mdl-38009589

Manganese-based materials are regarded as the most prospective cathode materials because of their high natural abundance, low toxicity, and high specific capacity. Nevertheless, the low conductivity, poor cycling performance, and controversial energy storage mechanisms hinder their practical application. Here, the MnS0.5Se0.5 microspheres are synthesized by a two-step hydrothermal approach and employed as cathode materials for aqueous zinc-ion batteries (AZIBs) for the first time. Interestingly, in-depth ex situ tests and electrochemical kinetic analyses reveal that MnS0.5Se0.5 is first irreversibly converted into low-crystallinity ZnMnO3 and MnOx by in situ electrooxidation (MnS0.5Se0.5-EOP) during the first charging process, and then a reversible co-insertion/extraction of H+/Zn2+ occurs in the as-obtained MnS0.5Se0.5-EOP electrode during the subsequent discharging and charging processes. Benefiting from the increased surface area, shortened ion transport path, and stable lamellar microsphere structure, the MnS0.5Se0.5-EOP electrodes deliver high reversible capacity (272.8 mAh g-1 at 0.1 A g-1), excellent rate capability (91.8 mAh g-1 at 2 A g-1), and satisfactory cyclic stability (82.1% capacity retention after 500 cycles at 1 A g-1). This study not only provides a powerful impetus for developing new types of manganese-based chalcogenides, but also puts forward a novel perspective for exploring the intrinsic mechanisms of in situ electrooxidation behavior.

13.
Environ Monit Assess ; 195(12): 1423, 2023 Nov 07.
Article En | MEDLINE | ID: mdl-37934331

Industrial wastewater from drug production is one of the contributors to water pollution. For drug wastewater treatment, photodegradation-based chemical technology has gained more attention because of the drug's microbicidal nature and stability. A zinc-chromium-nickel trimetallic-layered double hydroxide compounding with graphene oxide catalyst (ZnCrNi/GO) was synthesized and exhibited a clustered crumb sheet morphology. The prepared catalyst was characterized by a scanning electron microscope (SEM) equipped with an energy-dispersive X-ray spectrometer (EDS), Fourier transform infrared (FTIR) spectra, and X-ray photoelectron spectroscopy (XPS). The results of material analysis established the crystallographic structures of catalysts and evidenced the successful synthesis. The ZnCrNi/GO nanohybrid revealed a higher activity of approximately 90% degradation of tolysin under high-pressure mercury lamp irradiation. The optimized condition of the catalyst dosage of 500 mg/L and the natural pH of the solution at 7.0 under the tylosin concentration of 10 mg/L with high photocatalytic efficiency was explored. In addition, the main reactive species involved in this photocatalysis degradation were explored as the active cavity h+ and ·O2- to a certain extent by the radical trapping experiments. Reuse experiments have shown that as-prepared catalysts possessed the properties of high efficiency and long-lasting catalytic performance, which could meet pharmaceutical wastewater treatment. A three-metal-layered double hydroxide composed by the metal of Ni, Zn, and Cr was synthesized and attached onto graphene oxide. The catalytic materials obtained in this way have a significant catalysis efficiency to tylosin with the likely degradation mechanism of the active cavity h+ and the oxidative capacity of hydroxyl radials.


Environmental Monitoring , Tylosin , Hydroxides
14.
Sci Rep ; 13(1): 12657, 2023 Aug 04.
Article En | MEDLINE | ID: mdl-37542076

The neutron capture cross section of [Formula: see text]Ta is relevant to s-process of nuclear astrophysics, extraterrestrial samples analysis in planetary geology and new generation nuclear energy system design. The [Formula: see text]Ta([Formula: see text]) cross section had been measured between 1 eV and 800 keV at the back-streaming white neutron facility (Back-n) of China spallation neutron source(CSNS) using the time-of-flight (TOF) technique and [Formula: see text] liquid scintillator detectors. The experimental results are compared with the data of several evaluated libraries and previous experiments in the resolved and unresolved resonance region. Resonance parameters are extracted using the R-Matrix code SAMMY in the 1-700 eV region. The astrophysical Maxwell average cross section(MACS) from kT = 5 to 100 keV is calculated over a sufficiently wide range of neutron energies. For the characteristic thermal energy of an astrophysical site, at kT = 30keV the MACS value of [Formula: see text]Ta is 834 ± 75 mb, which shows an obvious discrepancy with the Karlsruhe Astrophysical Database of Nucleosynthesis in Stars (KADoNiS) recommended value 766 ± 15 mb. The new measurements strongly constrain the MACS of [Formula: see text]Ta([Formula: see text]) reaction in the stellar s-process temperatures.

15.
World J Clin Cases ; 11(10): 2308-2314, 2023 Apr 06.
Article En | MEDLINE | ID: mdl-37122521

BACKGROUND: Conservative treatments have been reported to diminish or resolve clinical symptoms of lumbar intervertebral disc herniation (LIDH) within a few weeks. CASE SUMMARY: Computed tomography and magnetic resonance imaging (MRI) of the lumbar region of a 25-year-old male diagnosed with LIDH showed prolapse of the L5/S2 disc. The disc extended 1.0 cm beyond the vertebral edge and hung along the posterior vertebral edge. The patient elected a conservative treatment regimen that included traditional Chinese medicine (TCM), acupuncture, and massage. During a follow-up period of more than 12 mo, good improvement in pain was reported without complications. MRI of the lumbar region after 12 mo showed obvious reabsorption of the herniation. CONCLUSION: A conservative treatment regimen of TCM, acupuncture, and massage promoted reabsorption of a prolapsed disc.

16.
Acta Biochim Biophys Sin (Shanghai) ; 55(6): 948-955, 2023 May 30.
Article En | MEDLINE | ID: mdl-37249335

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases and features a strong predilection for early metastasis and extremely poor prognosis. Despite being highly sensitive to chemotherapy and/or radiotherapy initially, most SCLC patients develop therapeutic resistance within one year and die of distant metastases. Multiple studies have revealed the high heterogeneity and strong plasticity of SCLC associated with frequent metastases and early development of therapeutic resistance as well as poor clinical outcome. Importantly, different SCLC subtypes are associated with different therapeutic vulnerabilities, and the inflamed subtype tends to have the best response to immunotherapy, which highlights the importance of precision medicine in the clinic. Here, we review recent advances in SCLC heterogeneity and plasticity and their link to distant metastases and chemotherapy resistance. We hope that a better understanding of the molecular mechanisms underlying SCLC malignant progression will help to develop better intervention strategies for this deadly disease.


Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/pathology , Lung Neoplasms/pathology
17.
Cell Stress Chaperones ; 28(2): 133-144, 2023 03.
Article En | MEDLINE | ID: mdl-36652120

Mitochondria are dynamic organelles that alter their morphology through fission (fragmentation) and fusion (elongation). These morphological changes correlate highly with mitochondrial functional adaptations to stressors, such as hypoxia, pressure overload, and inflammation, and are important in the setting of heart failure. Pathological mitochondrial remodeling, characterized by increased fission and reduced fusion, is associated with impaired mitochondrial respiration, increased mitochondrial oxidative stress, abnormal cytoplasmic calcium handling, and increased cardiomyocyte apoptosis. Considering the impact of the mitochondrial morphology on mitochondrial behavior and cardiomyocyte performance, altered mitochondrial dynamics could be expected to induce or exacerbate the pathogenesis and progression of heart failure. However, whether alterations in mitochondrial fission and fusion accelerate or retard the progression of heart failure has been the subject of intense debate. In this review, we first describe the physiological processes and regulatory mechanisms of mitochondrial fission and fusion. Then, we extensively discuss the pathological contributions of mitochondrial fission and fusion to heart failure. Lastly, we examine potential therapeutic approaches targeting mitochondrial fission/fusion to treat patients with heart failure.


Heart Failure , Mitochondrial Dynamics , Humans , Mitochondrial Dynamics/physiology , Mitochondria/pathology , Apoptosis , Mitochondrial Proteins
18.
Mol Ecol Resour ; 23(1): 253-272, 2023 Jan.
Article En | MEDLINE | ID: mdl-35932461

Locoweeds are perennial forbs poisonous to livestock and cause extreme losses to animal husbandry. Locoweed toxicity is attributed to the symbiotic endophytes in Alternaria sect. Undifilum, which produce a mycotoxin swainsonine (SW). We performed a de novo whole genome sequencing of the most common locoweed in China, Oxytropis ochrocephala (2n = 16), and assembled a high-quality, chromosome-level reference genome. Its genome size is 958.83 Mb with 930.94 Mb (97.09%) anchored and oriented onto eight chromosomes, and 31,700 protein-coding genes were annotated. Phylogenetic and collinearity analysis showed it is closely related to Medicago truncatula with a pair of large interchromosomal rearrangements, and both species underwent a whole-genome duplication event. We also derived the genome of A. oxytropis at 74.48 Mb with a contig N50 of 8.87 Mb and 10,657 protein-coding genes, and refined the genes of SW biosynthesis. Multiple Alternaria species containing the swnK gene were grouped into a single clade, but in other genera, swnK's homologues are diverse. Resequencing of 41 A. oxytropis strains revealed one SNP in the SWN cluster causing changes in SW concentration. Comparing the transcriptomes of symbiotic and nonsymbiotic interactions identified differentially expressed genes (DEGs) linked to defence and secondary metabolism in the host. Within the endophyte DEGs were linked to cell wall degradation, fatty acids and nitrogen metabolism. Symbiosis induced the upregulation of most of the SW biosynthetic genes. These two genomes and relevant sequencing data should provide valuable genetic resources for the study of the evolution, interaction, and SW biosynthesis in the symbiont.


Ascomycota , Oxytropis , Swainsonine/analysis , Swainsonine/metabolism , Oxytropis/genetics , Oxytropis/metabolism , Endophytes/genetics , Endophytes/metabolism , Alternaria/genetics , Alternaria/metabolism , Symbiosis/genetics , Phylogeny , Ascomycota/metabolism
19.
Cancer Cell ; 41(1): 88-105.e8, 2023 01 09.
Article En | MEDLINE | ID: mdl-36525973

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.


Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , Animals , Humans , Mice , Carcinogenesis/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/genetics , Cell Transformation, Neoplastic , Lung/metabolism , Lung Neoplasms/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , ras Proteins/antagonists & inhibitors , ras Proteins/metabolism
20.
Int J Mol Sci ; 23(23)2022 Dec 06.
Article En | MEDLINE | ID: mdl-36499701

Brassinolide (BR) is the "sixth class" plant hormone, which plays an important role in various physiological and biochemical processes of plants. The wide variety of functions of Pinellia ternata means that there is huge demand for it and thus it is in short supply. This paper mainly assessed the changes of yield and quality in P. ternata at different stages after BR treatments by principal component analysis, in order to improve the yield and quality of P. ternata and at the same time determine the best harvest time. The results showed that the tuber yield of P. ternata was significantly increased by BR treatments at different stages (except for the 15th day). After the 15th, 45th, 60th, 75th, 90th, and 105th day of treatments, the tuber yield of P. ternata reached peak values at 0.10 (0.65 g), 0.50 (1.97 g), 0.50 (1.98 g), 1.00 (2.37 g), 1.00 (2.84 g), and 2.00 mg/L (3.76 g) BR treatment, respectively. The optimal harvest time was the 75th day after 0.10, 0.50, and 1.00 mg/L BR treatments, which not only significantly improved the yield of P. ternata, but also retained high level of total alkaloids in the tubers (20.89, 5.37, and 13.44%) and bulbils (9.74, 20.42, and 13.62%), high total flavone content in the tubers (17.66, 16.26, and 12.74%) and bulbils (52.63, 12.79, and 38.69%), and high ß-sitosterol content in the tubers (25.26, 16.65, and 0.62%) of P. ternata, compared with the control, respectively.


Alkaloids , Pinellia , Pinellia/chemistry , Principal Component Analysis , Plant Tubers/chemistry , Plant Growth Regulators/analysis , Alkaloids/analysis
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