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1.
PLoS One ; 19(7): e0305358, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39008492

RESUMO

BACKGROUND: Huntington's disease (HD) is an extremely harmful autosomal inherited neurodegenerative disease. Motor dysfunction, mental disorder, and cognitive deficits are the characteristic features of this disease. The current study examined whether 6-shogaol has a protective effect against 3-Nitropropionic Acid (3-NPA)-induced HD in rats. METHODS: A total of thirty male Wistar rats received 6-shogaol (10 and 20 mg/kg, per oral) an hour before injection of 3-NPA (10 mg/kg i.p.) for 15 days. Behavioral tests were performed, including narrow beam walk, rotarod test, and grip strength test. Biochemical tests promoting oxidative stress were evaluated [superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and malondialdehyde (MDA)], including changes to neurotransmitters serotonin (5-HT), dopamine (DA), norepinephrine (NE), homovanillic acid (HVA), (3,4-dihydroxyphenylacetic acid (DOPAC), γ-aminobutyric acid (GABA), and 5-hydroxy indole acetic acid (5-HIAA), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interleukins-1ß (IL-1ß), IL-6, brain-derived neurotrophic factor (BDNF), and nuclear factor erythroid 2-related factor 2 (Nrf2). The 6-shogaol was docked to the active site of TNF-α (2AZ5), NF-κB (1SVC), BDNF) [1B8M], and Nrf2 [5FZN] proteins using AutoDock tools. RESULTS: The 6-shogaol group significantly improved behavioral activity over the 3-NPA-injected control rats. Moreover, 3-NPA-induced significantly altered neurotransmitters, biochemical and neuroinflammatory indices, which could efficiently be reversed by 6-shogaol. The 6-shogaol showed favorable negative binding energies at -9.271 (BDNF) kcal/mol. CONCLUSIONS: The present investigation demonstrated the neuroprotective effects of 6-shogaol in an experimental animal paradigm against 3-NPA-induced HD in rats. The suggested mechanism is supported by immunohistochemical analysis and western blots, although more research is necessary for definite confirmation.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Catecóis , Citocinas , Doença de Huntington , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2 , NF-kappa B , Nitrocompostos , Propionatos , Ratos Wistar , Animais , Doença de Huntington/metabolismo , Doença de Huntington/induzido quimicamente , Doença de Huntington/tratamento farmacológico , Propionatos/farmacologia , Masculino , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ratos , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Catecóis/farmacologia , Catecóis/química , Citocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia
2.
Transl Psychiatry ; 14(1): 283, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38997258

RESUMO

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERß in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERß agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERß across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERß agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERß expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERß's impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERß expression across several different brain regions showed that females only had greater expression of ERß in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERß agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.


Assuntos
Sinais (Psicologia) , Receptor beta de Estrogênio , Extinção Psicológica , Heroína , Rememoração Mental , Animais , Masculino , Feminino , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Heroína/farmacologia , Ratos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Nitrilas/farmacologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Propionatos/farmacologia , Fatores Sexuais , Autoadministração , Ratos Sprague-Dawley , Dependência de Heroína/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Molecules ; 29(13)2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38999077

RESUMO

Various cancer-associated morbidities remain a growing global health challenge, resulting in a significant burden on healthcare systems worldwide due to high mortality rates and a frequent lack of novel therapeutic options for advanced and localized disease. Reactive oxygen species (ROS) play an important role in cancer pathogenesis and response to chemotherapeutics; therefore, it is crucial to develop novel compounds with both antioxidant and anticancer activity. In this study, a series of previously reported 3-((4-hydroxyphenyl)amino)propanoic acid derivatives (compounds 1-36) were evaluated for their anticancer and antioxidant activities. Compounds 12, 20-22, and 29 were able to reduce A549 cell viability by 50% and suppress A549 cell migration in vitro. These compounds also showed favorable cytotoxicity properties towards noncancerous Vero cells. The most promising candidate, compound 20, exhibited potent antioxidant properties in the DPPH radical scavenging assay. These results demonstrate that 3-((4-hydroxyphenyl)amino)propanoic acid could be further explored as an attractive scaffold for the development of novel anticancer and antioxidant candidates.


Assuntos
Antineoplásicos , Antioxidantes , Sobrevivência Celular , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antioxidantes/farmacologia , Antioxidantes/química , Células Vero , Chlorocebus aethiops , Animais , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Propionatos/farmacologia , Propionatos/química , Movimento Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular
4.
Nutrients ; 16(13)2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38999878

RESUMO

Resveratrol, acting as a prebiotic, and propionate, functioning as a postbiotic, hold promise for preventing hypertension in chronic kidney disease (CKD). Previously, we employed propionate to enhance the bioavailability of resveratrol through esterification, resulting in the production of a resveratrol propionate ester (RPE) mixture. In this study, we purified 3-O-propanoylresveratrol (RPE2) and 3,4'-di-O-propanoylresveratrol (RPE4) and investigated their protective effects in a juvenile rat adenine-induced CKD model. To this end, male Sprague Dawley rats aged three weeks (n = 40) were divided into five groups: control; CKD (rats fed adenine); CKRSV (CKD rats treated with 50 mg/L resveratrol); CDRPE2 (CKD rats treated with 25 mg/L RPE2); and CKRPE4 (CKD rats treated with 25 mg/L RPE 4). RPE2 and PRE4 similarly exhibited blood pressure-lowering effects comparable to those of resveratrol, along with increased nitric oxide (NO) availability. Furthermore, RPE2 and RPE4 positively influenced plasma short-chain fatty acid (SCFA) levels and induced distinct alterations in the gut microbial composition of adenine-fed juvenile rats. The supplementation of RPE2 and RPE4, by restoring NO, elevating SCFAs, and modulating the gut microbiota, holds potential for ameliorating CKD-induced hypertension.


Assuntos
Adenina , Anti-Hipertensivos , Pressão Sanguínea , Suplementos Nutricionais , Microbioma Gastrointestinal , Hipertensão , Ratos Sprague-Dawley , Insuficiência Renal Crônica , Resveratrol , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Resveratrol/farmacologia , Masculino , Adenina/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ratos , Hipertensão/tratamento farmacológico , Propionatos , Óxido Nítrico/metabolismo , Ácidos Graxos Voláteis/metabolismo , Modelos Animais de Doenças , Dieta
5.
Skin Therapy Lett ; 29(4): 5-7, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38963912

RESUMO

Acne is a common inflammatory condition of the skin worldwide. The skin is an endocrine organ and hormones are a key pathogenic factor in all types of acne with a particularly important role in adult female acne pathogenesis and management. In females, we have the unique opportunity to manipulate hormones systemically to successfully manage acne and, more recently with the approval of clascoterone 1% cream, we can target the hormones topically in both genders. The intent of this paper is to provide physicians with an up-to-date clinically relevant review of the role of hormones in acne, the impact of currently available contraceptives and therapies available to target hormones in acne.


Assuntos
Acne Vulgar , Humanos , Acne Vulgar/tratamento farmacológico , Feminino , Adulto , Cortodoxona/uso terapêutico , Cortodoxona/análogos & derivados , Propionatos
6.
PLoS One ; 19(7): e0307411, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39024309

RESUMO

The microbiological environment and their corresponding secreted metabolite spectrum are an essential modulator of the enterocyte function, effecting the whole organism. Intestinal porcine jejunal epithelial cell line (IPEC-J2) is an established in vitro model for differentiation of enterocytes in different cell culture models. An improved oxygen supply seems to be the main reason for differentiation in an air-liquid-interface culture, but this has not yet been conclusively clarified. In this context, the nutrition of the cell and its influence on the metabolism is also of crucial importance. The interest in short-chain fatty acids (SCFAs) has grown steadily in recent years due to their clinical relevance in certain diseases such as multiple sclerosis and other inflammatory diseases, but not much is known of FFAR2 and FFAR3 (free fatty acid receptor 2 and 3) in pigs. We want to address the questions: 1. about the distribution of FFAR2 and FFAR3 in vivo and in vitro in sus scrofa 2. whether there is an influence of propionic acid, glucose content and cultivation on metabolism of enterocytes? The morphological analysis of FFAR2 and FFAR3 in vivo was investigated through immunostaining of frozen sections of the porcine gut segments jejunum, ileum and colon. Both receptors are expressed along the gut and were found in the smooth muscle cells of the tunica muscularis and lamina muscularis mucosae. Furthermore, a high expression of FFAR2 and a low expression of FFAR3 in the enteric nerve system was also observed in jejunum, ileum and colon of sus scrofa. In addition, FFAR2 and FFAR3 within the vessels was investigated. FFAR3 showed a strong expression on endothelial cells of veins and lymphatic vessels but was not detectable on arteries. Furthermore, we demonstrate for the first time, FFAR2 and FFAR3 in IPEC-J2 cells on RNA- and protein level, as well as with confocal microscopy. In addition, ENO1 and NDUFA4 were investigated on RNA-level in IPEC-J2 cells as 2 important genes, which play an essential role in metabolism. Here, NDUFA4 is detected in the model animal sus scrofa as well as in the porcine cell line IPEC-J2. A potential impact of propionic acid and/or glucose and/or cultivation method on the metabolism of the cells was tested with the Seahorse analyzer. Here, a significant higher ECAR was observed in the SMC than in the OCR. In summary, we were able to show that the cultivation system appears to have a greater influence than the medium composition or nutrition of the cells. However, this can be modulated by incubation time or combination of different SCFAs.


Assuntos
Glucose , Propionatos , Animais , Propionatos/metabolismo , Glucose/metabolismo , Suínos , Linhagem Celular , Técnicas de Cultura de Células/métodos , Metaboloma , Receptores Acoplados a Proteínas G/metabolismo , Jejuno/metabolismo , Jejuno/citologia , Enterócitos/metabolismo , Mucosa Intestinal/metabolismo
7.
Appl Microbiol Biotechnol ; 108(1): 419, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39012392

RESUMO

Waste glycerol is produced in excess by several industries, such as during biodiesel production. In this work, the metabolic versatility of anaerobic sludge was explored towards waste glycerol valorization. By applying different environmental (methanogenic and sulfate-reducing) conditions, three distinct microbial cultures were obtained from the same inoculum (anaerobic granular sludge), with high microbial specialization, within three different phyla (Thermodesulfobacteriota, Euryarchaeota and Pseudomonadota). The cultures are capable of glycerol conversion through different pathways: (i) glycerol conversion to methane by a bacterium closely related to Solidesulfovibrio alcoholivorans (99.8% 16S rRNA gene identity), in syntrophic relationship with Methanofollis liminatans (98.8% identity), (ii) fermentation to propionate by Propionivibrio pelophilus strain asp66 (98.6% identity), with a propionate yield of 0.88 mmol mmol-1 (0.71 mg mg-1) and a propionate purity of 80-97% and (iii) acetate production coupled to sulfate reduction by Desulfolutivibrio sulfoxidireducens (98.3% identity). In conclusion, starting from the same inoculum, we could drive the metabolic and functional potential of the microbiota towards the formation of several valuable products that can be used in industrial applications or as energy carriers. KEY POINTS: Versatility of anaerobic cultures was explored for waste glycerol valorization Different environmental conditions lead to metabolic specialization Biocommodities such as propionate, acetate and methane were produced.


Assuntos
Fermentação , Glicerol , Metano , RNA Ribossômico 16S , Esgotos , Glicerol/metabolismo , Esgotos/microbiologia , Anaerobiose , RNA Ribossômico 16S/genética , Metano/metabolismo , Filogenia , Sulfatos/metabolismo , Propionatos/metabolismo , Biocombustíveis , Acetatos/metabolismo , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética
8.
J Drugs Dermatol ; 23(6): 433-437, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38834220

RESUMO

BACKGROUND: Clascoterone cream 1% is a topical androgen receptor inhibitor approved to treat acne vulgaris in patients =>12 years of age. This report provides details of patients who developed laboratory signs of hypothalamic-pituitary-adrenal (HPA) axis suppression without clinical signs of adrenal suppression during the clascoterone development program. METHODS: Two open-label, multicenter, Phase 2 trials evaluated HPA axis suppression in patients with moderate-to-severe acne vulgaris. Study 1 (NCT01831960) enrolled cohorts of adults =>18 years of age and adolescents =>12 to <18 years of age. Study 2 (NCT02720627) enrolled adolescents 9 to <12 years of age. Patients applied clascoterone twice daily at maximum-exposure dosages for 14 days. Adrenal suppression was evaluated via cosyntropin stimulation test (CST) at baseline and day 14. Patients with an abnormal CST result (serum cortisol level =<18 µg/dL) had a follow-up CST approximately 4 weeks later. Blood was collected for pharmacokinetic analysis. Other safety assessments included adverse events (AEs), physical examination/vital signs, and electrocardiography. RESULTS: Overall, 5/69 clascoterone-treated patients had an abnormal CST result on day 14, including 1/20 adults, 2/22 patients aged =>12 to <18 years, and 2/27 patients aged 9 to <12 years. All patients had normal cortisol levels at follow-up testing approximately 4 weeks later. No relationship was observed between abnormal CST results and clascoterone plasma concentrations or the amount of study drug applied. No clinically relevant AEs or clinically significant changes in safety measures were observed in patients with adrenal suppression. CONCLUSION: Clascoterone induced laboratory evidence of mild, reversible HPA axis suppression under maximum-use exposure. J Drugs Dermatol. 2024;23(6):433-437.     doi:10.36849/JDD.7997.


Assuntos
Acne Vulgar , Hidrocortisona , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Acne Vulgar/tratamento farmacológico , Adolescente , Masculino , Feminino , Adulto , Criança , Adulto Jovem , Hidrocortisona/sangue , Cortodoxona/administração & dosagem , Cortodoxona/análogos & derivados , Cortodoxona/sangue , Administração Cutânea , Creme para a Pele/administração & dosagem , Creme para a Pele/efeitos adversos , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Resultado do Tratamento , Cosintropina/administração & dosagem , Propionatos
9.
Behav Brain Res ; 470: 115094, 2024 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-38844057

RESUMO

Estrogen receptor (ER) activation by 17-ß estradiol (E2) can attenuate neuronal injury and behavioral impairments following global cerebral ischemia (GCI) in rodents. This study sought to further examine the discrete roles of ERs through characterization of the effects of selective ER activation on post-ischemic pro-inflammatory microglial activation, hippocampal neuronal injury, and anxiety-like behaviors. Forty-six ovariectomized (OVX) adult female Wistar rats received daily s.c injections (100 µg/kg/day) of propylpyrazole triol (PPT; ERα agonist), diarylpropionitrile (DPN; ERß agonist), G-1 (G-protein coupled ER agonist; GPER), E2 (activating all receptors), or vehicle solution (VEH) for 21 days. After final injection, rats underwent GCI via 4-vessel occlusion (n=8 per group) or sham surgery (n=6, vehicle injections). The Open Field Test (OFT), Elevated Plus Maze (EPM), and Hole Board Test (HBT) assessed anxiety-like behaviors. Microglial activation (Iba1, CD68, CD86) in the basolateral amygdala (BLA), CA1 of the hippocampus, and paraventricular nucleus of the hypothalamus (PVN) was determined 8 days post-ischemia. Compared to sham rats, Iba1 activation and CA1 neuronal injury were increased in all ischemic groups except DPN-treated rats, with PPT-treated ischemic rats also showing increased PVN Iba1-ir expression. Behaviorally, VEH ischemic rats showed slightly elevated anxiety in the EPM compared to sham counterparts, with no significant effects of agonists. While no changes were observed in the OFT, emotion regulation via grooming in the HBT was increased in G-1 rats compared to E2 rats. Our findings support selective ER activation to regulate post-ischemic microglial activation and coping strategies in the HBT, despite minimal impact on hippocampal injury.


Assuntos
Ansiedade , Isquemia Encefálica , Região CA1 Hipocampal , Microglia , Fenóis , Pirazóis , Ratos Wistar , Animais , Feminino , Microglia/metabolismo , Microglia/efeitos dos fármacos , Ratos , Ansiedade/metabolismo , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Pirazóis/farmacologia , Fenóis/farmacologia , Ovariectomia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Propionatos/farmacologia , Propionatos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Estradiol/farmacologia , Modelos Animais de Doenças , Receptores de Estrogênio/metabolismo , Nitrilas/farmacologia
10.
Nutrients ; 16(11)2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38892659

RESUMO

CONTEXT: Short-chain fatty acids (SCFAs) have been reported to be associated with the pathogenesis of irritable bowel syndrome (IBS), but the results are conflicting. OBJECTIVE: Here, a systematic review of case-control studies detecting fecal SCFAs in IBS patients compared with healthy controls (HCs) and self-controlled studies or randomized controlled trials (RCTs) investigating fecal SCFA alterations after interventions were identified from several databases. DATA SOURCES: A systematic search of databases (PubMed, Web of Science, and Embase) identified 21 studies published before 24 February 2023. Data extractions: Three independent reviewers completed the relevant data extraction. DATA ANALYSIS: It was found that the fecal propionate concentration in IBS patients was significantly higher than that in HCs, while the acetate proportion was significantly lower. Low-FODMAP diets significantly reduced the fecal propionate concentration in the IBS patients while fecal microbiota transplantation and probiotic administration did not significantly change the fecal propionate concentration or acetate proportion. CONCLUSIONS: The results suggested that the fecal propionate concentration and acetate proportion could be used as biomarkers for IBS diagnosis. A low-FODMAP diet intervention could potentially serve as a treatment for IBS while FMT and probiotic administration need more robust trials.


Assuntos
Ácidos Graxos Voláteis , Fezes , Síndrome do Intestino Irritável , Síndrome do Intestino Irritável/dietoterapia , Síndrome do Intestino Irritável/terapia , Humanos , Fezes/química , Fezes/microbiologia , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/metabolismo , Transplante de Microbiota Fecal , Probióticos , Propionatos/metabolismo , Propionatos/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Acetatos/análise , Feminino , Microbioma Gastrointestinal , Biomarcadores/análise , Masculino , Adulto , Estudos de Casos e Controles
11.
ISME J ; 18(1)2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38836495

RESUMO

The Southern green shield bug, Nezara viridula, is an invasive piercing and sucking pest insect that feeds on crop plants and poses a threat to global food production. Given that insects are known to live in a close relationship with microorganisms, our study provides insights into the community composition and function of the N. viridula-associated microbiota and its effect on host-plant interactions. We discovered that N. viridula hosts both vertically and horizontally transmitted microbiota throughout different developmental stages and their salivary glands harbor a thriving microbial community that is transmitted to the plant while feeding. The N. viridula microbiota was shown to aid its host with the detoxification of a plant metabolite, namely 3-nitropropionic acid, and repression of host plant defenses. Our results demonstrate that the N. viridula-associated microbiota plays an important role in interactions between insects and plants and could therefore be considered a valuable target for the development of sustainable pest control strategies.


Assuntos
Microbiota , Animais , Heterópteros/microbiologia , Glândulas Salivares/microbiologia , Propionatos/metabolismo , Defesa das Plantas contra Herbivoria , Inativação Metabólica , Nitrocompostos/metabolismo
12.
Ecotoxicol Environ Saf ; 280: 116521, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38850708

RESUMO

The aim of this study is to investigate the role of estrogen receptor ß (ERß) in nonylphenol (NP) - induced depression - like behavior in rats and its impact on the regulation of the TPH2/5-HT pathway. In the in vitro experiment, rat basophilic leukaemia cells (RBL-2H3) cells were divided into the four groups: blank group, NP group (20 µM), ERß agonist group (0.01 µM), and NP+ERß agonist group (20 µM+0.01 µM). For the in vivo experiment, 72 adult male Sprague-Dawley rats were randomly divided into following six groups: the Control, NP (40 mg/kg) group, ERß agonist (2 mg/kg, Diarylpropionitrile (DPN)) group, ERß inhibitor (0.1 mg/kg, 4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl) phenol (PHTPP)) group, NP+ERß agonist (40 mg/kg NP + 2 mg/kg DPN) group, and NP+ERß inhibitor (40 mg/kg NP + 0.1 mg/kg PHTPP) group, with 12 rats in each group. Each rat in drug group were given NP by gavage and/or received a single intraperitoneal injection of DPN 2 mg/kg or PHTPP 0.1 mg/kg. Both in vivo and in vitro, NP group showed a decrease in the expression levels of ERß, tryptophan hydroxylase (TPH1), and tryptophan hydroxylase-2 (TPH2) genes and proteins, and reduced levels of DA, NE, and 5-hydroxytryptophan (5-HT) neurotransmitters. RBL-2H3 cells showed signs of cell shrinkage, with rounded cells, increased suspension and more loosely arranged cells. The effectiveness of the ERß agonist stimulation exhibited an increase exceeding 60% in RBL-2H3 cells. The application of ERß agonist resulted in an alleviation the aforementioned alterations. ERß agonist activated the TPH2/5-HT signaling pathways. Compared to the control group, the NP content in the brain tissue of the NP group was significantly increased. The latency to eat for the rats was longer and the amount of food consumed was lower, and the rats had prolonged immobility time in the behavioral experiment of rats. The expression levels of ERß, TPH1, TPH2, 5-HT and 5-HITT proteins were decreased in the NP group, suggesting NP-induced depression-like behaviours as well as disturbances in the secretion of serum hormones and monoamine neurotransmitters. In the NP group, the midline raphe nucleus showed an elongated nucleus with a dark purplish-blue colour, nuclear atrophy, displacement and pale cytoplasm. ERß might ameliorate NP-induced depression-like behaviors, and secretion disorders of serum hormones and monoamine neurotransmitters via activating TPH2/5-HT signaling pathways.


Assuntos
Depressão , Receptor beta de Estrogênio , Fenóis , Ratos Sprague-Dawley , Serotonina , Triptofano Hidroxilase , Animais , Triptofano Hidroxilase/metabolismo , Receptor beta de Estrogênio/metabolismo , Fenóis/toxicidade , Masculino , Ratos , Serotonina/metabolismo , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/metabolismo , Neurotransmissores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Nitrilas/toxicidade , Nitrilas/farmacologia , Propionatos/toxicidade , Propionatos/farmacologia , Pirazóis , Pirimidinas
13.
Eur J Gastroenterol Hepatol ; 36(7): 890-896, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38829943

RESUMO

OBJECTIVE: Short-chain fatty acids (SCFAs) are produced when the microbiota in the large intestine cause fermentation of dietary carbohydrates and fibers. These fatty acids constitute the primary energy source of colon mucosa cells and have a protective effect in patients suffering from inflammatory bowel disease (IBD). This study aimed to compare the SCFA levels in the stools of patients with IBD and healthy controls. METHOD: Healthy controls and patients with IBD aged 18 and over were included in the study. Stool samples from all patients and healthy controls were collected, and stool acetic acid, propionic acid, and butyric acid levels were measured using a gas chromatography-mass spectrometry measurement method. RESULTS: In this study, 64 participants were divided into two groups: 34 were in IBD (Crohn disease and ulcerative colitis) and 30 were in healthy control group. When fecal SCFA concentrations of IBD and healthy control groups were compared, a statistically significant difference was observed between them. When the fecal SCFA concentrations of Crohn's disease and ulcerative colitis patients in the IBD group were compared, however, no statistically significant difference was observed between them. Furthermore, when the participants' diet type (carbohydrate-based, vegetable-protein-based and mixed diet) and the number of meals were compared with fecal SCFA concentrations, no statistically significant difference was observed between them. CONCLUSION: In general, fecal SCFA levels in patients with IBD were lower than those in healthy controls. Moreover, diet type and the number of meals had no effect on stool SCFA levels in patients with IBD and healthy individuals.


Assuntos
Colite Ulcerativa , Doença de Crohn , Ácidos Graxos Voláteis , Fezes , Humanos , Fezes/química , Fezes/microbiologia , Masculino , Feminino , Adulto , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/metabolismo , Colite Ulcerativa/metabolismo , Colite Ulcerativa/microbiologia , Pessoa de Meia-Idade , Estudos de Casos e Controles , Doença de Crohn/metabolismo , Adulto Jovem , Cromatografia Gasosa-Espectrometria de Massas , Dieta , Propionatos/metabolismo , Propionatos/análise , Ácido Acético/análise , Ácido Acético/metabolismo , Microbioma Gastrointestinal , Ácido Butírico/análise , Ácido Butírico/metabolismo
14.
J Drugs Dermatol ; 23(6): 404-409, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38834219

RESUMO

Acne vulgaris is prevalent among adolescents and adults worldwide and can significantly impact patients' quality of life. Steroidal molecules, including oral and intralesional corticosteroids, combined oral contraceptives (COCs), oral spironolactone, and topical clascoterone, are an important part of the acne treatment armamentarium. The recommended use, mechanism of action, and available evidence supporting the use of steroids for acne treatment are reviewed, and differences in acne clinical presentation and treatment approaches based on patient characteristics relevant to the selection of an appropriate steroid are also discussed. Steroid-based approaches target the systemic or local hormones (ie, testosterone and androgens) and inflammation that contribute to acne pathogenesis. Oral corticosteroids are primarily used as a short-term adjunctive therapy early in treatment, whereas intralesional corticosteroid injections are used for individual acne lesions. COCs and oral spironolactone are limited to female patients who wish to avoid pregnancy. Topical clascoterone can be used by female and male patients 12 years of age and older. Patients' characteristics (including age and patients with darker skin color) and preferences for the route of administration can impact treatment response and adherence, respectively. Overall, healthcare providers must be aware of the differences among steroidal acne treatments and use shared decision-making to select the optimal therapy. J Drugs Dermatol. 2024;23(6):404-409.     doi:10.36849/JDD.7846.


Assuntos
Acne Vulgar , Espironolactona , Humanos , Acne Vulgar/tratamento farmacológico , Espironolactona/administração & dosagem , Espironolactona/efeitos adversos , Resultado do Tratamento , Feminino , Masculino , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Qualidade de Vida , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/uso terapêutico , Administração Cutânea , Administração Oral , Cortodoxona/análogos & derivados , Propionatos
15.
Nutrients ; 16(11)2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38892708

RESUMO

Propionate defects (PDs) mainly include methylmalonic (MMA) and propionic acidemia (PA) defects. Lifelong PD patients progress from the compensated to the decompensated stages, the latter of which are characterized by life-threatening acidemia and hyperammonemia crises. PD patients can suffer immunocompromise, especially during the decompensation stage. There is a significant gap in the research regarding the humoral immune response in PD patients. Here, we analyzed serum immunoglobulin concentrations and hemograms across compensated and decompensated stages in PD patients. Nutritional status and crisis triggers of decompensation were also explored. Twenty patients were studied, and 25 decompensation events (DE) and 8 compensation events (CE) were recorded. Compared with those in the CE group, the IgG levels in the DE group (513.4 ± 244.5 mg/dL) were significantly lower than those in the CE group (860.8 ± 456.5 mg/dL) (p < 0.0087). The mean hemoglobin concentration was significantly lower in the DE group (11.8 g/dL) than in the CE group (13.4 g/dL) (p < 0.05). The most frequent (48%) possible decompensation trigger factor was infection. Most of the events were registered in eutrophic patients (87.9%), despite which 65.2% and 50% of patients who experienced decompensated and compensated events, respectively, presented with hypogammaglobulinemia G. These findings provide evidence of the immunodeficiency of PD patients, independent of their nutritional status. We suggest that PD patients be managed as immunocompromised independently of their nutritional status or metabolic state (compensated or decompensated).


Assuntos
Agamaglobulinemia , Estado Nutricional , Humanos , Masculino , Feminino , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Agamaglobulinemia/complicações , Pessoa de Meia-Idade , Idoso , Imunoglobulina G/sangue , Adulto , Propionatos/sangue , Acidemia Propiônica
16.
Cell Metab ; 36(6): 1394-1410.e12, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38838644

RESUMO

A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.


Assuntos
Encéfalo , Glucose , Propionatos , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Animais , Doença da Deficiência do Complexo de Piruvato Desidrogenase/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Glucose/metabolismo , Propionatos/metabolismo , Camundongos , Dieta Cetogênica , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Masculino , Glicólise
17.
Nat Microbiol ; 9(7): 1812-1827, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38858593

RESUMO

Dietary intake of phytate has various reported health benefits. Previous work showed that the gut microbiota can convert phytate to short-chain fatty acids (SCFAs), but the microbial species and metabolic pathway are unclear. Here we identified Mitsuokella jalaludinii as an efficient phytate degrader, which works synergistically with Anaerostipes rhamnosivorans to produce the SCFA propionate. Analysis of published human gut taxonomic profiles revealed that Mitsuokella spp., in particular M. jalaludinii, are prevalent in human gut microbiomes. NMR spectroscopy using 13C-isotope labelling, metabolomic and transcriptomic analyses identified a complete phytate degradation pathway in M. jalaludinii, including production of the intermediate Ins(2)P/myo-inositol. The major end product, 3-hydroxypropionate, was converted into propionate via a synergistic interaction with Anaerostipes rhamnosivorans both in vitro and in mice. Upon [13C6]phytate administration, various 13C-labelled components were detected in mouse caecum in contrast with the absence of [13C6] InsPs or [13C6]myo-inositol in plasma. Caco-2 cells incubated with co-culture supernatants exhibited improved intestinal barrier integrity. These results suggest that the microbiome plays a major role in the metabolism of this phytochemical and that its fermentation to propionate by M. jalaludinii and A. rhamnosivorans may contribute to phytate-driven health benefits.


Assuntos
Microbioma Gastrointestinal , Ácido Fítico , Ácido Fítico/metabolismo , Humanos , Animais , Camundongos , Células CACO-2 , Clostridiales/metabolismo , Clostridiales/genética , Ácidos Graxos Voláteis/metabolismo , Propionatos/metabolismo , Interações Microbianas , Redes e Vias Metabólicas , Metabolômica/métodos , Inositol/metabolismo , Inositol/análogos & derivados
18.
Int J Mol Sci ; 25(12)2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38928337

RESUMO

3-(4-Hydroxy-3-methoxyphenyl)propionic acid (HMPA), also known as dihydroferulic acid, is a hydroxycinnamic acid derivative that can be derived from the microbial transformation of dietary polyphenols or naturally obtained from fermented foods. Although numerous studies have documented its antioxidant and anti-obesity effects, the effect of HMPA on muscle function remains unknown. This study investigated the effects of HMPA on muscle strength and exercise endurance capacity. Mice were orally administered low and high doses of HMPA for 14 days and subjected to grip force and treadmill exhaustion tests to evaluate muscle function. Our results showed that HMPA-administered groups significantly enhanced absolute grip strength (p = 0.0256) and relative grip strength (p = 0.0209), and low-dose HMPA decreased the plasma level of blood urea nitrogen after exercise (p = 0.0183), but HMPA did not affect endurance performance. Low-dose HMPA administration increased Myf5 expression in sedentary mice (p = 0.0106), suggesting that low-dose HMPA may promote muscle development. Additionally, HMPA improved hepatic glucose and lipid metabolism, and inhibited muscular lipid metabolism and protein catabolism, as indicated by changes in mRNA expression levels of related genes. These findings suggest that HMPA may be a promising dietary supplement for muscle health and performance.


Assuntos
Músculo Esquelético , Condicionamento Físico Animal , Animais , Camundongos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Propionatos/farmacologia , Força da Mão , Força Muscular/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos
19.
Microbiome ; 12(1): 114, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38915127

RESUMO

BACKGROUND: Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. RESULTS: We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. CONCLUSIONS: Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract.


Assuntos
Ácido Elágico , Encefalomielite Autoimune Experimental , Microbioma Gastrointestinal , Esclerose Múltipla , Propionatos , Ácido Elágico/farmacologia , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/microbiologia , Propionatos/metabolismo , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/microbiologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Feminino , Autoimunidade/efeitos dos fármacos , Disbiose/microbiologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Humanos , Administração Oral
20.
Pestic Biochem Physiol ; 202: 105952, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38879306

RESUMO

The citrus red mite, Panonychus citri, is one of the most notorious and devastating citrus pests around the world that has developed resistance to multiple chemical acaricides. In previous research, we found that spirodiclofen-resistant is related to overexpression of P450, CCE, and ABC transporter genes in P. citri. However, the regulatory mechanisms of these detoxification genes are still elusive. This study identified all hormone receptor 96 genes of P. citri. 8 PcHR96 genes contained highly conserved domains. The expression profiles showed that PcHR96h was significantly upregulated in spirodiclofen resistant strain and after exposure to spirodiclofen. RNA interference of PcHR96h decreased expression of detoxification genes and increased spirodiclofen susceptibility in P. citri. Furthermore, molecular docking, heterologous expression, and drug affinity responsive target stability demonstrated that PcHR96h can interact with spirodiclofen in vitro. Our research results indicate that PcHR96h plays an important role in regulating spirodiclofen susceptibility and provides theoretical support for the resistance management of P. citri.


Assuntos
Compostos de Espiro , Animais , Compostos de Espiro/farmacologia , Compostos de Espiro/metabolismo , Acaricidas/farmacologia , Propionatos/farmacologia , Propionatos/metabolismo , Tetranychidae/efeitos dos fármacos , Tetranychidae/genética , Tetranychidae/metabolismo , Simulação de Acoplamento Molecular , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/metabolismo , Resistência a Medicamentos/genética , 4-Butirolactona/análogos & derivados
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