RESUMO
The continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study aims to discover a potential new class of tuberculosis drug candidates different from existing tuberculosis drugs. By screening a library of compounds, methyl (S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 µg/ml, respectively. PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested. PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Mutants selected in vitro suggest that the drug targets the PE-PGRS57, which has been found only in the genomes of the M. tuberculosis complex, highlighting the specificity and safety potency of this compound. As PPs show an excellent safety profile and highly selective toxicity specific to M. tuberculosis, PPs are considered a promising new candidate for the treatment of drug-resistant tuberculosis while maintaining microbiome homeostasis.
Assuntos
Anti-Infecciosos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Animais , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Camundongos , Tuberculose/tratamento farmacológicoRESUMO
Mycobacterium tuberculosis, a lethal pathogen in human history, causes millions of deaths annually, which demands the development of new concepts of drugs. Considering this fact, earlier research has explored the anti-tuberculosis potential of a probiotic strain, Lactocaseibacillus rhamnosus PMC203, leading to a subsequent focus on the molecular mechanism involved in its effect, particularly on autophagy. In this current study, immunoblotting-based assay exhibited a remarkable expression of autophagy marker LC3-II in the PMC203 treated group compared to an untreated group. A remarkable degradation of p62 was also noticed within treated cells compared to control. Furthermore, the immunofluorescence-based assay showed significant fold change in fluorescence intensity for alexa-647-LC3 and alexa-488-LC3, whereas p62 was degraded noticeably. Moreover, lysosomal biogenesis generation was elevated significantly in terms of LAMP1 and acidic vesicular organelles. As a result, PMC203-induced autophagy played a vital role in reducing M. tuberculosis burden within the macrophages in treated groups compared to untreated group. A colony -forming unit assay also revealed a significant reduction in M. tuberculosis in the treated cells over time. Additionally, the candidate strain significantly upregulated the expression of autophagy induction and lysosomal biogenesis genes. Together, these results could enrich our current knowledge of probiotics-mediated autophagy in tuberculosis and suggest its implications for innovatively managing tuberculosis.
Assuntos
Autofagia , Lacticaseibacillus rhamnosus , Macrófagos , Mycobacterium tuberculosis , Probióticos , Mycobacterium tuberculosis/genética , Lacticaseibacillus rhamnosus/fisiologia , Lacticaseibacillus rhamnosus/metabolismo , Macrófagos/microbiologia , Humanos , Lisossomos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Carga Bacteriana , Tuberculose/microbiologiaRESUMO
Many human pathologies, such as malignancy, are linked with specific bacteria and changes in the constituents of the microbiome. In order to examine the association between an imbalance of bacteria and prostate carcinoma, a comparison of the microbiomes present in patients with biochemical recurrence (BCR) or NO BCR (NBCR) was performed. Additionally, 16S rRNA-based next-generation sequencing was applied to identify the bacterial profiles within these tumors in terms of the bacteria and operational genes present. The percentage average taxonomic composition between the taxa indicated no difference between BCR and NBCR. In addition, alpha and beta diversity indices presented no distinction between the cohorts in any statistical method. However, taxonomic biomarker discovery indicated a relatively higher population of Lactobacillus in the NBCR group, and this finding was supported by PCR data. Along with that, differences in the operational activity of the bacterial genes were also determined. It is proposed that the biochemical recurrence was linked to the quantity of Lactobacillus present. The aim of this study was to investigate the microbiome involved in prostate carcinoma and the potential association between them.
Assuntos
Carcinoma , Microbiota , Neoplasias da Próstata , Masculino , Humanos , Lactobacillus/genética , RNA Ribossômico 16S/genética , Microbiota/genética , Bactérias/genética , Neoplasias da Próstata/patologiaRESUMO
The infectious disease tuberculosis remains a serious global health issue and is responsible for nearly 1.8 million deaths every year. In our previous study, DFC-2 was confirmed to show anti-tubercular activity against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. To support the safety-in-use of DFC-2 as an anti-tubercular drug, DFC-2 was tested via single- and 28-day repeated-dose oral toxicity study and mutagenicity assays. In the oral toxicity study, a single oral dose of DFC-2 at 2000â¯mg/kg did not produce deaths or abnormal lesions in the internal organs of rats. The results of a 28-day orally repeated dose of DFC-2 did not show treatment-related deaths or obvious toxicity symptoms in the animals treated with a dose of 300â¯mg/kg/day during the experimental period. Therefore, the no-observed-adverse-effect level (NOAEL) of DFC-2 was determined as 300â¯mg/kg/day for both male and female rats. In addition, DFC-2 showed no genetic toxicity in in vitro bacterial reverse mutation test, in vitro chromosomal aberration test, and in vivo mouse bone marrow micronucleus formation test. These results indicate that DFC-2 is a promising anti-tubercular drug candidate with a favorable safety profile.
Assuntos
Antituberculosos/farmacocinética , Antituberculosos/toxicidade , Animais , Antituberculosos/sangue , Feminino , Masculino , Camundongos Endogâmicos ICR , Testes de Mutagenicidade , Nível de Efeito Adverso não Observado , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subcrônica , ToxicocinéticaRESUMO
This study explores the antitubercular activity of α-viniferin, a bioactive phytochemical compound obtained from Carex humilis. α-Viniferin was active against both drug-susceptible and -resistant strains of Mycobacterium tuberculosis at MIC50s of 4.6 µM in culture broth medium and MIC50s of 2.3-4.6 µM inside macrophages and pneumocytes. In combination with streptomycin and ethambutol, α-viniferin exhibited an additive effect and partial synergy, respectively, against M. tuberculosis H37Rv. α-Viniferin also did not show cytotoxicity in any of the cell lines tested up to a concentration of 147 µM, which gives this compound a selectivity index of >32. Moreover, α-viniferin was active against 3 Staphylococcus species, including methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis (MRSE).
Assuntos
Antituberculosos/farmacologia , Benzofuranos/farmacologia , Carex (Planta)/química , Mycobacterium tuberculosis/efeitos dos fármacos , Células A549 , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antituberculosos/administração & dosagem , Antituberculosos/isolamento & purificação , Benzofuranos/administração & dosagem , Benzofuranos/isolamento & purificação , Farmacorresistência Bacteriana , Sinergismo Farmacológico , Etambutol/administração & dosagem , Etambutol/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Raízes de Plantas , Células RAW 264.7 , Estreptomicina/administração & dosagem , Estreptomicina/farmacologiaRESUMO
BACKGROUND: Human tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis, remains a major public health concern. Increasing drug resistance poses a threat of disease resurgence and continues to cause considerable mortality worldwide, which necessitates the development of new drugs with improved efficacy. Thymoquinone (TQ), an essential compound of Nigella sativa, was previously reported as an active anti-tuberculosis agent. METHODS: In this study, the effects of TQ on intracellular mycobacterial replication are examined in macrophages. In addition, its effect on mycobacteria-induced NO production and pro-inflammatory responses were investigated in Mycobacterium tuberculosis (MTB)-infected Type II human alveolar and human myeloid cell lines. RESULTS: TQ at concentrations ranging from 12.5 to 25 µg/mL and 6.25 to 12.5 µg/mL reduced intracellular M. tuberculosis H37Rv and extensively drug-resistant tuberculosis (XDR-TB) 72 h post-infection in RAW 264.7 cells. TQ treatment also produced a concentration-dependent reduction in nitric oxide production in both H37Rv and XDR-TB infected RAW 264.7 cells. Furthermore, TQ reduced the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory molecules such as tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL-6) in H37Rv-infected cells and eventually reduced pathogen-derived stress in host cells. CONCLUSIONS: TQ inhibits intracellular H37Rv and XDR-TB replication and MTB-induced production of NO and pro-inflammatory molecules. Therefore, along with its anti-inflammatory effects, TQ represents a prospective treatment option to combat Mycobacterium tuberculosis infection.
Assuntos
Antituberculosos/farmacologia , Benzoquinonas/farmacologia , Macrófagos/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/fisiologia , Nigella sativa/química , Óxido Nítrico/metabolismo , Extratos Vegetais/farmacologia , Tuberculose/microbiologia , Animais , Linhagem Celular , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Tuberculose/genética , Tuberculose/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Responsible for nearly 1.5 million deaths every year, the infectious disease tuberculosis remains one of the most serious challenges to global health. The emergence of multidrug-resistant tuberculosis and, more recently, extensively drug-resistant tuberculosis poses a significant threat in our effort to control this epidemic. New drugs are urgently needed to combat the growing threat of antimicrobial resistance. To achieve this goal, we screened approximately 500 species of medicinal plant methanol extracts and their solvent partitioned fractions for potential inhibitors of Mycobacterium tuberculosis growth. Using microdilution screening, the ethyl acetate solvent partitioned fraction from the heartwood of Caesalpinia sappan exhibited strong antitubercular activity. We isolated the active compound and identified it as 3-deoxysappanchalcone. The extracted 3-deoxysappanchalcone possessed activity against both drug-susceptible and drug-resistant strains of M. tuberculosis at MIC50 s of 3.125-12.5 µg/mL in culture broth and MIC50 s of 6.25-12.5 µg/mL inside macrophages and pneumocytes. 3-Deoxysappanchalcone was also found to act in partial synergy with streptomycin/ethambutol against M. tuberculosis H37Rv. 3-Deoxysappanchalcone had no cytotoxicity against the A549 cell line up to a concentration of 100 µg/mL (selectivity index > 8-32). Further studies are warranted to establish the in vivo effect and therapeutic potential of 3-deoxysappanchalcone. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Antituberculosos/farmacologia , Caesalpinia/química , Chalconas/farmacologia , Extratos Vegetais/farmacologia , Células A549 , Animais , Humanos , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Plantas Medicinais/química , Células RAW 264.7 , Madeira/químicaRESUMO
OBJECTIVE: In order to protect against Mycobacterium tuberculosis (MTB) infection, novel drugs and new targets should be screened from the vast source of plants. We investigated the potentiality of the herbal plant of Artemisia capillaris extract (AC) against Mycobacterium tuberculosis. DESIGN: In this study, we isolated ursolic acid and hydroquinone by bio-activity guided fractionation from the methanol extracts of AC, and tested the inhibitory effects against several strains of MTB. Anti-mycobacterial evaluation of these compounds was carried out using the MGIT™ 960 and resazurin assay. Mycobacterial morphological changes due to the treatment of these compounds were further evaluated by Transmission electron microscopy (TEM). RESULTS: Ursolic acid (UA) and hydroquinone (HQ) inhibited the growth of both susceptible and resistant strains of M. tuberculosis. The MIC (minimum inhibitory concentration) values of both UA and HQ were 12.5 µg/ml against the susceptible strains of M. tuberculosis. Also both UA and HQ showed 12.5-25 µg/ml of MIC values against MDR/XDR MTB strains. However, against clinical strains of MTB, UA was found sensitive against those strains that are sensitive against both INH and RFP but resistant against those strains that are resistant to INH. On the other hand HQ was sensitive against all clinical strains. TEM image-analysis of the strain H37Ra after treatment with UA revealed cell wall lysis, whereas HQ-treated cells showed deformed cytoplasmic morphology. CONCLUSION: All these results indicate that AC extracts containing UA and HQ possess promising chemotherapeutic potency against MTB for future use.
Assuntos
Antituberculosos/farmacologia , Artemisia/química , Hidroquinonas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Sinergismo Farmacológico , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/ultraestrutura , República da Coreia , Ácido UrsólicoRESUMO
Mycobacterium tuberculosis is a dangerous intracellular pathogen. In order to protect against mycobacterium infection, novel agents with anti-mycobacterial activity should be given emergency priority for evaluation. Ursolic acid (UA), a plant triterpenoid, shows promising bioactivities, including anti-mycobacterial potency. In this study, the action of UA against Mycobacterium tuberculosis H37Ra was evaluated, and the inhibitory concentration was found to range between 10 and 20 µg/ml in a resazurin assay and MGIT 960 instrument. The total mycolic acid in UA-treated H37Ra was detected and compared with INH-treated and non-treated bacterium by LC-MS/MS. Quantitative LC-MS/MS data confirmed that both UA and INH decreased mycolic acid biosynthesis in a dose-dependent manner. Thin-layer chromatogram (TLC) analysis showed that all mycolic acid subtypes were affected by UA treatment in the wild type but not in strains resistant to UA. Electron microscopy images also confirmed that UA treatment affected both H37Ra cell and intracellular content of H37Ra. Altogether, these data confirmed the promise of the inhibitory action of UA in mycolic acid, which might further delineate the mechanistic pathway of mycobacterial inhibition by UA.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Ácidos Micólicos/metabolismo , Triterpenos/farmacologia , Antituberculosos/administração & dosagem , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Cromatografia Líquida/métodos , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Microscopia Eletrônica , Espectrometria de Massas em Tandem/métodos , Triterpenos/administração & dosagem , Ácido UrsólicoRESUMO
Methanol ingestion is neurotoxic in humans due to its metabolites, formaldehyde and formic acid. Here, we compared the cytotoxicity of methanol and its metabolites on different types of cells. While methanol and formic acid did not affect the viability of the cells, formaldehyde (200-800 µg/mL) was strongly cytotoxic in all cell types tested. We investigated the effects of formaldehyde on oxidative stress, mitochondrial respiratory functions, and apoptosis on the sensitive neuronal SK-N-SH cells. Oxidative stress was induced after 2 h of formaldehyde exposure. Formaldehyde at a concentration of 400 µg/mL for 12 h of treatment greatly reduced cellular adenosine triphosphate (ATP) levels. Confocal microscopy indicated that the mitochondrial membrane potential (MMP) was dose-dependently reduced by formaldehyde. A marked and dose-dependent inhibition of mitochondrial respiratory enzymes, viz., NADH dehydrogenase (complex I), cytochrome c oxidase (complex IV), and oxidative stress-sensitive aconitase was also detected following treatment with formaldehyde. Furthermore, formaldehyde caused a concentration-dependent increase in nuclear fragmentation and in the activities of the apoptosis-initiator caspase-9 and apoptosis-effector caspase-3/-7, indicating apoptosis progression. Our data suggests that formaldehyde exerts strong cytotoxicity, at least in part, by inducing oxidative stress, mitochondrial dysfunction, and eventually apoptosis. Changes in mitochondrial respiratory function and oxidative stress by formaldehyde may therefore be critical in methanol-induced toxicity.
Assuntos
Formaldeído/toxicidade , Formiatos/toxicidade , Metanol/toxicidade , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurotoxinas/toxicidade , Aconitato Hidratase/genética , Aconitato Hidratase/metabolismo , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 7/genética , Caspase 7/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Relação Dose-Resposta a Droga , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Regulação da Expressão Gênica , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/enzimologia , NADH Desidrogenase/genética , NADH Desidrogenase/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo , Transdução de SinaisRESUMO
BACKGROUND: The objective of the present study was to determine whether Dioscorea batatas (DB) extract reduces visceral fat accumulation and obesity-related biomarkers in mice fed a high-fat diet (HFD) and whether genes associated with adipogenesis and inflammation could be modulated by a diet containing DB extract. MATERIAL AND METHODS: Male C57BL/6J mice were divided into 4 groups (n=10 per group): normal diet (ND), HFD, 100 mg/kg DB extract-gavage with HFD, and 200 mg/kg DB extract-gavage with HFD. The mice were fed the experimental diets for 14 weeks. At 12 weeks, micro-computed X-ray tomography (micro-CT) was performed. RESULTS: Supplementation of the diet with DB extract for 14 weeks significantly prevented HFD-induced increases in body weight, visceral adipose tissue, plasma lipid levels, and leptins. The area of visceral fat was reduced by DB extract supplementation when examined by micro-CT. Supplementation with DB extract resulted in the downregulation of the adipogenic transcription factor (C/ERBa) and its target gene (CD36) in epididymal adipose tissue, compared to HFD alone. DB extract decreased the expression of proinflammatory cytokines (TNF-α, MCP-1, and IL-6) in epididymal adipose tissue. CONCLUSIONS: Our results suggest that DB extract may prevent HFD-induced obesity by downregulating the expression of genes related to adipogenesis and inflammation in visceral adipose tissue.
Assuntos
Adipogenia/efeitos dos fármacos , Biomarcadores/metabolismo , Citocinas/metabolismo , Dioscorea/química , Regulação da Expressão Gênica/efeitos dos fármacos , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Gordura Intra-Abdominal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Receptores alfa dos Hormônios Tireóideos/metabolismo , Microtomografia por Raio-XRESUMO
The mechanism underlying the wogonin-mediated increase in the expression of suppressor of cytokine signaling 3 (SOCS3) is unclear. Promoter deletion assay results revealed that wogonin-induced SOCS3 expression is dependent on the AP-1 consensus sequences and two STAT responsive elements (TTACAAGAA and TTCCAGGAA) in the 5'-flanking region of the SOCS3 gene in SH-SY5Y cells. Wogonin-induced SOCS3 expression was blocked by inhibitors of PI3K, Akt, Raf, p38, JNK, MEK, and STAT3, respectively. However, JAK2 inhibitors did not inhibit wogonin-induced SOCS3 expression. These results indicate that SOCS3-inducing effect of wogonin is caused by the activation of PI3K-mediated MAPK signaling pathways (Akt, ERK1/2, p38, and JNK), and the subsequent activation of AP-1 consensus sequences and STAT responsive elements in SH-SY5Y cells.
Assuntos
Flavanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína 3 Supressora da Sinalização de CitocinasRESUMO
Mucins are highly glycosylated secretary proteins produced by most epithelial cells. Hypersecretion of mucins is one of the prominent symptoms of several airway diseases, including asthma, cystic fibrosis, nasal allergy, rhinitis, and sinusitis. Paraquat (PQ), a common herbicide, has been associated with pulmonary damage and is a potent reactive oxygen species (ROS) producer. However, until now the role of PQ on mucin overproduction has not been studied. The aim of this study is to explore how kaempferol (KM), a widely used dietary flavonoid, affects the protection of human PQ-exposed bronchial epithelium BEAS-2B cells by suppressing Mucin gene expression via nuclear factor-kappa B (NF-κB). We observed that PQ generates intracellular ROS, and also induces lipid peroxidation in BEAS-2B cells. Additionally, we found that PQ effectively induces the expression of the MUC5AC gene; however, co-treatment of PQ with KM drastically reduces its expression. Furthermore, we observed that PQ activates NF-κB, while co-treatment with KM occludes its nuclear translocation, and additionally KM repressed the PQ phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in BEAS-2B cells. Based on our data, we believe that KM can suppress the over-expression of the MUC5AC gene. This would contribute to the protection of PQ cytotoxicity to exposed BEAS-2B cells, and allow further study toward a better understanding of ROS-associated diseases.
Assuntos
Células Epiteliais/efeitos dos fármacos , Herbicidas/toxicidade , Quempferóis/farmacologia , Mucina-5AC/genética , Paraquat/toxicidade , Substâncias Protetoras/farmacologia , Linhagem Celular , Citoproteção/efeitos dos fármacos , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Tuberculosis is a highly contagious disease caused by Mycobacterium tuberculosis, and the increase in antibiotic resistance threatens humankind. Therefore, there is an urgent need to develop new anti-tuberculosis drugs that can overcome the limitations of existing drugs. Here, we report the anti-tuberculosis effect of microbiome therapeutic PMC205, a strain of Bacillus subtilis. METHODS: The anti-tuberculosis activity of probiotics was evaluated in mouse models of lethal and latent pulmonary tuberculosis induced by high or low-dose infection of the extensively drug-resistant strain. Probiotics were administered by inhalation, and the burden of M. tuberculosis in the lungs, along with mortality and clinical observations, were monitored for 12 weeks and 8 months, respectively. For an in-depth understanding, analysis of the microbiome and inflammatory profile of the lung microenvironment and induction of autophagy in vitro were explored. RESULTS: After inhalation administration of PMC205 for 3 months, the survival rate was 100%, unlike all deaths in the saline-treated group, and the burden of M. tuberculosis in the lungs was reduced by log 1.3 in the 8-month latent tuberculosis model. Moreover, PMC205 induced recovery of disrupted lung microflora, increased butyric acid, and suppressed excessive inflammation. It also promoted autophagy. CONCLUSIONS: These results confirm PMC205's anti-tuberculosis effect, suggesting that it can be developed as an adjuvant to current antibiotic therapy to solve the drug-resistant tuberculosis problem.
RESUMO
BACKGROUND: The excessive production and accumulation of melanin in the epidermal skin layer can result in skin hyperpigmentation and darkening. Current technologies for regulating melanin are based on inhibiting melanin biosynthesis. They have low effectiveness and safety issues. AIMS: This study aimed to evaluate the potential role of Pediococcus acidilactici PMC48 as a probiotic strain in medicines and cosmetics for skin treatment. MATERIALS AND METHODS: Meanwhile, our research team has reported that P. acidilactici PMC48 strain isolated from sesame leaf kimchi can directly decompose the already synthesized melanin. It can also inhibit melanin biosynthesis. In the present study, we investigated the skin-whitening effect of this strain by arranging an 8-week clinical trial with 22 participants. PMC48 was applied to each participant's artificially UV-induced tanned skin in the clinical trial. Its whitening effect was investigated based on visual evaluation, skin brightness, and melanin index. RESULTS: PMC48 showed a significant effect on the artificially induced pigmented skin. The color intensity of the tanned skin was decreased by 47.647%, and skin brightness was increased by 8.098% after the treatment period. PMC48 also significantly decreased the melanin index by 11.818%, indicating its tyrosinase inhibition capacity. Also, PMC48 improved skin moisture content level by 20.943%. Additionally, 16S rRNA-based amplicon sequencing analysis showed a distinct increase in Lactobacillaceae in the skin by up to 11.2% at the family level without affecting other skin microbiota. Furthermore, it showed no toxicity in in vitro or in vivo analyses. DISCUSSION: These results indicate that P. acidilactici PMC48 is a promising probiotic strain that can be used to develop medicines and cosmetic products to solve skin-related problems. CONCLUSIONS: These results demonstrate that P. acidilactici PMC48 can be a potential probiotic for the cosmetic industry against different skin disorders.
Assuntos
Cosméticos , Hiperpigmentação , Pediococcus acidilactici , Humanos , Pediococcus acidilactici/genética , Melaninas , RNA Ribossômico 16S , Pele , Hiperpigmentação/tratamento farmacológico , Cosméticos/farmacologiaRESUMO
Ellagic acid (EA) is a natural dietary polyphenol whose benefits in a variety of diseases shown in epidemiological and experimental studies involve anti-inflammation, anti-proliferation, anti-angiogenesis, anti-carcinogenesis and anti-oxidation properties. This study aimed to evaluate the effect of EA against paraquat (PQ)-induced oxidative stress. PQ decreased the viability of A549 cells in dose- and time-dependent manners, which was associated with the massive generation of reactive oxygen species (ROS). However, cell viability was significantly recovered by the treatment of EA, from 47.01±1.59% to 66.04±2.84%. The release of lactate dehydrogenase (LDH) was also decreased with the treatment of EA in PQ-treated A549 cells. EA induced the level of expression and activation of nuclear factor-erythroid 2-related factor (Nrf2) and its target cytoprotective and antioxidant genes, heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1). The antioxidant potential of EA might be directly correlated with the increased expression of HO-1 and NQO1, whose expression may have surmounted the oxidative stress generated by PQ. Notably, EA treatment significantly reduced the levels of biochemical markers as lipid peroxidation, reduced the intracellular ROS level, and surmounted total glutathione level in A549 cells. Data indicate that the antioxidant and cytoprotective properties of EA reduce PQ-induced cytotoxicity in human alveolar A549 cells.
Assuntos
Antioxidantes/farmacologia , Ácido Elágico/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Herbicidas , Humanos , L-Lactato Desidrogenase/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Alpha-lipoic acid (LA), a metabolic antioxidant, is a natural compound and its biological function has been well studied in various human diseases. The present study was designed to investigate the cytoprotective effect and the molecular mechanisms of LA in paraquat (PQ)-induced oxidative stress injury using BEAS-2B human bronchial epithelial cells. LA co-treatment prevented PQ-induced BEAS-2B cell death. LA also prevented PQ-induced increases in total reactive oxygen species (ROS), lactate dehydrogenase (LDH) and malondialdehyde (MDA). LA also increased the expression of detoxifying phase II enzyme encoding genes and antioxidant genes including HO-1, NQO1, CAT, GPX3 and GPX4, resulting in the attenuation of the decreases of antioxidants during PQ-induced oxidative stress. Nuclear factor erythroid related factor 2 (Nrf2) was induced by LA. Additionally, translocation of Nrf2 from the cytoplasm to the nucleus was promoted by LA treatment. While LA was responsible for the upregulation of Nrf2, it also activated and up-regulated the downstream proteins heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) quinone oxidoreductase 1 (NQO1). The data collectively suggest that the beneficial effect of LA involving the activation of cytoprotective antioxidant genes make LA a potential candidate in the prevention of PQ-induced oxidative stress-related bronchial cell death, pending clinically relevant studies.
Assuntos
Antioxidantes/farmacologia , Células Epiteliais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Tióctico/farmacologia , Brônquios/citologia , Catalase/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Células Epiteliais/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Herbicidas/toxicidade , Humanos , L-Lactato Desidrogenase/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Paraquat/toxicidade , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: To determine whether initial reactive oxygen species (ROS)-induced endothelial cell injury is involved in early death after paraquat intoxication and concentrations of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and von Willebrand factor (VWF) reflecting endothelial cell injury, we investigated the initial endothelial cell injury marker involved in the pathogenesis of death within 5 days after paraquat ingestion. MATERIAL/METHODS: Sixty patients with paraquat poisoning were prospectively enrolled. Plasma samples were collected at admission. Plasma concentrations of Ang-1, Ang-2, and VWF were measured by enzyme-linked immunosorbent assay. The patients were classified into 3 categories: survivors, early death (died within 5 days after ingestion), and late death (died more than 5 days after ingestion). RESULTS: The baseline concentration of Ang-2 and the Ang-2: Ang-1 ratio were significantly higher in patients who died (Ang-2 [pg/mL], 1012.75 ± 468.02 vs. 1986.07 ± 1675.37 [p=0.002]; Ang-2: Ang-1, 0.90 ± 0.49 vs. 2.16 ± 2.28 [p=0.002]). The Ang-2: Ang-1 ratio was significantly higher in the early death group (2.41 ± 2.54) than in the survivors (0.90 ± 0.49) and the late death group (1.33 ± 0.64). The Ang-2: Ang-1 ratio was significantly associated with early death (OR, 2.602; 95% CI, 1.106-6.117; p=0.028) after adjusting for plasma levels of paraquat, age, PCO2, and creatinine. VWF did not predict mortality. CONCLUSIONS: Endothelial cell damage could be involved in the pathogenesis of early death following paraquat ingestion.
Assuntos
Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/mortalidade , Angiopoietina-1/sangue , Angiopoietina-2/sangue , Paraquat/intoxicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Oxidative injury can occur in the lung through the generation of reactive oxygen species (ROS) via redox cycling owing to intentional or accidental ingestion of paraquat (PQ), a common herbicide. A wide array of phytochemicals has been shown to reduce cellular oxidative damage by modulating cytoprotective genes. Quercetin, a well-known flavonoid, has been reported to display cytoprotective effects by up-regulating certain cytoprotective genes. In this context, we investigated the effect of quercetin on PQ-induced cytotoxicity in alveolar A549 cells, modulation of antioxidant genes, activation of transcription factor-Nrf2 and its target HO-1 expression. Quercetin reduced PQ-induced cytotoxicity in A549 cells that was evaluated by both 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Modulation of antioxidant genes was compared when cells were treated with PQ, quercetin and both using qRT-PCR. Activation of transcription factor-Nrf2 and induction of its target gene, HO-1 was demonstrated by western blot analysis. A remarkable reduction in the ROS level as well as an increase in the total cellular glutathione (GSH) level occurred when PQ-exposed cells were treated with quercetin. Our findings suggest that quercetin may be used to mitigate or minimize oxidative stress via reducing the generation of ROS.
Assuntos
Antioxidantes/farmacologia , Expressão Gênica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Paraquat/toxicidade , Quercetina/farmacologia , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Glutationa/metabolismo , Heme Oxigenase-1/genética , Humanos , Fator 2 Relacionado a NF-E2/genética , Espécies Reativas de Oxigênio/metabolismoRESUMO
Specific microorganisms and changes in the constituents of the microbiome are linked with pathologies in humans, such as malignancy. Within the prostate, certain bacterial communities may locate advantageous conditions and establish themselves, thus outperforming alternative species. In this study, a comparison of malignant (MT) and benign prostate tissues (BT) or benign prostate hyperplasia (BPH) was performed in order to delineate the respective microbiomes in each sample type and to determine their pertinence to prostatic tumourigenesis. Specimens of MT (n = 26) and PT (n = 13)/BPH (n = 10) were acquired from patients. No variations in the make-up of the microbiome were seen when MT and PT specimens were compared. Changes in the bacterial constituents and functional genes were seen in the specimens obtained from patients with MT when contrasted against samples from those with BPH. Pelomonas was the genus with the highest abundance in MT specimens. It is proposed that dissimilar microbiome gene functions are present in the contexts of MT and PT samples.