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1.
J Hepatol ; 72(3): 391-400, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31606552

RESUMO

BACKGROUND & AIMS: Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease. METHODS: C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin. RESULTS: The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the ß-glucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis. CONCLUSIONS: Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis. LAY SUMMARY: Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the ß-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.

2.
Proc Natl Acad Sci U S A ; 116(30): 15184-15193, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31289229

RESUMO

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates glucose, lipid, and energy homeostasis. While gene expression of FGF21 is regulated by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha in the fasted state, little is known about the regulation of trafficking and secretion of FGF21. We show that mice with a mutation in the Yip1 domain family, member 6 gene (Klein-Zschocher [KLZ]; Yipf6 KLZ/Y ) on a high-fat diet (HFD) have higher plasma levels of FGF21 than mice that do not carry this mutation (controls) and hepatocytes from Yipf6 KLZ/Y mice secrete more FGF21 than hepatocytes from wild-type mice. Consequently, Yipf6 KLZ/Y mice are resistant to HFD-induced features of the metabolic syndrome and have increased lipolysis, energy expenditure, and thermogenesis, with an increase in core body temperature. Yipf6 KLZ/Y mice with hepatocyte-specific deletion of FGF21 were no longer protected from diet-induced obesity. We show that YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies packaging of FGF21 into coat protein complex II (COPII) vesicles during development of obesity in mice. Levels of YIPF6 protein in human liver correlate with hepatic steatosis and correlate inversely with levels of FGF21 in serum from patients with nonalcoholic fatty liver disease (NAFLD). YIPF6 is therefore a newly identified regulator of FGF21 secretion during development of obesity and could be a target for treatment of obesity and NAFLD.

3.
Dig Dis Sci ; 64(7): 1878-1892, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31076986

RESUMO

BACKGROUND: Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease. AIMS: (1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease. METHODS: We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid, and docosahexaenoic acid in a patient cohort with alcohol-related liver disease. RESULTS: Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease score. Especially, higher level of serum 20-HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality. CONCLUSIONS: Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.


Assuntos
Alcoolismo/sangue , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Fezes/química , Hepatite Alcoólica/sangue , Oxilipinas/sangue , Adulto , Idoso , Alcoolismo/diagnóstico , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Feminino , Hepatite Alcoólica/diagnóstico , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
4.
Gut ; 68(8): 1504-1515, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30448775

RESUMO

OBJECTIVE: Antimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease. DESIGN: Interleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model). RESULTS: In a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered Lactobacillus reuteri to produce IL-22 (L. reuteri/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, L. reuteri/IL-22 did not reduce ethanol-induced liver disease in Reg3g-/- mice. CONCLUSION: Ethanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.


Assuntos
Disbiose , Etanol , Microbioma Gastrointestinal/fisiologia , Interleucinas/imunologia , Intestino Delgado/imunologia , Lactobacillus reuteri/imunologia , Hepatopatias Alcoólicas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Modelos Animais de Doenças , Disbiose/complicações , Disbiose/etiologia , Disbiose/imunologia , Etanol/efeitos adversos , Etanol/metabolismo , Imunidade Inata , Ácidos Indolacéticos/metabolismo , Inflamação/metabolismo , Hepatopatias Alcoólicas/imunologia , Hepatopatias Alcoólicas/microbiologia , Hepatopatias Alcoólicas/terapia , Camundongos , Camundongos Knockout , Proteínas Associadas a Pancreatite/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo
5.
J Invest Dermatol ; 138(11): 2355-2364, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29964032

RESUMO

Inflammatory acne vulgaris afflicts hundreds of millions of people globally. Propionibacterium acnes, an opportunistic skin bacterium, has been linked to the pathogenesis of acne vulgaris. Our results show that a secretory Christie-Atkins-Munch-Petersen (CAMP) factor of P. acnes is up-regulated in anaerobic cultures. Mutation of CAMP factor significantly diminishes P. acnes colonization and inflammation in mice, demonstrating the essential role of CAMP factor in the cytotoxicity of P. acnes. Vaccination of mice with CAMP factor considerably reduced the growth of P. acnes and production of MIP-2, a murine counterpart of human IL-8. Acne lesions were collected from patients to establish an ex vivo acne model for validation of the efficacy of CAMP factor antibodies in the neutralization of the acne inflammatory response. The P. acnes CAMP factor and two proinflammatory cytokines (IL-8 and IL-1ß) were expressed at higher levels in acne lesions than those in nonlesional skin. Incubation of ex vivo acne explants with monoclonal antibodies to CAMP factor markedly attenuated the amounts of IL-8 and IL-1ß. Our work using an ex vivo acne model shows that P. acnes CAMP factor is an essential source of inflammation in acne vulgaris.


Assuntos
Acne Vulgar/imunologia , Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Proteínas Hemolisinas/imunologia , Propionibacterium acnes/fisiologia , Pele/patologia , Fatores de Virulência/imunologia , Acne Vulgar/genética , Animais , Anticorpos Bloqueadores/farmacologia , Proteínas de Bactérias/genética , Células Cultivadas , Quimiocina CXCL2/metabolismo , Feminino , Proteínas Hemolisinas/genética , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Mutação , Propionibacterium acnes/patogenicidade , Pele/microbiologia , Vacinação , Virulência , Fatores de Virulência/genética
6.
Hepatol Commun ; 2(4): 393-406, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29619418

RESUMO

C-type regenerating islet derived-3 (Reg3) lectins defend against pathogens and keep commensal bacteria at a distance. Deficiency of Reg3g and Reg3b facilitates alcohol-induced bacterial translocation and alcoholic liver disease. Intestinal Reg3g is down-regulated in animal models of diet-induced obesity, but the functional consequences for nonalcoholic steatohepatitis (NASH) are unknown. The aim of this study was to investigate the role of Reg3 lectins in NASH. NASH was induced by a Western-style fast-food diet in mice deficient for Reg3g or Reg3b and in transgenic mice overexpressing Reg3g in intestinal epithelial cells (Reg3gTg). Glucose tolerance was assessed after 18 weeks and insulin resistance after 19 weeks of feeding. After 20 weeks, mice were assessed for features of the metabolic syndrome. Obesity was not different in genetically modified mice compared with their respective wild-type littermates. Glucose intolerance, liver injury, hepatic inflammation, steatosis, fibrosis, and bacterial translocation to mesenteric lymph nodes and to the liver were not different in Reg3g-deficient mice compared with wild-type littermates. Plasma endotoxin levels were higher in Reg3g-deficient mice. Reg3b deficiency protected against glucose intolerance, but liver disease, bacterial translocation, and plasma endotoxin levels were similar to wild-type littermates. Absence of either REG3G or REG3B protein in the ileum was not compensated for by up-regulation of the respective other REG3 protein. Transgenic Reg3g mice also developed liver injury, steatosis, and fibrosis similar to their wild-type littermates. Conclusion: In contrast to alcoholic liver disease, loss of intestinal Reg3 lectins is not sufficient to aggravate diet-induced obesity and NASH. This supports a multi-hit pathogenesis in NASH. Only glucose metabolism is affected by Reg3b deficiency. (Hepatology Communications 2018;2:393-406).

7.
J Immunol Res ; 2018: 3710961, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29577048

RESUMO

Transgene introgression is a major concern associated with transgenic plant-based vaccines. Agroinfiltration can be used to selectively transform nonreproductive organs and avoid introgression. Here, we introduce a new vaccine modality in which Staphylococcal enterotoxin B (SEB) genes are agroinfiltrated into radishes (Raphanw sativus L.), resulting in transient expression and accumulation of SEB in planta. This approach can simultaneously express multiple antigens in a single leaf. Furthermore, the potential of high-throughput vaccine production was demonstrated by simultaneously agroinfiltrating multiple radish leaves using a multichannel pipette. The expression of SEB was detectable in two leaf cell types (epidermal and guard cells) in agroinfiltrated leaves. ICR mice intranasally immunized with homogenized leaves agroinfiltrated with SEB elicited detectable antibody to SEB and displayed protection against SEB-induced interferon-gamma (IFN-γ) production. The concept of encapsulating antigens in leaves rather than purifying them for immunization may facilitate rapid vaccine production during an epidemic disease.


Assuntos
Enterotoxinas/genética , Epiderme Vegetal/genética , Extratos Vegetais/imunologia , Folhas de Planta/genética , Raphanus , Staphylococcus aureus/genética , Vacinas/imunologia , Animais , Anticorpos Antibacterianos/sangue , Células Cultivadas , Enterotoxinas/imunologia , Imunidade Humoral , Camundongos , Camundongos Endogâmicos ICR , Plantas Geneticamente Modificadas/genética , Engenharia de Proteínas , Staphylococcus aureus/imunologia
8.
Medicine (Baltimore) ; 96(49): e9179, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29245366

RESUMO

Many trials have shown improvements in left ventricular function, exercise capacity, and quality of life after catheter ablation (CA) of atrial fibrillation (AF) in patients with heart failure (HF). We sought to evaluate the impact of CA on hard outcomes in a retrospective cohort study. AF patients with symptomatic HF from 3 hospitals were included. Our primary endpoint was major adverse cardiac events (MACEs), a composite of all-cause mortality, stroke, and unplanned hospitalization. In total, 90 patients underwent CA and 304 ones received rate control (RaC) were included. After a mean follow-up of 13.5 ±â€Š5.3 months, 82.2% of patients in CA group got freedom from AF; all patients in RaC group remained in AF. CA group had a significant decreased risk of MACEs compared with RaC group (13.3% vs 29.3%, hazard ratio [HR] 0.51, 95% confidence interval [CI]: 0.32-0.82, P = .005). After propensity score matched for confounding factors, difference in MACEs remained significant between groups (13.3% vs 25.6%, HR 0.50, 95% CI: 0.26-0.98, P = .044). Multivariate regression analysis also indicated that CA was significantly associated with a lower risk of MACEs in overall cohort (HR 0.486, 95% CI: 0.253-0.933, P = .030) and in propensity-matched cohort (HR 0.482, 95% CI: 0.235-0.985, P = .045). Besides, age and NYHA class were associated with an increased risk of MACEs. In conclusion, the present study demonstrated that CA for AF in HF patients could reduce the risk of MACEs in a mid-term follow-up. Thus, CA may be a reasonable option for this population.


Assuntos
Fibrilação Atrial/complicações , Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Insuficiência Cardíaca/complicações , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco
9.
J Nat Sci ; 3(2)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28492063

RESUMO

There is a need for a fast and simple method for vaccine production to keep up with the pace of a rapidly spreading virus in the early phases of the influenza pandemic. The use of whole viruses produced in chicken eggs or recombinant antigens purified from various expression systems has presented considerable challenges, especially with lengthy processing times. Here, we use the killed but metabolically active (KBMA) Escherichia coli (E. coli) to harbor the hemagglutinin (HA) of swine origin influenza A (H1N1) virus (S-OIV) San Diego/01/09 (SD/H1N1-S-OIV). Intranasal vaccination of mice with KBMA E. coli SD/H1N1-S-OIV HA without adding exogenous adjuvants provoked detectable neutralizing antibodies against the virus-induced hemagglutination within three weeks. Boosting vaccination enhanced the titers of neutralizing antibodies, which can decrease viral infectivity in Madin-Darby canine kidney (MDCK) cells. The antibodies were found to specifically neutralize the SD/H1N1-S-OIV-, but not seasonal influenza viruses (H1N1 and H3N2), -induced hemagglutination. The use of KBMA E. coli as an egg-free system to produce anti-influenza vaccines makes unnecessary the rigorous purification of an antigen prior to immunization, providing an alternative modality to combat influenza virus in future outbreaks.

10.
J Invest Dermatol ; 137(1): 46-56, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27498050

RESUMO

We show that Staphylococcus epidermidis, a commensal bacterium in the human skin microbiome, produces short-chain fatty acids by glycerol fermentation that can induce adipogenesis. Although the antimicrobial and anti-inflammatory activities of short-chain fatty acids have been previously well characterized, little is known about the contribution of short-chain fatty acids to the adipogenic differentiation of adipose-derived stem cells (ADSCs). We show that ADSCs differentiated into adipocytes and accumulated lipids in the cytoplasm when cultured with butyric acid, a principal short-chain fatty acid in the fermentation metabolites of S. epidermidis. Additionally, a co-drug, butyric acid 2-(2-butyryloxyethoxy) ethyl ester (BA-DEG-BA), released active butyric acid when it was intradermally injected into mouse ears and induced ADSC differentiation, characterized by an increased expression of cytoplasmic lipids and perilipin A. The BA-DEG-BA-induced adipogenic differentiation was mediated via peroxisome proliferator-activated receptor gamma. Furthermore, intradermal injection of ADSCs along with BA-DEG-BA into mouse ears markedly enhanced the adipogenic differentiation of ADSCs, leading to dermal augmentation. Our study introduces BA-DEG-BA as an enhancer of ADSC adipogenesis and suggests an integral interaction between the human skin microbiome and ADSCs.


Assuntos
Tecido Adiposo/citologia , Ácido Butírico/farmacologia , Microbiota/efeitos dos fármacos , Staphylococcus epidermidis/metabolismo , Células-Tronco/citologia , Adipócitos/citologia , Adipócitos/fisiologia , Tecido Adiposo/metabolismo , Animais , Diferenciação Celular , Meios de Cultivo Condicionados , Feminino , Humanos , Camundongos , Camundongos Knockout , Microbiota/fisiologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Pele/citologia , Pele/microbiologia , Staphylococcus epidermidis/efeitos dos fármacos
11.
Int J Mol Sci ; 17(11)2016 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-27834859

RESUMO

Acne dysbiosis happens when there is a microbial imbalance of the over-growth of Propionibacterium acnes (P. acnes) in the acne microbiome. In our previous study, we demonstrated that Staphylococcus epidermidis (S. epidermidis, a probiotic skin bacterium) can exploit glycerol fermentation to produce short-chain fatty acids (SCFAs) which have antimicrobial activities to suppress the growth of P. acnes. Unlike glycerol, sucrose is chosen here as a selective fermentation initiator (SFI) that can specifically intensify the fermentation activity of S. epidermidis, but not P. acnes. A co-culture of P. acnes and fermenting S. epidermidis in the presence of sucrose significantly led to a reduction in the growth of P. acnes. The reduction was abolished when P. acnes was co-cultured with non-fermenting S. epidermidis. Results from nuclear magnetic resonance (NMR) analysis revealed four SCFAs (acetic acid, butyric acid, lactic acid, and succinic acid) were detectable in the media of S. epidermidis sucrose fermentation. To validate the interference of S. epidermidis sucrose fermentation with P. acnes, mouse ears were injected with both P. acnes and S. epidermidis plus sucrose or phosphate buffered saline (PBS). The level of macrophage-inflammatory protein-2 (MIP-2) and the number of P. acnes in ears injected with two bacteria plus sucrose were considerably lower than those in ears injected with two bacteria plus PBS. Our results demonstrate a precision microbiome approach by using sucrose as a SFI for S. epidermidis, holding future potential as a novel modality to equilibrate dysbiotic acne.


Assuntos
Acne Vulgar/terapia , Antibiose , Disbiose/terapia , Fermentação/efeitos dos fármacos , Probióticos/farmacologia , Staphylococcus epidermidis/efeitos dos fármacos , Sacarose/farmacologia , Acne Vulgar/microbiologia , Acne Vulgar/patologia , Animais , Carga Bacteriana/efeitos dos fármacos , Biomarcadores/metabolismo , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Técnicas de Cocultura , Disbiose/microbiologia , Disbiose/patologia , Orelha/microbiologia , Orelha/patologia , Feminino , Expressão Gênica , Glicerol/metabolismo , Glicerol/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos ICR , Microbiota , Probióticos/metabolismo , Propionibacterium acnes/efeitos dos fármacos , Propionibacterium acnes/crescimento & desenvolvimento , Propionibacterium acnes/patogenicidade , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Staphylococcus epidermidis/crescimento & desenvolvimento , Staphylococcus epidermidis/metabolismo , Sacarose/metabolismo
12.
J Microb Biochem Technol ; 8(4): 259-265, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28111598

RESUMO

Many human skin diseases, such as seborrheic dermatitis, potentially occur due to the over-growth of fungi. It remains a challenge to develop fungicides with a lower risk of generating resistant fungi and non-specifically killing commensal microbes. Our probiotic approaches using a selective fermentation initiator of skin commensal bacteria, fermentation metabolites or their derivatives provide novel therapeutics to rein in the over-growth of fungi. Staphylococcus lugdunensis (S. lugdunensis) bacteria and Candida parapsilosis (C. parapsilosis) fungi coexist in the scalp microbiome. S. lugdunensis interfered with the growth of C. parapsilosis via fermentation. A methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) copolymer functioned as a selective fermentation initiator of S. lugdunensis, selectively triggering the S. lugdunensis fermentation to produce acetic and isovaleric acids. The acetic acid and its pro-drug diethyleneglycol diacetate (Ac-DEG-Ac) effectively suppressed the growth of C. parapsilosis in vitro and impeded the fungal expansion in the human dandruff. We demonstrate for the first time that S. lugdunensis is a skin probiotic bacterium that can exploit mPEG-PCL to yield fungicidal short-chain fatty acids (SCFAs). The concept of bacterial fermentation as a part of skin immunity to re-balance the dysbiotic microbiome warrants a novel avenue for studying the probiotic function of the skin microbiome in promoting health.

13.
Appl Microbiol Biotechnol ; 98(1): 411-24, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24265031

RESUMO

Increasing evidence demonstrates that commensal microorganisms in the human skin microbiome help fight pathogens and maintain homeostasis of the microbiome. However, it is unclear how these microorganisms maintain biological balance when one of them overgrows. The overgrowth of Propionibacterium acnes (P. acnes), a commensal skin bacterium, has been associated with the progression of acne vulgaris. Our results demonstrate that skin microorganisms can mediate fermentation of glycerol, which is naturally produced in skin, to enhance their inhibitory effects on P. acnes growth. The skin microorganisms, most of which have been identified as Staphylococcus epidermidis (S. epidermidis), in the microbiome of human fingerprints can ferment glycerol and create inhibition zones to repel a colony of overgrown P. acnes. Succinic acid, one of four short-chain fatty acids (SCFAs) detected in fermented media by nuclear magnetic resonance (NMR) analysis, effectively inhibits the growth of P. acnes in vitro and in vivo. Both intralesional injection and topical application of succinic acid to P. acnes-induced lesions markedly suppress the P. acnes-induced inflammation in mice. We demonstrate for the first time that bacterial members in the skin microbiome can undergo fermentation to rein in the overgrowth of P. acnes. The concept of bacterial interference between P. acnes and S. epidermidis via fermentation can be applied to develop probiotics against acne vulgaris and other skin diseases. In addition, it will open up an entirely new area of study for the biological function of the skin microbiome in promoting human health.


Assuntos
Acne Vulgar/microbiologia , Antibiose , Propionibacterium acnes/crescimento & desenvolvimento , Propionibacterium acnes/fisiologia , Staphylococcus epidermidis/metabolismo , Staphylococcus epidermidis/fisiologia , Acne Vulgar/terapia , Animais , Antibacterianos/metabolismo , DNA Bacteriano/química , DNA Bacteriano/genética , Fermentação , Glicerol/metabolismo , Humanos , Camundongos , Dados de Sequência Molecular , Probióticos/administração & dosagem , Propionibacterium acnes/efeitos dos fármacos , Análise de Sequência de DNA , Pele/microbiologia , Ácido Succínico/metabolismo
14.
PLoS One ; 8(2): e55380, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23405142

RESUMO

Bacterial interference creates an ecological competition between commensal and pathogenic bacteria. Through fermentation of milk with gut-friendly bacteria, yogurt is an excellent aid to balance the bacteriological ecosystem in the human intestine. Here, we demonstrate that fermentation of glycerol with Propionibacterium acnes (P. acnes), a skin commensal bacterium, can function as a skin probiotic for in vitro and in vivo growth suppression of USA300, the most prevalent community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). We also promote the notion that inappropriate use of antibiotics may eliminate the skin commensals, making it more difficult to fight pathogen infection. This study warrants further investigation to better understand the role of fermentation of skin commensals in infectious disease and the importance of the human skin microbiome in skin health.


Assuntos
Staphylococcus aureus Resistente à Meticilina/metabolismo , Microbiota , Probióticos/metabolismo , Propionibacterium acnes/metabolismo , Pele/metabolismo , Pele/microbiologia , Infecções Cutâneas Estafilocócicas/microbiologia , Animais , Fermentação , Glicerol/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Staphylococcus aureus Resistente à Meticilina/genética , Camundongos , Camundongos Endogâmicos ICR , Propionibacterium acnes/genética , Infecções Cutâneas Estafilocócicas/metabolismo , Infecções Cutâneas Estafilocócicas/prevenção & controle , Staphylococcus aureus/metabolismo
15.
PLoS One ; 7(10): e47798, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23133525

RESUMO

Recent global radiation fears reflect the urgent need for a new modality that can simply determine if people are in a radiation risk of developing cancer and other illnesses. Ultraviolet (UV) radiation has been thought to be the major risk factor for most skin cancers. Although various biomarkers derived from the responses of human cells have been revealed, detection of these biomarkers is cumbersome, probably requires taking live human tissues, and varies significantly depending on human immune status. Here we hypothesize that the reaction of Propionibacterium acnes (P. acnes), a human resident skin commensal, to UV radiation can serve as early surrogate markers for radiation risk because the bacteria are immediately responsive to radiation. In addition, the bacteria can be readily accessible and exposed to the same field of radiation as human body. To test our hypothesis, P. acnes was exposed to UV-B radiation. The production of porphyrins in P. acnes was significantly reduced with increasing doses of UV-B. The porphyrin reduction can be detected in both P. acnes and human skin bacterial isolates. Exposure of UV-B to P. acnes- inoculated mice led to a significant decrease in porphyrin production in a single colony of P. acnes and simultaneously induced the formation of cyclobutane pyrimidine dimers (CPD) in the epidermal layers of mouse skin. Mass spectrometric analysis via a linear trap quadrupole (LTQ)-Orbitrap XL showed that five peptides including an internal peptide (THLPTGIVVSCQNER) of a peptide chain release factor 2 (RF2) were oxidized by UV-B. Seven peptides including three internal peptides of 60 kDa chaperonin 1 were de-oxidized by UV-B. When compared to UV-B, gamma radiation also decreased the porphyrin production of P. acnes in a dose-dependent manner, but induced a different signature of protein oxidation/de-oxidation. We highlight that uncovering response of skin microbiome to radiation will facilitate the development of pre-symptomatic diagnosis of radiation risk in a battlefield exposure, nuclear accidents, terrorist attacks, or cancer imaging/therapy.


Assuntos
Porfirinas/biossíntese , Pele/microbiologia , Sequência de Aminoácidos , Animais , Relação Dose-Resposta à Radiação , Humanos , Camundongos , Dados de Sequência Molecular , Neoplasias/prevenção & controle , Peptídeos/química , Propionibacterium acnes/metabolismo , Pele/efeitos da radiação , Espectrometria de Fluorescência/métodos , Raios Ultravioleta
16.
J Microbiol Biotechnol ; 21(4): 391-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21532323

RESUMO

Free fatty acids (FFAs) are known to have bacteriocidal activity and are important components of the innate immune system. Many FFAs are naturally present in human and animal skin, breast milk, and in the bloodstream. Here, the therapeutic potential of FFAs against methicillin-resistant Staphylococcus aureus (MRSA) is demonstrated in cultures and in mice. Among a series of FFAs, only oleic acid (OA) (C18:1, cis-9) can effectively eliminate Staphylococcus aureus (S. aureus) through cell wall disruption. Lauric acid (LA, C12:0) and palmitic acid (PA, C16:0) do not have this ability. OA can inhibit growth of a number of Gram-positive bacteria, including hospital and community-associated MRSA at a dose that did not show any toxicity to human sebocytes. The bacteriocidal activities of FFAs were also demonstrated in vivo through injection of OA into mouse skin lesions previously infected with a strain of MRSA. In conclusion, our results suggest a promising therapeutic approach against MRSA through boosting the bacteriocidal activities of native FFAs, which may have been co-evolved during the interactions between microbes and their hosts.


Assuntos
Antibacterianos/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Ácido Oleico/uso terapêutico , Dermatopatias Infecciosas/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/efeitos adversos , Modelos Animais de Doenças , Feminino , Humanos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Ácido Oleico/efeitos adversos , Dermatopatias Infecciosas/microbiologia , Infecções Estafilocócicas/microbiologia
17.
Zhongguo Zhong Yao Za Zhi ; 35(7): 869-71, 2010 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-20575388

RESUMO

OBJECTIVE: To study on the chemical consitituents of Lagotis brevituba. METHOD: The chemical consitituents were isolated by silica gel column chromatography, polyamide column chromatography and semi-preparative HPLC, and their structures were identified by spectroscopic methods. RESULT: Eight compounds were isolated and they were identified as beta-sitosterol (1), succinic acid (2), luteolin-7-O-beta-D-glucoside (3), uracil (4), apigenin (5), chrysoeriol (6), chrysoeriol-7-O-beta-D-glucoside (7), and apigenin-7-O-beta-D-glucoside (8). CONCLUSION: Compound 4-8 were isolated from L. brevituba for the first time, and among them, compound 7 and 8 were isolated from genus Lagotis for the first time.


Assuntos
Plantago/química , Cromatografia Líquida de Alta Pressão , Compostos Orgânicos/análise , Compostos Orgânicos/isolamento & purificação
18.
Zhongguo Zhong Yao Za Zhi ; 34(16): 2054-6, 2009 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-19938544

RESUMO

OBJECTIVE: To study the chemical constituents of Lagotis brevituba. METHOD: The chemical constituents were isolated and purified by silica gel column chromatography, polyamide column chromatography, and semi-preparative HPLC, and their structures were elucidated on the basis of analysis of IR,NMR, 2D-NMR, and MS spectra. RESULT: Two compounds were obtained and were identified as phenylethanoid glucosides, lagotiside A (1) and acteoside (2), respectively. CONCLUSION: Compound 1 is a new compound and named as lagotiside A.


Assuntos
Glucosídeos/química , Extratos Vegetais/química , Plantago/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular
19.
Chem Biodivers ; 3(3): 359-69, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17193273

RESUMO

The chloroplast mat-K region and rpL16 intron region were sequenced for 14 species of Schisandraceae, representing both genera Kadsura Kaempf. ex Juss. and Schisandra Michx, to discuss the phylogeny of this family. Analyses were performed both in separate and combined sequence data sets (including the rbc-L sequence), with Illicium angustispealum A. C. Smith as the out-group. The results showed that the Schisandraceae are monophyletic. In all the analyses, Schisandra propinqua var. chinensis Oliva and Schisandra plena A. C. Smith were nested within Kadsura, which implies that the genera Kadsura and Schisandra are closely related. They might have originated from a common ancestor, but then evolved via different routes. The result inferred from the combined data showed a greater resolution within Schisandra than those from the two separate data sets. High bootstrap values supported the monophyly of most subgenera according to Law's system (1996). A combination of morphological, anatomical, and chemical analyses indicates that S. chinensis and S. rubriflora may be the primitive taxa in Schisandra.


Assuntos
DNA de Cloroplastos/genética , Íntrons/genética , Filogenia , Schisandraceae/genética , DNA de Cloroplastos/isolamento & purificação , Extratos Vegetais/genética , Extratos Vegetais/isolamento & purificação , Folhas de Planta
20.
Zhongguo Zhong Yao Za Zhi ; 28(8): 706-10, 2003 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-15015346

RESUMO

OBJECTIVE: To find the patterns of the rDNA ITS sequence variation of Schisandra sphenanthera and S. viridis, and to establish the molecular biological method for the identification of Fructus Schisandrae Sphenantherae and the fruits of S. viridis. METHOD: PCR products were sequenced directly and the sequences were analyzed with PAUP 4.0b10. NJ systematic tree was obtained with neighbor-joining method. RESULT: The Complete ITS sequence of S. sphenanthera was 691-692 bp, of which there were 282 bp of ITS1 and 246-247 bp of ITS2. The complete sequence of S. viridis was 694-695 bp, consisting of 285-286 bp of ITS1 and 246-247 bp of ITS2. There were three informative sites in ITS1 regions for the two species. In the NJ tree with Kadsura anamosma and K. coccinea as outgroups, five different populations of S. viridis were the monophyletic group with the bootstrap value of 68%. These populations included one from Tianmushan, Zhejiang province, three populations from Jigongshan, Henan Province and the other two populations of S. viridis cited the sequences from GeneBank (registration numbers are AF263438 and AF163703 respectively). CONCLUSION: The rDNA internal transcribed spacer is a good marker to distinguish the Fructus Schisandrae Sphenantherae from the fruits of S. viridis.


Assuntos
DNA de Plantas/genética , DNA Espaçador Ribossômico/genética , Plantas Medicinais/genética , RNA Ribossômico 5,8S/genética , Schisandra/genética , Sequência de Bases , Contaminação de Medicamentos , Frutas/genética , Dados de Sequência Molecular , Filogenia , Plantas Medicinais/classificação , Schisandra/classificação , Análise de Sequência de DNA
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