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1.
Sci Total Environ ; 954: 176350, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39304142

RESUMO

Polylactic acid (PLA), as a biodegradable plastic, exhibits high sensitivity to ultraviolet (UV) radiation, yet the mechanisms and environmental risks of its photoaging remain unclear. This study uses quantum chemical calculations (DFT and TD-DFT) and kinetic simulations to explore the direct and indirect photoaging of PLA. Direct photoaging indicates that the highest oscillator intensity absorption peaks occurred at 172 and 246 nm, corresponding to the 13th singlet (S13) and 48th triplet (T48) states, thereby initiating the Norrish I and Norrish II mechanisms. The innovative "electron-hole" technology effectively clarifies the variations in photoaging mechanisms under different wavelengths. Indirect photoaging involves multiple reactive oxygen species (ROS) like •OH, 1O2, •O2-, and •HO2. The study confirms the anhydride production hypothesis and proposes two novel •OH-induced mechanisms: carbonyl carbon addition and branched methyl hydrogen dehydrogenation. Both mechanisms are thermodynamically advantageous, but their products pose potential environmental risks. ROS species and concentrations impact both PLA's photoaging mechanisms and environmental persistence. Low •OH concentration in northeast China, especially in winter, suggests a significant photoaging risk. This study offers pioneering insights into photoaging mechanisms and emphasizes the pivotal role of ROS, offering recommendations for managing PLA environmental impacts and fates in China.

2.
Cancer Lett ; 595: 217006, 2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-38823763

RESUMO

Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid ß oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver cancer mTOR-addicted and sensitivity to mTOR inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. CONCLUSION: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.


Assuntos
Carcinoma Hepatocelular , Carnitina O-Palmitoiltransferase , Neoplasias Hepáticas , Mutação , Proteína Supressora de Tumor p53 , Humanos , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Metabolismo dos Lipídeos/genética , Transdução de Sinais , Acetilcoenzima A/metabolismo , Regulação Neoplásica da Expressão Gênica , Masculino
3.
J Immunother Cancer ; 12(6)2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38908854

RESUMO

BACKGROUND AND AIMS: The immunosuppressive tumor microenvironment (TME) plays an essential role in cancer progression and immunotherapy response. Despite the considerable advancements in cancer immunotherapy, the limited response to immune checkpoint blockade (ICB) therapies in patients with hepatocellular carcinoma (HCC) remains a major challenge for its clinical implications. Here, we investigated the molecular basis of the protein O-fucosyltransferase 1 (POFUT1) that drives HCC immune evasion and explored a potential therapeutic strategy for enhancing ICB efficacy. METHODS: De novo MYC/Trp53-/- liver tumor and the xenograft tumor models were used to evaluate the function of POFUT1 in immune evasion. Biochemical assays were performed to elucidate the underlying mechanism of POFUT1-mediated immune evasion. RESULTS: We identified POFUT1 as a crucial promoter of immune evasion in liver cancer. Notably, POFUT1 promoted HCC progression and inhibited T-cell infiltration in the xenograft tumor and de novo MYC/Trp53-/- mouse liver tumor models. Mechanistically, we demonstrated that POFUT1 stabilized programmed death ligand 1 (PD-L1) protein by preventing tripartite motif containing 21-mediated PD-L1 ubiquitination and degradation independently of its protein-O-fucosyltransferase activity. In addition, we further demonstrated that PD-L1 was required for the tumor-promoting and immune evasion effects of POFUT1 in HCC. Importantly, inhibition of POFUT1 could synergize with anti-programmed death receptor 1 therapy by remodeling TME in the xenograft tumor mouse model. Clinically, POFUT1 high expression displayed a lower response rate and worse clinical outcome to ICB therapies. CONCLUSIONS: Our findings demonstrate that POFUT1 functions as a novel regulator of tumor immune evasion and inhibition of POFUT1 may be a potential therapeutic strategy to enhance the efficacy of immune therapy in HCC.


Assuntos
Antígeno B7-H1 , Fucosiltransferases , Imunoterapia , Neoplasias Hepáticas , Fucosiltransferases/metabolismo , Fucosiltransferases/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/tratamento farmacológico , Humanos , Camundongos , Animais , Antígeno B7-H1/metabolismo , Imunoterapia/métodos , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Evasão Tumoral , Microambiente Tumoral , Evasão da Resposta Imune , Linhagem Celular Tumoral
4.
Food Chem ; 450: 139287, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-38640541

RESUMO

The effects of ultrasonic pretreatment on the drying characteristics and microstructure of strawberry slices were investigated. The rehydration characteristics of freeze-dried products, which were pre-frozen at -20 °C and - 80 °C were explored, with a focus on water mobility and distribution. The ultrasonic pretreatment significantly increased the water mobility of the strawberry slices, resulting in a reduction in their water content. However, the application of ultrasound significantly decreased the rehydration speed, indicating a lower moisture absorption capacity in the pretreated sample. The micrographs revealed that the structure of the tissue was more uniform after ultrasonic treatment, and water loss was accelerated. In addition, the contact angle measurements showed that the samples were more hydrophobic after ultrasonic treatment, and the eutectic temperature and fold point of the samples increased. Therefore, this study found that ultrasonic-assisted freeze vacuum drying technology effectively reduces hygroscopicity, improves product storage, and represents a potential method for dried production.


Assuntos
Fragaria , Liofilização , Frutas , Água , Fragaria/química , Água/química , Frutas/química , Ultrassom , Dessecação/métodos , Dessecação/instrumentação , Interações Hidrofóbicas e Hidrofílicas
5.
Neural Netw ; 174: 106222, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38442490

RESUMO

Recent years have witnessed increasing interest in the few-shot knowledge graph completion due to its potential to augment the coverage of few-shot relations in knowledge graphs. Existing methods often use the one-hop neighbors of the entity to enhance its embedding and match the query instance and support set at the instance level. However, such methods cannot handle inter-neighbor interaction, local entity matching and the varying significance of feature dimensions. To bridge this gap, we propose the Multi-Level Attention-enhanced matching Network (MuLAN) for few-shot knowledge graph completion. In MuLAN, a multi-head self-attention neighbor encoder is designed to capture the inter-neighbor interaction and learn the entity embeddings. Then, entity-level attention and instance-level attention are responsible for matching the query instance and support set from the local and global perspectives, respectively, while feature-level attention is utilized to calculate the weights of the feature dimensions. Furthermore, we design a consistency constraint to ensure the support instance embeddings are close to each other. Extensive experiments based on two well-known datasets (i.e., NELL-One and Wiki-One) demonstrate significant advantages of MuLAN over 11 state-of-the-art competitors. Compared to the best-performing baseline, MuLAN achieves 14.5% higher MRR and 13.3% higher Hits@K on average.


Assuntos
Conhecimento , Reconhecimento Automatizado de Padrão , Aprendizagem
6.
Environ Res ; 250: 118505, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38387497

RESUMO

In arid regions, montane lakes are valuable water sources and play important ecological roles. However, recent human-induced inputs of organic pollutants are threatening lake ecology in such regions and becoming a matter of great concern. To investigate pollutant histories and sources, we measured polycyclic aromatic hydrocarbons (PAHs) and n-alkanes in a dated sediment core that spans the last ∼350 years, from montane Lake Issyk-Kul (Kyrgyzstan, Central Asia). Results showed that organic pollutants were delivered to Lake Issyk-Kul in four stages and that their concentrations increased from Stage I (∼1670-1800 CE) to Stage IV (∼2000-2010 CE). Furthermore, we tracked the sources of sedimented PAHs using their ratios combined with n-alkanes data. Ratios of PAHs Ant/(Ant + Phe), Flt/(Flt + Pyr) and Bap/BghiP indicated that inputs during Stage II (∼1800-1970 CE) and Stage III (∼1970-2000 CE) came mainly from high-temperature combustion of coal and vehicle emissions. PAHs in Stage I and Stage IV, however, were mainly derived from low-temperature combustion and petrogenic sources. Diagnostic PAH ratios, combined with the natural n-alkane ratio (NAR<0) and unresolved complex mixtures (UCM), showed that the sources of PAHs in Stage I were mainly from erosion of bedrock and partly influenced by forest wildfires, different from the source during Stage IV, which was mainly from refined petroleum caused by accidental spills. Our assessment of the contamination history of the lake indicates that toxicity risk to the waterbody from sediment PAHs is low, but recent discharges arising from traffic deserve attention.


Assuntos
Monitoramento Ambiental , Sedimentos Geológicos , Lagos , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , Lagos/química , Sedimentos Geológicos/análise , Sedimentos Geológicos/química , Poluentes Químicos da Água/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Quirguistão , Alcanos/análise
7.
Behav Sci (Basel) ; 14(2)2024 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-38392482

RESUMO

School bullying is widespread in countries around the world and has a continuous negative impact on the physical and mental health of students. However, few studies have explored the influence mechanism of a competitive school climate on school bullying among Chinese secondary vocational school students. This study aims to explore the relationship between a competitive school climate and bullying in secondary vocational schools in the Chinese context, as well as the mediating role of school belonging and the moderating role of gender. Logit regression analysis and a moderated mediation model were used to analyze 1964 secondary vocational students from China based on PISA 2018 data from Beijing, Shanghai, Zhejiang, and Jiangsu, China. (1) The detection rate of school bullying in secondary vocational schools in China is 17.8%, lower than the world average. (2) A competitive school climate is significantly and positively correlated with secondary vocational school students' exposure to school bullying. (3) A moderated mediation model suggests that school belonging is an important mechanism by which a competitive school climate influences the occurrence of school bullying, whereas gender moderates the direct effect of a competitive school climate and the indirect effect of school belonging, which mitigates the negative effects of a competitive school climate to some extent. The research results show that creating a healthy competitive climate in schools, cultivating students' sense of belonging, and facing up to gender differences are helpful to prevent school bullying in secondary vocational schools.

8.
Sci Total Environ ; 918: 170776, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38336050

RESUMO

Biomarkers n-alkanes and pertinent indices in lake sediments are frequently used to infer past changes in climate and environmental conditions in and around lakes. Interpretation of n-alkane records can be confounded by a lack of understanding of the multiple factors that control n-alkanes in sediments. Here, we studied n-alkanes in sediment cores from two alpine lakes, Lakes Son-Kul and Issyk-Kul, and from terminal Lake Balkhash, in arid Central Asia to identify natural and human-mediated influences on sediment n-alkane profiles. Altitudinal differences in climate, as well as in lake trophic status, proved to be important drivers of n-alkane compositional differences in the lake sediments. In the alpine lakes, the distribution of n-alkanes was biased toward long-chain components (n-C29, n-C31, and n-C33), and showed higher carbon preference index (CPIH) values, which come from dense terrestrial plant communities, promoted by greater precipitation. In contrast, n-alkanes in the core from the terminal lake displayed higher proportions of short-chain n-alkanes (n-C17, n-C19, and n-C21) because a greater proportion of the organic matter (OM) input to the sediments was derived from algae, a consequence of higher temperatures and trophic status. In recent decades, increasing nutrient inputs from human activities have caused greater accumulation of short-chain n-alkanes in sediments of alpine, oligotrophic Lake Issyk-Kul. In Lake Balkhash, n-C20 and n-C22 alkanes are exceptionally abundant, suggesting large contributions from microbial reworking of terrestrial OM. In all three study lakes, ∑(n-C29-n-C33) was elevated in sediments that correspond to periods of intense agricultural exploitation. Moreover, expansion of agriculture from low to high altitudes resulted in both synchronous and asynchronous peaks in ∑ (n-C29-n-C33) in the studied cores, suggesting the n-alkanes faithfully record the history of agricultural expansion. These findings provide insights into applications of n-alkane proxies and the response of the lake system to climate and anthropogenic impacts.

9.
Ecotoxicol Environ Saf ; 271: 115999, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38262096

RESUMO

The hypothesis of paternal origins of health and disease (POHaD) indicates that paternal exposure to adverse environment could alter the epigenetic modification in germ line, increasing the disease susceptibility in offspring or even in subsequent generations. p,p'-Dichlorodiphenyldichloroethylene (p,p'-DDE) is an anti-androgenic chemical and male reproductive toxicant. Gestational p,p'-DDE exposure could impair reproductive development and fertility in male offspring. However, the effect of paternal p,p'-DDE exposure on fertility in male offspring remains uncovered. From postnatal day (PND) 35 to 119, male rats (F0) were given 10 mg/body weight (b.w.) p,p'-DDE or corn oil by gavage. Male rats were then mated with the control females to generate male offspring. On PND35, the male offspring were divided into 4 groups according whether to be given the high-fat diet (HF): corn oil treatment with control diet (C-C), p,p'-DDE treatment with control diet (DDE-C), corn oil treatment with high-fat diet (C-HF) or p,p'-DDE treatment with high-fat diet (DDE-HF) for 35 days. Our results indicated that paternal p,p'-DDE exposure did not affect the male fertility of male offspring directly, but decreased sperm quality and induced testicular apoptosis after the high-fat diet treatment. Further analysis demonstrated that paternal exposure to p,p'-DDE and pre-pubertal high-fat diet decreased sperm Igf2 DMR2 methylation and gene expression in male offspring. Hence, paternal exposure to p,p'-DDE and pre-pubertal high-fat diet increases the susceptibility to male fertility impairment and sperm Igf2 DMR2 hypo-methylation in male offspring, posing a significant implication in the disease etiology.


Assuntos
Diclorodifenil Dicloroetileno , Exposição Paterna , Humanos , Feminino , Masculino , Ratos , Animais , Exposição Paterna/efeitos adversos , Diclorodifenil Dicloroetileno/toxicidade , Dieta Hiperlipídica/efeitos adversos , Óleo de Milho/farmacologia , Sêmen , Espermatozoides , Fertilidade , Metilação
10.
Phys Chem Chem Phys ; 25(44): 30670-30678, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37933752

RESUMO

Previous research is predominantly in consensus on the reaction mechanism between formaldehyde (HCHO) and oxygen (O2) over catalysts. However, water vapor (H2O) always remains present during the reaction, and the intrinsic role of H2O in the oxidation of HCHO still needs to be fully understood. In this study, a single-atom catalyst, Al-doped C2N substrate, Al1/C2N, can be adopted as an example to investigate the relationship and interaction among O2, H2O, and HCHO. Density functional theory (DFT) calculations and microkinetic simulations were carried out to interpret the enhancement mechanism of H2O on HCHO oxidation over Al1/C2N. The outcome demonstrates that H2O directly breaks down a surface hydroxyl group on Al1/C2N, considerably lowering the energy required to form crucial intermediates, thus promoting oxidation. Without H2O, Al1/C2N cannot effectively oxidize HCHO at ambient temperature. During oxidation, H2O takes the major catalytic responsibility, delaying the entrance of O2 into the reaction, which is not only the product but also the crucial reactant to initiate catalysis, thereby sustaining the catalytic cycle. Moreover, this study predicts the catalytic behavior at various temperatures and presents feasible recommendations for regulating the reaction rates. The oxidation mechanism of HCHO is explained at the molecular level in this study, emphasizing the intrinsic role of water on Al1/C2N, which fills in the relevant studies for HCHO oxidation on two-dimensional carbon materials.

11.
Front Endocrinol (Lausanne) ; 14: 1267612, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37908753

RESUMO

Purpose: Thyroid hormones sensitivity is a newly proposed clinical entity closely related with metabolic health. Prior studies have reported the cross-sectional relationship between thyroid hormones sensitivity and diabetes; however, the longitudinal association is unclear to date. We aimed to explore the relationship between impaired thyroid hormone sensitivity at baseline and diabetes onset using a cohort design. Methods: This study enrolled 7283 euthyroid participants at the first visit between 2008 and 2009, and then annually followed until diabetes onset or 2019. Thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) were measured to calculate thyroid hormone sensitivity by thyroid feedback quantile-based index (TFQI), Chinese-referenced parametric thyroid feedback quantile-based index (PTFQI), thyrotropin index (TSHI), thyrotroph thyroxine resistance index (TT4RI) and FT3/FT4 ratio. Cox proportional hazard model and cross-lagged panel analysis were used. Results: The mean baseline age was 44.2 ± 11.9 years, including 4170 (57.3%) male. During a median follow-up of 5.2 years, 359 cases developed diabetes. There was no significant association between thyroid hormones sensitivity indices and diabetes onset, and adjusted hazard ratios per unit (95% CIs) were 0.89 (0.65-1.23) for TFQI, 0.91 (0.57-1.45) for PTFQI, 0.95 (0.70-1.29) for TSHI, 0.98 (0.70-1.01) for TT4RI and 2.12 (0.17-5.78) for FT3/FT4 ratio. Cross-lagged analysis supported the temporal association from fasting glucose to impaired thyroid hormones sensitivity indices. Conclusions: Our findings could not demonstrate that thyroid hormones sensitivity status is a predictor of diabetes onset in the euthyroid population. Elevated fasting glucose (above 7.0 mmol/L) appeared to precede impaired sensitivity indices of thyroid hormones.


Assuntos
Diabetes Mellitus , Glândula Tireoide , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Feminino , Glândula Tireoide/metabolismo , Tiroxina/metabolismo , Hormônios Tireóideos/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Tireotropina/metabolismo , Glucose/metabolismo
12.
Clin Transl Med ; 13(10): e1452, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37846441

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of death from cancer and has a very poor prognosis with few effective therapeutic options. Despite the approval of lenvatinib for the treatment of patients suffering from advanced HCC, only a small number of patients can benefit from this targeted therapy. METHODS: Diethylnitrosamine (DEN)-CCL4 mouse liver tumour and the xenograft tumour models were used to evaluate the function of KDM6A in HCC progression. The xenograft tumour model and HCC cell lines were used to evaluate the role of KDM6A in HCC drug sensitivity to lenvatinib. RNA-seq and ChIP assays were conducted for mechanical investigation. RESULTS: We revealed that KDM6A exhibited a significant upregulation in HCC tissues and was associated with an unfavourable prognosis. We further demonstrated that KDM6A knockdown remarkably suppressed HCC cell proliferation and migration in vitro. Moreover, hepatic Kdm6a loss also inhibited liver tumourigenesis in a mouse liver tumour model. Mechanistically, KDM6A loss downregulated the FGFR4 expression to suppress the PI3K-AKT-mTOR signalling pathway, leading to a glucose and lipid metabolism re-programming in HCC. KDM6A and FGFR4 levels were positively correlated in HCC specimens and mouse liver tumour tissues. Notably, KDM6A knockdown significantly inhibited the efficacy of lenvatinib therapy in HCC cells in vitro and in vivo. CONCLUSIONS: Our findings revealed that KDM6A promoted HCC progression by activating FGFR4 expression and may be an essential molecule for influencing the efficacy of lenvatinib in HCC therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinases , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética
13.
Nat Commun ; 14(1): 6366, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37821440

RESUMO

The direct and selective coupling of benzenes with aliphatic hydrocarbons is a promising strategy for C(sp2)-C(sp3) bond formation using readily available starting materials, yet it remains a significant challenge. In this study, we have developed a simplified photochemical system that incorporates catalytic amounts of iron(III) halides as multifunctional reagents and air as a green oxidant to address this synthetic problem. Under mild conditions, the reaction between a strong C(sp2)-H bond and a robust C(sp3)-H bond has been achieved, affording a broad range of cross-coupling products with high yields and commendable chemo-, site-selectivity. The iron halide acts as a multifunctional reagent that responds to visible light, initiates C-centered radicals, induces single-electron oxidation to carbocations, and participates in a subsequent Friedel-Crafts-type process. The gradual release of radical species and carbocation intermediates appears to be critical for achieving desirable reactivity and selectivity. This eco-friendly, cost-efficient approach offers access to various building blocks from abundant hydrocarbon feedstocks, and demonstrates the potential of iron halides in sustainable synthesis.

14.
Chemistry ; 29(72): e202302542, 2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-37800464

RESUMO

Direct C-H methylation is a highly valuable approach for introducing methyl groups into organic molecules, particularly in pharmaceutical chemistry. Among the various methodologies available, photo-induced methylation stands out as an exceptional choice due to its mild reaction conditions, energy efficiency, and compatibility with functional groups. This article offers a comprehensive review of photochemical strategies employed for the direct and selective methylation of C(sp3 )-H, C(sp2 )-H, and C(sp)-H bonds in various organic molecules. The discussed methodologies encompass transition-metal-based photocatalysis, organophotocatalysis, as well as other metal-free approaches, including electron donor-acceptor (EDA)-enabled transformations. Importantly, a wide range of easily accessible agents such as tert-butyl peroxide, methanol, DMSO, methyl tert-butyl ether, TsOMe, N-(acetoxy)phthalimide, acetic acid, methyl halides, and even methane can serve as effective methylating reagents for modifying diverse targets. These advancements in photochemical C-H methylation are anticipated to drive further progress in the fields of organic synthesis, photocatalysis, and pharmaceutical development, opening up exciting avenues for creating novel organic molecules and discovering new drug compounds.

15.
Hepatology ; 2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37556368

RESUMO

BACKGROUND AND AIMS: Epigenetic plasticity is a major challenge in cancer-targeted therapy. However, the molecular basis governing this process has not yet been clearly defined. Despite the considerable success of poly(ADP-ribose) polymerase inhibitors (PARPi) in cancer therapy, the limited response to PARPi, especially in HCC, has been a bottleneck in its clinical implications. Herein, we investigated the molecular basis of the histone methyltransferase KMT5C (lysine methyltransferase 5C) that governs PARPi sensitivity and explored a potential therapeutic strategy for enhancing PARPi efficacy. APPROACH AND RESULTS: We identified KMT5C, a trimethyltransferase of H4K20, as a targetable epigenetic factor that promoted liver tumor growth in mouse de novo MYC/Trp53-/- and xenograft liver tumor models. Notably, induction of KMT5C by environmental stress was crucial for DNA repair and HCC cell survival. Mechanistically, KMT5C interacted with the pivotal component of homologous recombination repair, RAD51, and promoted RAD51/RAD54 complex formation, which was essential for the activation of dsDNA breaks repair. This effect depended on the methyltransferase activity of KMT5C. We further demonstrated that the function of KMT5C in promoting HCC progression was dependent on RAD51. Importantly, either a pharmacological inhibitor (A196) or genetic inhibition of KMT5C sensitized liver cancer cells to PARPi. CONCLUSIONS: KMT5C played a vital role in promoting liver cancer progression by activating the DNA repair response. Our results revealed a novel therapeutic approach using the KMT5C inhibitor A196, concurrent with olaparib, as a potential HCC therapy.

16.
J Cell Physiol ; 238(8): 1876-1890, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37269543

RESUMO

Epithelial keratinocyte proliferation is an essential element of wound repair, and chronic wound conditions, such as diabetic foot, are characterized by aberrant re-epithelialization. In this study, we examined the functional role of retinoic acid inducible-gene I (RIG-I), a key regulator of epidermal keratinocyte proliferation, in promoting TIMP-1 expression. We found that RIG-I is overexpressed in keratinocytes of skin injury and underexpressed in skin wound sites of diabetic foot and streptozotocin-induced diabetic mice. Moreover, mice lacking RIG-I developed an aggravated phenotype when subjected to skin injury. Mechanistically, RIG-I promoted keratinocyte proliferation and wound repair by inducing TIMP-1 via the NF-κB signaling pathway. Indeed, recombinant TIMP-1 directly accelerated HaCaT cell proliferation in vitro and promoted wound healing in Ddx58-/- and diabetic mice in vivo. In summary, we demonstrated that RIG-I is a crucial factor that mediates epidermal keratinocyte proliferation and may be a potential biomarker for skin injury severity, thus making it an attractive locally therapeutic target for the treatment of chronic wounds such as diabetic foot.


Assuntos
Diabetes Mellitus Experimental , Pé Diabético , Animais , Camundongos , Movimento Celular , Proliferação de Células , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Pé Diabético/genética , Pé Diabético/metabolismo , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Pele/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Cicatrização/genética
17.
Neural Netw ; 164: 323-334, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37163848

RESUMO

Few-shot Knowledge Graph Completion (FKGC) has recently attracted significant research interest due to its ability to expand few-shot relation coverage in Knowledge Graphs. Prevailing FKGC approaches focus on exploiting the one-hop neighbor information of entities to enhance few-shot relation embedding. However, these methods select one-hop neighbors randomly and neglect the rich multi-aspect information of entities. Although some methods have attempted to leverage Long Short-Term Memory (LSTM) to learn few-shot relation embedding, they are sensitive to the input order. To address these limitations, we propose the Capsule Neural Tensor Networks with Multi-Aspect Information approach (short for InforMix-FKGC). InforMix-FKGC employs a one-hop neighbor selection strategy based on how valuable they are and encodes multi-aspect information of entities, including one-hop neighbors, attributes and literal description. Then, a capsule network is responsible for integrating the support set and deriving few-shot relation embedding. Moreover, a neural tensor network is used to match the query set with the support set. In this way, InforMix-FKGC can learn few-shot relation embedding more precisely so as to enhance the accuracy of FKGC. Extensive experiments on the NELL-One and Wiki-One datasets demonstrate that InforMix-FKGC significantly outperforms ten state-of-the-art methods in terms of Mean Reciprocal Rank and Hits@K.


Assuntos
Conhecimento , Reconhecimento Automatizado de Padrão , Aprendizagem , Memória de Longo Prazo , Redes Neurais de Computação
18.
New Phytol ; 238(6): 2345-2362, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36960539

RESUMO

Terrestrial biosphere models (TBMs) include the representation of vertical gradients in leaf traits associated with modeling photosynthesis, respiration, and stomatal conductance. However, model assumptions associated with these gradients have not been tested in complex tropical forest canopies. We compared TBM representation of the vertical gradients of key leaf traits with measurements made in a tropical forest in Panama and then quantified the impact of the observed gradients on simulated canopy-scale CO2 and water fluxes. Comparison between observed and TBM trait gradients showed divergence that impacted canopy-scale simulations of water vapor and CO2 exchange. Notably, the ratio between the dark respiration rate and the maximum carboxylation rate was lower near the ground than at the top-of-canopy, leaf-level water-use efficiency was markedly higher at the top-of-canopy, and the decrease in maximum carboxylation rate from the top-of-canopy to the ground was less than TBM assumptions. The representation of the gradients of leaf traits in TBMs is typically derived from measurements made within-individual plants, or, for some traits, assumed constant due to a lack of experimental data. Our work shows that these assumptions are not representative of the trait gradients observed in species-rich, complex tropical forests.


Assuntos
Dióxido de Carbono , Árvores , Florestas , Fotossíntese , Folhas de Planta
19.
Molecules ; 28(3)2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36770809

RESUMO

Neuroblastoma has obvious heterogeneity. It is one of the few undifferentiated malignant tumors that can spontaneously degenerate into completely benign tumors. However, for its high-risk type, even with various intensive treatment options, the prognosis is still unsatisfactory. At the same time, a large number of research data show that the abnormal amplification and high-level expression of the MYCN gene are positively correlated with the malignant progression, poor prognosis, and mortality of neuroblastoma. In this context, this article explores the role of the N-Myc, MYCN gene expression product on its target genes related to the cell cycle and reveals its regulatory network in promoting tumor proliferation and malignant progression. We hope it can provide ideas and direction for the research and development of drugs targeting N-Myc and its downstream target genes.


Assuntos
Neuroblastoma , Proteínas Nucleares , Humanos , Proteínas Nucleares/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Genes myc , Ciclo Celular/genética , Neuroblastoma/patologia , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral
20.
Crit Rev Food Sci Nutr ; : 1-26, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36651301

RESUMO

Food spoilage caused by foodborne microorganisms will not only cause significant economic losses, but also the toxins produced by some microorganisms will also pose a serious threat to human health. Essential oil (EOs) has significant antimicrobial activity, but its application in the field of food preservation is limited because of its volatile, insoluble in water and sensitive to light and heat. Therefore, in order to solve these problems effectively, this paper first analyzed the antibacterial effect of EOs as an antimicrobial agent on foodborne bacteria and its mechanism. Then, the application strategies of EOs as a sustained-release antimicrobial agent in food preservation were reviewed. On this basis, the release mechanism and application cases of EOs in different antibacterial composites were analyzed. The purpose of this paper is to provide technical support and solutions for the preparation of new antibacterial packaging materials based on plant active components to ensure food safety and reduce food waste.

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