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2.
Environ Microbiol ; 26(10): e70000, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39413807

RESUMO

The impact of Borrelia miyamotoi on human health, facilitated by the expanding geographical distribution and increasing population of Ixodes ticks, remains obscure in the context of global climate change. We employed multiple models to evaluate the effect of global climate change on the risk of B. miyamotoi worldwide across various scenarios. The habitat suitability index of four primary vector tick species for B. miyamotoi, including Ixodes persulcatus, Ixodes ricinus, Ixodes pacificus and Ixodes scapularis, was projected using a boosted regression tree model, considering multiple shared socio-economic pathway scenarios over various time periods. The modelling analysis reveals that, apart from I. scapularis, future global warming will result in a northward shift in the other three vector tick species and a gradual reduction in suitable habitats. Random forest models indicate consistent changes in B. miyamotoi and its primary tick species, with potential risk areas shrinking and shifting northward, particularly in the eastern USA, northeastern and northern Europe and northeast Asia. These findings highlight the urgent need for enhanced active surveillance of B. miyamotoi infection in primary vector tick species across projected potential risk areas. The effect of climate change on B. miyamotoi distribution might have significant implications for public health decision-making regarding tick-borne pathogens.


Assuntos
Borrelia , Mudança Climática , Ecossistema , Ixodes , Animais , Ixodes/microbiologia , Humanos , Infecções por Borrelia/epidemiologia , Infecções por Borrelia/microbiologia , Vetores Aracnídeos/microbiologia
3.
J Agric Food Chem ; 2024 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-39460697

RESUMO

Recently, research and development of novel pesticides from natural plant products have received much attention. To accelerate the application of sophocarpine as the agrochemical candidate, a series of novel sophocarpine-based isoxazoline derivatives were prepared by the 1,3-dipolar [2 + 3] cycloaddition reaction of sophocarpine with different chloroximes. Their structures were well characterized by high-resolution mass spectra, infrared spectra, and proton/carbon-13 nuclear magnetic resonance spectra. Eight steric configurations of compounds 5a, 5e', 5f, 5g, 5h, 5i, 5r, and 5u' were further determined by X-ray single-crystallography. Against Aphis citricola Van der Goot, compounds 5n (LD50: 0.032 µg/nymph) and 5o (LD50: 0.024 µg/nymph) exhibited greater than 3.7- and 4.9-fold potent aphicidal activity compared to sophocarpine (LD50: 0.118 µg/nymph). Against Tetranychus cinnabarinus Boisduval, derivative 5g displayed the most promising acaricidal activity with the LC50 value of 0.247 mg/mL, which was 14.2-fold that of sophocarpine. Compounds 5d and 5g also exhibited good control efficacy against T. cinnabarinus. Scanning electron microscopy images indicated that compound 5g can destroy the mite cuticle layer. These results will provide the foundation for the structural modification and use of sophocarpine derivatives as agrochemicals in the future.

4.
Artigo em Inglês | MEDLINE | ID: mdl-39465985

RESUMO

The self-similar fractal morphology mediated by nonequilibrium processes is widely observed in low-dimensional materials grown by various techniques. Understanding how these fractal geometries affect the physical and chemical properties of materials and devices is crucial for both fundamental studies and various applications. In particular, the interplay between superconducting phase fluctuations and disorder can give rise to intriguing phenomena depending on the dimensionality. However, current experimental studies on low-dimensional superconductors are limited to two- and one-dimensional systems, leaving fractional dimensional systems largely unexplored. Here, we use chemical vapor deposition to successfully synthesize ultrathin NbC crystals with a well-defined fractal geometry at the nanoscale. By performing electrical transport measurements, we find that both the superconducting and normal-state properties are strongly affected in the fractal samples, where the intrinsic and geometric disorder is induced. In contrast to the 2D crystal, the fractal NbC crystals show a significant low-temperature resistive upturn before the onset of superconducting transition, which can be attributed to the disorder-enhanced electron-electron interaction effect. From transport data analysis, we demonstrate that the superconducting transition in NbC is correlated to the strength of disorder and the fractional dimensions, revealing that nanoscale fractal structures can significantly modify the electronic properties of low-dimensional superconductors. Our work paves the way for the explorations of mesoscopic transport and intriguing superconducting phenomena in fractional dimensions.

5.
J Diabetes ; 16(9): e13607, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39264012

RESUMO

Highlights Maturity-onset diabetes of the young type 6 (MODY6) is a rare form of monogenic diabetes mellitus due to NEUROD1 gene mutation on chromosome 2q32. A 21-year-old woman exhibiting weight loss, polyuria, and hyperglycemia was initially misdiagnosed with type 1 diabetes mellitus. Considering the early-onset age, a three-generation family history of diabetes, and negative autoimmune antibodies, a MODY diagnosis was suspected. Genetic analysis revealed that she inherited a novel heterozygous nonsense NEUROD1 mutation c.747C>G (p.Tyr249*) from her father. Correct MODY6 diagnosis facilitates appropriate interventions.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Códon sem Sentido , Diabetes Mellitus Tipo 2 , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , China , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , População do Leste Asiático/genética , Linhagem
6.
J Virol ; 98(10): e0112924, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39287389

RESUMO

Because host kinases are key regulators of multiple signaling pathways in response to viral infections, we previously screened a kinase inhibitor library using rhabdomyosarcoma cells and human intestinal organoids in parallel to identify potent inhibitors against EV-A71 infection. We found that Rho-associated coiled-coil-containing protein kinase (Rock) inhibitor efficiently suppressed the EV-A71 replication and further revealed Rock1 as a novel EV-A71 host factor. In this study, subsequent analysis found that a variety of vascular endothelial growth factor receptor (VEGFR) inhibitors also had potent antiviral effects. Among the hits, Pazopanib, with a selectivity index as high as 254, which was even higher than that of Pirodavir, a potent broad-spectrum picornavirus inhibitor targeting viral capsid protein VP1, was selected for further analysis. We demonstrated that Pazopanib not only efficiently suppressed the replication of EV-A71 in a dose-dependent manner, but also exhibited broad-spectrum anti-enterovirus activity. Mechanistically, Pazopanib probably induces alterations in host cells, thereby impeding viral genome replication and transcription. Notably, VEGFR2 knockdown and overexpression suppressed and facilitated EV-A71 replication, respectively, indicating that VEGFR2 is a novel host dependency factor for EV-A71 replication. Transcriptome analysis further proved that VEGFR2 potentially plays a crucial role in combating EV-A71 infection through the TSAd-Src-PI3K-Akt pathway. These findings expand the range of potential antiviral candidates of anti-enterovirus therapeutics and suggest that VEGFR2 may be a key host factor involved in EV-A71 replication, making it a potential target for the development of anti-enterovirus therapeutics. IMPORTANCE: As the first clinical case was identified in the United States, EV-A71, a significant neurotropic enterovirus, has been a common cause of hand, foot, and mouth disease (HFMD) in infants and young children. Developing an effective antiviral agent for EV-A71 and other human enteroviruses is crucial, as these viral pathogens consistently cause outbreaks in humans. In this study, we demonstrated that multiple inhibitors against VEGFRs effectively reduced EV-A71 replication, with Pazopanib emerging as the top candidate. Furthermore, Pazopanib also attenuated the replication of other enteroviruses, including CVA10, CVB1, EV-D70, and HRV-A, displaying broad-spectrum anti-enterovirus activity. Given that Pazopanib targets various VEGFRs, we narrowed the focus to VEGFR2 using knockdown and overexpression experiments. Transcriptomic analysis suggests that Pazopanib's potential downstream targets involve the TSAd-Src-PI3K-Akt pathway. Our work may contribute to identifying targets for antiviral inhibitors and advancing treatments for human enterovirus infections.


Assuntos
Antivirais , Enterovirus Humano A , Pirimidinas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Replicação Viral , Humanos , Replicação Viral/efeitos dos fármacos , Pirimidinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Enterovirus Humano A/efeitos dos fármacos , Enterovirus Humano A/fisiologia , Antivirais/farmacologia , Infecções por Enterovirus/virologia , Infecções por Enterovirus/tratamento farmacológico , Infecções por Enterovirus/metabolismo , Sulfonamidas/farmacologia , Indazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Piperidinas , Piridazinas
7.
Trends Cell Biol ; 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39261152

RESUMO

Ferroptosis is programmed cell death induced by iron-driven lipid peroxidation. Numerous studies have shown that ferroptosis is implicated in the progression of colorectal cancer (CRC) and has emerged as a promising strategy to combat therapy-resistant CRC. While the intrinsic antiferroptotic and proferroptotic pathways in CRC cells have been well characterized, extrinsic metabolism pathways regulating ferroptosis in CRC pathogenesis remain less understood. Emerging evidence shows that gut microbial metabolism is tightly correlated with the progression of CRC. This review provides an overview of gut microbial metabolism and discusses how these metabolites derived from intestinal microflora contribute to cancer plasticity through ferroptosis. Targeting gut microbe-mediated ferroptosis is a potential approach for CRC treatment.

8.
Theranostics ; 14(12): 4730-4746, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39239523

RESUMO

Rationale: Mechanical force plays crucial roles in extracellular vesicle biogenesis, release, composition and activity. However, it is unknown whether mechanical force regulates apoptotic vesicle (apoV) production. Methods: The effects of mechanical unloading on extracellular vesicles of bone marrow were evaluated through morphology, size distribution, yield, and protein mass spectrometry analysis using hindlimb unloading (HU) mouse model. Apoptosis resistance and aging related phenotype were assessed using HU mouse model in vivo and cell microgravity model in vitro. The therapeutic effects of apoVs on HU mouse model were assessed by using microcomputed tomography, histochemical and immunohistochemical, as well as histomorphometry analyses. SiRNA and chemicals were used for gain and loss-of-function assay. Results: In this study, we show that loss of mechanical force led to cellular apoptotic resistance and aging related phenotype, thus reducing the number of apoVs in the circulation due to down-regulated expression of Piezo1 and reduced calcium influx. And systemic infusion of apoVs was able to rescue Piezo1 expression and calcium influx, thereby, rescuing mechanical unloading-induced cellular apoptotic resistance, senescent cell accumulation. Conclusions: This study identified a previously unknown role of mechanical force in maintaining apoptotic homeostasis and eliminating senescent cells. Systemic infusion of mesenchymal stem cell-derived apoVs can effectively rescue apoptotic resistance and eliminate senescent cells in mechanical unloading mice.


Assuntos
Apoptose , Senescência Celular , Vesículas Extracelulares , Animais , Camundongos , Apoptose/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Senescência Celular/efeitos dos fármacos , Senoterapia/farmacologia , Canais Iônicos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Elevação dos Membros Posteriores , Cálcio/metabolismo , Masculino , Estresse Mecânico
9.
MedComm (2020) ; 5(9): e712, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39263607

RESUMO

Despite being one of the most prevalent RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A-related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole-exome sequencing cohorts, encompassing 508 ALS patients and 1660 population-matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X-linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC-34 cells overexpressing mutant TDP43Q331K results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single-cell sequencing data from the primary motor cortex indicates that RBMX-regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS-implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A-mediated mRNA metabolism.

10.
Environ Res ; 263(Pt 1): 120067, 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39341542

RESUMO

BACKGROUND: Scrub typhus is underdiagnosed and underreported but emerging as a global public health problem. To inform future burden and prediction studies we examined through a systematic review the potential effect of environmental covariates on scrub typhus occurrence and the methods which have been used for its prediction. METHODS: In this systematic review, we searched PubMed, Scopus, Web of Science, China National Knowledge Infrastructure and other databases, with no language and publication time restrictions, for studies that investigated environmental covariates or utilized methods to predict the spatial or temporal human. Data were manually extracted following a set of queries and systematic analysis was conducted. RESULTS: We included 68 articles published in 1978-2024 with relevant data from 7 countries/regions. Significant environmental risk factors for scrub typhus include temperature (showing positive or inverted-U relationships), precipitation (with positive or inverted-U patterns), humidity (exhibiting complex positive, inverted-U, or W-shaped associations), sunshine duration (with positive, inverted-U associations), elevation, the normalized difference vegetation index (NDVI), and the proportion of cropland. Socioeconomic and biological factors were rarely explored. Autoregressive Integrated Moving Average (ARIMA) (n = 8) and ecological niche modelling (ENM) approach (n = 11) were the most popular methods for predicting temporal trends and spatial distribution of scrub typhus, respectively. CONCLUSIONS: Our findings summarized the evidence on environmental covariates affecting scrub typhus occurrence and the methodologies used for predictive modelling. We review the existing knowledge gaps and outline recommendations for future studies modelling disease prediction and burden. TRIAL REGISTRATION: PROSPERO CRD42022315209.

11.
Pest Manag Sci ; 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39118390

RESUMO

BACKGROUND: Owing to large amounts of synthetic pesticides being extensively and unreasonably used for crop protection, currently, resistance and negative impacts on human health and environment safety have appeared. Therefore, development of potential pesticide candidates is highly urgent. Herein, a series of ester derivatives of osthole were designed and synthesized as pesticidal agents. RESULTS: Six spatial configurations of 4'-(p-toluenoyloxy)osthole (4b), 4'-(m-fluorobenzoyloxy)osthole (4f), 4'-(p-fluorophenylacetyloxy)osthole (4m), 4'-(3'',4''-methylenedioxybenzoyloxy)osthole (4q), 4'-formyloxyosthole (4u) and 4'-acetyloxyosthole (4v) were determined by X-ray mono-crystal diffraction. Compounds 4b, 4'-(p-chlorobenzoyloxy)osthole (4g), 4'-(m-chlorobenzoyloxy)osthole (4h), 4'-(p-bromobenzoyloxy)osthole (4i) and 4'-(2''-chloropyridin-3''-ylcarbonyloxy)osthole (4p) showed higher insecticidal activity than toosendanin against Mythimna separata Walker; notably, compound 4b displayed 1.8 times insecticidal activity of the precursor osthole. Against Tetranychus cinnabarinus Boisduval, compounds 4g and 4h showed 3.3 and 2.6 times acaricidal activity of osthole, and good control effects in the glasshouse. Scanning electron microscopy assay demonstrated that compound 4g can damage the cuticle layer of T. cinnabarinus resulting in death. CONCLUSION: Compounds 4g and 4h can be further studied as lead pesticidal agents for the management of M. separata and T. cinnabarinus. These results will pave the way for application of osthole derivatives as agrochemicals. © 2024 Society of Chemical Industry.

12.
World J Gastrointest Oncol ; 16(8): 3705-3715, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39171170

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. Over the past two decades, numerous researchers have provided important evidence regarding the role of tight junction (TJ) proteins in the occurrence and progression of CRC. The causal relationship between the presence of specific TJ proteins and the development of CRC has also been confirmed. Despite the large number of publications in this field, a bibliometric study to review the current state of research and highlight the research trends and hotspots in this field has not yet been performed. AIM: To analyze research on TJs and CRC, summarize the field's history and current status, and predict future research directions. METHODS: We searched the Science Citation Index Expanded database for all literature on CRC and TJs from 2001-2023. We used bibliometrics to analyze the data of these papers, such as the authors, countries, institutions, and references. Co-authorship, co-citation, and co-occurrence analyses were the main methods of analysis. CiteSpace and VOSviewer were used to visualize the results. RESULTS: A total of 205 studies were ultimately identified. The number of publications on this topic has steadily increased since 2007. China and the United States have made the largest contributions to this field. Anticancer Research was the most prolific journal, publishing 8 articles, while the journal Oncogene had the highest average citation rate (68.33). Professor Dhawan P was the most prolific and cited author in this field. Co-occurrence analysis of keywords revealed that "tight junction protein expression", "colorectal cancer", "intestinal microbiota", and "inflammatory bowel disease" had the highest frequency of occurrence, revealing the research hotspots and trends in this field. CONCLUSION: This bibliometric analysis evaluated the scope and trends of TJ proteins in CRC, providing valuable research perspectives and future directions for studying the connection between the two. It is recommended to focus on emerging research hotspots, such as the correlations among intestinal microbiota, inflammatory bowel disease, TJ protein expression, and CRC.

13.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 46(3): 402-408, 2024 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-38953264

RESUMO

There are mutual neural projections between the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC),which form a circuit.Recent studies have shown that this circuit is vital in regulating arousal from sleep and general anesthesia.This paper introduces the anatomical structures of VTA and mPFC and the roles of various neurons and projection pathways in the regulation of arousal,aiming to provide new ideas for further research on the mechanism of arousal from sleep and general anesthesia.


Assuntos
Nível de Alerta , Córtex Pré-Frontal , Área Tegmentar Ventral , Córtex Pré-Frontal/fisiologia , Área Tegmentar Ventral/fisiologia , Nível de Alerta/fisiologia , Humanos , Animais , Vias Neurais/fisiologia
14.
Cancer Cell ; 42(8): 1401-1414.e4, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39059389

RESUMO

Recurrence risks of cancer patient can change during treatment as a result of treatment-related tumor evolution. However, biomarkers that can monitor these changes are lacking. Here, we investigated whether tracking circulating tumor DNA (ctDNA) dynamics through liquid biopsy can inform real-time recurrence risk. Nasopharyngeal carcinoma (NPC) provides an ideal model where cell-free Epstein-Barr virus (EBV) DNA (cfEBV DNA), a ctDNA, can be sensitively detected. We conducted the EP-SEASON study (NCT03855020) and prospectively recruited 1,000 NPC patients undergoing per-protocol cfEBV DNA assessments at 11 time points and receiving sequential chemo-radiotherapy. Longitudinal cfEBV DNA displayed distinct patterns during neoadjuvant chemotherapy and radiotherapy. Despite the prognostic significance of cfEBV DNA at each time point, real-time recurrence risks changed in sync with cfEBV DNA dynamics. Furthermore, we identified phenotypes of whole-course ctDNA changing dynamics associated with different survival outcomes. In conclusion, tracking longitudinal on-treatment ctDNA can forecast real-time recurrence risk, facilitating risk-adapted, individualized patient management.


Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Recidiva Local de Neoplasia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Biópsia Líquida/métodos , Estudos Longitudinais , Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/virologia , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/diagnóstico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/sangue , Prognóstico , Estudos Prospectivos
15.
Nat Commun ; 15(1): 4921, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858361

RESUMO

Complicated associations between multiplexed environmental factors and aging are poorly understood. We manipulated aging using multidimensional metrics such as phenotypic age, brain age, and brain volumes in the UK Biobank. Weighted quantile sum regression was used to examine the relative individual contributions of multiplexed environmental factors to aging, and self-organizing maps (SOMs) were used to examine joint effects. Air pollution presented a relatively large contribution in most cases. We also found fair heterogeneities in which the same environmental factor contributed inconsistently to different aging metrics. Particulate matter contributed the most to variance in aging, while noise and green space showed considerable contribution to brain volumes. SOM identified five subpopulations with distinct environmental exposure patterns and the air pollution subpopulation had the worst aging status. This study reveals the heterogeneous associations of multiplexed environmental factors with multidimensional aging metrics and serves as a proof of concept when analyzing multifactors and multiple outcomes.


Assuntos
Envelhecimento , Poluição do Ar , Encéfalo , Exposição Ambiental , Material Particulado , Humanos , Envelhecimento/fisiologia , Material Particulado/análise , Exposição Ambiental/efeitos adversos , Poluição do Ar/análise , Feminino , Encéfalo/diagnóstico por imagem , Masculino , Idoso , Pessoa de Meia-Idade , Reino Unido , Adulto
16.
Int J Biol Macromol ; 274(Pt 2): 133451, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38944088

RESUMO

SARS-CoV-2 main protease (Mpro) is a well-recognized target for COVID-19 therapy. Green tea (-)-epigallocatechin-3-gallate (EGCG) possesses Mpro-inhibitory activity; however, the influence of EGCG oxidation on its inhibition activity remains obscure, given its high oxidation propensity. This study reveals that prolonged EGCG oxidation in the presence of Mpro dramatically increases its inhibitory activity with an IC50 of 0.26 µM. The inhibitory mechanism is that EGCG-quinone preferentially binds the active site Mpro-Cys145-SH, which forms a quinoprotein. Though Mpro is present in the cell lysate, EGCG preferentially depletes its thiols. Non-cytotoxic EGCG effectively generates a quinoprotein in living cells, thus EGCG might selectively inhibit Mpro in SARS-CoV-2 infected cells. Chlorogenic acid facilitates EGCG oxidation. Together, they synergistically deplete multiple Mpro thiols though this is not more beneficial than EGCG alone. By contrast, excessive EGCG oxidation prior to incubation with Mpro largely compromises its inhibitory activity. Overall, the low IC50 and the high selectivity imply that EGCG is a promising dietary Mpro inhibitor. While EGCG oxidation in the presence of Mpro has a pivotal role in inhibition, enhancing EGCG oxidation by chlorogenic acid no longer increases its inhibitory potential. EGCG oxidation in the absence of Mpro should be avoided to maximize its Mpro-inhibitory activity.


Assuntos
Catequina , Proteases 3C de Coronavírus , Oxirredução , SARS-CoV-2 , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Humanos , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/química , Ácido Clorogênico/farmacologia , Ácido Clorogênico/química , Ácido Clorogênico/análogos & derivados , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Antivirais/farmacologia , Antivirais/química , Tratamento Farmacológico da COVID-19 , COVID-19/virologia , Domínio Catalítico
17.
J Asian Nat Prod Res ; 26(11): 1339-1347, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38860546

RESUMO

Pegmolesatide, a synthetic, polyethylene-glycolylated, peptide-based erythropoiesis-stimulating agent (ESA), has been recently approved in China. Pegmolesatide is derived from the structure of endogenous erythropoietin (EPO), a natural product in mammals. This study compared the in vitro effects and selectivity of pegmolesatide to those of recombinant EPO and carbamylated EPO (CEPO) through computer-aided analyses and biological tests. The findings indicate that pegmolesatide exhibited the same stimulating effect on erythropoiesis as EPO with fewer side effects than EPO and CEPO.


Assuntos
Eritropoese , Eritropoetina , Hematínicos , Eritropoetina/farmacologia , Eritropoetina/química , Eritropoetina/análogos & derivados , Eritropoese/efeitos dos fármacos , Humanos , Hematínicos/farmacologia , Hematínicos/química , Estrutura Molecular , Animais , Proteínas Recombinantes
18.
J Genet Genomics ; 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38880354

RESUMO

Mitochondria play a key role in lipid metabolism, and mitochondrial DNA (mtDNA) mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function. In this study, we investigated mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from three independent populations. The association analysis of 16 basal mtDNA haplogroups with body mass index, waist circumference, and waist-to-hip ratio revealed that only haplogroup M7 was significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort, verified by the analysis of a single population, i.e., the Zhengzhou population. Furthermore, subhaplogroup analysis suggested that M7b1a1 was the most likely haplogroup associated with a decreased obesity risk, and the variation T12811C (causing Y159H in ND5) harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function. Specifically, we found that proportionally more nonsynonymous mutations accumulated in M7b1a1 carriers, indicating that M7b1a1 was either under positive selection or subject to a relaxation of selective constraints. We also found that nuclear variants, especially in DACT2 and PIEZO1, may functionally interact with M7b1a1.

19.
Cell Signal ; 121: 111258, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38866351

RESUMO

Adenosine deaminases acting on RNA 1(ADAR1), an RNA editing enzyme that converts adenosine to inosine by deamination in double-stranded RNAs, plays an important role in occurrence and progression of various types of cancer. Ferroptosis has emerged as a hot topic of cancer research in recent years. We have previously reported that ADAR1 promotes breast cancer progression by regulating miR-335-5p and METTL3. However, whether ADAR1 has effects on ferroptosis in breast cancer cells is largely unknown. In this study, we knocked down ADAR1 using CRISPR-Cas9 technology or over-expressed ADAR1 protein using plasmid expressing ADAR1 in MCF-7 and MDA-MB-231 breast cancer cell lines, then detected cell viability, and levels of ROS, MDA, GSH, Fe2+, GPX4 protein and miR-335-5p. We showed that the cell proliferation was inhibited, levels of ROS, MDA, Fe2+, and miR-335-5p were increased, while GSH and GPX4 levels were decreased after loss of ADAR1, compared to the control group. The opposite effects were observed after ADAR1 overexpression in the cells. Further, we demonstrated that ADAR1-controlled miR-335-5p targeted Sp1 transcription factor of GPX4, a known ferroptosis molecular marker, leading to inhibition of ferroptosis by ADAR1 in breast cancer cells. Moreover, RNA editing activity of ADAR1 is not essential for inducing ferroptosis. Collectively, loss of ADAR1 induces ferroptosis in breast cancer cells by regulating miR-335-5p/Sp1/GPX4 pathway. The findings may provide insights into the mechanism by which ADAR1 promotes breast cancer progression via inhibiting ferroptosis.


Assuntos
Adenosina Desaminase , Neoplasias da Mama , Ferroptose , Proteínas de Ligação a RNA , Ferroptose/genética , Humanos , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Feminino , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Linhagem Celular Tumoral , Proliferação de Células , Células MCF-7 , Espécies Reativas de Oxigênio/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Regulação Neoplásica da Expressão Gênica
20.
J Anal Methods Chem ; 2024: 9962574, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38817340

RESUMO

The current quality control method for Turkish gall (TG) is limited to assessing total tannin or gallic acid (GA), which offers a basic level of quality control but does not fully capture the true quality of TG. Therefore, it is essential to establish a comprehensive method that utilizes multiple indicators to assess the intrinsic quality of TG. This research utilized UPLC-Q-TOF-MS/MS technology to qualitatively analyze the chemical composition of TG. Subsequently, the potential main active ingredients, targets, and pathways of TG in treating recurrent aphthous ulcers (RAU) were explored and analyzed using network pharmacology technology. Quantitative analysis of multicomponents by single marker (QAMS) was then employed to quantify the primary pharmacodynamic components in TG. Finally, chemometrics analysis was utilized to interpret the measured results and identify the markers of scavenging quality. The study identified 36 chemical components in TG, highlighting ellagic acid (EA), GA, and so on as key components in treating RAU. A method for simultaneously determining GA, EA, 1,2,3,6-tetra-O-galloyl-ß-D-glucose (TEGG) and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (PEGG) in TG was established. Statistical analysis revealed significant differences in the content of these 4 components across 14 batches of TG, with GA and PEGG identified as the primary contributors to the variations. This study determined a quality index for TG, providing a reference for quality evaluation and introducing a cost-effective and efficient quality control method. Furthermore, it addressed the challenge of developing new Chinese medicine by overcoming the lack of reference substances.

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