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Chloroplasts are green plastids in the cytoplasm of eukaryotic algae and plants responsible for photosynthesis. The plastid-encoded RNA polymerase (PEP) plays an essential role during chloroplast biogenesis from proplastids and functions as the predominant RNA polymerase in mature chloroplasts. The PEP-centered transcription apparatus comprises a bacterial-origin PEP core and more than a dozen eukaryotic-origin PEP-associated proteins (PAPs) encoded in the nucleus. Here, we determined the cryo-EM structures of Nicotiana tabacum (tobacco) PEP-PAP apoenzyme and PEP-PAP transcription elongation complexes at near-atomic resolutions. Our data show the PEP core adopts a typical fold as bacterial RNAP. Fifteen PAPs bind at the periphery of the PEP core, facilitate assembling the PEP-PAP supercomplex, protect the complex from oxidation damage, and likely couple gene transcription with RNA processing. Our results report the high-resolution architecture of the chloroplast transcription apparatus and provide the structural basis for the mechanistic and functional study of transcription regulation in chloroplasts.
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RNA Polimerases Dirigidas por DNA , Plastídeos , Cloroplastos/metabolismo , Microscopia Crioeletrônica , RNA Polimerases Dirigidas por DNA/genética , Nicotiana/genética , Fotossíntese , Plastídeos/enzimologiaRESUMO
Liver can sense the nutrient status and send signals to other organs to regulate overall metabolic homoeostasis. Herein, we demonstrate that ketone bodies act as signals released from the liver that specifically determine the distribution of excess lipid in epididymal white adipose tissue (eWAT) when exposed to a ketogenic diet (KD). An acute KD can immediately result in excess lipid deposition in the liver. Subsequently, the liver sends the ketone body ß-hydroxybutyrate (BHB) to regulate white adipose expansion, including adipogenesis and lipogenesis, to alleviate hepatic lipid accumulation. When ketone bodies are depleted by deleting 3-hydroxy-3-methylglutaryl-CoA synthase 2 gene in the liver, the enhanced lipid deposition in eWAT but not in inguinal white adipose tissue is preferentially blocked, while lipid accumulation in liver is not alleviated. Mechanistically, ketone body BHB can significantly decrease lysine acetylation of peroxisome proliferator-activated receptor gamma in eWAT, causing enhanced activity of peroxisome proliferator-activated receptor gamma, the key adipogenic transcription factor. These observations suggest that the liver senses metabolic stress first and sends a corresponding signal, that is, ketone body BHB, to specifically promote eWAT expansion to adapt to metabolic challenges.
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Tecido Adiposo Branco , Dieta Cetogênica , Fígado Gorduroso , Corpos Cetônicos , Humanos , Tecido Adiposo Branco/metabolismo , Fígado Gorduroso/metabolismo , Corpos Cetônicos/metabolismo , Lipídeos , Fígado/metabolismo , PPAR gama/metabolismoRESUMO
Catalytic electron donor-acceptor (EDA) complexes have recently emerged as a powerful and sustainable alternative to iridium- and ruthenium-based photoredox synthetic methods. Yet, these complexes remain underexplored and reliant on the use of meticulously designed acceptors that require previous installation. Herein, we report a novel EDA complex employing tris(4-methoxyphenyl) amine as a catalytic donor for the sulfonylation of alkenes using inexpensive and readily available sulfonyl chlorides. Applying this operationally simple, visible-light-mediated general platform, we report both the redox-neutral and net-reductive functionalization of more than 60 substrates, encompassing vinylic or allylic sulfonylation, hydrosulfonylation, and sulfamoylation of activated and unactivated alkenes and alkynes.
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Phosphorescence in carbon dots (CDs) from triplet exciton radiative recombination at room temperature has achieved significant advancement. Confinement and nanoconfinement, serving as valuable techniques, are commonly utilized to brighten triplet exciton in CDs, thereby enhancing their phosphorescence. However, a comprehensive and universally applicable physical description of confinement-enhanced phosphorescence is still lacking, despite efforts to understand its underlying nature. In this study, the dominance of entropy is revealed in triplet exciton emission from CDs through the establishment of a microscopic vibration state model. CDs with varying entropy levels are studied, indicating that in a low entropy system, the multi-energy triplet exciton emission in CDs exhibits enhanced brightness, accompanied by a corresponding increase in their lifetimes. The product of lifetime and intensity in CDs serves as a descriptor for their phosphorescence properties. Moreover, an entropy-dependent information variation system based on the CDs is demonstrated. Specifically, in a low-entropy system, information is retained, whereas the corresponding information is erased in a high-entropy system. This work elucidates the underlying physical nature of confinement-enhanced triplet exciton emission, offering a deeper understanding of achieving ultralong phosphorescence in the future.
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The homolysis of chemical bonds represents one of the most fundamental reactivities of excited molecules. Historically, it has been exploited to generate radicals under ultraviolet (UV) light irradiation. However, unlike most contemporary radical-generating mechanisms, the direct excitation to homolyze chemical bonds and produce aliphatic carbon-centered radicals under visible light remains rare, especially in metallaphotoredox cross couplings. Herein, we present our design of the dihydropyrimidoquinolinone (DHPQ) reagents derived from ketones, which can undergo formal deacylation and homolytic C-C bond cleavage to release alkyl radicals without external photocatalysts. Spectroscopic and computational analysis reveal unique optical and structural features of DHPQs, rationalizing their faster kinetics in alkyl radical generation than a structurally similar but visible-light transparent radical precursor. Such a capability allows DHPQ to facilitate a wide range of Ni-metallaphotoredox cross couplings with aryl, alkynyl and acyl halides. Other catalytic and non-catalyzed alkylative transformations of DHPQs are also feasible with various radical acceptors. We believe this work would be of broad interest, aiding the synthetic planning with simplified operation and expanding the synthetic reach of photocatalyst-free approaches in cutting-edge research.
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The condensation of amino acids into peptides plays a crucial role in protein synthesis and is thus essential for understanding the origins of life. However, the spontaneous formation of peptides from amino acids in bulk aqueous media is energetically unfavorable, posing a challenge for elucidating plausible abiotic mechanisms. In this study, we investigate the formation of amide bonds between amino acids within highly supersaturated aerosol droplets containing dicyandiamide (DCD), a cyanide derivative potentially present on primordial Earth. Metastable states, i.e. supersaturation, within individual micron-sized droplets are studied using both an optical trap and a linear quadrupole electrodynamic balance. When irradiated with intense visible light, amide bond formation is observed to occur and can be monitored using vibrational bands in Raman spectra. The reaction rate is found to be strongly influenced by droplet size and kinetic modelling suggests that it is driven by the photochemical product of a DCD self-reaction. Our results highlight the potential of atmospheric aerosol particles as reaction environments for peptide synthesis and have potential implications for the prebiotic chemistry of early Earth.
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Adaptation to nutrient deprivation depends on the activation of metabolic programs to use reserves of energy. When outside a host plant, second-stage juveniles (J2) of the root-knot nematode (Meloidogyne spp.), an important group of pests responsible for severe losses in the production of crops (e.g., rice, wheat, and tomato), are unable to acquire food. Although lipid hydrolysis has been observed in J2 nematodes, its role in fitness and the underlying mechanisms remain unknown. Using RNA-seq analysis, here, we demonstrated that in the absence of host plants, the pathway for the biosynthesis of polyunsaturated fatty acids was upregulated, thereby increasing the production of arachidonic acid in middle-stage J2 Meloidogyne incognita worms. We also found that arachidonic acid upregulated the expression of the transcription factor hlh-30b, which in turn induced lysosomal biogenesis. Lysosomes promoted lipid hydrolysis via a lysosomal lipase, LIPL-1. Furthermore, our data demonstrated that blockage of lysosomal lipolysis reduced both lifespan and locomotion of J2 worms. Strikingly, disturbance of lysosomal lipolysis resulted in a decline in infectivity of these juveniles on tomato roots. Our findings not only reveal the molecular mechanism of lipolysis in J2 worms but also suggest potential novel strategies for the management of root-knot nematode pests.
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Solanum lycopersicum , Tylenchoidea , Animais , Ácidos Araquidônicos/metabolismo , Metabolismo dos Lipídeos , Lipólise , Solanum lycopersicum/parasitologia , Lisossomos , Tylenchoidea/metabolismo , Tylenchoidea/fisiologiaRESUMO
Gonadal white adipose tissue (gWAT) can regulate gametogenesis via modulation of neuroendocrine signaling. However, the effect of gWAT on the local microenvironment of the gonad was largely unknown. Herein, we ruled out that gWAT had a neuroendocrine effect on gonad function through a unilateral lipectomy strategy, in which cutting off epididymal white adipose tissue could reduce seminiferous tubule thickness and decrease sperm counts only in the adjacent testis and epididymis of the affected gonad. Consistent with the results in males, in females, ovary mass was similarly decreased by lipectomy. We determined that the defects in spermatogenesis were mainly caused by augmented apoptosis and decreased proliferation of germ cells. Transcriptome analysis suggested that lipectomy could disrupt immune privilege and activate immune responses in both the testis and ovary on the side of the lipectomy. In addition, lipidomics analysis in the testis showed that the levels of lipid metabolites such as free carnitine were elevated, whereas the levels of glycerophospholipids such as phosphatidylcholines and phosphatidylethanolamines were decreased, which indicated that the metabolic niche was also altered. Finally, we show that supplementation of phosphatidylcholine and phosphatidylethanolamine could partially rescue the observed phenotype. Collectively, our findings suggest that gWAT is important for gonad function by not only affecting whole-body homeostasis but also via maintaining local metabolic and immune niches.
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Tecido Adiposo Branco , Gônadas , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Epididimo , Feminino , Masculino , Camundongos , Espermatogênese , Testículo/metabolismoRESUMO
BACKGROUND: Depression is two-to-three times more frequent among women. The hypothalamus, a sexually dimorphic area, has been implicated in the pathophysiology of depression. Neuroinflammation-induced hypothalamic dysfunction underlies behaviors associated with depression. The lipopolysaccharide (LPS)-induced mouse model of depression has been well-validated in numerous laboratories, including our own, and is widely used to investigate the relationship between neuroinflammation and depression. However, the sex-specific differences in metabolic alterations underlying depression-associated hypothalamic neuroinflammation remain unknown. METHODS: Here, we employed the LPS-induced mouse model of depression to investigate hypothalamic metabolic changes in both male and female mice using a metabolomics approach. Through bioinformatics analysis, we confirmed the molecular pathways and biological processes associated with the identified metabolites. Furthermore, we employed quantitative real-time PCR, enzyme-linked immunosorbent assay, western blotting, and pharmacological interventions to further elucidate the underlying mechanisms. RESULTS: A total of 124 and 61 differential metabolites (DMs) were detected in male and female mice with depressive-like behavior, respectively, compared to their respective sex-matched control groups. Moreover, a comparison between female and male model mice identified 37 DMs. We capitalized on biochemical clustering and functional enrichment analyses to define the major metabolic changes in these DMs. More than 55% of the DMs clustered into lipids and lipid-like molecules, and an imbalance in lipids metabolism was presented in the hypothalamus. Furthermore, steroidogenic pathway was confirmed as a potential sex-specific pathway in the hypothalamus of female mice with depression. Pregnenolone, an upstream component of the steroid hormone biosynthesis pathway, was downregulated in female mice with depressive-like phenotypes but not in males and had considerable relevance to depressive-like behaviors in females. Moreover, exogenous pregnenolone infusion reversed depressive-like behaviors in female mice with depression. The 5α-reductase type I (SRD5A1), a steroidogenic hub enzyme involved in pregnenolone metabolism, was increased in the hypothalamus of female mice with depression. Its inhibition increased hypothalamic pregnenolone levels and ameliorated depressive-like behaviors in female mice with depression. CONCLUSIONS: Our study findings demonstrate a marked sexual dimorphism at the metabolic level in depression, particularly in hypothalamic steroidogenic metabolism, identifying a potential sex-specific pathway in female mice with depressive-like behaviors.
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Depressão , Doenças Neuroinflamatórias , Humanos , Camundongos , Masculino , Feminino , Animais , Depressão/metabolismo , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Hipotálamo/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Pregnenolona/metabolismoRESUMO
Male fertility declines with age. The mevalonate pathway, through which cholesterol and nonsteroidal isoprenoids are synthesized, plays key role in metabolic processes and is an essential pathway for cholesterol production and protein prenylation. Male reproductive aging is accompanied by dramatic changes in the metabolic microenvironment of the testis. Since the mevalonate pathway has an important role in spermatogenesis, we attempted to explore the association between male reproductive aging and the mevalonate pathway to explain the mechanism of male reproductive aging. Alterations in the mevalonate pathway may affect male reproductive aging by decreasing cholesterol synthesis and altering testis protein prenylation. Decreased cholesterol levels affect cholesterol modification, testosterone production, and remodeling of germ cell membranes. Aging-related metabolic disorders also affect the metabolic coupling between somatic cells and spermatogenic cells, leading to male fertility decline. Therefore, we hypothesized that alterations in the mevalonate pathway represent one of the metabolic causes of reproductive aging.
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Colesterol , Ácido Mevalônico , Masculino , Humanos , Ácido Mevalônico/metabolismo , Colesterol/metabolismo , Reprodução , Testículo/metabolismoRESUMO
BACKGROUND: Conduction disturbances requiring permanent pacemaker implantation (PPI) are common following transcatheter aortic valve replacement (TAVR). There were conflicting data regarding the impact of new PPI on clinical outcomes after TAVR. OBJECTIVES: The study sought to evaluate the impact of new PPI on clinical outcomes in patients undergoing TAVR. METHODS: This study was a retrospective analysis of prospectively collected data. Data were from 210 consecutive patients without prior PPI who underwent TAVR due to severe symptomatic aortic stenosis at our center between June 2018 and July 2020. Clinical, echocardiographic, and pacing data were assessed at 30-day, 1- and 2-year follow-up. RESULTS: New PPI was required in 35 (16.7%) patients within 30 days after TAVR. The median time from TAVR to PPI was 3 days. The most common indication for PPI was high-degree or complete atrioventricular block. The median follow-up was 798.0 (interquartile range, 669.0-1115.0) days. There were no differences in all-cause mortality (adjusted hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.85-2.36; p = 0.415) and cardiovascular mortality (adjusted HR: 0.92; 95% CI: 0.57-1.89; p = 0.609) between groups. However, PPI group had a higher risk of heart failure (HF) rehospitalization (adjusted HR: 1.53; 95% CI: 1.26-2.28; p = 0.027). Echocardiography showed no significant improvement of LVEF over time in patients with PPI. At the latest follow-up, 31.3% of patients exhibited low (≤10%) pacing burdens, whereas 28.1% of patients had near constant (>90%) right ventricular pacing. CONCLUSIONS: New PPI within 30 days following TAVR was not associated with an increased risk of all-cause or cardiovascular mortality. However, patients with PPI had a higher risk of HF rehospitalization and lack of LVEF improvement.
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Estenose da Valva Aórtica , Marca-Passo Artificial , Substituição da Valva Aórtica Transcateter , Humanos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Prognóstico , Estudos Retrospectivos , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Estimulação Cardíaca Artificial/efeitos adversos , Resultado do Tratamento , Fatores de Risco , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgiaRESUMO
As the "chemical chameleon", sulfonyl-containing compounds and their variants have been merged with various types of reactions for the efficient construction of diverse molecular architectures by taking advantage of their incredible reactive flexibility. Currently, their involvement in radical transformations, in which the sulfonyl group typically acts as a leaving group via selective C-S, N-S, O-S, S-S, and Se-S bond cleavage/functionalization, has facilitated new bond formation strategies which are complementary to classical two-electron cross-couplings via organometallic or ionic intermediates. Considering the great influence and synthetic potential of these novel avenues, we summarize recent advances in this rapidly expanding area by discussing the reaction designs, substrate scopes, mechanistic studies, and their limitations, outlining the state-of-the-art processes involved in radical-mediated desulfonylation and related transformations. With a specific emphasis on their synthetic applications, we believe this review will be useful for medicinal and synthetic organic chemists who are interested in radical chemistry and radical-mediated desulfonylation in particular.
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Elétrons , Técnicas de Química SintéticaRESUMO
BACKGROUND: Evidence about safety and efficacy of transcatheter aortic valve replacement (TAVR) with the Venus A-Valve system (Venus Medtech, Hangzhou, China) remains limited for patients with pure native aortic regurgitation (PNAR). OBJECTIVES: The single-center study sought to report the one-year clinical outcomes of the Venus A-Valve in the treatment of PNAR. METHODS: This study was a retrospective analysis of prospectively collected data. Data was from all consecutive patients who had PNAR and underwent TAVR with the Venus A-Valve system at our center from July 2020 and June 2021. Procedural and clinical outcomes up to one year were analyzed using Valve Academic Research Consortium-2 criteria. RESULTS: A total of 45 consecutive patients with PNAR underwent transfemoral TAVR with the Venus A-Valve system. The Mean age was 73.5 ± 5.5 years and 26.7% were female. All the TAVR procedures were performed via transfemoral access. Implantations were successful in 44 cases (97.8%). Only one patient was converted to surgical aortic valve replacement. No patient died intraoperatively. No second valve was implanted. In-hospital mortality rate was 2.3%. The one-year all-cause mortality rate was 4.7% without cardiovascular related death. No patient had moderate or severe paravalvular leakage during follow-up. At one year, the mean pressure gradient was 8.8 ± 0.9 mmHg, and left ventricular ejection fraction increased to 61.5 ± 3.6%. CONCLUSIONS: This single-center study demonstrated the safety and efficacy of transfemoral TAVR with the Venus A-Valve in the treatment of patients with PNAR.
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Insuficiência da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Humanos , Feminino , Idoso , Masculino , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/etiologia , Insuficiência da Valva Aórtica/cirurgia , Substituição da Valva Aórtica Transcateter/efeitos adversos , Estudos Retrospectivos , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Acute coronary syndrome (ACS),with increasing mortality year by year,has become a major public health problem in China.Exercise rehabilitation as an important part of the out-of-hospital rehabilitation for the patients with heart diseases can further reduce the mortality of patients on the basis of drug treatment.The available studies have proved that high-intensity interval training (HIIT) is more effective and efficient than moderate-intensity continuous training (MICT) such as walking and jogging on chronic cardiovascular diseases such as heart failure,stable coronary heart disease,and hypertension and has high security.According to the latest research,HIIT can reduce the platelet response,mitigate myocardial ischemia-reperfusion injury,and increase the exercise compliance of ACS patients more significantly than MICT.Moreover,it does not increase the risk of thrombotic adverse events or malignant arrhythmia.Therefore,HIIT is expected to become an important part of exercise prescription in out-of-hospital cardiac rehabilitation strategy for the patients with ACS.
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Síndrome Coronariana Aguda , Reabilitação Cardíaca , Insuficiência Cardíaca , Treinamento Intervalado de Alta Intensidade , Humanos , PlaquetasRESUMO
BACKGROUND: Metal screws are the most widely used in treating syndesmotic injuries, but failure and the rigidity of the screws can threaten the success of the treatment and increase the cost of care. We have provided an alternative with an olive wire and external fixator(OWEF) used for syndesmotic fixation. METHODS: A retrospective longitudinal follow-up study was conducted. From February 2011 to January 2018, 58 of 72 patients with ankle fractures and associated syndesmotic disruption were treated with either screw or OWEF fixation. The costs, complications, and clinical outcomes using Olerud-Molander score and Visual Analog score in screw and OWEF fixation group were compared. RESULTS: We found the severity of the injury, BMI of the patients and the different fixation methods were determinants of the complications and clinical outcomes. But if no malreduction of the syndesmosis was present, no difference in clinical result was detected. CONCLUSION: The OWEF method appeared to be at least equally functional and effective to screw fixation while maintaining possible lower complication rate. LEVELS OF CLINICAL EVIDENCE: Level 3.
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Fraturas do Tornozelo , Olea , Humanos , Fraturas do Tornozelo/diagnóstico por imagem , Fraturas do Tornozelo/cirurgia , Seguimentos , Estudos Retrospectivos , Articulação do Tornozelo/cirurgia , Fixação Interna de Fraturas/métodos , Resultado do Tratamento , Parafusos Ósseos , Fixadores ExternosRESUMO
A novel method for the formation of Csp3 -PIII bonds via the nickel-catalyzed cross-coupling of Umpolung carbonyls and phosphine chlorides is reported herein. This process leads to a series of alkylphosphines, which are characterized as sulfides or borane-phosphine complexes after undergoing further transformation with moderate to good yields. Invaluable free alkylphosphines can be easily obtained by desulfurization or deboration of the products. A possible mechanistic pathway is also discussed. This report represents the first example of using renewable carbonyls as latent organometallic reagent surrogates for cross-coupling with heteroatom electrophiles.
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Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.
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Corpos de Inclusão Intranuclear/patologia , Doenças Neurodegenerativas/patologia , Receptores Notch/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Feminino , Humanos , Corpos de Inclusão Intranuclear/genética , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Linhagem , Sequenciamento do ExomaRESUMO
The synthesis of arylamines from renewable resources under mild reaction conditions is highly desired for the sustainability of the chemical industry, where the production of hazardous waste is a prime concern. However, to date, there are very few tools in chemists' toolboxes that are able to produce arylamines in a sustainable manner. Herein, a robust one-pot approach for constructing bio-based arylamines via a combined photooxidative dearomatization-rearomatization strategy is presented. The developed methodology enables the synthesis of structurally complex amines in moderate-to-good isolated yields using biomass-derived phenols, natural α-amino acids, and naphthols under remarkably mild reaction conditions. For the photooxygenation of phenols, a novel chrysazine-based catalyst system was introduced, demonstrating its efficiency for the synthesis of natural products - hallerone, rengyolone, and the pharmaceutically relevant prodrug DHED.
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Aminas , Naftóis , Aminas/química , Catálise , Naftóis/química , FenóisRESUMO
BACKGROUND: Non-small cell lung carcinoma (NSCLC) is one of the most common human cancers, comprising approximately 80-85% of all lung carcinomas. An estimated incidence of NSCLC is approximately 2 million new cases per year worldwide. RESULTS: In recent decade, the treatment of NSCLC has made breakthrough progress owing to a large number of targeted therapies which were approved for clinical use. Epidemiology, genetic susceptibility, and molecular profiles in patients are likely to play an important factor in response rates and survival benefits to these targeted treatments and thus warrant further investigation on ethnic differences in NSCLC. In this study, a total number of 1500 Chinese patient samples,1000 formalin fixed paraffin-embedded (FFPE) and 500 blood samples, from patients with NSCLC were analyzed by targeted sequencing to explore mutational landscape in ethnic groups associated with China. CONCLUSIONS: Overall, the data presented here provide a comprehensive analysis of NSCLC mutational landscape in Chinese patients and findings are discussed in the context of similar studies on different ethnic groups.
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Carcinoma Pulmonar de Células não Pequenas/genética , Sequenciamento do Exoma , Exoma/genética , Idoso , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , China/epidemiologia , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genéticaRESUMO
Hepatocellular carcinoma (HCC) is a common liver cancer that accounts for 90% of cases. Doxorubicin exhibits a broad spectrum of antitumor activity and is one of the most active agents in HCC. WW domain-containing protein 2 (WWP2) is highly expressed in HCC tissues and activates protein kinase B (AKT) signaling pathway to enhance tumor metastasis. However, the role of WWP2 in the glycolysis and antitumor effects of doxorubicin and the epigenetic alterations of WWP2 in HCC remain to be elucidated. The levels of WWP2 and N6-methyladenosine methyltransferase-like 3 (METTL3) in clinical samples and cells were investigated. WWP2 were silenced or overexpressed to study the role of WWP2 in regulating cell proliferation, colony formation, and glycolysis. RNA immunoprecipitation was performed to test m6 A levels. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot were used to measure mRNA and protein, respectively. WWP2 silencing inhibits cell proliferation, colony formation, and glycolysis, while WWP2 overexpression has the inverse effects via the AKT signaling pathway. Silencing WWP2 enhances doxorubicin's antitumor effect, while WWP2 overexpression suppresses doxorubicin's antitumor effect. Data also support that METTL3 mediates WWP2 m6A modification, and m6A reader, IGF2BP2, binds to the methylated WWP2 to promote the stability of WWP2, leading to upregulation of WWP2. METTL3 mediates WWP2 m6A modification, which can be recognized and bound by IGF2BP2 to increase the stability of WWP2, leading to WWP2 overexpression which inhibits the antitumor effects of doxorubicin through METTL3/WWP2/AKT/glycolysis axis.