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1.
Cell ; 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32437658

RESUMO

Very low-carbohydrate, high-fat ketogenic diets (KDs) induce a pronounced shift in metabolic fuel utilization that elevates circulating ketone bodies; however, the consequences of these compounds for host-microbiome interactions remain unknown. Here, we show that KDs alter the human and mouse gut microbiota in a manner distinct from high-fat diets (HFDs). Metagenomic and metabolomic analyses of stool samples from an 8-week inpatient study revealed marked shifts in gut microbial community structure and function during the KD. Gradient diet experiments in mice confirmed the unique impact of KDs relative to HFDs with a reproducible depletion of bifidobacteria. In vitro and in vivo experiments showed that ketone bodies selectively inhibited bifidobacterial growth. Finally, mono-colonizations and human microbiome transplantations into germ-free mice revealed that the KD-associated gut microbiota reduces the levels of intestinal pro-inflammatory Th17 cells. Together, these results highlight the importance of trans-kingdom chemical dialogs for mediating the host response to dietary interventions.

2.
Gut Microbes ; : 1-15, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32223398

RESUMO

Owing to their health benefits, dietary fermentable fibers, such as refined inulin, are increasingly fortified in processed foods to enhance their nutritional value. However, we previously demonstrated that when inulin was fed to Toll-like receptor 5 deficient (T5KO) mice susceptible to dysbiosis, a subset of them developed cholestasis and subsequently liver cancer in a gut microbiota-dependent manner. Therefore, we hypothesized that clearance of bacterial taxa, and thereby gut metabolites, involved in the onset and progression to liver cancer could abate the disease in these mice. Such a reshaping of microbiota by vancomycin treatment was sufficient to halt the development of liver cancer in inulin-fed T5KO mice; however, this intervention did not remedy disease penetrance for cholestatic liver injury and its sequelae, including hyperbilirubinemia, hypolipidemia, cholemia and liver fibrosis. Selective depletion of gut bacterial communities was observed in vancomycin-treated mice, including Gram-positive Lachnospiraceae and Ruminococcaceae belonging to the phylum Firmicutes, Bifidobacteria of the phylum Actinobacteria, which ferment fibers, and Clostridium cluster XIVa, which produce secondary bile acids. Lack of liver cancer in vancomycin-treated mice strongly correlated with the substantial loss of secondary bile acids in circulation. Although cholemia was unabated by vancomycin, the composition of serum bile acids shifted toward an abundance of hydrophilic primary bile acids, denoted by the increase in conjugated-to-unconjugated bile acid ratio. Taken together, the present study suggests that microbiotal regulation of bile acid metabolism is one of the critical mediators of fermentable fiber-induced liver cancer in dysbiotic mice.

3.
Nat Microbiol ; 5(6): 838-847, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32284564

RESUMO

Initial microbial colonization and later succession in the gut of human infants are linked to health and disease later in life. The timing of the appearance of the first gut microbiome, and the consequences for the early life metabolome, are just starting to be defined. Here, we evaluated the gut microbiome, proteome and metabolome in 88 African-American newborns using faecal samples collected in the first few days of life. Gut bacteria became detectable using molecular methods by 16 h after birth. Detailed analysis of the three most common species, Escherichia coli, Enterococcus faecalis and Bacteroides vulgatus, did not suggest a genomic signature for neonatal gut colonization. The appearance of bacteria was associated with reduced abundance of approximately 50 human proteins, decreased levels of free amino acids and an increase in products of bacterial fermentation, including acetate and succinate. Using flux balance modelling and in vitro experiments, we provide evidence that fermentation of amino acids provides a mechanism for the initial growth of E. coli, the most common early colonizer, under anaerobic conditions. These results provide a deep characterization of the first microbes in the human gut and show how the biochemical environment is altered by their appearance.

4.
Gut Microbes ; : 1-18, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138583

RESUMO

Bile acids are potent antibacterial compounds and play an important role in shaping the microbial ecology of the gut. Here, we combined flow cytometry, growth rate measurements (OD600), and NMR- and mass spectrometry-based metabolomics to systematically profile the impact of bile acids on the microbiome using in vitro and in vivo models. This study confirmed that (1) unconjugated bile acids possess more potent antibacterial activity than conjugated bile acids; (2) Gram-positive bacteria are more sensitive to bile acids than Gram-negative bacteria; (3) some probiotic bacteria such as Lactobacillus and Bifidobacterium and 7α-dehydroxylating bacteria such as Clostridium scindens show bile acid resistance that is associated with activation of glycolysis. Moreover, we demonstrated that (4) as one of most hydrophobic bile acids, lithocholic acid (LCA) shows reduced toxicity to bacteria in the cecal microbiome in both in vivo and in vitro models; (5) bile acids directly and rapidly affect bacterial global metabolism including membrane damage, disrupted amino acid, nucleotide, and carbohydrate metabolism; and (6) in vivo, short-term exposure to bile acids significantly affected host metabolism via alterations of the bacterial community structure. This study systematically profiled interactions between bile acids and gut bacteria providing validation of previous observation and new insights into the interaction of bile acids with the microbiome and mechanisms related to bile acid tolerance.

5.
Cardiovasc Pathol ; 47: 107210, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32142924

RESUMO

Nonbacterial thrombotic endocarditis is a form of a thrombotic angiopathy involving the endothelial lined endocardial surfaces of the heart which includes valves and the chamber walls. Underlying etiologies for nonbacterial thrombotic endocarditis include autoimmune diseases, hypercoagulable states, in the setting of certain malignant neoplasms, and physical injury. The pathogenesis for these processes is that of primary endothelial injury resulting in a thrombotic angiopathy. We present a patient with heart failure being evaluated before hematopoietic stem cell transplantation who had previously been provided with chemotherapy and whose cardiac magnetic resonance imaging reveals findings suggestive of amyloidosis. A subsequent endomyocardial biopsy instead showed nonbacterial thrombotic endocarditis characterized by the endocardium with fibromyxoid thickening and overlying fresh fibrin. This case highlights histopathologic findings of chemotherapy-associated nonbacterial thrombotic endocarditis involving the right ventricle wall of the endocardium, therefore expanding the radiological differential in patients with cardiac magnetic resonance imaging findings suggestive of amyloidosis.

6.
Infect Immun ; 88(6)2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32205405

RESUMO

Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA; ursodiol) inhibits the life cycles of various strains of C. difficile in vitro, suggesting that the FDA-approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose-dependent manner in vitro In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid-activated receptors nuclear farnesoid X receptor (FXR) and transmembrane G-protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable nonantibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid-activated receptors FXR and TGR5 represents a new potential treatment strategy for patients with CDI.

7.
Sci Rep ; 10(1): 1808, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020031

RESUMO

Ferumoxytol is an ultrasmall super paramagnetic particles of iron oxide (USPIO) agent recently used for magnetic resonance (MR) vascular imaging. Other USPIOs have been previously used for assessing inflammation within atheroma. We aim to assess feasibility of ferumoxytol in imaging carotid atheroma (with histological assessment); and the optimum MR imaging time to detect maximum quantitative signal change post-ferumoxytol infusion. Ten patients with carotid artery disease underwent high-resolution MR imaging of their carotid arteries on a 1.5 T MR system. MR imaging was performed before and at 24, 48, 72 and 96 hrs post ferumoxytol infusion. Optimal ferumoxytol uptake time was evaluated by quantitative relaxometry maps indicating the difference in T2* (ΔT2*) and T2 (ΔT2) between baseline and post-Ferumoxytol MR imaging using 3D DANTE MEFGRE qT2*w and iMSDE black-blood qT2w sequences respectively. 20 patients in total (10 symptomatic and 10 with asymptomatic carotid artery disease) had ferumoxytol-enhanced MR imaging at the optimal imaging window. 69 carotid MR imaging studies were completed. Ferumoxytol uptake (determined by a decrease in ΔT2* and ΔT2) was identified in all carotid plaques (symptomatic and asymptomatic). Maximum quantitative decrease in ΔT2* (10.4 [3.5-16.2] ms, p < 0.001) and ΔT2 (13.4 [6.2-18.9] ms; p = 0.001) was found on carotid MR imaging at 48 hrs following the ferumoxytol infusion. Ferumoxytol uptake by carotid plaques was assessed by histopathological analysis of excised atheroma. Ferumoxytol-enhanced MR imaging using quantitative 3D MR pulse sequences allows assessment of inflammation within carotid atheroma in symptomatic and asymptomatic patients. The optimum MR imaging time for carotid atheroma is 48 hrs after its administration.

8.
PLoS One ; 15(2): e0228966, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084167

RESUMO

OBJECTIVE: To assess the value of the inability to walk unassisted to predict hospital mortality in patients with suspected infection in a resource-limited setting. METHODS: This is a post hoc study of a prospective trial performed in rural Rwanda. Patients hospitalized because of a suspected acute infection and who were able to walk unassisted before this disease episode were included. At hospital presentation, the walking status was graded into: 1) can walk unassisted, 2) can walk assisted only, 3) cannot walk. Receiver operating characteristic (ROC) analyses and two-by-two tables were used to determine the sensitivity, specificity, negative and positive predictive values of the inability to walk unassisted to predict in-hospital death. RESULTS: One-thousand-sixty-nine patients were included. Two-hundred-one (18.8%), 315 (29.5%), and 553 (51.7%) subjects could walk unassisted, walk assisted or not walk, respectively. Their hospital mortality was 0%, 3.8% and 6.3%, respectively. The inability to walk unassisted had a low specificity (20%) but was 100% sensitive (CI95%, 90-100%) to predict in-hospital death (p = 0.00007). The value of the inability to walk unassisted to predict in-hospital mortality (AUC ROC, 0.636; CI95%, 0.564-0.707) was comparable to that of the qSOFA score (AUC ROC, 0.622; CI95% 0.524-0.728). Fifteen (7.5%), 34 (10.8%) and 167 (30.2%) patients who could walk unassisted, walk assisted or not walk presented with a qSOFA score count ≥2 points, respectively (p<0.001). The inability to walk unassisted correlated with the presence of risk factors for death and danger signs, vital parameters, laboratory values, length of hospital stay, and costs of care. CONCLUSIONS: Our results suggest that the inability to walk unassisted at hospital admission is a highly sensitive predictor of in-hospital mortality in Rwandese patients with a suspected acute infection. The walking status at hospital admission appears to be a crude indicator of disease severity.


Assuntos
Testes Diagnósticos de Rotina/métodos , Índice de Gravidade de Doença , Triagem/métodos , Adolescente , Adulto , Área Sob a Curva , Criança , Feminino , Mortalidade Hospitalar/tendências , Hospitalização , Humanos , Infecções , Unidades de Terapia Intensiva/tendências , Tempo de Internação , Masculino , Prognóstico , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Ruanda/epidemiologia , Sensibilidade e Especificidade , Sepse/mortalidade , Caminhada/fisiologia
9.
Proc Natl Acad Sci U S A ; 117(4): 2092-2098, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31964840

RESUMO

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.

10.
Toxicology ; 431: 152365, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926186

RESUMO

Perfluorooctane sulfonate (PFOS) is a persistent environmental chemical whose biological effects are mediated by multiple mechanisms. Recent evidence suggests that the gut microbiome may be directly impacted by and/or alter the fate and effects of environmental chemicals in the host. Thus, the aim of this study was to determine whether PFOS influences the gut microbiome and its metabolism, and the host metabolome. Four groups of male C57BL/6 J mice were fed a diet with or without 0.003 %, 0.006 %, or 0.012 % PFOS, respectively. 16S rRNA gene sequencing, metabolomic, and molecular analyses were used to examine the gut microbiota of mice after dietary PFOS exposure. Dietary PFOS exposure caused a marked change in the gut microbiome compared to controls. Dietary PFOS also caused dose-dependent changes in hepatic metabolic pathways including those involved in lipid metabolism, oxidative stress, inflammation, TCA cycle, glucose, and amino acid metabolism. Changes in the metabolome correlated with changes in genes that regulate these pathways. Integrative analyses also demonstrated a strong correlation between the alterations in microbiota composition and host metabolic profiles induced by PFOS. Further, using isolated mouse cecal contents, PFOS exposure directly affected the gut microbiota metabolism. Results from these studies demonstrate that the molecular and biochemical changes induced by PFOS are mediated in part by the gut microbiome, which alters gene expression and the host metabolome in mice.

12.
Eur Radiol ; 30(3): 1436-1450, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31786616

RESUMO

The European Society of Breast Radiology (EUSOBI) established an International Breast DWI working group. The working group consists of clinical breast MRI experts, MRI physicists, and representatives from large vendors of MRI equipment, invited based upon proven expertise in breast MRI and/or in particular breast DWI, representing 25 sites from 16 countries. The aims of the working group are (a) to promote the use of breast DWI into clinical practice by issuing consensus statements and initiate collaborative research where appropriate; (b) to define necessary standards and provide practical guidance for clinical application of breast DWI; (c) to develop a standardized and translatable multisite multivendor quality assurance protocol, especially for multisite research studies; (d) to find consensus on optimal methods for image processing/analysis, visualization, and interpretation; and (e) to work collaboratively with system vendors to improve breast DWI sequences. First consensus recommendations, presented in this paper, include acquisition parameters for standard breast DWI sequences including specifications of b values, fat saturation, spatial resolution, and repetition and echo times. To describe lesions in an objective way, levels of diffusion restriction/hindrance in the breast have been defined based on the published literature on breast DWI. The use of a small ROI placed on the darkest part of the lesion on the ADC map, avoiding necrotic, noisy or non-enhancing lesion voxels is currently recommended. The working group emphasizes the need for standardization and quality assurance before ADC thresholds are applied. The working group encourages further research in advanced diffusion techniques and tailored DWI strategies for specific indications. Key Points • The working group considers breast DWI an essential part of a multiparametric breast MRI protocol and encourages its use. • Basic requirements for routine clinical application of breast DWI are provided, including recommendations on b values, fat saturation, spatial resolution, and other sequence parameters. • Diffusion levels in breast lesions are defined based on meta-analysis data and methods to obtain a reliable ADC value are detailed.

13.
Cell Metab ; 31(1): 115-130.e6, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31708445

RESUMO

Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.

14.
Pediatr Crit Care Med ; 20(12): e524-e530, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31805020

RESUMO

OBJECTIVES: To deploy machine learning tools (random forests) to develop a model that reliably predicts hospital mortality in children with acute infections residing in low- and middle-income countries, using age and other variables collected at hospital admission. DESIGN: Post hoc analysis of a single-center, prospective, before-and-after feasibility trial. SETTING: Rural district hospital in Rwanda, a low-income country in Sub-Sahara Africa. PATIENTS: Infants and children greater than 28 days and less than 18 years of life hospitalized because of an acute infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Age, vital signs (heart rate, respiratory rate, and temperature) capillary refill time, altered mental state collected at hospital admission, as well as survival status at hospital discharge were extracted from the trial database. This information was collected for 1,579 adult and pediatric patients admitted to a regional referral hospital with an acute infection in rural Rwanda. Nine-hundred forty-nine children were included in this analysis. We predicted survival in study subjects using random forests, a machine learning algorithm. Five prediction models, all including age plus two to five other variables, were tested. Three distinct optimization criteria of the algorithm were then compared. The in-hospital mortality was 1.5% (n = 14). All five models could predict in-hospital mortality with an area under the receiver operating characteristic curve ranging between 0.69 and 0.8. The model including age, respiratory rate, capillary refill time, altered mental state exhibited the highest predictive value area under the receiver operating characteristic curve 0.8 (95% CI, 0.78-0.8) with the lowest possible number of variables. CONCLUSIONS: A machine learning-based algorithm could reliably predict hospital mortality in a Sub-Sahara African population of 949 children with an acute infection using easily collected information at admission which includes age, respiratory rate, capillary refill time, and altered mental state. Future studies need to evaluate and strengthen this algorithm in larger pediatric populations, both in high- and low-/middle-income countries.

17.
Clin Cosmet Investig Dermatol ; 12: 625-637, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564944

RESUMO

Background:  New military members undergo a highly-regimented 7-week training course during which trainees live and work within the same group of approximately 50 subjects for nearly 24 hours a day. This creates an optimal environment for assessing the impact of communal living on the collective skin microbiome. Purpose : The objective of this pilot study was to investigate dynamic changes of the skin microbiome in basic military trainees (BMT), in light of the unique environmental influences faced by this population. Patients and methods:  We evaluated collective changes in the skin microbiome of normal healthy adult basic trainees in response to communal living and universal Group A Strep prophylaxis with penicillin over the course of their initial 7-week training course. Samples from 10 flights of trainees were collected by swabbing upon arrival at Lackland AFB for their training (week 0) which is prior to prophylaxis with penicillin, at the 4 week point, and at the conclusion of their 7-week course of basic military training. Three separate high-throughput sequencing platforms and three bioinformatic pipeline analysis tools were utilized to assess the data. Results : At all three time points we found that the top three bacterial genus identified were Propionibacterium, Staphylococcus, and Corynebacterium. We detected a community membership difference between the initial week 0 samples and the week 4 and 7 samples. A strong inverse correlation between Propionibacterium and Staphylococcus was noted with Propionibacterium being high at week 0 and much lower at weeks 4 and 7; conversely, Staphylococcus was low at week 0 and higher at weeks 4 and 7, this relationship was noted in both the individual and collective specimens. Conclusion : The collective dermatologic microbiome in the military trainee population examined exhibited a relative increase in Staphylococcus and Corynebacterium abundance coupled with a relative decrease in Propionibacterium abundance in this observational pilot study. Additional studies are needed to further assess the causal impact of communal living and widespread penicillin chemoprophylaxis.

18.
Sci Rep ; 9(1): 14132, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575956

RESUMO

Transient receptor potential melastatin channel subfamily member 2 (TRPM2) has an essential role in protecting cell viability through modulation of oxidative stress. TRPM2 is highly expressed in cancer. When TRPM2 is inhibited, mitochondria are dysfunctional, ROS levels are increased, and cell viability is reduced. Here, the importance of NF-E2-related factor (Nrf2) in TRPM2-mediated suppression of oxidant stress was explored. In TRPM2 depleted cells, antioxidant cofactors glutathione, NADPH, and NADH were significantly reduced. Cytoplasmic and nuclear expression of Nrf2 and of IQGAP1, a modulator of Nrf2 stability regulated by intracellular calcium, were decreased. Antioxidant enzymes transcriptionally regulated by Nrf2 and involved in GSH, NADPH, and NADH generation were significantly lower including PRX1 and PRX3, GPX4, GSTP1, GCLC, and MTHFD2. The glutamine pathway leading to GSH production was suppressed, and ATP and GTP levels were impaired. Reconstitution with wild type TRPM2 or Nrf2, but not TRPM2 pore mutant E960D, rescued expression of enzymes downstream of Nrf2 and restored GSH and GTP. Cell viability, ROS, NADPH, NADH, and ATP levels were fully rescued by TRPM2 and partially by Nrf2. These data show that TRPM2 maintains cell survival following oxidative stress through modulation of antioxidant pathways and cofactors regulated by Nrf2.

19.
NPJ Precis Oncol ; 3: 26, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602402

RESUMO

The peroxisome proliferator-activated-ß/δ (PPARß/δ) was identified in 1994, but not until 1999 was PPARß/δ suggested to be involved in carcinogenesis. Initially, it was hypothesized that expression of PPARß/δ was increased during colon cancer progression, which led to increased transcription of yet-to-be confirmed target genes that promote cell proliferation and tumorigenesis. It was also hypothesized at this time that lipid-metabolizing enzymes generated lipid metabolites that served as ligands for PPARß/δ. These hypothetical mechanisms were attractive because they potentially explained how non-steroidal anti-inflammatory drugs inhibited tumorigenesis by potentially limiting the concentration of endogenous PPARß/δ ligands that could activate this receptor that was increased in cancer cells. However, during the last 20 years, considerable research was undertaken describing expression of PPARß/δ in normal and cancer cells that has led to a significant impact on the mechanisms by which PPARß/δ functions in carcinogenesis. Whereas results from earlier studies led to much uncertainty about the role of PPARß/δ in cancer, more recent analyses of large databases have revealed a more consistent understanding. The focus of this review is on the fundamental level of PPARß/δ expression in normal tissues and cancerous tissue as described by studies during the past two decades and what has been delineated during this timeframe about how PPARß/δ expression influences carcinogenesis, with an emphasis on colon cancer.

20.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533250

RESUMO

Some parasites have evolved the ability to adaptively manipulate host behavior. One notable example is the fungus Ophiocordyceps unilateralis sensu lato, which has evolved the ability to alter the behavior of ants in ways that enable fungal transmission and lifecycle completion. Because host mandibles are affected by the fungi, we focused on understanding changes in the metabolites of muscles during behavioral modification. We used High-Performance Liquid Chromatography-Mass/Mass (HPLC-MS/MS) to detect the metabolite difference between controls and O. unilateralis-infected ants. There was a significant difference between the global metabolome of O. unilateralis-infected ants and healthy ants, while there was no significant difference between the Beauveria bassiana treatment ants group compared to the healthy ants. A total of 31 and 16 of metabolites were putatively identified from comparisons of healthy ants with O. unilateralis-infected ants and comparisons of B. bassiana with O. unilateralis-infected samples, respectively. This result indicates that the concentrations of sugars, purines, ergothioneine, and hypoxanthine were significantly increased in O. unilateralis-infected ants in comparison to healthy ants and B. bassiana-infected ants. This study provides a comprehensive metabolic approach for understanding the interactions, at the level of host muscles, between healthy ants and fungal parasites.


Assuntos
Ascomicetos/fisiologia , Interações Hospedeiro-Patógeno , Mandíbula , Músculos da Mastigação/microbiologia , Animais , Formigas , Espectrometria de Massas , Músculos da Mastigação/metabolismo , Metaboloma , Metabolômica/métodos , Micoses/metabolismo , Micoses/microbiologia , Espectrometria de Massas em Tandem
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