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1.
Sci Rep ; 14(1): 14557, 2024 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-38914736

RESUMO

The study aims to develop an abnormal body temperature probability (ABTP) model for dairy cattle, utilizing environmental and physiological data. This model is designed to enhance the management of heat stress impacts, providing an early warning system for farm managers to improve dairy cattle welfare and farm productivity in response to climate change. The study employs the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm to analyze environmental and physiological data from 320 dairy cattle, identifying key factors influencing body temperature anomalies. This method supports the development of various models, including the Lyman Kutcher-Burman (LKB), Logistic, Schultheiss, and Poisson models, which are evaluated for their ability to predict abnormal body temperatures in dairy cattle effectively. The study successfully validated multiple models to predict abnormal body temperatures in dairy cattle, with a focus on the temperature-humidity index (THI) as a critical determinant. These models, including LKB, Logistic, Schultheiss, and Poisson, demonstrated high accuracy, as measured by the AUC and other performance metrics such as the Brier score and Hosmer-Lemeshow (HL) test. The results highlight the robustness of the models in capturing the nuances of heat stress impacts on dairy cattle. The research develops innovative models for managing heat stress in dairy cattle, effectively enhancing detection and intervention strategies. By integrating advanced technologies and novel predictive models, the study offers effective measures for early detection and management of abnormal body temperatures, improving cattle welfare and farm productivity in changing climatic conditions. This approach highlights the importance of using multiple models to accurately predict and address heat stress in livestock, making significant contributions to enhancing farm management practices.


Assuntos
Temperatura Corporal , Indústria de Laticínios , Animais , Bovinos , Temperatura Corporal/fisiologia , Indústria de Laticínios/métodos , Fatores de Risco , Doenças dos Bovinos/diagnóstico , Doenças dos Bovinos/fisiopatologia , Transtornos de Estresse por Calor/veterinária , Transtornos de Estresse por Calor/fisiopatologia , Feminino , Mudança Climática , Probabilidade , Medição de Risco/métodos
2.
Aging Clin Exp Res ; 36(1): 106, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38714627

RESUMO

BACKGROUND: Given the rising prevalence of depression among older adults and the associated increase in caregiving responsibilities, understanding factors influencing caregiver burden is crucial. Previous research has not extensively explored the impact of caregivers' attributional styles, that is, how individuals interpret the causes of life events, on their care burden. AIM: This study examined the relationship between caregivers' attributional styles and their care burden for older patients with depression. METHODS: This cross-sectional study enrolled older adults aged ≥ 65 years diagnosed with depression and their caregivers. Depression was diagnosed according to the DSM-V criteria for Major Depressive Disorder or Persistent Depressive Disorder. Caregivers completed the Chinese Depression Caregiver Burden Scale (CDCBS) to assess care burden, the Hamilton Depression Rating Scale (HAM-D) to evaluate patient symptom severity, the Center for Epidemiological Studies Depression Scale (CES-D) for measuring caregivers' depression, and the Chinese Depression Patient Caregiver Attribution Style Scale (CDPCAS) to assess attributional styles. Hierarchical regression analysis was used to identify the factors independently associated with the caregiver's subjectively assessed care burden. RESULTS: The sample included 146 caregivers of geriatric patients with depression. Most depression patients were women (74.7%) with a mean age of 74.3 years, whereas the mean age of caregivers was 57.7 years. Hierarchical regression analysis identified that caregivers' gender (ß = - 0.14, p = .044), educational level (ß = 0.19, p = .008), caregivers' own depression assessed by the Center for Epidemiological Studies Depression Scale (ß = 0.41, p < .001), and attributional styles, particularly manipulation (ß = 0.29, p < .001) and illness/stress attributional style (ß = 0.23, p = .002) as independent factors associated with care burden. Patient symptom severity assessed using the Hamilton Depression Scale was not significantly correlated with care burden after controlling for attributional styles. CONCLUSIONS: Certain attributional styles, particularly the manipulation and illness/stress attributional styles, significantly increased self-reported care burden. These findings highlight the need for educational resources to change the attribution style, along with support systems and accessible mental health services for caregivers to potentially ease the care burden.


Assuntos
Cuidadores , Depressão , Humanos , Masculino , Feminino , Idoso , Cuidadores/psicologia , Estudos Transversais , Depressão/psicologia , Depressão/epidemiologia , Pessoa de Meia-Idade , Taiwan/epidemiologia , Idoso de 80 Anos ou mais , Sobrecarga do Cuidador/psicologia , Efeitos Psicossociais da Doença
3.
Cell ; 187(12): 3120-3140.e29, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38714197

RESUMO

Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.


Assuntos
Medula Óssea , Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Proteômica , Análise de Célula Única , Transcriptoma , Humanos , Análise de Célula Única/métodos , Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Proteômica/métodos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Hematopoese , Nicho de Células-Tronco , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia
4.
bioRxiv ; 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38559168

RESUMO

The bone marrow is the organ responsible for blood production. Diverse non-hematopoietic cells contribute essentially to hematopoiesis. However, these cells and their spatial organization remain largely uncharacterized as they have been technically challenging to study in humans. Here, we used fresh femoral head samples and performed single-cell RNA sequencing (scRNA-Seq) to profile 29,325 enriched non-hematopoietic bone marrow cells and discover nine transcriptionally distinct subtypes. We next employed CO-detection by inDEXing (CODEX) multiplexed imaging of 18 individuals, including both healthy and acute myeloid leukemia (AML) samples, to spatially profile over one million single cells with a novel 53-antibody panel. We discovered a relatively hyperoxygenated arterio-endosteal niche for early myelopoiesis, and an adipocytic, but not endosteal or perivascular, niche for early hematopoietic stem and progenitor cells. We used our atlas to predict cell type labels in new bone marrow images and used these predictions to uncover mesenchymal stromal cell (MSC) expansion and leukemic blast/MSC-enriched spatial neighborhoods in AML patient samples. Our work represents the first comprehensive, spatially-resolved multiomic atlas of human bone marrow and will serve as a reference for future investigation of cellular interactions that drive hematopoiesis.

5.
Int J Biol Sci ; 20(5): 1563-1577, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481798

RESUMO

Fetuin-A, a hepatokine secreted by hepatocytes, binds to insulin receptors and consequently impairs the activation of the insulin signaling pathway, leading to insulin resistance. Apigenin, a flavonoid isolated from plants, has beneficial effects on insulin resistance; however, its regulatory mechanisms are not fully understood. In the present study, we investigated the molecular mechanisms underlying the protective effects of apigenin on insulin resistance. In Huh7 cells, treatment with apigenin decreased the mRNA expression of fetuin-A by decreasing reactive oxygen species-mediated casein kinase 2α (CK2α)-nuclear factor kappa-light-chain-enhancer of activated B activation; besides, apigenin decreased the levels of CK2α-dependent fetuin-A phosphorylation and thus promoted fetuin-A degradation through the autophagic pathway, resulting in a decrease in the protein levels of fetuin-A. Moreover, apigenin prevented the formation of the fetuin-A-insulin receptor (IR) complex and thereby rescued the PA-induced impairment of the insulin signaling pathway, as evidenced by increased phosphorylation of IR substrate-1 and Akt, and translocation of glucose transporter 2 from the cytosol to the plasma membrane. Similar results were observed in the liver of HFD-fed mice treated with apigenin. Collectively, our findings revealed that apigenin ameliorates obesity-induced insulin resistance in the liver by targeting fetuin-A.


Assuntos
Resistência à Insulina , Camundongos , Animais , alfa-2-Glicoproteína-HS/metabolismo , Apigenina/farmacologia , Apigenina/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Insulina/metabolismo , alfa-Fetoproteínas/metabolismo
6.
Exp Anim ; 73(3): 336-346, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38508727

RESUMO

Transient receptor potential vanilloid 1 (TRPV1), a ligand-gated cation channel, is a receptor for vanilloids on sensory neurons and is also activated by capsaicin, heat, protons, arachidonic acid metabolites, and inflammatory mediators on neuronal or non-neuronal cells. However, the role of the TRPV1 receptor in pro-inflammatory cytokine secretion and its potential regulatory mechanisms in lipopolysaccharide (LPS)-induced inflammation has yet to be entirely understood. To investigate the role and regulatory mechanism of the TRPV1 receptor in regulating LPS-induced inflammatory responses, bone marrow-derived macrophages (BMDMs) harvested from wild-type (WT) and TRPV1 deficient (Trpv1-/-) mice were used as the cell model. In WT BMDMs, LPS induced an increase in the levels of tumor necrosis factor-α, IL-1ß, inducible nitric oxide synthase, and nitric oxide, which were attenuated in Trpv1-/- BMDMs. Additionally, the phosphorylation of inhibitor of nuclear factor kappa-Bα and mitogen-activated protein kinases, as well as the translocation of nuclear factor kappa-B and activator protein 1, were all decreased in LPS-treated Trpv1-/- BMDMs. Immunoprecipitation assay revealed that LPS treatment increased the formation of TRPV1-Toll-like receptor 4 (TLR4)-cluster of differentiation 14 (CD14) complex in WT BMDMs. Genetic deletion of TRPV1 in BMDMs impaired the LPS-triggered immune-complex formation of TLR4, myeloid differentiation protein 88, and interleukin-1 receptor-associated kinase, all of which are essential regulators in LPS-induced activation of the TLR4 signaling pathway. Moreover, genetic deletion of TRPV1 prevented the LPS-induced lethality and pro-inflammatory production in mice. In conclusion, the TRPV1 receptor may positively regulate the LPS-mediated inflammatory responses in macrophages by increasing the interaction with the TLR4-CD14 complex and activating the downstream signaling cascade.


Assuntos
Inflamação , Receptores de Lipopolissacarídeos , Lipopolissacarídeos , Macrófagos , Transdução de Sinais , Canais de Cátion TRPV , Receptor 4 Toll-Like , Animais , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/fisiologia , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/fisiologia , Macrófagos/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Receptores de Lipopolissacarídeos/genética , Inflamação/metabolismo , Inflamação/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Masculino
7.
bioRxiv ; 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38496580

RESUMO

Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities to adult glioma, it is increasingly recognized as a molecularly distinct, yet highly heterogeneous disease. In this study, we longitudinally profiled a molecularly diverse cohort of 16 pHGG patients before and after standard therapy through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of the tumor microenvironment during progression following treatment. We found that the canonical neoplastic cell phenotypes of adult glioblastoma are insufficient to capture the range of tumor cell states in a pediatric cohort and observed differential tumor-myeloid interactions between malignant cell states. We identified key transcriptional regulators of pHGG cell states and did not observe the marked proneural to mesenchymal shift characteristic of adult glioblastoma. We showed that essential neuromodulators and the interferon response are upregulated post-therapy along with an increase in non-neoplastic oligodendrocytes. Through in vitro pharmacological perturbation, we demonstrated novel malignant cell-intrinsic targets. This multiomic atlas of longitudinal pHGG captures the key features of therapy response that support distinction from its adult counterpart and suggests therapeutic strategies which are targeted to pediatric gliomas.

8.
PEC Innov ; 4: 100254, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38298557

RESUMO

Objective: Nurses have opportunities to engage in goals of care conversations that can promote palliative care communication. The purpose of this study was to describe nurses' experiences in goals of care communication as summarized in the literature and to present a conceptual model of communication pathways for nurses. Methods: An integrative review of the literature (2016-2022) addressing nurses' experiences in goals of care communication was conducted using PubMed, CINAHL, and PsychInfo databases. A total of 92 articles were retrieved. A total of 12 articles were included for this review after applying the inclusion and exclusion criteria. Results: Of the 12 articles, the majority were qualitative studies (n = 8). Qualitative analysis of findings from all articles revealed three dominant themes: nurses' ambiguous role responsibilities, goals of care as end-of-life communication, and the need for nurse communication training. Conclusion: This article suggests an innovative conceptual model for advancing nurse communication about goals of care to facilitate primary palliative care. Innovation: The framework characterizes two communication pathways for Advanced Practice Nurses who direct goals of care discussions and Registered Nurses who support goals of care communication. The model informs future communication training aimed at supporting primary palliative care.

9.
Biomed Pharmacother ; 171: 116192, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38262153

RESUMO

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A, are widely used to treat hypercholesterolemia. In addition, statins have been suggested to reduce the risk of cardiovascular events owing to their pleiotropic effects on the vascular system, including vasodilation, anti-inflammation, anti-coagulation, anti-oxidation, and inhibition of vascular smooth muscle cell proliferation. The major beneficial effect of statins in maintaining vascular homeostasis is the induction of nitric oxide (NO) bioavailability by activating endothelial NO synthase (eNOS) in endothelial cells. The mechanisms underlying the increased NO bioavailability and eNOS activation by statins have been well-established in various fields, including transcriptional and post-transcriptional regulation, kinase-dependent phosphorylation and protein-protein interactions. However, the mechanism by which statins affect the metabolism of L-arginine, a precursor of NO biosynthesis, has rarely been discussed. Autophagy, which is crucial for energy homeostasis, regulates endothelial functions, including NO production and angiogenesis, and is a potential therapeutic target for cardiovascular diseases. In this review, in addition to summarizing the molecular mechanisms underlying increased NO bioavailability and eNOS activation by statins, we also discuss the effects of statins on the metabolism of L-arginine.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Óxido Nítrico/metabolismo , Células Endoteliais/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Endotélio Vascular , Arginina/metabolismo , Biologia
10.
Res Sq ; 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37961674

RESUMO

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL.

11.
Bio Protoc ; 13(18): e4825, 2023 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-37753470

RESUMO

Inflammation of the gastrointestinal tract is a prevalent pathology in diseases such as inflammatory bowel disease (IBD). Currently, there are no therapies to prevent IBD, and available therapies to treat IBD are often sub-optimal. Thus, an unmet need exists to better understand the molecular mechanisms underlying intestinal tissue responses to damage and regeneration. The recent development of single-cell RNA (sc-RNA) sequencing-based techniques offers a unique opportunity to shed light on novel signaling pathways and cellular states that govern tissue adaptation or maladaptation across a broad spectrum of diseases. These approaches require the isolation of high-quality cells from tissues for downstream transcriptomic analyses. In the context of intestinal biology, there is a lack of protocols that ensure the isolation of epithelial and non-epithelial compartments simultaneously with high-quality yield. Here, we report two protocols for the isolation of epithelial and stromal cells from mouse and human colon tissues under inflammatory conditions. Specifically, we tested the feasibility of the protocols in a mouse model of dextran sodium sulfate (DSS)-induced colitis and in human biopsies from Crohn's patients. We performed sc-RNA sequencing analysis and demonstrated that the protocol preserves most of the epithelial and stromal cell types found in the colon. Moreover, the protocol is suitable for immunofluorescence staining of surface markers for epithelial, stromal, and immune cell lineages for flow cytometry analyses. This optimized protocol will provide a new resource for scientists to study complex tissues such as the colon in the context of tissue damage and regeneration. Key features • This protocol allows the isolation of epithelial and stromal cells from colon tissues. • The protocol has been optimized for tissues under inflammatory conditions with compromised cell viability. • This protocol is suitable for experimental mouse models of colon inflammation and human biopsies.

12.
BMC Public Health ; 23(1): 1233, 2023 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-37365562

RESUMO

BACKGROUND: Young adulthood is an important period for smoking cessation; however, there is limited evidence of smoking-cessation interventions for young adults. The aims of this study were to identify evidence-based smoking-cessation strategies for young adults, examine gaps in the literature regarding smoking cessation among young adults, and discuss methodological issues/challenges related to smoking-cessation studies for young adults. METHODS: Studies tested interventions for smoking cessation among young adults (18 to 26 years old), excluding pilot studies. Five main search engines were used, including PubMed, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), EMBASE, PsycINFO, and Web of Science. The search was conducted for articles published from January 2009 to December 2019. Intervention characteristics and cessation outcomes were reviewed, and methodological quality was evaluated. RESULTS: A total of 14 articles met inclusion criteria, including randomized controlled studies and repeated cross-sectional studies. Interventions included the following: text messaging (4/14, 28.6%), social media use (2/14, 14.3%), web-or app-based intervention (2/14, 14.3%), telephone counseling (1/14, 7.1%), in-person counseling (3/14, 21.4%), pharmacological (1/14, 7.1%), and self-help booklet (1/14, 7.1%). The intervention duration and frequency of contact with participants differed and yielded varied outcomes. CONCLUSIONS: Multiple interventions have been examined to aid young adults in achieving smoking cessation. While several approaches seem promising, at the present time, the published literature is inconclusive about the type of intervention that is most effective for young adults. Future studies should compare the relative effectiveness of these intervention modalities.


Assuntos
Abandono do Hábito de Fumar , Produtos do Tabaco , Adolescente , Adulto , Humanos , Adulto Jovem , Estudos Transversais , Comportamentos Relacionados com a Saúde
13.
Healthcare (Basel) ; 11(9)2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-37174804

RESUMO

Swallowing safety is one of the top health concerns of dementia. Coughing and choking (coughing/choking) are signs of impaired swallowing safety. This study aimed to investigate the effectiveness of regular physical exercise-based swallowing intervention for reducing coughing-choking at the dementia day-care center. This was a retrospective analysis with data from medical records, including age, the clinical dementia rating (CDR), and the frequencies of coughing/choking in ten days (10-day coughing/choking). Those who complied with the exercise programs were assigned to the exercise-based group (n = 22), and those who could not comply were assigned to the non-exercised-based group (n = 7). The non-exercised-based group showed more advanced age and higher CDR than the exercise-based group (p < 0.05). The 10-day coughing/choking showed significant decreases at the 5-month and 19-month in the exercise-based group and at the 5-month in the non-exercise-based group (p < 0.05). Our findings suggested that regular physical exercise-based swallowing intervention effectively alleviated coughing/choking problems of older adults with dementia and its effectiveness was long-lasting. For those who could not comply with exercise programs, noticeably with more advanced age and dementia, the effective swallowing intervention period was short-term.

14.
Front Oncol ; 13: 1137050, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36860320

RESUMO

Monoamine oxidase A (MAOA), a mitochondrial enzyme degrading biogenic and dietary amines, has been studied in the contexts of neuropsychiatry and neurological disorders for decades, but its importance in oncology, as best exemplified in prostate cancer (PC) to date, was only realized recently. PC is the most commonly diagnosed non-skin cancer and the second deadliest malignancy for men in the United States. In PC, the increased expression level of MAOA is correlated with dedifferentiated tissue microarchitecture and a worse prognosis. A wealth of literature has demonstrated that MAOA promotes growth, metastasis, stemness and therapy resistance in PC, mainly by increasing oxidative stress, augmenting hypoxia, inducing epithelial-to-mesenchymal transition, and activating the downstream principal transcription factor Twist1-dictated multiple context-dependent signaling cascades. Cancer-cell-derived MAOA also enables cancer-stromal cell interaction involving bone stromal cells and nerve cells by secretion of Hedgehog and class 3 semaphorin molecules respectively to modulate the tumor microenvironment in favor of invasion and metastasis. Further, MAOA in prostate stromal cells promotes PC tumorigenesis and stemness. Current studies suggest that MAOA functions in PC in both cell autonomous and non-autonomous manners. Importantly, clinically available monoamine oxidase inhibitors have shown promising results against PC in preclinical models and clinical trials, providing a great opportunity to repurpose them as a PC therapy. Here, we summarize recent advances in our understanding of MAOA roles and mechanisms in PC, present several MAOA-targeted strategies that have been nominated for treating PC, and discuss the unknowns of MAOA function and targeting in PC for future exploration.

15.
Antioxidants (Basel) ; 12(2)2023 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-36830035

RESUMO

Dialysis prevents death from uremia in patients with end-stage renal disease (ESRD). Nevertheless, during hemodialysis, circulating levels of di-(2-ethylhexyl) phthalate (DEHP) are increased due to phthalates leaching from medical tubes. Statins are an effective therapy for reducing the risks associated with cardiovascular diseases in patients with chronic kidney disease; however, the mechanism by which statins fail to reduce cardiovascular events in hemodialysis ESRD patients remains unclear. In this study, we investigated whether DEHP and its metabolites interfere with the lipid-lowering effect of statins in hepatocytes. In Huh7 cells, treatment with DEHP and its metabolites abolished the simvastatin-conferred lipid-lowering effect. Mechanistically, DEHP down-regulated the expression of low-density lipoprotein receptor (LDLR) and led to a decrease in LDL binding, which was mediated by the activation of the PPARγ-PCSK9 and LXRα-IDOL signaling pathways. Additionally, the NOX-ROS-TRPA1 pathway is involved in the DEHP-mediated inhibition of LDLR expression and LDL binding activity. Blockage of this pathway abrogated the DEHP-mediated inhibition in the LDLR expression and LDL binding of simvastatin. Collectively, DEHP induces the activation of the NOX-ROS-TRPA1 pathway, which in turn activates PPARγ-PCSK9- and LXRα-IDOL-dependent signaling, and, ultimately, diminishes the statin-mediated lipid-lowering effect in hepatocytes.

16.
Cancer Immunol Res ; 11(1): 13-19, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36255409

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has been a clinical breakthrough for pediatric B-cell acute lymphoblastic leukemia (B-ALL), and loss of the CD19 target antigen on leukemic cells represents a major mechanism of relapse. Previous studies have observed CD19 mutations specific to CD19- relapses, and we sought to clarify and strengthen this relationship using deep whole-exome sequencing in leukemic cells expanded in a patient-derived xenograft. By assessing pre-treatment and relapse cells from 13 patients treated with CAR T-cell therapy, 8 of whom developed CD19- relapse and 5 of whom developed CD19+ relapse, we demonstrate that relapse-specific single-nucleotide variants and small indels with high allele frequency combined with deletions in the CD19 gene in a manner specific to those patients with CD19- relapse. Before CAR T-cell infusion, one patient was found to harbor a pre-existing CD19 deletion in the context of genomic instability, which likely represented the first hit leading to the patient's subsequent CD19- relapse. Across patients, preexisting mutations and genomic instability were not significant predictors of subsequent CD19- relapse across patients, with sample size as a potential limiting factor. Together, our results clarify and strengthen the relationship between genomic events and CD19- relapse, demonstrating this intriguing mechanism of resistance to a targeted cancer immunotherapy.


Assuntos
Imunoterapia Adotiva , Linfócitos T , Humanos , Criança , Imunoterapia Adotiva/métodos , Imunoterapia , Recidiva , Antígenos CD19 , Proteínas Adaptadoras de Transdução de Sinal , Genômica , Receptores de Antígenos de Linfócitos T
17.
Environ Pollut ; 313: 120080, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36057326

RESUMO

Ractopamine, a synthetic ß-adrenoreceptor agonist, is used as an animal feed additive to increase food conversion efficiency and accelerate lean mass accretion in farmed animals. The U.S. Food and Drug Administration claimed that ingesting products containing ractopamine residues at legal dosages might not cause short-term harm to human health. However, the effect of ractopamine on chronic inflammatory diseases and atherosclerosis is unclear. Therefore, we investigated the effects of ractopamine on atherosclerosis and its action mechanism in apolipoprotein E-null (apoe-/-) mice and human endothelial cells (ECs) and macrophages. Daily treatment with ractopamine for four weeks increased the body weight and the weight of brown adipose tissues and gastrocnemius muscles. However, it decreased the weight of white adipose tissues in apoe-/- mice. Additionally, ractopamine exacerbated hyperlipidemia and systemic inflammation, deregulated aortic cholesterol metabolism and inflammation, and accelerated atherosclerosis. In ECs, ractopamine treatment induced endothelial dysfunction and increased monocyte adhesion and transmigration across ECs. In macrophages, ractopamine dysregulated cholesterol metabolism by increasing oxidized low-density lipoprotein (oxLDL) internalization and decreasing reverse cholesterol transporters, increasing oxLDL-induced lipid accumulation. Collectively, our findings revealed that ractopamine induces EC dysfunction and deregulated cholesterol metabolism of macrophages, which ultimately accelerates atherosclerosis progression.


Assuntos
Aterosclerose , Células Espumosas , Animais , Apolipoproteínas E/genética , Aterosclerose/induzido quimicamente , Colesterol , Células Endoteliais/metabolismo , Humanos , Inflamação/metabolismo , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Camundongos , Fenetilaminas
18.
Hu Li Za Zhi ; 69(3): 58-67, 2022 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-35644598

RESUMO

BACKGROUND: Myocardial perfusion imaging (MPI) is the method most commonly used to assess patients with suspected coronary artery disease for the presence of myocardial ischemia and risk of subsequent adverse cardiac events. Studies are limited on the incidence of major adverse cardiac event (MACE) in patients with normal MPI results. PURPOSE: The aim of this study was to investigate the incidence and risk factors of MACE in patients with normal or near-normal MPI results. METHODS: In this single-center retrospective chart review study, patients who had received MPI tests at a nuclear medicine department of a medical center in 2017 were consecutively enrolled. All of the participants in this study were patients with normal or near-normal MPI results, and were followed for two years to assess the incidence of MACE (death, hospitalized for percutaneous coronary intervention; CABG, heart failure and stroke). Participants with or without MACE were compared to determine whether demographic, comorbidity, and MPI data were significant risk factors. RESULTS: Of the 1,629 participants (age = 70.4 ± 11.3 years, 49.4% male) enrolled, 387 (23.8%) were classified into the normal MPI group and 1,242 (76.2%) were classified into the near-normal MPI group. Notably, 61 participants (15.8%) in the normal MPI group and 206 (16.6%) in the near-normal MPI group experienced MACE events during the two-year follow-up. The risk factors of MACE identified in this study included being older in age, being male, and having poor myocardial perfusion parameters (i.e., ejection fraction) during MPI. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Over the two-year study period, 15.8% of the participants with normal MPI results and 16.6% of those with near-normal MPI results experienced major adverse cardiac events. Thus, it is critical to inform patients regarding the potential risk of MACE risk and to educate them on how to mitigate this risk by actively managing their hyperlipidemia level and left ventricular ejection fraction.


Assuntos
Doença da Artéria Coronariana , Imagem de Perfusão do Miocárdio , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio/métodos , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda
19.
Nutrients ; 14(11)2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35684129

RESUMO

Bromelain, an enzyme extracted from the stems of pineapples, exerts anticoagulant effects; however, the regulatory mechanisms are not fully understood. Here, we aimed to investigate the effects of bromelain on non-alcoholic fatty liver disease (NAFLD)-induced deregulation of blood coagulation and the underlying molecular mechanisms. C57BL/6 mice were fed a high-fat diet (HFD), with or without bromelain (20 mg/kg/day) administration, for 12 weeks. Treatment with bromelain decreased thrombus formation in the liver and prolonged HFD-induced shortened prothrombin, activated partial thromboplastin, and fibrinogen times. Moreover, liquid chromatography-mass spectrometry/mass spectrometry and Western blot analysis showed that bromelain inhibited NAFLD-induced activation of the intrinsic, extrinsic, and common pathways by upregulating the protein expression of antithrombin III, serpin family G member 1, and α1-antitrypsin, and downregulating the protein expression of fibrinogen in the liver and plasma. Bromelain also upregulated the level of plasminogen and downregulating factor XIII expression in the liver and plasma. Collectively, these findings suggest that bromelain exerts anticoagulant effects on NAFLD-induced deregulation of coagulation by inhibiting the activation of the coagulation cascade, decreasing the stability of clots, and promoting fibrinolytic activity. The present study provides new insights into the potential therapeutic value of bromelain for the prevention and treatment of thrombosis-related diseases.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Anticoagulantes/farmacologia , Coagulação Sanguínea , Bromelaínas/farmacologia , Bromelaínas/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Fibrinogênio/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia
20.
BMC Public Health ; 22(1): 1135, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35668485

RESUMO

BACKGROUND: Electronic cigarettes (e-cigarettes) are relatively new tobacco products that are attracting public attention due to their unique features, especially their many flavor options and their potential as an alternative to cigarettes. However, uncertainties remain regarding the determinants and consequences of e-cigarette use because current research on e-cigarettes is made more difficult due to the lack of psychometrically sound instruments that measure e-cigarette related constructs. This systematic review therefore seeks to identify the instruments in the field that are designed to assess various aspects of e-cigarette use or its related constructs and analyze the evidence presented regarding the psychometric properties of the identified instruments. METHODS: This systematic review utilized six search engines: PubMed, Medline, CINAHL, PsycINFO, Web of Science, and EMBASE, to identify articles published in the peer-reviewed journals from inception to February 2022 that contained development or validation processes for these instruments. RESULTS: Eighteen articles describing the development or validation of 22 unique instruments were identified. Beliefs, perceptions, motives, e-cigarette use, and dependence, were the most commonly assessed e-cigarette related constructs. The included studies reported either construct or criterion validity, with 14 studies reporting both. Most studies did not report the content validity; for reliability, most reported internal consistencies using Cronbach's alpha, with 15 instruments reporting Cronbach's alpha > 0.70 for the scale or its subscales. CONCLUSIONS: Twenty-two instruments with a reported development or validation process to measure e-cigarette related constructs are currently available for practitioners and researchers. This review provides a guide for practitioners and researchers seeking to identify the most appropriate existing instruments on e-cigarette use based on the constructs examined, target population, psychometric properties, and instrument length. The gaps identified in the existing e-cigarette related instruments indicate that future studies should seek to extend the validity of the instruments for diverse populations, including adolescents. Instruments that explore additional aspects of e-cigarette use and e-cigarette related constructs to help build a strong theoretical background and expand our current understanding of e-cigarette use and its related constructs, should also be developed.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Produtos do Tabaco , Adolescente , Humanos , Psicometria , Reprodutibilidade dos Testes
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