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Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo purine synthesis and signaling in activated T cells to promote proliferation and inflammatory cytokine production. In pathogenic T helper-17 (Th17) cells, MTHFD2 prevented aberrant upregulation of the transcription factor FoxP3 along with inappropriate gain of suppressive capacity. MTHFD2 deficiency also promoted regulatory T (Treg) cell differentiation. Mechanistically, MTHFD2 inhibition led to depletion of purine pools, accumulation of purine biosynthetic intermediates, and decreased nutrient sensor mTORC1 signaling. MTHFD2 was also critical to regulate DNA and histone methylation in Th17 cells. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. MTHFD2 is thus a metabolic checkpoint to integrate purine metabolism with pathogenic effector cell signaling and is a potential therapeutic target within 1C metabolism pathways.
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Inflamação/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Purinas/biossíntese , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular , Citocinas/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Ativação Linfocitária , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Camundongos , Camundongos Transgênicos , Mutação/genética , Transdução de SinaisRESUMO
Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.
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Neoplasias , Obesidade , Receptor de Morte Celular Programada 1 , Macrófagos Associados a Tumor , Animais , Feminino , Humanos , Masculino , Camundongos , Apresentação de Antígeno/efeitos dos fármacos , Antígeno B7-2/antagonistas & inibidores , Antígeno B7-2/imunologia , Antígeno B7-2/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Ativação Linfocitária , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/imunologia , Obesidade/metabolismo , Fagocitose/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacosRESUMO
Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.
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Diazo-Oxo-Norleucina , Neoplasias , Animais , Camundongos , Diazo-Oxo-Norleucina/farmacologia , Glutamina/metabolismo , Neoplasias/terapia , Neoplasias/metabolismo , Linfócitos T CD8-Positivos/metabolismoRESUMO
Glycoproteins account for numerous biological processes including those associated with diseases and infections. The advancement of glycopeptides has emerged as a promising strategy for unraveling biological pathways and discovering novel medicines. In this arena, a key challenge arises from the absence of efficient synthetic strategies to access glycopeptides and glycoproteins. Here, we present a highly concise approach to bridging saccharides with amino acids and peptides through an amide linkage. Our amide-linked C-glycosyl amino acids and peptides are synthesized through cooperative Ni-catalyzed and photoredox processes. The catalytic process generates a glycosyl radical and an amide carbonyl radical, which subsequently combine to yield the C-glycosyl products. The saccharide reaction partners encompass mono-, di-, and trisaccharides. All 20 natural amino acids, peptides, and their derivatives can efficiently undergo glycosylations with yields ranging from acceptable to high, demonstrating excellent stereoselectivities. As a substantial expansion of applications, we have shown that simple C-glycosyl amino acids can function as versatile building units for constructing C-glycopeptides with intricate spatial complexities.
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Amidas , Aminoácidos , Níquel/química , Peptídeos , Carboidratos/química , Glicopeptídeos , Glicoproteínas , CatáliseRESUMO
Spatial-spectral interferometry (SSI) is a technique used to reconstruct the electrical field of an ultrafast laser. By analyzing the spectral phase distribution, SSI provides valuable information about the optical dispersion affecting the spectral phase, which is related to the energy distribution of the laser pulses. SSI is a single-shot measurement process and has a low laser power requirement. However, the reconstruction algorithm involves numerous Fourier transform and filtering operations, which limits the applicability of SSI for real-time dispersion analysis. To address this issue, this Letter proposes a field-programmable gate array (FPGA)-based deep neural network to accelerate the spectral phase reconstruction and dispersion estimation process. The results show that the analysis time is improved from 124 to 9.27â ms, which represents a 13.4-fold improvement on the standard Fourier transform-based reconstruction algorithm.
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A previous combined experimental and theoretical study found that the position of anchoring groups on a phenanthrene (PHE) backbone played a large role in determining the single-molecule conductance of the PHE derivative. However, a consistent 0.1 G0 feature was found across all PHE derivatives. To understand this, the previously investigated PHE derivatives were placed flat on a simulated Au substrate with a scanning tunneling microscope (STM) tip over PHE and conductance was calculated using the non-equilibrium Green's function technique in conjunction with density functional theory (NEGF-DFT). The location of the tip was varied to find the most conductive and most energetically favorable arrangements, which did not coincide. Furthermore, the variation in conductance found in erect junctions was not present when PHE derivatives were lying flat, with all derivatives calculated to have conductance values around 0.1 G0.
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OBJECTIVE: This study aims to determine whether persistent T1-weighted lesions signify a complete pathological response (pCR) in breast cancer patients treated with neoadjuvant chemotherapy and surgery, and to evaluate their correlation with imaging responses on MRI. MATERIALS AND METHODS: A retrospective review was conducted on data from breast cancer patients treated between January 2011 and December 2018. Patients who underwent breast MRI and pre- and post-neoadjuvant chemotherapy followed by surgery were included. Those with distant metastasis, no planned surgery, pre-surgery radiation, ineligibility for neoadjuvant chemotherapy, or unavailable surgical pathology were excluded. Groups with and without persistent T1-weighted lesions were compared using the chi-square test for categorical variables and the Student t test or Wilcox rank sum test for continuous variables. Univariate logistic regression was used to evaluate the association of the final pathological response with the presence of T1-persistent lesion and other characteristics. RESULTS: Out of 319 patients, 294 met the inclusion criteria (breast cancer patients treated with neoadjuvant chemotherapy and subsequent surgery); 157 had persistent T1 lesions on post-chemotherapy MRI and 137 did not. A persistent T1 lesion indicated reduced likelihood of complete pathological response (14% vs. 39%, p < 0.001) and imaging response (69% vs. 93%, p < 0.001). Multivariable analysis confirmed these findings: OR 0.37 (95% CI 0.18-0.76), p = 0.007. No other characteristics correlated with T1 residual lesions. CONCLUSION: Persistent T1-weighted lesions without associated abnormal enhancement on post-treatment breast MRI correlate with lower complete pathological and imaging response rates. CLINICAL RELEVANCE STATEMENT: The study underscores the importance of persistent T1-weighted lesions on breast MRI as vital clinical markers, being inversely related to a complete pathological response following neoadjuvant chemotherapy; they should be a key factor in guiding post-neoadjuvant chemotherapy treatment decisions. KEY POINTS: ⢠Persistent T1 lesions on post-chemotherapy breast MRI indicate a reduced likelihood of achieving a complete pathological response (14% vs. 39%, p < 0.001) and imaging response (69% vs. 93%, p < 0.001). ⢠Through multivariable analysis, it was confirmed that the presence of a persistent T1 lesion on breast MRI post-chemotherapy is linked to a decreased likelihood of complete pathological response, with an odds ratio (OR) of 0.37 (95% CI 0.18-0.76; p = 0.007). ⢠In addition to the convention of equating the absence of residual enhancement to complete imaging response, our results suggest that the presence or absence of residual T1 lesions should also be considered.
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The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.
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Proteína Quinase Ativada por DNA , Inibidores de Proteínas Quinases , Humanos , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Estrutura Molecular , Desenvolvimento de Medicamentos , AnimaisRESUMO
Natural products represent a paramount source of novel drugs. Numerous plant-derived natural products have demonstrated potent anti-tumor properties, thereby garnering considerable interest in their potential as anti-tumor drugs. This review compiles an overview of 242 recently discovered natural products, spanning the period from 2018 to the present. These natural products, which include 69 terpenoids, 42 alkaloids, 39 flavonoids, 21 steroids, 14 phenylpropanoids, 5 quinolines and 52 other compounds, are characterized by their respective chemical structures, anti-tumor activities, and mechanisms of action. By providing an essential reference and fresh insights, this review aims to support and inspire researchers engaged in the fields of natural products and anti-tumor drug discovery.
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Alcaloides , Antineoplásicos , Produtos Biológicos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Alcaloides/farmacologia , Alcaloides/química , Plantas/química , Flavonoides/química , Antineoplásicos/farmacologiaRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.
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BACKGROUND: There is a paucity of literature examining the differences between patient-reported outcome measures after planned and unplanned cesarean delivery using a validated quality of recovery tool. The Obstetric Quality of Recovery-10 (ObsQoR-10) scoring tool has been validated to quantify functional recovery after cesarean delivery. We aimed to use the ObsQoR-10 to compare the postoperative recovery characteristics of patients undergoing planned and unplanned cesarean deliveries. METHODS: We conducted a prospective single-center observational study. Patients undergoing planned and unplanned cesarean deliveries under neuraxial anesthesia were asked to complete the ObsQoR-10 questionnaire 24 hours, 48 hours, and 1 week postpartum. We collected information on total in-hospital postoperative opioid consumption and patients´ perception of readiness for discharge at 24 and 48 hours postpartum. Additionally, patient characteristics were collected to assess their correlation with our findings. RESULTS: We included 112 patients (56 in each group). No statistical differences in ObsQoR-10 scores at 24 hours, 48 hours, and 1 week postpartum were observed between the planned and unplanned cesarean deliveries. Additionally, there was no difference between the groups in patients' perception of readiness for hospital discharge at 24 and 48 hours and opioid consumption in the first 2 days after surgery. Most patients in both groups did not think they would be ready for discharge at 24 hours postpartum. Analysis of the individual components of ObsQoR-10 at 24 hours showed a difference in the responses assessing the severity of shivering (higher in unplanned cesarean deliveries) and the ability to look after personal hygiene (lower in unplanned cesarean deliveries). CONCLUSIONS: As assessed by the ObsQoR-10, no significant difference in the quality of recovery was observed between patients undergoing planned and unplanned cesarean delivery.
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BACKGROUND: With the advent of the smart phone era, managing blood glucose at home through apps will become more common for older individuals with diabetes. Adult children play important roles in glucose management of older parents. Few studies have explored how adult children really feel about engaging in the glucose management of their older parents with type 2 diabetes mellitus (T2DM) through mobile apps. This study provides insights into the role perceptions and experiences of adult children of older parents with T2DM participating in glucose management through mobile apps. METHODS: In this qualitative study, 16 adult children of older parents with T2DM, who had used mobile apps to manage blood glucose for 6 months, were recruited through purposive sampling. Semi-structured, in-depth, face-to-face interviews to explore their role perceptions and experiences in remotely managing their older parents' blood glucose were conducted. The Consolidated Criteria for Reporting Qualitative Research (COREQ) were followed to ensure rigor in the study. The data collected were analyzed by applying Colaizzi's seven-step qualitative analysis method. RESULTS: Six themes and eight sub-themes were identified in this study. Adult children's perceived roles in glucose management of older parents with T2DM through mobile apps could be categorized into four themes: health decision-maker, remote supervisor, health educator and emotional supporter. The experiences of participation could be categorized into two themes: facilitators to participation and barriers to participation. CONCLUSION: Some barriers existed for adult children of older parents with T2DM participating in glucose management through mobile apps; however, the findings of this study were generally positive. It was beneficial and feasible for adult children to co-manage the blood glucose of older parents. Co-managing blood glucose levels in older parents with T2DM can enhance both adherence rates and confidence in managing blood glucose effectively.
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Filhos Adultos , Diabetes Mellitus Tipo 2 , Aplicativos Móveis , Pais , Pesquisa Qualitativa , Humanos , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/psicologia , Diabetes Mellitus Tipo 2/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Pais/psicologia , Filhos Adultos/psicologia , Adulto , Idoso , Glicemia/metabolismo , Automonitorização da Glicemia/métodos , Automonitorização da Glicemia/psicologiaRESUMO
PURPOSE: A zone of differential block to cold has been recently documented during labour epidural analgesia, with an upper sensory block level (USBL) and a lower sensory block level (LSBL). We aimed to determine the correlation between USBL and LSBL to cold and pinprick and sensory block level to light touch during labour epidural analgesia. METHODS: We conducted a prospective observational study in patients requesting labour epidural analgesia. We placed an epidural catheter at L2/L3 or L3/L4, followed by a programmed intermittent epidural bolus plus patient-controlled epidural analgesia regimen. We assessed the sensory block levels 140 min after administering the loading dose. The primary outcomes were the USBL and LSBL to cold and pinprick and the sensory block level to light touch. RESULTS: We studied 30 patients. The median [interquartile range (IQR)] USBL and LSBL to ice were T7 [T7-T6] and T9 [T10-T8], respectively. The median [IQR] USBL and LSBL to pinprick were T8 [T10-T6] and T10 [T12-T10], respectively. There was a strong correlation between USBL to ice and pinprick (Spearman correlation coefficient, 0.57) and between LSBL to ice and pinprick (Spearman correlation coefficient, 0.52). There was no significant correlation between sensory block level to light touch and either USBL or LSBL to ice or pinprick. CONCLUSION: We observed two sensory block levels to ice and pinprick. Further studies are required to understand if one modality-cold or pinprick-is superior to the other in assessing sensory block levels in this context. Light touch is unreliable as a modality of sensory block assessment during labour epidural analgesia. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05187962); registered 12 January 2022.
RéSUMé: OBJECTIF: Une zone de bloc différentiel de réaction au froid a récemment été documentée pendant l'analgésie péridurale obstétricale, avec un niveau de bloc sensoriel supérieur (USBL, pour upper sensory block level) et un niveau de bloc sensoriel inférieur (LSBL, pour lower sensory block level). Notre objectif était de déterminer la corrélation entre l'USBL et le LSBL au contact du froid et de la piqûre et le niveau de bloc sensoriel au toucher léger pendant l'analgésie péridurale obstétricale. MéTHODE: Nous avons mené une étude observationnelle prospective chez des patient·es demandant une analgésie péridurale obstétricale. Nous avons placé un cathéter péridural au niveau L2/L3 ou L3/L4, suivi d'une administration programmée de bolus périduraux plus un régime d'analgésie péridurale contrôlée par le/la patient·e. Nous avons évalué les niveaux de bloc sensoriel 140 min après l'administration de la dose de charge. Les critères d'évaluation principaux étaient l'USBL et le LSBL en réaction au froid et à la piqûre d'épingle et le niveau de bloc sensoriel en réaction au toucher léger. RéSULTATS: Nous avons étudié 30 patient·es. Les USBL et LSBL médians [écart interquartile (ÉIQ)] à la glace étaient situés au niveau T7 [T7-T6] et T9 [T10-T8], respectivement. Les USBL et LSBL médians [écart interquartile (ÉIQ)] à la piqûre étaient localisés au niveau T8 [T10T6] et T10 [T12T10], respectivement. Il y avait une forte corrélation entre l'USBL à la glace et à la piqûre (coefficient de corrélation de Spearman, 0,57) et entre le LSBL à la glace et à la piqûre (coefficient de corrélation de Spearman, 0,52). Il n'y avait pas de corrélation significative entre le niveau de bloc sensoriel en réaction au toucher léger et l'USBL ou le LSBL en réaction à la glace ou à la piqûre. CONCLUSION: Nous avons observé deux niveaux de bloc sensoriel à la glace et à la piqûre. D'autres études sont nécessaires pour comprendre si une modalité le froid ou la piqûre est supérieure à l'autre pour évaluer les niveaux de bloc sensoriel dans ce contexte. Le toucher léger n'est pas fiable en tant que modalité d'évaluation du bloc sensoriel pendant l'analgésie péridurale obstétricale. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT05187962); enregistré le 12 janvier 2022.
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Analgesia Epidural , Analgesia Obstétrica , Temperatura Baixa , Tato , Humanos , Estudos Prospectivos , Feminino , Analgesia Epidural/métodos , Gravidez , Analgesia Obstétrica/métodos , Adulto , Analgesia Controlada pelo Paciente/métodos , Bloqueio Nervoso/métodosRESUMO
Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.
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Eicosanoides/metabolismo , Epóxido Hidrolases/biossíntese , Macrófagos/imunologia , Metástase Neoplásica/patologia , Receptores de Prostaglandina E Subtipo EP4/biossíntese , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica/prevenção & controle , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Fagocitose/imunologia , Células RAW 264.7RESUMO
AIMS: To systematically evaluate and analyse literature concerning the factors influencing the implementation of clinical practice guidelines related to enteral nutrition in the adult intensive care unit. BACKGROUND: Guidelines serve as crucial tools for guiding clinical practice. However, a significant gap persists between current clinical practice and guidelines pertaining to enteral nutrition. It is essential to identify the reasons behind this disparity to foster clinical transformation. METHODS: A mixed-methods systematic review. DATA SOURCES: A systematic search was conducted across PubMed, Embase, Medline, Cochrane, PsycINFO and CNKI databases to identify impediments and facilitators to the implementation of ICU clinical practice guidelines related to enteral nutrition. The types of studies included quantitative, qualitative and mixed-methods studies. The search spanned from January 2003 to January 2024 and was updated in May 2024. The quality assessment of the included literature was conducted using the Mixed-Methods Study Evaluation Tool (MMAT). Data analysis was performed using a data-based convergent integration approach. The protocol for this study was prospectively registered (PROSPERO2023, CRD42023483287). RESULTS: Twenty papers were finally included, and 65 findings were extracted, integrating a total of three categories, Category 1: healthcare provider factors, including three sub-themes: knowledge of guideline-related knowledge and awareness of guideline application; social/professional roles and identity domains; beliefs, attitudes and self-efficacy; collaboration, Category 2: practice environments, including two sub-themes: environmental factors and resource areas; systems and behavioural norms, Category 3: patient values and nutritional support preferences including two sub-themes: patient disease status and value orientation. CONCLUSION: Healthcare professionals should analyse obstacles and facilitators to guideline implementation from multiple perspectives, strengthen healthcare collaboration, improve education and training systems, correct misperceptions and increase awareness of evidence-based practice.
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Respiratory syncytial virus (RSV) is a significant viral pathogen that causes respiratory infections in infants, the elderly, and immunocompromised individuals. RSV-related illnesses impose a substantial economic burden worldwide annually. The molecular structure, function, and in vivo interaction mechanisms of RSV have received more comprehensive attention in recent times, and significant progress has been made in developing inhibitors targeting various stages of the RSV replication cycle. These include fusion inhibitors, RSV polymerase inhibitors, and nucleoprotein inhibitors, as well as FDA-approved RSV prophylactic drugs palivizumab and nirsevimab. The research community is hopeful that these developments might provide easier access to knowledge and might spark new ideas for research programs.
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Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Lactente , Idoso , Antivirais/farmacologia , Antivirais/uso terapêutico , Palivizumab/farmacologia , Palivizumab/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Antirretrovirais/uso terapêuticoRESUMO
BACKGROUND: Whey protein isolate (WPI) is a high-quality animal protein resource. The modification of WPI through physical, chemical and biological methods can substantially improve the functional properties of proteins. This study investigated the effect of electron beam irradiation (EBI) on the modification of WPI-xylose glycosylation. RESULTS: The degree of grafting and browning revealed that EBI promoted WPI glycosylation. The maximum emission wavelength of intrinsic fluorescence was red-shifted and the fluorescence intensity was reduced, suggesting that irradiation induced the unfolding of the WPI structure, thereby promoting glycosylation. Fourier-transformed infrared spectroscopy revealed that the covalent binding of the conjugates occurred on the introduction of the hydrophilic groups, resulting in decreased surface hydrophobicity. When compared with conventional wet-heat glycosylation, irradiation-assisted glycosylation improved the emulsifying activity of WPI from 179.76 ± 0.83 to 277.83 ± 1.44 m2 g-1, and the emulsifying and rheological properties improved. CONCLUSION: These results confirmed that EBI can increase the degree of WPI glycosylation and improve the functional properties of proteins, thereby laying a theoretical foundation for the further application of WPI. © 2024 Society of Chemical Industry.
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Genetics, age, environmental factors, and oxidative stress have all been implicated in the development of Parkinson's disease (PD); however, a complete understanding of its pathology remains elusive. At present, there is no cure for PD, and currently available therapeutics are insufficient to meet patient needs. Ferroptosis, a distinctive iron-dependent cell death mode characterized by lipid peroxidation and oxidative stress, has pathophysiological features similar to those of PD, including iron accumulation, reactive oxygen species-induced oxidative damage, and mitochondrial dysfunction. Ferroptosis has been identified as a specific pathway of neuronal death and is closely related to the pathogenesis of PD. Despite the similarities in the biological targets involved in PD pathogenesis and ferroptosis, the relationship between novel targets in PD and ferroptosis has been neglected in the literature. In this review, the mechanism of ferroptosis is discussed, and the potential therapeutic targets implicated in both PD and ferroptosis are compared. Furthermore, the anti-PD effects of several ferroptosis inhibitors, as well as clinical studies thereof, and the identification of novel lead compounds for the treatment of PD and the inhibition of ferroptosis are reviewed. It is hoped that this review can promote research to further elucidate the relationship between ferroptosis and PD and provide new strategies for the development of novel ferroptosis-targeting PD therapy.
Assuntos
Ferroptose , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Ferro/metabolismo , Morte Celular , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model-HBGP (based on hepatitis B surface antigen, gamma-glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval [CI]: 0.839-0.892) and 0.885 (95% CI: 0.845-0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839-0.892), 0.868 (95% CI: 0.838-0.898), 0.865 (95% CI: 0.828-0.901), and 0.853 (95% CI: 0.798-0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.