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1.
Am J Physiol Lung Cell Mol Physiol ; 326(3): L252-L265, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38226418

RESUMO

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by significant lung endothelial cell (EC) dysfunction. Prior work has shown that microvascular endothelial cells (MVECs) isolated from animals with experimental PAH and patients with PAH exhibit significant abnormalities in metabolism and calcium signaling. With regards to metabolism, we and others have shown evidence of increased aerobic glycolysis and evidence of increased utilization of alternate fuel sources (such as fatty acids) in PAH EC. In the realm of calcium signaling, our prior work linked increased activity of the transient receptor potential vanilloid-4 (TRPV4) channel to increased proliferation of MVECs isolated from the Sugen/Hypoxia rat model of PAH (SuHx-MVECs). However, the relationship between metabolic shifts and calcium abnormalities was not clear. Specifically, whether shifts in metabolism were responsible for increasing TRPV4 channel activity in SuHx-MVECs was not known. In this study, using human data, serum samples from SuHx rats, and SuHx-MVECs, we describe the consequences of increased MVEC fatty acid oxidation in PAH. In human samples, we observed an increase in long-chain fatty acid levels that was associated with PAH severity. Next, using SuHx rats and SuHx-MVECs, we observed increased intracellular levels of lipids. We also show that increasing intracellular lipid content increases TRPV4 activity, whereas inhibiting fatty acid oxidation normalizes basal calcium levels in SuHx-MVECs. By exploring the fate of fatty acid-derived carbons, we observed that the metabolite linking increased intracellular lipids to TRPV4 activity was ß-hydroxybutyrate (BOHB), a product of fatty acid oxidation. Finally, we show that BOHB supplementation alone is sufficient to sensitize the TRPV4 channel in rat and mouse MVECs. Returning to humans, we observe a transpulmonary BOHB gradient in human patients with PAH. Thus, we establish a link between fatty acid oxidation, BOHB production, and TRPV4 activity in MVECs in PAH. These data provide new insight into metabolic regulation of calcium signaling in lung MVECs in PAH.NEW & NOTEWORTHY In this paper, we explore the link between metabolism and intracellular calcium levels in microvascular endothelial cells (MVECs) in pulmonary arterial hypertension (PAH). We show that fatty acid oxidation promotes sensitivity of the transient receptor potential vanilloid-4 (TRPV4) calcium channel in MVECs isolated from a rodent model of PAH.


Assuntos
Antineoplásicos , Hipertensão Arterial Pulmonar , Animais , Humanos , Camundongos , Ratos , Cálcio/metabolismo , Células Endoteliais/metabolismo , Hipertensão Pulmonar Primária Familiar/metabolismo , Ácidos Graxos/metabolismo , Lipídeos , Pulmão/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Canais de Cátion TRPV/metabolismo
2.
Prostate ; 84(7): 644-655, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38409853

RESUMO

BACKGROUND: Lipid reprogramming is a known mechanism to increase the energetic demands of proliferating cancer cells to drive and support tumorigenesis and progression. Elevated lipid droplets (LDs) are a well-known alteration of lipid reprogramming in many cancers, including prostate cancer (PCa), and are associated with high tumor aggressiveness as well as therapy resistance. The mechanism of LD accumulation and specific LD functions are still not well understood; however, it has been shown that LDs can form as a protective mechanism against lipotoxicity and lipid peroxidation in the cell. METHODS: This study investigated the significance of LDs in PCa. This was done by staining, imaging, image quantification, and flow cytometry analysis of LDs in PCa cells. Additionally, lipidomics and metabolomics experiments were performed to assess the difference of metabolites and lipids in control and treatment surviving cancer cells. Lastly, to assess clinical significance, multiple publicly available datasets were mined for LD-related data. RESULTS: Our study demonstrated that prostate and breast cancer cells that survive 72 h of chemotherapy treatment have elevated LDs. These LDs formed in tandem with elevated reactive oxygen species levels to sequester damaged and excess lipids created by oxidative stress, which promoted cell survival. Additionally, by inhibiting diacylglycerol O-acyltransferase 1 (DGAT1) (which catalyzes triglyceride synthesis into LDs) and treating with chemotherapy simultaneously, we were able to decrease the overall amount of LDs and increase cancer cell death compared to treating with chemotherapy alone. CONCLUSIONS: Overall, our study proposes a potential combination therapy of DGAT1 inhibitors and chemotherapy to increase cancer cell death.


Assuntos
Gotículas Lipídicas , Neoplasias da Próstata , Masculino , Humanos , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Próstata/patologia , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia
3.
Front Immunol ; 15: 1354128, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38558806

RESUMO

Importance: Disease models for atopic dermatitis (AD) have primarily focused on understanding underlying environmental, immunologic, and genetic etiologies. However, the role of metabolic mechanisms in AD remains understudied. Objective: To investigate the circulating blood metabolomic and cytokine profile of AD as compared to healthy control patients. Design: This study collected plasma from 20 atopic dermatitis with moderate-to-severe itch (score of ≥5 on the itch Numeric Rating Scale and IGA score ≥3) and 24 healthy control patients. Mass-spectrometry based metabolite data were compared between AD and healthy controls. Unsupervised and supervised machine learning algorithms and univariate analysis analyzed metabolic concentrations. Metabolite enrichment and pathway analyses were performed on metabolites with significant fold change between AD and healthy control patients. To investigate the correlation between metabolites levels and cytokines, Spearman's rank correlation coefficients were calculated between metabolites and cytokines. Setting: Patients were recruited from the Johns Hopkins Itch Center and dermatology outpatient clinics in the Johns Hopkins Outpatient Center. Participants: The study included 20 atopic dermatitis patients and 24 healthy control patients. Main outcomes and measures: Fold changes of metabolites in AD vs healthy control plasma. Results: In patients with AD, amino acids isoleucine, tyrosine, threonine, tryptophan, valine, methionine, and phenylalanine, the amino acid derivatives creatinine, indole-3-acrylic acid, acetyl-L-carnitine, L-carnitine, 2-hydroxycinnamic acid, N-acetylaspartic acid, and the fatty amide oleamide had greater than 2-fold decrease (all P-values<0.0001) compared to healthy controls. Enriched metabolites were involved in branched-chain amino acid (valine, leucine, and isoleucine) degradation, catecholamine biosynthesis, thyroid hormone synthesis, threonine metabolism, and branched and long-chain fatty acid metabolism. Dysregulated metabolites in AD were positively correlated cytokines TARC and MCP-4 and negatively correlated with IL-1a and CCL20. Conclusions and relevance: Our study characterized novel dysregulated circulating plasma metabolites and metabolic pathways that may be involved in the pathogenesis of AD. These metabolic pathways serve as potential future biomarkers and therapeutic targets in the treatment of AD.


Assuntos
Dermatite Atópica , Humanos , Citocinas/metabolismo , Isoleucina , Prurido , Valina , Treonina
4.
Sci Rep ; 14(1): 17472, 2024 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-39080299

RESUMO

Chronic pruritus of unknown origin (CPUO) is characterized by chronic itch for 6 weeks or greater without an identifiable primary cause. Studies are needed to investigate circulating blood biomarkers to elucidate disease pathogenesis. The objective of this study was to investigate changes in circulating blood metabolites in CPUO patients and to identify potential therapeutic targets. Our cross-sectional study collected plasma from 11 CPUO patients and 11 matched control patients for mass-spectrometry based metabolite data analysis. 15 metabolites differed significantly in the blood of CPUO patients compared to controls, including nine amino acids (isoleucine, L-tyrosine, threonine, DL-tryptophan, L-valine, methionine, glycine, lysine, and L-phenylalanine), four amino acid derivatives (creatinine, DL-carnitine, acetyl-L-carnitine, and indole-3-acrylic acid), and two aromatic and fatty acid derivatives (2-hydroxycinnamic acid and oleamide). These metabolites were also correlated with itch severity. Metabolic set enrichment analysis (MSEA) identified downregulation of several pathways in CPUO: phenylalanine, tyrosine, tryptophan biosynthesis; catecholamine biosynthesis; and glycine, serine, and threonine metabolism. Our study identified decreases in several circulating plasma metabolites in CPUO patients and downregulation of pathways related to catecholamine biosynthesis and tryptophan biosynthesis, providing insight into the pathogenesis of CPUO.


Assuntos
Biomarcadores , Metabolômica , Prurido , Humanos , Biomarcadores/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Prurido/sangue , Prurido/etiologia , Metabolômica/métodos , Adulto , Idoso , Doença Crônica , Estudos Transversais , Estudos de Casos e Controles , Metaboloma , Aminoácidos/sangue
5.
Aging Cell ; 23(4): e14102, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38481042

RESUMO

Tryptophan catabolism is highly conserved and generates important bioactive metabolites, including kynurenines, and in some animals, NAD+. Aging and inflammation are associated with increased levels of kynurenine pathway (KP) metabolites and depleted NAD+, factors which are implicated as contributors to frailty and morbidity. Contrastingly, KP suppression and NAD+ supplementation are associated with increased life span in some animals. Here, we used DGRP_229 Drosophila to elucidate the effects of KP elevation, KP suppression, and NAD+ supplementation on physical performance and survivorship. Flies were chronically fed kynurenines, KP inhibitors, NAD+ precursors, or a combination of KP inhibitors with NAD+ precursors. Flies with elevated kynurenines had reduced climbing speed, endurance, and life span. Treatment with a combination of KP inhibitors and NAD+ precursors preserved physical function and synergistically increased maximum life span. We conclude that KP flux can regulate health span and life span in Drosophila and that targeting KP and NAD+ metabolism can synergistically increase life span.


Assuntos
Cinurenina , Triptofano , Animais , Cinurenina/metabolismo , Triptofano/metabolismo , Longevidade , NAD/metabolismo , Drosophila/metabolismo
6.
Cell Rep Med ; 5(5): 101547, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38703764

RESUMO

Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC from MTSCC. This study expands our knowledge of proteogenomic signatures, biomarkers, and potential therapeutic targets in non-ccRCC.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Neoplasias Renais , Proteogenômica , Humanos , Proteogenômica/métodos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Transcriptoma/genética , Masculino , Feminino , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica
7.
Can Commun Dis Rep ; 49(11-12): 477-486, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-38504874

RESUMO

Background: The bacteria Mycoplasma genitalium has been identified as a causative agent of urethritis in men, especially in gay, bisexual and other men who have sex with men (gbMSM). Canadian clinic-based data have identified a high prevalence of M. genitalium and resistance to antibiotic treatments. This article estimates the prevalence of M. genitalium infections among Montréal gbMSM, explores correlates for M. genitalium infection and estimates the prevalence of mutations associated with antimicrobial resistance (AMR). Methods: Engage Cohort Study is a multi-site longitudinal study on sexually active gbMSM, aged 16 years and older, recruited via respondent-driven sampling in Montréal, Toronto and Vancouver. Participants completed a questionnaire on behaviour and were tested for sexually transmitted and blood-borne infections at each visit. For this sub-study, Montréal participants with a follow-up visit that occurred between November 2018 and November 2019 were included. Results: A total of 2,064 samples were provided by 716 participants. Prevalence of M. genitalium infection was 5.7% at rectal and/or urethral sites, 4.0% at rectal site and 2.2% at urethral site. Correlates for M. genitalium infection were younger age and reporting six or more sexual partners in the past six months. Prevalence of macrolide resistance associated mutations (MRAM), quinolone resistance associated mutations (QRAM) and either MRAM or QRAM, was 82%, 29% and 85%, respectively. Conclusion: This first population-based study among gbMSM in Canada documents a high prevalence of urethral and rectal M. genitalium infection and high levels of AMR. Our results highlight the importance of access to testing and AMR detection when indicated.

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