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The diagnosis of Parkinson's Disease (PD) presents ongoing challenges. Advances in imaging techniques like 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) have highlighted metabolic alterations in PD, yet the dynamic network interactions within the metabolic connectome remain elusive. To this end, we examined a dataset comprising 49 PD patients and 49 healthy controls. By employing a personalized metabolic connectome approach, we assessed both within- and between-network connectivities using Standard Uptake Value (SUV) and Jensen-Shannon Divergence Similarity Estimation (JSSE). A random forest algorithm was utilized to pinpoint key neuroimaging features differentiating PD from healthy states. Specifically, the results revealed heightened internetwork connectivity in PD, specifically within the somatomotor (SMN) and frontoparietal (FPN) networks, persisting after multiple comparison corrections (P < 0.05, Bonferroni adjusted for 10% and 20% sparsity). This altered connectivity effectively distinguished PD patients from healthy individuals. Notably, this study utilizes 18F-FDG PET imaging to map individual metabolic networks, revealing enhanced connectivity in the SMN and FPN among PD patients. This enhanced connectivity may serve as a promising imaging biomarker, offering a valuable asset for early PD detection.
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Encéfalo , Conectoma , Fluordesoxiglucose F18 , Doença de Parkinson , Tomografia por Emissão de Pósitrons , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Feminino , Masculino , Tomografia por Emissão de Pósitrons/métodos , Pessoa de Meia-Idade , Idoso , Conectoma/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Biomarcadores , Redes e Vias Metabólicas/fisiologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Imageamento por Ressonância Magnética/métodos , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologiaRESUMO
Bacteria possess the ability to enter a growth-arrested state known as persistence in order to survive antibiotic exposure. Clinically, persisters are regarded as the main causative agents for chronic and recurrent infectious diseases. To combat this antibiotic-tolerant population, a better understanding of the molecular physiology of persisters is required. In this study, we collected samples at different stages of the biphasic kill curve to reveal the dynamics of the cellular molecular changes that occur in the process of persister formation. After exposure to antibiotics with different modes of action, namely, vancomycin and enrofloxacin, similar persister levels were obtained. Both shared and distinct stress responses were enriched for the respective persister populations. However, the dynamics of the presence of proteins linked to the persister phenotype throughout the biphasic kill curve and the molecular profiles in a stable persistent population did show large differences, depending on the antibiotic used. This suggests that persisters at the molecular level are highly stress specific, emphasizing the importance of characterizing persisters generated under different stress conditions. Additionally, although generated persisters exhibited cross-tolerance toward tested antibiotics, combined therapies were demonstrated to be a promising approach to reduce persister levels. In conclusion, this investigation sheds light on the stress-specific nature of persisters, highlighting the necessity of tailored treatment approaches and the potential of combined therapy.
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Infecções Estafilocócicas , Staphylococcus aureus , Humanos , Antibacterianos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Bactérias , FenótipoRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by inflammation of the synovial tissue and joint bone destruction, often leading to significant disability. The main pathological manifestation of joint deformity in RA patients is bone destruction, which occurs due to the differentiation and proliferation of osteoclasts. The transcription factor nuclear factor-activated T cell 1 (NFATc1) plays a crucial role in this process. The regulation of NFATc1 in osteoclast differentiation is influenced by three main factors. Firstly, NFATc1 is activated through the upstream nuclear factor kappa-B ligand (RANKL)/RANK signaling pathway. Secondly, the Ca2+-related co-stimulatory signaling pathway amplifies NFATc1 activity. Finally, negative regulation of NFATc1 occurs through the action of cytokines such as B-cell Lymphoma 6 (Bcl-6), interferon regulatory factor 8 (IRF8), MAF basic leucine zipper transcription factor B (MafB), and LIM homeobox 2 (Lhx2). These three phases collectively govern NFATc1 transcription and subsequently affect the expression of downstream target genes including TRAF6 and NF-κB. Ultimately, this intricate regulatory network mediates osteoclast differentiation, fusion, and the degradation of both organic and inorganic components of the bone matrix. This review provides a comprehensive summary of recent advances in understanding the mechanism of NFATc1 in the context of RA-related bone destruction and discusses potential therapeutic agents that target NFATc1, with the aim of offering valuable insights for future research in the field of RA. To assess their potential as therapeutic agents for RA, we conducted a drug-like analysis of potential drugs with precise structures.
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Artrite Reumatoide , Fatores de Transcrição NFATC , Humanos , Artrite Reumatoide/genética , Diferenciação Celular/fisiologia , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Linfócitos T/metabolismoRESUMO
Manganese-based lithium-rich layered oxides (Mn-LLOs) are promising candidate cathode materials for lithium-ion batteries, however, the severe voltage decay during cycling is the most concern for their practical applications. Herein, an Mn-based composite nanostructure constructed Li2MnO3 (LMO@Li2MnO3) is developed via an ultrathin amorphous functional oxide LixMnOy coating at the grain surface. Due to the thin and universal LMO amorphous surface layer etched from the lithiation process by the high-concentration alkaline solution, the structural and interfacial stability of Li2MnO3 are enhanced apparently, showing the significantly improved voltage maintenance, cycle stability, and energy density. In particular, the LMO@Li2MnO3 cathode exhibits zero voltage decay over 200 cycles. Combining with ex situ spectroscopic and microscopic techniques, the Mn2+/4+ coexisted behavior of the amorphous LMO is revealed, which enables the stable electrochemistry of Li2MnO3. This work provides new possible routes for suppressing the voltage decay of Mn-LLOs by modifying with the composite functional unit construction.
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Photodynamic therapy (PDT) is long-standing suffered from elevated tumor interstitial fluid pressure (TIFP) and prevalent hypoxic microenvironment within the solid malignancies. Herein, sound-activated flexocatalysis is developed to overcome the dilemma of PDT through both enhancing tumor penetration of photosensitizers by reducing TIFP and establishing an oxygen-rich microenvironment. In detail, a Schottky junction is constructed by flexocatalyst MoSe2 nanoflowers and Pt. Subsequently, the Schottky junction is loaded with the photosensitizer indocyanine green (ICG) and encapsulated within tumor cytomembrane to constitute a bionic-flexocatalytic nanomedicine (MPI@M). After targeting the tumor, MPI@M orchestrates flexocatalytic water splitting in tumor interstitial fluid under acoustic stimulation to lower TIFP, which boosted the tumor penetration of ICG. Concurrently, the oxygen released from the flexocatalytic water splitting overcomes the limitation of hypoxia against PDT. Furthermore, superfluous singlet oxygen generated by PDT can induce mitochondrial dysfunction for further tumor cell apoptosis. After 60 min of flexocatalysis, both the 30% decrease of TIFP and the relieved tumor hypoxia are observed, significantly promoting the therapeutic effect of PDT. Consequently, MoSe2/Pt junction nanoflowers, with the excellent flexocatalytic performance, hold significant potential for future applications in biocatalytic cancer therapies.
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OBJECTIVE: We conducted a prospective randomized clinical trial to compare the efficacy of low- and high-dose radioiodine for remnant ablation in patients with low-risk differentiated thyroid cancer (DTC) in China. The first-stage results showed equivalence was observed between the two groups. Here, we report recurrence and survival at 3-5 and 6-10 years and biochemical parameters. DESIGN, PATIENTS AND METHODS: Between January 2013 and December 2014, adult patients with DTC were enroled. Patients had undergone total or near-total thyroidectomy, with or without cervical lymph node dissection, with tumour stages T1-T3 with or without lymph node metastasis, but without distant metastasis. Patients were randomly assigned to the low-dose (1850 MBq) or high-dose (3700 MBq) radioiodine group. They were then followed up for 3-5 and 6-10 years. Data on biochemical abnormalities, recurrence and survival were analysed using Kolmogorov-Smirnov and χ2 tests. RESULTS: The data of 228 patients (mean age = 42 years; 70.6% women) were analysed, with 117 patients in the low-dose group and 111 in the high-dose group. There were no significant differences in biochemical abnormalities, recurrence, or survival rates at the 6-10-year follow-up (all p > .05). Nine patients experienced recurrence in the low-dose group (8.7%), while eight patients experienced recurrence in the high-dose group (8.2%). The survival rates were 100% and 98.2% in the low- and high-dose groups, respectively. CONCLUSIONS: The long-term effectiveness and safety of low-dose (1850 MBq) radioiodine are the same as those of high-dose (3700 MBq) radioiodine for thyroid remnant ablation in Chinese patients with low-risk DTC.
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Radioisótopos do Iodo , Neoplasias da Glândula Tireoide , Tireoidectomia , Humanos , Radioisótopos do Iodo/uso terapêutico , Radioisótopos do Iodo/administração & dosagem , Feminino , Adulto , Masculino , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Pessoa de Meia-Idade , Resultado do Tratamento , Estudos Prospectivos , Recidiva Local de Neoplasia , Glândula Tireoide/cirurgia , Glândula Tireoide/efeitos da radiação , Glândula Tireoide/patologia , ChinaRESUMO
BACKGROUND: Tumor-associated macrophages (TAMs) constitute a substantial part of human hepatocellular carcinoma (HCC). The present study was devised to explore TAM diversity and their roles in HCC progression. METHODS: Through the integration of multiple 10 × single-cell transcriptomic data derived from HCC samples and the use of consensus nonnegative matrix factorization (an unsupervised clustering algorithm), TAM molecular subtypes and expression programs were evaluated in detail. The roles played by these TAM subtypes in HCC were further probed through pseudotime, enrichment, and intercellular communication analyses. Lastly, vitro experiments were performed to validate the relationship between CD63, which is an inflammatory TAM expression program marker, and tumor cell lines. RESULTS: We found that the inflammatory expression program in TAMs had a more obvious interaction with HCC cells, and CD63, as a marker gene of the inflammatory expression program, was associated with poor prognosis of HCC patients. Both bulk RNA-seq and vitro experiments confirmed that higher TAM CD63 expression was associated with the growth of HCC cells as well as their epithelial-mesenchymal transition, metastasis, invasion, and the reprogramming of lipid metabolism. CONCLUSIONS: These analyses revealed that the TAM inflammatory expression program in HCC is closely associated with malignant tumor cells, with the hub gene CD63 thus representing an ideal target for therapeutic intervention in this cancer type.
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Carcinoma Hepatocelular , Progressão da Doença , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas , Tetraspanina 30 , Macrófagos Associados a Tumor , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Transição Epitelial-Mesenquimal/genética , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/patologia , Tetraspanina 30/metabolismo , Tetraspanina 30/genética , Metabolismo dos Lipídeos/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Prognóstico , Reprogramação Celular/genéticaRESUMO
This study aimed to assess how Bacillus subtilis and Enterococcus faecium co-fermented feed (FF) affects the antioxidant capacity, muscle fibre types and muscle lipid profiles of finishing pigs. In this study, a total of 144 Duroc × Berkshire × Jiaxing Black finishing pigs were randomly assigned into three groups with four replicates (twelve pigs per replication). The three treatments were a basal diet (0 % FF), basal diet + 5 % FF and basal diet + 10 % FF, respectively. The experiment lasted 38 d after 4 d of acclimation. The study revealed that 10 % FF significantly increased the activity of superoxide dismutase (SOD) and catalase (CAT) compared with 0 % FF group, with mRNA levels of up-regulated antioxidant-related genes (GPX1, SOD1, SOD2 and CAT) in 10 % FF group. 10 % FF also significantly up-regulated the percentage of slow-twitch fibre and the mRNA expression of MyHC I, MyHC IIa and MyHC IIx, and slow MyHC protein expression while reducing MyHC IIb mRNA expression. Lipidomics analysis showed that 5 % FF and 10 % FF altered lipid profiles in longissimus thoracis. 10 % FF particularly led to an increase in the percentage of TAG. The Pearson correlation analysis indicated that certain molecular markers such as phosphatidic acid (PA) (49:4), Hex2Cer (d50:6), cardiolipin (CL) (72:8) and phosphatidylcholine (PC) (33:0e) could be used to indicate the characteristics of muscle fibres and were closely related to meat quality. Together, our findings suggest that 10 % FF improved antioxidant capacity, enhanced slow-twitch fibre percentage and altered muscle lipid profiles in finishing pigs.
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Antioxidantes , Enterococcus faecium , Suínos , Animais , Antioxidantes/metabolismo , Bacillus subtilis/genética , Enterococcus faecium/genética , Fibras Musculares Esqueléticas/metabolismo , RNA Mensageiro/metabolismo , LipídeosRESUMO
BACKGROUND: The Japanese government has instituted border control measures against COVID-19, including entry and exit screening of people arriving from overseas. We sought to evaluate the effectiveness of the exit screening policy in Japan in reducing the risk of importing COVID-19 cases among travelers from Asian and Pacific countries. METHODS: The study period was stratified based on the timing of exit screening: (i) the control period (the pre-exit screening period from 25 October 2020 to 16 January 2021), (ii) the time period with the Alpha variant from 17 January to 10 April 2021, and (iii) the time period with the Delta variant from 2 May to 2 October 2021. Incidence data in the countries of origin were used to adjust for the risk of infection among travelers. The positivity rate of entry screening in Japan was compared among the three different study periods, adjusting for the risk of infection in the country of origin. RESULTS: The adjusted relative risk of positivity was greatly reduced and substantially below the value of 1 during the Alpha variant period compared with the control period. Although the relative risks increased when comparing the Delta variant period against control, the estimate remained below 1, except for among travelers from India and Myanmar. The relative risk reduction was greatest in high-income countries, with estimates of 100% and 96% risk reduction during the Alpha and Delta variant periods, respectively, followed by upper-middle-income countries with estimates of 90% and 76%, respectively. CONCLUSIONS: Even in the presence of the Alpha and Delta variants, exit screening clearly reduced the risk of infection among travelers arriving from Asian and Pacific nations. As the testing relies on the country of origin, the effectiveness varied greatly by the socioeconomic income status and epidemiological situation of those countries. Test standardization and quality assurance may be required in low- and middle-income countries.
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COVID-19 , Viagem , Humanos , COVID-19/epidemiologia , COVID-19/diagnóstico , COVID-19/prevenção & controle , Japão/epidemiologia , Programas de Rastreamento , SARS-CoV-2/isolamento & purificação , Incidência , ÁsiaRESUMO
BACKGROUND: A major epidemic of COVID-19 caused by the Delta variant (B.1.617.2) occurred in India from March to July 2021, resulting in 19 million documented cases. Given the limited healthcare and testing capacities, the actual number of infections is likely to have been greater than reported, and several modelling studies and excess mortality research indicate that this epidemic involved substantial morbidity and mortality. METHODS: To estimate the incidence during this epidemic, we used border entry screening data in Japan to estimate the daily incidence and cumulative incidence of COVID-19 infection in India. Analysing the results of mandatory testing among non-Japanese passengers entering Japan from India, we calculated the prevalence and then backcalculated the incidence in India from February 28 to July 3, 2021. RESULTS: The estimated number of infections ranged from 448 to 576 million people, indicating that 31.8% (95% confidence interval (CI): 26.1, 37.7) - 40.9% (95% CI: 33.5, 48.4) of the population in India had experienced COVID-19 infection from February 28 to July 3, 2021. In addition to obtaining cumulative incidence that was consistent with published estimates, we showed that the actual incidence of COVID-19 infection during the 2021 epidemic in India was approximately 30 times greater than that based on documented cases, giving a crude infection fatality risk of 0.47%. Adjusting for test-negative certificate before departure, the quality control of which was partly questionable, the cumulative incidence can potentially be up to 2.3-2.6 times greater than abovementioned estimates. CONCLUSIONS: Our estimate of approximately 32-41% cumulative infection risk from February 28 to July 3, 2021 is roughly consistent with other published estimates, and they can potentially be greater, given an exit screening before departure. The present study results suggest the potential utility of border entry screening data to backcalculate the incidence in countries with limited surveillance capacity owing to a major surge in infections.
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COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Incidência , Japão/epidemiologia , Aeroportos , Índia/epidemiologiaRESUMO
BACKGROUND: Japan implemented strict border control measures and all incoming passengers were subject to entry screening with reverse transcription-polymerase chain reaction or antigen testing. From late 2020, exit screening within 72 h of departure to Japan also became mandatory. In this study, we evaluated the effectiveness of the exit screening policy in Japan by analyzing airport screening data from October 2020 to April 2022. METHODS: In addition to assessing entry screening data over time of passengers from the United Kingdom, we examined the prevalence of coronavirus disease 2019 (COVID-19) in the United Kingdom based on the Office of National Statistics infection survey. We constructed a statistical model that described entry screening positivity over time using Office of National Statistics prevalence data as the explanatory variable. Ideally, the time-dependent patterns of entry screening and Office of National Statistics prevalence data should resemble each other; however, we found that, sometimes, they were different and regarded the difference to statistically partly reflect the effectiveness of exit screening. RESULTS: The average proportion positive in one month before mandatory exit screening was implemented among Japanese passengers was 0.67% (95% confidence interval [CI]: 0.45, 0.98), whereas the proportion positive decreased to 0.49% (95% CI: 0.21, 1.15) in the first month of exit screening. Adjusting for time-dependent prevalence at the origin, we concluded that exit screening contributed to reducing passenger positivity by 59.3% (95% CI: 19.6, 81.3). The overall positivity values among passengers during the Delta and Omicron variant periods were 3.46 times and 1.46 times that during the pre-Delta variant period, respectively. CONCLUSIONS: We used a simplistic statistical model and empirical data from passengers arriving in Japan from the United Kingdom to support that exit screening helped to reduce the proportion positive by 59%. Although the proportion positive later increased considerably and precluded preventing the introduction of imported cases, submitting a certificate for a negative test result contributed to reducing the positivity among travelers.
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Aeroportos , COVID-19 , Programas de Rastreamento , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , COVID-19/diagnóstico , Japão/epidemiologia , Reino Unido/epidemiologia , SARS-CoV-2/isolamento & purificação , Programas de Rastreamento/métodos , Prevalência , Viagem/estatística & dados numéricos , Teste para COVID-19/métodos , Teste para COVID-19/estatística & dados numéricosRESUMO
AIM: Microvascular invasion (MVI) is an independent risk factor for postoperative recurrence and metastasis in hepatocellular carcinoma (HCC). However, the specific protein expression profiles that differentiate HCC with MVI from those without MVI remain unclear. METHODS: The profiles of proteins in early-stage HCC tissues and normal liver tissues were characterized by quantitative proteomics techniques. Immunohistochemical (IHC) staining was undertaken on tissue microarrays from 80 HCC patients to assess the expression of MSH2 and MSH6. Cell counting, colony formation, migration, and invasion assays were carried out in vitro. RESULTS: We identified 5164 proteins in both HCC tissues and adjacent normal liver tissues. Compared to HCC without MVI, 148 upregulated proteins and 97 downregulated proteins were found in HCC with MVI. Particularly noteworthy was the remarkable upregulation of MSH6/MSH2 among these dysregulated proteins in HCC with MVI. Further validation through bioinformatics prediction and IHC confirmed the elevated expression of MSH6/MSH2, which correlated with aggressive disease characteristics and poor prognosis. Receiver operating characteristic curve analyses revealed a substantial area under the curve of 0.761 (specificity 71.79%, sensitivity 73.17%) for the combined use of MSH6/MSH2. Knockdown of MSH6/MSH2 significantly inhibited HCC cell proliferation and invasion in vitro. CONCLUSIONS: Our study establishes MSH6 or MSH2 as an oncogene that is prominently overexpressed during HCC progression, which provides new targets for HCC with MVI.
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OBJECTIVE: To systematically evaluate the impact of physical exercise intervention on children with acute lymphoblastic leukemia (ALL) during the treatment and rehabilitation consolidation periods. METHOD: Randomized controlled trials (RCTs) were retrieved from PubMed, Scopus, Web of Science, CNKI, and Cochrane databases, with a search time range from database establishment to September 1, 2023. The quality of the included RCTs was evaluated using the Cochrane risk assessment tool, and a systematic evaluation was conducted using RevMan 5.4. The study has been registered with INPLASY (registration number: 202390100). RESULT: A total of 12 RCTs including 423 subjects was included. The meta-analysis results showed that long-term exercise intervention can effectively improve the endurance performance (SMD = 1.37, 95% CI 0.45 to 2.29, p = 0.004), functional mobility (MD = - 1.17, 95% CI - 1.85 to - 0.49, p = 0.0008), cancer-related fatigue (CRF) (MD = - 1.25, 95% CI - 1.69 to - 0.80, p < 0.00001), and quality of life (QOL) (MD = 4.93, 95% CI 1.80 to 8.05, p = 0.002) of ALL children during the treatment and rehabilitation consolidation periods. Its promoting effect on the muscle strength (SMD = 0.53, 95% CI - 0.33 to 1.39, p = 0.23) and bone mineral density (BMD) (SMD = 0.48, 95% CI 0.20 to 0.77, p = 0.05) of the subjects was not significant. Further meta-analysis showed that exercise intervention with a duration of less than 1 year (SMD = 0.91, 95% CI 0.55 to 1.28, p < 0.00001) rather than more than 1 year (SMD = - 0.16, 95% CI - 0.61 to 0.29, p = 0.49) can effectively reduce subject BMD, while in terms of strength, exercise intervention can effectively improve strength during the treatment period (SMD = 0.97, 95% CI 0.40 to 1.54, p = 0.0008) rather than the consolidation period (SMD = - 0.27, 95% CI - 1.08 to 0.53, p = 0.51). CONCLUSION: Long-term regular exercise can effectively improve the endurance, functional mobility, CRF, and QOL of children with ALL in the rehabilitation and treatment consolidation stages. Their strength and BMD may be influenced by the timing of treatment and the intervention cycle, respectively. Considering the limited number of included literature and the instability of some outcome indicators, it is necessary to design more comprehensive and rigorous high-quality RCTs in the future to test the exercise efficacy of ALL children.
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Terapia por Exercício , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Densidade Óssea , Bases de Dados Factuais , Fadiga/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Força Muscular , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The aim of this study was to establish a simple, fast, and sensitive method with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneously determining ibuprofen enantiomers using mouse blood in very small volumes. LC-MS/MS equipped with an electrospray ionization (ESI) source was used in negative ion mode and multiple-reaction monitoring mode. Enantiomer chromatographic separation was carried out on a Lux® 5 µm Cellulose-3 (250 × 4.6 mm, 5 µm) column at a flow rate of 0.6 mL/min. Samples were pretreated by extracting only 5 µL of blood with 40 µL of acetonitrile (containing 1.3% formic acid) so that a concentration-time profile could be completed using a single mouse. 2-(4-Propylphenyl) propanoic acid was used as an internal standard. Standard curves for each enantiomer were linear from 0.04 to 80.00 µg/mL, demonstrating a lower limit of quantitation (LLOQ) than all previously reported methods. This method was completely validated and successfully executed to investigate the pharmacokinetics of ibuprofen enantiomers after intravenous administration of racemic ibuprofen, (S)-(+)-ibuprofen, and (R)-(-)-ibuprofen in Kunming mice, respectively. The results showed that the pharmacokinetic profiles of the (R)-(-)-ibuprofen and (S)-(+)-ibuprofen were significantly different, indicating the unidirectional inversion of R-(-)-ibuprofen to (S)-(+)-ibuprofen.
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Ibuprofeno , Espectrometria de Massas em Tandem , Animais , Ibuprofeno/farmacocinética , Ibuprofeno/sangue , Ibuprofeno/química , Espectrometria de Massas em Tandem/métodos , Estereoisomerismo , Camundongos , Cromatografia Líquida/métodos , Masculino , Reprodutibilidade dos Testes , Limite de DetecçãoRESUMO
BACKGROUND: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. RESULTS: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. CONCLUSIONS: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy.
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Chlorella , Portadores de Fármacos , Fotossíntese , Animais , Camundongos , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Terapia Combinada , Fotoquimioterapia/métodos , Neoplasias/terapia , Antineoplásicos/farmacologia , Camundongos Endogâmicos BALB C , Sistemas de Liberação de Medicamentos/métodos , Verde de Indocianina/farmacocinética , Verde de Indocianina/química , FemininoRESUMO
BACKGROUND: Obesity, characterized by excessive white adipose tissue expansion, is associated with several metabolic complications. Identifying new adipogenesis regulators may lead to effective therapies for obesity-induced metabolic disorders. RESULTS: Here, we identified the growth arrest and DNA damage-inducible A (GADD45A), a stress-inducible histone-folding protein, as a novel regulator of subcutaneous adipose metabolism. We found that GADD45A expression was positively correlated with subcutaneous fat deposition and obesity in humans and fatty animals. In vitro, the gain or loss function of GADD45A promoted or inhibited subcutaneous adipogenic differentiation and lipid accumulation, respectively. Using a Gadd45a-/- mouse model, we showed that compared to wild-type (WT) mice, knockout (KO) mice exhibited subcutaneous fat browning and resistance to high-fat diet (HFD)-induced obesity. GADD45A deletion also upregulated the expression of mitochondria-related genes. Importantly, we further revealed that the interaction of GADD45A with Stat1 prevented phosphorylation of Stat1, resulting in the impaired expression of Lkb1, thereby regulating subcutaneous adipogenesis and lipid metabolism. CONCLUSIONS: Overall, our results reveal the critical regulatory roles of GADD45A in subcutaneous fat deposition and lipid metabolism. We demonstrate that GADD45A deficiency induces the inguinal white adipose tissue (iWAT) browning and protects mice against HFD-induced obesity. Our findings provide new potential targets for combating obesity-related metabolic diseases and improving human health.
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Metabolismo dos Lipídeos , Obesidade , Animais , Humanos , Camundongos , Adipogenia/genética , Tecido Adiposo Branco/metabolismo , Proteínas de Ciclo Celular/metabolismo , Metabolismo dos Lipídeos/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/farmacologia , Gordura Subcutânea/metabolismoRESUMO
Milk thermal treatment, such as pasteurization, high-temperature short-time processing, and the emerging ultra-short-time processing (<0.5 s), are crucial for ensuring milk safety and extending its shelf life. Milk is a nutritive food matrix with various macro/micro-nutrients and other constituents that are possibly affected by thermal treatment for reasons associated with processing strength. Therefore, understanding the relationship between heating strength and milk quality is vital for the dairy industry. This review summarizes the impact of thermal treatment strength on milk's nutritional and sensory properties, the synthesizing of the structural integrity and bioavailability of milk proteins, the profile and stability of fatty acids, the retention of macro/micro-nutrients, as well as the overall flavor profile. Additionally, it examines the formation of heat-induced markers, such as Maillard reaction products, lactulose, furosine, and alkaline phosphatase activity, which serve as indicators of heating intensity. Flavor and heating markers are commonly used to assess the quality of pasteurized milk. By examining former studies, we conclude that ultra-short-time-processing-treated milk is comparable to pasteurized milk in terms of specific parameters (such as whey protein behavior, furosine, and ALP contents). This review aims to better summarize how thermal treatments influence the milk matrix, guiding the dairy industry's development and balancing milk products' safety and nutritional value.
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Ácidos Graxos , Leite , Animais , Leite/química , Ácidos Graxos/análise , Temperatura Alta , Proteínas do Leite/análise , Proteínas do Leite/química , Pasteurização/métodos , Manipulação de Alimentos/métodos , Paladar , Humanos , Nutrientes/análise , BiomarcadoresRESUMO
Carotenoids are essential nutrients for humans and animals, and carotenoid coloration represents an important meat quality parameter for many farmed animals. Increasingly, studies have demonstrated that vertebrate carotenoid cleavage oxygenases (CCOs) are essential enzymes in carotenoid metabolism and are therefore potential candidate genes for improving carotenoid deposition. However, our understanding of carotenoid bioavailability and CCOs functions in invertebrates, particularly marine species, is currently quite limited. We previously identified that a CCO homolog, PyBCO-like 1, was the causal gene for carotenoid coloration in the 'Haida golden scallop', a variety of Yesso scallop (Patinopecten yessoensis) characterized by carotenoid enrichment. Here, we found that another CCO-encoding gene named PyBCO2 (ß-carotene oxygenase 2) was widely expressed in P. yessoensis organs/tissues, with the highest expression in striated muscle. Inhibiting BCO2 expression in P. yessoensis through RNA interference led to increased carotenoid (pectenolone and pectenoxanthin) deposition in the striated muscle, and the color of the striated muscle changed from white to light orange. Our results indicate that PyBCO2 might be a candidate gene used for improving carotenoid content in normal Yesso scallops, and also in 'Haida golden scallops'.
Assuntos
Dioxigenases , Pectinidae , Animais , Humanos , beta Caroteno , Músculo Esquelético , Carotenoides , Pectinidae/genética , Dioxigenases/genéticaRESUMO
Ruminal microbes can efficiently ferment biomass waste to produce volatile fatty acids (VFAs). However, keeping long-term efficient VFA production efficiency has become a bottleneck. In this study, yeast culture (YC) was used to enhance the VFA production in long-term fermentation. Results showed that YC group improved the volatile solid removal and VFA concentration to 47.8% and 7.82 g/L, respectively, 18.6% and 16.1% higher than the control, mainly enhancing the acetic, propionic, and butyric acid production. YC addition reduced the bacterial diversity, changed the bacterial composition, and improved interactions among bacteria. The regulation mechanism of YC was to increase the abundance and activity of hydrolytic and acidogenic bacteria such as Prevotella and Treponema, improve bacterial interactions, and further promote expression of functional genes. Ultimately, a long-term efficient ruminal fermentation of corn straw into VFAs was achieved.
RESUMO
Microplastics (MPs) can provide a unique niche for microbiota in waters, thus regulating the nutrients and carbon cycling. Following the vertical transport of MPs in waters, the compositions of attached biofilm may be dramatically changed. However, few studies have focused on the related ecological function response, including the carbon metabolism. In this study, we investigated the microbial carbon metabolism patterns of attached biofilm on different MPs in the vertical profile of urban rivers. The results showed that the carbon metabolism capacity of biofilm on the degradable polylactic acid (PLA) MPs was higher than that in the non-degradable polyethylene terephthalate (PET) MPs. In the vertical profile, the carbon metabolism rates of biofilm on two MPs both decreased with water depth, being 0.74 and 0.91 folds in bottom waters of that in surface waters. Specifically, the utilization of polymers, carbohydrate, and amine of PLA biofilm was significantly inhibited in the bottom waters, which were not altered on the PET. Compared with surface waters, the microbial metabolism function index of PLA biofilm was inhibited in deep waters, but elevated in the PET biofilm. In addition, the water quality parameters (e.g., nutrients) in the vertical profile largely shaped carbon metabolism patterns. These findings highlight the distinct carbon metabolism patterns in aquatic environments in the vertical profile, providing new insights into the effects of MPs on global carbon cycle.