RESUMEN
Cutibacterium acnes is an opportunistic pathogen recognized as a contributing factor to acne vulgaris. The accumulation of keratin and sebum plugs in hair follicles facilitates C. acnes proliferation, leading to inflammatory acne. Although numerous antimicrobial cosmetic products for acne-prone skin are available, their efficacy is commonly evaluated against planktonic cells of C. acnes. Limited research has assessed the antimicrobial effects on microorganisms within keratin and sebum plugs. This study investigates whether an antibacterial toner can penetrate keratin and sebum plugs, exhibiting bactericidal effects against C. acnes. Scanning electron microscopy and next-generation sequencing analysis of the keratin and sebum plug suggest that C. acnes proliferate within the plug, predominantly in a biofilm-like morphology. To clarify the potential bactericidal effect of the antibacterial toner against C. acnes inside keratin and sebum plugs, we immersed the plugs in the toner, stained them with LIVE/DEAD BacLight Bacterial Viability Kit to visualize microorganism viability, and observed them using confocal laser scanning microscopy. Results indicate that most microorganisms in the plugs were killed by the antibacterial toner. To quantitatively evaluate the bactericidal efficacy of the toner against C. acnes within keratin and sebum, we immersed an artificial plug with inoculated C. acnes type strain and an isolate collected from acne-prone skin into the toner and obtained viable cell counts. The number of the type strain and the isolate inside the artificial plug decreased by over 2.2 log and 1.2 log, respectively, showing that the antibacterial toner exhibits bactericidal effects against C. acnes via keratin and sebum plug penetration.
Asunto(s)
Acné Vulgar , Antibacterianos , Queratinas , Sebo , Sebo/metabolismo , Antibacterianos/farmacología , Humanos , Queratinas/metabolismo , Acné Vulgar/microbiología , Acné Vulgar/tratamiento farmacológico , Biopelículas/efectos de los fármacos , Viabilidad Microbiana/efectos de los fármacos , Propionibacteriaceae/efectos de los fármacos , Propionibacteriaceae/metabolismo , Propionibacteriaceae/genética , Propionibacterium acnes/efectos de los fármacos , Propionibacterium acnes/metabolismo , Folículo Piloso/microbiología , Folículo Piloso/metabolismo , Microscopía Electrónica de RastreoRESUMEN
It is becoming increasingly apparent that commensal skin bacteria have an important role in wound healing and infection progression. However, the precise mechanisms underpinning many of these probiotic interactions remain to be fully uncovered. In this work, we demonstrate that the common skin commensal Cutibacterium acnes can limit the pathogenicity of the prevalent wound pathogen Pseudomonas aeruginosa in vivo. We show that this impact on pathogenicity is independent of any effect on growth, but occurs through a significant downregulation of the Type Three Secretion System (T3SS), the primary toxin secretion system utilised by P. aeruginosa in eukaryotic infection. We also show a downregulation in glucose acquisition systems, a known regulator of the T3SS, suggesting that glucose availability in a wound can influence infection progression. C. acnes is well known as a glucose fermenting organism, and we demonstrate that topically supplementing a wound with glucose reverses the probiotic effects of C. acnes. This suggests that introducing carbon source competition within the wound microenvironment may be an effective way to prevent or limit wound infection.
Asunto(s)
Glucosa , Pseudomonas aeruginosa , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidad , Glucosa/metabolismo , Animales , Sistemas de Secreción Tipo III/metabolismo , Sistemas de Secreción Tipo III/genética , Propionibacterium acnes/crecimiento & desarrollo , Propionibacterium acnes/fisiología , Propionibacterium acnes/metabolismo , Infección de Heridas/microbiología , Ratones , Infecciones por Pseudomonas/microbiología , Piel/microbiología , Carbono/metabolismo , Cicatrización de Heridas , Antibiosis , Progresión de la Enfermedad , HumanosRESUMEN
BACKGROUND: Although cervical intervertebral disc (IVD) degeneration is closely associated with neck pain, its cause remains unclear. In this study, an animal model of cervical disc degeneration and discogenic neck pain induced by a low concentration of Propionibacterium acnes (P. acnes-L) is investigated to explore the possible mechanisms of cervical discogenic pain. METHODS: Cervical IVD degeneration and discitis was induced in 8-week-old male rats in C3-C6 IVDs through the anterior intervertebral puncture with intradiscal injections of low and high concentrations of P. acnes (P. acnes-L, n = 20 and P. acnes-H, n = 15) or Staphylococcus aureus (S. aureus, n = 15), compared to control (injection with PBS, n = 20). The structural changes in the cervical IVD using micro-CT, histological evaluation, and gene expression assays after MRI scans at 2 and 6 weeks post-modeling. The P. acnes-L induced IVD degeneration model was assessed for cervical spine MRI, histological degeneration, pain-like behaviors (guarding behavior and forepaw von Frey), nerve fiber growth in the IVD endplate region, and DRG TNF-α and CGRP. RESULTS: IVD injection with P. acnes-L induced IVD degeneration with decreased IVD height and MRI T2 values. IVD injection with P. acnes-H and S. aureus both lead to discitis-like changes on T2-weighted MRI, trabecular bone remodeling on micro-CT, and osseous fusion after damage in the cartilage endplate adjacent to the injected IVD. Eventually, rats in the P. acnes-L group exhibited significant nociceptive hypersensitivity, nerve fiber ingrowth was observed in the IVD endplate region, inflammatory activity in the DRG was significantly increased compared to the control group, and the expression of the pain neurotransmitter CGRP was significantly upregulated. CONCLUSION: P. acnes-L was validated to induce cervical IVD degeneration and discogenic pain phenotype, while P. acnes-H induced was identified to resemble septic discitis comparable to those caused by S. aureus infection.
Asunto(s)
Discitis , Degeneración del Disco Intervertebral , Disco Intervertebral , Masculino , Ratas , Animales , Degeneración del Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/metabolismo , Propionibacterium acnes/metabolismo , Discitis/metabolismo , Discitis/patología , Dolor de Cuello/metabolismo , Dolor de Cuello/patología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Staphylococcus aureus , Disco Intervertebral/diagnóstico por imagen , Disco Intervertebral/metabolismo , Modelos Animales de EnfermedadRESUMEN
Acne vulgaris is a type of chronic skin disorder caused by Propionibacterium acnes (P. acnes). Neutrophil extrinsic traps (NETs) play key role in many types of inflammatory skin diseases. Adipose-derived stem cells (ADSCs) was reported modulate immune responses and neutrophil activity. Here, we explored the potential role of ADSCs and the potential mechanism associated with neutrophil extracellular traps (NETs) in relieving acne vulgaris. In the P. acnes-infected ear skin model, histological staining was used to evaluate the inflammatory infiltration and NET formation in control, P. acnes, and P. acnes + ADSCs groups. Besides, western blot was used to detect the expression levels of cit-H3, MPO, and Nrf2 in ear tissue. In vitro, the immunofluorescence staining of MPO and cit-H3, and SYTOX green staining were performed to measure the NET formation. CCK-8 assay, EdU staining, and wound healing assay were used to detect the proliferation and migration abilities of keratinocytes. ELISA assay was utilized to detect the secretion of inflammatory cytokines. In P. acnes-infected ear skin, ADSC treatment significantly attenuated inflammation and NET formation via activating Nrf2 signaling pathway. In vitro, the conditioned medium of ADSCs reduced the formation of P. acne-induced NETs. Besides, ADSCs could inhibit that the NETs efficiently promoted the proliferation, migration, and inflammatory cytokine secretion of keratinocytes. Our study suggested that ADSCs could attenuate P. acne-related inflammation by inhibiting NET formation. This study provides a novel therapeutic perspective of ADSCs in combating acne vulgaris.
Asunto(s)
Acné Vulgar , Trampas Extracelulares , Humanos , Trampas Extracelulares/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Acné Vulgar/microbiología , Inflamación , Células Madre/metabolismo , Propionibacterium acnes/metabolismoRESUMEN
Acne vulgaris caused by antibiotic-resistant Cutibacterium acnes (C. acnes) infection is difficult to treat conventionally. Phages have been suggested as a potential solution, but research on the mechanism of phage treatment is inadequate. This research investigates the underlying molecular mechanisms of phage φPaP11-13 attenuating C. acnes-induced inflammation in rat models. We found that rats infected with C. acnes had higher average ear thickness, greater enrichment of inflammatory cells as shown by hematoxylin-eosin (HE) staining, and fewer TUNEL (TdT-mediated dUTP Nick-End Labeling)-positive keratinocytes visualized by IF staining. Moreover, an increase of IGF-1 and IGF-1 receptor (IGF-1r) was detected using the immunohistochemical (IHC) staining method, Western blot (WB), and quantitative real-time PCR (qRT-PCR) when infected with C. acnes, which was decreased after the application of phage φPaP11-13. By applying the IGF-1 antibody, it was demonstrated that the severity of C. acnes-induced inflammation was relevant to the expression of IGF-1. Through WB and qRT-PCR, activation of the PI3K/Akt pathway and a down-regulation of the BAD-mediated apoptosis pathway were discovered after C. acnes infection. Subsequently, it was shown that the activation of the PI3K/Akt pathway against BAD-mediated apoptosis pathway was alleviated after applying phage φPaP11-13. Furthermore, applying the IGF-1r inhibitor, Pan-PI3K inhibitor, and Akt inhibitor reversed the changing trends of BAD induced by C. acnes and phage φPaP11-13. This study demonstrates that one of the critical mechanisms underlying the attenuation of acne vulgaris by phage φPaP11-13 is lysing C. acnes and regulating keratinocyte apoptosis via the PI3K/Akt signaling pathway.IMPORTANCECutibacterium acnes infection-induced acne vulgaris may cause severe physical and psychological prognosis. However, the overuse of antibiotics develops drug resistance, bringing challenges in treating Cutibacterium acnes. Bacteriophages are currently proven effective in MDR (multiple drug-resistant) Cutibacterium acnes, but there is a significant lack of understanding of phage therapy. This study demonstrated a novel way of curing acne vulgaris by using phages through promoting cell death of excessive keratinocytes in acne lesions by lysing Cutibacterium acnes. However, the regulation of this cell cycle has not been proven to be directly mediated by phages. The hint of ternary relation among "phage-bacteria-host" inspires huge interest in future phage therapy studies.
Asunto(s)
Acné Vulgar , Bacteriófagos , Animales , Ratas , Factor I del Crecimiento Similar a la Insulina/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Acné Vulgar/microbiología , Propionibacterium acnes/metabolismo , Inflamación/metabolismo , ApoptosisRESUMEN
BACKGROUND: Viaminate, a vitamin A acid drug developed in China, has been clinically used in acne treatment to regulate epithelial cell differentiation and proliferation, inhibit keratinization, reduce sebum secretion, and control immunological and anti-inflammatory actions; however, the exact method by which it works is unknown. METHODS: In the present study, acne was induced in the ears of rats using Propionibacterium acnes combined with sebum application. RESULTS: After 30 days of treatment with viaminate, the symptoms of epidermal thickening and keratin overproduction in the ears of rats were significantly improved. Transcriptomic analysis of rat skin tissues suggested that viaminate significantly regulated the biological pathways of cellular keratinization. Gene differential analysis revealed that the S100A8 and S100A9 genes were significantly downregulated after viaminate treatment. The results of qPCR and Western blotting confirmed that viaminate inhibited the expression of S100A8 and S100A9 genes and proteins in rat and HaCat cell acne models, while its downstream pathway MAPK (MAPK p38/JNK/ERK1/2) protein expression levels were suppressed. Additional administration of the S100A8 and S100A9 complex protein significantly reversed the inhibitory effect of viaminate on abnormal proliferation and keratinization levels in acne cell models. CONCLUSION: In summary, viaminate can improve acne by modulating S100A8 and S100A9 to inhibit MAPK pathway activation and inhibit keratinocyte proliferation and keratinization levels.
Asunto(s)
Acné Vulgar , Neoplasias Cutáneas , Ratas , Animales , Humanos , Sistema de Señalización de MAP Quinasas , Células HaCaT/metabolismo , Propionibacterium acnes/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Calgranulina B/farmacología , Tretinoina/metabolismo , Tretinoina/farmacología , Acné Vulgar/tratamiento farmacológico , Diferenciación Celular , Proliferación CelularRESUMEN
Sarcoidosis is a granulomatous disease of unknown etiology, with limited therapeutic options. Chronic sarcoidosis can result in pulmonary fibrosis and can be lethal. Enhanced expression of pro-inflammatory cytokines, such as interleukin-17A (IL-17A), has been observed in sarcoid granulomas in humans. However, the role of IL-17A in the pathogenesis of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis and its potential therapeutic effects remain unclear. This study investigated whether IL-17A is critical in granulomatosis and its role in chronic inflammation in a profibrotic manner. Wild-type and IL-17A-knockout C57BL/6 mice were repeatedly challenged with heat-killed Propionibacterium acnes (PA) to induce sarcoidosis-like granulomata and sarcoidosis-related pulmonary fibrosis. Wild-type mice with granulomatosis were treated with anti-IL-17A antibody. Administration of PA enhanced the expression of IL-17A, granulomatosis, and fibrosis in mouse lungs after boost stimulation. Neither granulomata nor fibrosis were observed in IL-17A-knockout mice, even in the presence of interferon-γ enhancement. Neutralizing IL-17A antibody reduced inflammatory cells in bronchoalveolar lavage fluid and ameliorated both granulomatosis and fibrosis in sarcoidosis mice. In conclusion, our data demonstrate that IL-17A plays a critical role in PA-induced sarcoidosis-like inflammation in both granulomatosis inflammation and disease progression to pulmonary fibrosis, thus providing novel insights into the treatment of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis.
Asunto(s)
Fibrosis Pulmonar , Sarcoidosis , Animales , Humanos , Ratones , Granuloma/patología , Inflamación , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Propionibacterium acnes/metabolismoRESUMEN
Viaminate, a retinoic acid derivative developed in China, has been clinically used for acne treatment to regulate and control keratinocyte cell differentiation and proliferation, inhibit keratinization, reduce sebum secretion, and regulate immune and anti-inflammatory functions; however, its potential molecular mechanism has not yet been elucidated. Therefore, we induced ear acne in rats using Propionibacterium acnes and sebum application. Symptoms of ear redness, epidermal thickening, inflammatory reaction, keratin overproduction, subcutaneous oil, and triglyceride (TG) accumulation improved significantly in acne model rats treated with viaminate for 30 days. Transcriptome analysis of rat skin tissues suggested that viaminate had significant regulatory effects on fatty acid metabolism and cellular keratinization pathways. Molecular target prediction suggested that toll-like receptor 2 (TLR2) may be a key target of viaminate's therapeutic mechanism. Western blotting results confirmed that viaminate inhibited the TLR2 and its downstream pathways, nuclear factor-kappa B (NF-κB) [NF-κB inhibitor alpha (IκBα)/NF-κB-p65] and mitogen-activated protein kinases (MAPKs) [MAPK p38/c-Jun N-terminal kinase (JNK)/extracellular regulated kinase 1/2 (ERK1/2)] in acne vulgaris rats. In vitro studies revealed that viaminate treatment attenuated P. acnes proliferation and P. acnes-induced inflammatory response in human keratinocytes and has an inhibitory effect on the activation of NF-κB and MAPKs, while overexpression of TLR2 attenuated these effects. In conclusion, viaminate ameliorates P. acnes-induced acne by inhibiting the proliferation and inflammatory response of keratinocytes, ascribed to the deactivation of the TLR2-mediated NF-κB and MAPK pathways.
Asunto(s)
Acné Vulgar , FN-kappa B , Ratas , Humanos , Animales , FN-kappa B/metabolismo , Propionibacterium acnes/metabolismo , Receptor Toll-Like 2 , Tretinoina , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/metabolismo , Proteínas Quinasas Activadas por MitógenosRESUMEN
The root of Smilax china L. is used in traditional Korean medicine. We found that the Smilax china L. root extract has strong antimicrobial activity against two Cutibacterium acnes strains (KCTC 3314 and KCTC 3320). The aim of this study was to identify the beneficial properties of Smilax china L. extracts for their potential use as active ingredients in cosmetics for the treatment of human skin acne. The high-performance liquid chromatography (HPLC) and liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC/QTOF/MS) methods were used to obtain the profile of secondary metabolites from the ethyl acetate-soluble fraction of the crude extract. Agar diffusion and resazurin-based broth microdilution assays were used to evaluate antimicrobial activity and minimum inhibitory concentrations (MIC), respectively. Among the 24 metabolites, quercetin, resveratrol, and oxyresveratrol were the most potent compounds against Cutibacterium acnes. Minimum inhibitory concentrations of quercetin, resveratrol, and oxyresveratrol were 31.25, 125, and 250 µg/mL, respectively.
Asunto(s)
Acné Vulgar , Antiinfecciosos , Smilax , Humanos , Smilax/química , Quercetina , Propionibacterium acnes/metabolismo , Extractos Vegetales/química , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/microbiología , Pruebas de Sensibilidad Microbiana , Resveratrol , Antiinfecciosos/farmacología , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
BACKGROUND: Curcumin has been employed as a photosensitizer agent during photodynamic therapy (PDT). Cutibacterium acnes (C. acnes) can cause an inflammatory response in human keratinocytes; however, no research has been conducted to determine whether curcumin and its photodynamic properties can prevent this inflammatory reaction. OBJECTIVE: We hypothesized that curcumin may control the C. acnes biofilm-induced inflammatory response in keratinocytes, either alone or in combination with blue light photodynamic therapy. METHODS: Following C. acnes biofilm stimulation, human primary keratinocytes were treated with 20 µM curcumin solution alone or 5 µM curcumin with combined blue light irradiation. The amount of secreted protein was measured using an ELISA kit. The expression levels of Toll-like receptor 2 (TLR2) and its downstream proteins were determined using western blot. RESULTS: Treatment with 20 µM curcumin, but not 5 µM curcumin, reduced the inflammatory response to C. acnes biofilms in keratinocytes by blocking the TLR2/MAPK/NF-κB pathway. Interestingly, 5 µM curcumin combined with blue light also reduced the C. acnes biofilm-induced inflammation indicated above by blocking the TLR2/MAPK/NF-κB pathway. CONCLUSION: Curcumin alone, in sufficient concentrations, or low-concentration curcumin with blue light had anti-inflammatory activity on keratinocytes stimulated by C. acnes biofilms through inhibition of MAPK and NF-κB signaling pathways by downregulating TLR2 expression.
Asunto(s)
Curcumina , Fotoquimioterapia , Humanos , FN-kappa B/metabolismo , Curcumina/farmacología , Fotoquimioterapia/métodos , Propionibacterium acnes/metabolismo , Queratinocitos/metabolismo , InflamaciónRESUMEN
OBJECTIVES: Particulate matter (PM) is an air pollutant that can damage human skin; antioxidants have shown some efficacy in alleviating PM-induced skin inflammation. We investigated the antioxidant effects of punicalagin, epigallocatechin-3-gallate (EGCG), and resveratrol on PM-induced changes in cultured human sebocytes, outer root sheath (ORS) cells, and Cutibacterium acnes-pretreated mice. METHODS: Sebocytes and ORS cells were cultured with 100 µg/mL PM10 and 5 µM punicalagin, 1 µM EGCG, or 1 µM resveratrol for 24 h. In C. acnes-pretreated mice, inflammatory nodules were treated with 100 µg/mL PM10 and 5 µM punicalagin, 1 µM EGCG, or 1 µM resveratrol. Cell viability was measured using an MTT assay. Antioxidant effects were analyzed according to RNA expression, using real-time PCR, as well as reactive oxygen species (ROS) and sebum measurements. RESULTS: Antioxidants inhibited the upregulation of inflammatory cytokines, matrix metalloproteinase, aryl hydrocarbon receptor, and NF-kB as well as the production of ROS induced by PM10 in cultured sebocytes and ORS cells. The preventative effects of punicalagin and EGCG on biomarker expression in cultured sebocytes and ORS cells were slightly greater than those of resveratrol, though the difference was not significant. In C. acnes-pretreated mice, the antioxidants inhibited inflammatory cytokine and matrix metalloproteinase expression as well as sebum production. CONCLUSIONS: Antioxidants effectively reduced the expression of inflammatory biomarkers and sebum production in cultured sebocytes, ORS cells, and C. acnes-pretreated mice.
Asunto(s)
Acné Vulgar , Antioxidantes , Material Particulado , Acné Vulgar/metabolismo , Acné Vulgar/microbiología , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Citocinas/metabolismo , Ratones , Material Particulado/metabolismo , Material Particulado/toxicidad , Propionibacterium acnes/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Resveratrol/farmacología , Glándulas Sebáceas/metabolismo , Glándulas Sebáceas/microbiologíaRESUMEN
BACKGROUND: Acne is a chronic facial disease caused by Propionibacterium acnes, which proliferates within sebum-blocked skin follicles and increases inflammatory cytokine production. Several therapeutic drugs and products have been proposed to treat acne, yet no single treatment that ensures long-term treatment efficacy for all patients is available. Here, we explored the use of facial autologous fat transplant of adipose-derived stem cells (ADSCs) to dramatically reduce acne lesions. METHODS: THP-1 cells were treated with active P. acnes for 24 h at different multiplicities of infection, and alterations in inflammatory factors were detected. To study the effect of THP-1 on inflammasome-related proteins, we first co-cultured ADSCs with THP-1 cells treated with P. acnes and evaluated the levels of these proteins in the supernatant. Further, an acne mouse model injected with ADSCs was used to assess inflammatory changes. RESULTS: Propionibacterium acnes-mediated stimulation of THP-1 cells had a direct correlation with the expression of active caspase-1 and interleukin (IL)-1ß in an infection-dependent manner. ADSCs significantly reduced the production of IL-1ß induced by P. acnes stimulation through the reactive oxygen species (ROS)/Nod-like receptor family pyrin domain-containing 3 (NLRP3)/caspase-1 pathway. The results showed that ADSCs inhibit the skin inflammation induced by P. acnes by blocking the NLRP3 inflammasome via reducing the secretion of IL-1ß in vivo. CONCLUSIONS: Our findings suggest that ADSCs can alter IL-1ß secretion by restricting the production of mitochondria ROS, thereby inhibiting the NLRP3/caspase-1 pathway in P. acnes-induced inflammatory responses. This study indicates that anti-acne therapy can potentially be developed by targeting the NLRP3 inflammasome.
Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Caspasa 1/metabolismo , Caspasa 1/farmacología , Inflamación/patología , Inflamación/terapia , Interleucina-1beta/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Propionibacterium acnes/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células Madre/metabolismoRESUMEN
Acne vulgaris is a common skin disease mainly caused by the Gram-positive pathogenic bacterium, Propionibacterium acnes. This bacterium stimulates the inflammation process in human sebaceous glands. The giant African snail (Achatina fulica) is an alien species that rapidly reproduces and seriously damages agricultural products in Thailand. There were several research reports on the medical and pharmaceutical benefits of these snail mucus peptides and proteins. This study aimed to in silico predict multifunctional bioactive peptides from A. fulica mucus peptidome using bioinformatic tools for the determination of antimicrobial (iAMPpred), anti-biofilm (dPABBs), cytotoxic (ToxinPred) and cell-membrane-penetrating (CPPpred) peptides. Three candidate peptides with the highest predictive score were selected and re-designed/modified to improve the required activities. Structural and physicochemical properties of six anti-P. acnes (APA) peptide candidates were performed using the PEP-FOLD3 program and the four previous tools. All candidates had a random coiled structure and were named APAP-1 ori, APAP-2 ori, APAP-3 ori, APAP-1 mod, APAP-2 mod, and APAP-3 mod. To validate the APA activity, these peptide candidates were synthesized and tested against six isolates of P. acnes. The modified APA peptides showed high APA activity on three isolates. Therefore, our biomimetic mucus peptides could be useful for preventing acne vulgaris and further examined on other activities important to medical and pharmaceutical applications.
Asunto(s)
Acné Vulgar , Propionibacterium acnes , Animales , Humanos , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/microbiología , Antibacterianos/química , Moco/química , Péptidos/química , Preparaciones Farmacéuticas/análisis , Propionibacterium acnes/metabolismo , Caracoles/químicaRESUMEN
Propionibacterium acnes infection in intervertebral discs (IVDs) is a newly identified cause of low back pain (LBP). In the present study, we aimed to determine whether the nerve growth factor (NGF), a critical pro-algesic factor, is involved in P. acnes-induced LBP. After co-culturing with P. acnes, nucleus pulposus cells (NPCs) produced NGF, which was upregulated after inoculation of P. acnes into IVDs of rats. In addition, administration of P. acnes into rat IVDs leads to significant mechanical allodynia and cold hyperreflexia, and significant upregulation of the pain-related factors, including substance P (SP), calcitonin gene-related peptide (CGRP), and Transient Receptor Potential Vanilloid 1 (TRPV1), in rat dorsal root ganglia (DRG), suggesting that P. acnes-inoculated rats had obvious discogenic LBP. However, inhibition of NGF bioactivity significantly ameliorated P. acnes-induced discogenic LBP, suggesting that P. acnes induced LBP via NGF. Finally, an in vitro mechanism study demonstrated that P. acnes stimulated NPCs to secrete NGF via TLR-2 receptor and NF-κB p65/JNK pathway, or ROS-related pathway. Therefore, P. acnes had a strong association with LBP by stimulating NPCs to secrete NGF via the TLR2-NF- κB/JNK or ROS-related pathway. These findings propose a novel potential therapeutic strategy for LBP.
Asunto(s)
Dolor de la Región Lumbar , Propionibacterium acnes , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , FN-kappa B/metabolismo , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Propionibacterium acnes/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Sustancia P/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Regulación hacia ArribaRESUMEN
Acne vulgaris is a common skin disease, affecting over 80% of adolescents. Inflammation is known to play a central role in acne development. Here, we aimed to investigate the role of the central clock gene Bmal1 in acne-associated inflammation in mice. To this end, mice were injected intradermally with Propionibacterium acnes (P. acnes) to induce acne-associated skin inflammation. We found that Bmal1 and its target genes Rev-erbα, Dbp, Per1 and Cry2 were down-regulated in the skin of P. acnes-treated mice, suggesting a role of Bmal1 in the condition of acne. Supporting this, Bmal1-deleted or jet-lagged mice showed exacerbated P. acnes-induced inflammation in the skin. Regulation of P. acnes-induced inflammation by Bmal1 was further confirmed in RAW264.7 cells and primary mouse keratinocytes. Transcriptomic and protein expression analyses suggested that Bmal1 regulated P. acnes-induced inflammation via the NF-κB/NLRP3 axis, which is known to be repressed by REV-ERBα (a direct target of BMAL1). Moreover, loss of Rev-erbα in mice exacerbated P. acnes-induced inflammation. In addition, Rev-erbα silencing attenuated the inhibitory effects of Bmal1 on P. acnes-induced inflammation. Bmal1 knockdown failed to modulate P. acnes-induced inflammation in Rev-erbα-silenced cells. It was thus proposed that Bmal1 restrained P. acnes-induced skin inflammation via its target REV-ERBα, which acts on the NF-κB/NLRP3 axis to repress inflammation. In conclusion, Bmal1 disruption is identified as a potential pathological factor of acne-associated inflammation. The findings increase our understanding of the crosstalk between skin clock and acne and suggest targeting circadian rhythms as a promising approach for management of acne.
Asunto(s)
Acné Vulgar , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Animales , Inflamación/genética , Ratones , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Propionibacterium acnes/metabolismoRESUMEN
Innate immune defense against deep tissue infection by Staphylococcus aureus is orchestrated by fibroblasts that become antimicrobial when triggered to differentiate into adipocytes. However, the role of this process in noninfectious human diseases is unknown. To investigate the potential role of adipogenesis by dermal fibroblasts in acne, a disorder triggered by Cutibacterium acnes, single-cell RNA sequencing was performed on human acne lesions and mouse skin challenged by C. acnes. A transcriptome consistent with adipogenesis was observed within specific fibroblast subsets from human acne and mouse skin lesions infected with C. acnes. Perifollicular dermal preadipocytes in human acne and mouse skin lesions showed colocalization of PREF1, an early marker of adipogenesis, and cathelicidin (Camp), an antimicrobial peptide. This capacity of C. acnes to specifically trigger production of cathelicidin in preadipocytes was dependent on TLR2. Treatment of wild-type mice with retinoic acid (RA) suppressed the capacity of C. acnes to form acne-like lesions, inhibited adipogenesis, and enhanced cathelicidin expression in preadipocytes, but lesions were unresponsive in Camp-/- mice, despite the anti-adipogenic action of RA. Analysis of inflamed skin of acne patients after retinoid treatment also showed enhanced induction of cathelicidin, a previously unknown beneficial effect of retinoids in difficult-to-treat acne. Overall, these data provide evidence that adipogenic fibroblasts are a critical component of the pathogenesis of acne and represent a potential target for therapy.
Asunto(s)
Acné Vulgar , Antiinfecciosos , Enfermedades de la Piel , Animales , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Humanos , Ratones , Propionibacterium acnes/metabolismo , Staphylococcus aureus , Tretinoina/farmacologíaRESUMEN
Acne vulgaris is a highly prevalent skin disorder requiring treatment and management by dermatologists. Antibiotics such as clindamycin are commonly used to treat acne vulgaris. However, from both medical and public health perspectives, the development of alternative remedies has become essential due to the increase in antibiotic resistance. Topical therapy is useful as a single or combined treatment for mild and moderate acne and is often employed as maintenance therapy. Thus, the current study investigated the anti-inflammatory, antibacterial, and restorative effects of sesquiterpene farnesol on acne vulgaris induced by Cutibacterium acnes (C. acnes) in vitro and in a rat model. The minimum inhibitory concentration (MIC) of farnesol against C. acnes was 0.14 mM, and the IC50 of 24 h exposure to farnesol in HaCaT keratinocytes was approximately 1.4 mM. Moreover, 0.8 mM farnesol exhibited the strongest effects in terms of the alleviation of inflammatory responses and abscesses and necrotic tissue repair in C.acnes-induced acne lesions; 0.4 mM farnesol and clindamycin gel also exerted similar actions after a two-time treatment. By contrast, nearly doubling the tissue repair scores, 0.4 mM farnesol displayed great anti-inflammatory and the strongest reparative actions after a four-time treatment, followed by 0.8 mM farnesol and a commercial gel. Approximately 2-10-fold decreases in interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, found by Western blot analysis, were predominantly consistent with the histopathological findings and tissue repair scores. The basal hydroxypropyl methylcellulose (HPMC) gel did not exert anti-inflammatory or reparative effects on rat acne lesions. Our results suggest that the topical application of a gel containing farnesol is a promising alternative remedy for acne vulgaris.
Asunto(s)
Antibacterianos/química , Farnesol/química , Propionibacterium acnes/metabolismo , Sesquiterpenos/química , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/metabolismo , Administración Cutánea , Animales , Antibacterianos/farmacología , Farnesol/farmacología , Células HaCaT , Humanos , Derivados de la Hipromelosa/metabolismo , Interleucinas/metabolismo , Masculino , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: Eradication of Helicobacter pylori (H. pylori) could not completely prevent the progression of gastric cancer (GC), suggesting that non-H. pylori bacteria may participate in the carcinogenesis of GC. The dysbiosis of microbiota in the stomach of GC has gradually been investigated, while the detailed mechanism that promotes GC in this process has not been elucidated. We aimed to identify a non-H. pylori bacteria that contribute to GC. DESIGN: GC tissues and adjacent normal tissues were collected to identify bacteria that significantly increased in GC tissues by 16S rRNA gene sequencing and fluorescence in situ hybridization (FISH) analysis. CCK8, wound healing assay, and trans-well assay were performed to analyze the tumor-promoting effect of this bacteria. Next, we detailed the mechanism for tumor-promoting effect of the bacteria by immunofluorescence, RT-qPCR, and western-blotting analysis. RESULTS: Comparing the microbial community from GC tissues and adjacent normal tissues, we found that Propionibacterium acnes (P. acnes) significantly increased in GC tissues, especially in H. pylori-negative tissues. We further found that the abundance of P. acnes correlated with TNM stages of GC patients. Interestingly, condition medium (CM) from P. acnes-primed macrophages promoted migration of GC cells, while P. acnes only could not. We next proved that P. acnes triggers M2 polarization of macrophages via TLR4/PI3K/Akt signaling. CONCLUSIONS: Together, our finding identified that P. acnes could be a possible agent for the progression of GC besides H. pylori. M2 polarization of macrophages could be promoted by P. acnes via TLR4/PI3K/Akt signaling, thus triggers the progression of GC.
Asunto(s)
Macrófagos/metabolismo , Propionibacterium acnes/metabolismo , Neoplasias Gástricas/microbiología , Disbiosis , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
Ultraviolet irradiation induces melanin accumulation, which can be reduced by the use of chemical whitening products. However, the associated safety concerns of such products have prompted the search for natural and harmless alternatives. This study aimed to identify a natural acidic formulation to reduce skin pigmentation. The metabolite propionic acid (CH3CH2COOH, PA) was the most abundant fatty acid in the filtrate from Pluronic F68 (PF68) fermentation of Cutibacterium acnes (C. acnes) and reduced the DOPA-positive melanocytes by significantly inhibiting cellular tyrosinase activity via binding to the free fatty acid receptor 2 (FFAR2). Moreover, 4 mM PA treatment did not alter melanocyte proliferation, indicating that it is an effective solution for hyperpigmentation, causing no cellular damage. The reduced DOPA-positive melanocytes and tyrosinase activity were also observed in mice ear skin tissue injected with a mixture of C. acnes and PF68, supporting that the inhibition of melanogenesis is likely to be mediated through fermentation metabolites from C. acnes fermentation using PF68 as a carbon source. Additionally, PA did not affect the growth of its parent bacteria C. acnes, hence is a potent fermentation metabolite that does not disrupt the balance of the skin microbiome.
Asunto(s)
Melaninas/síntesis química , Propionatos/metabolismo , Propionibacterium acnes/metabolismo , Animales , Proliferación Celular , Oído , Femenino , Fermentación , Humanos , Hiperpigmentación , Melanocitos/citología , Melanocitos/metabolismo , Metaboloma , Ratones Endogámicos ICR , Procesos Fotoquímicos , Propionatos/química , Receptores Acoplados a Proteínas G/efectos de la radiación , Piel , Pigmentación de la Piel , Rayos UltravioletaRESUMEN
Organic and inorganic antigens were studied simultaneously in the same cohort of sarcoidosis patients to investigate whether correlations between clinical characteristics and immunological sensitization could reveal new phenotypes. Sensitization to antigens of mycobacteria, Propionibacterium acnes catalase and vimentin was investigated in 201 sarcoidosis and 51 obstructive sleep apnoea patients, serving as control group. Sensitization to aluminium, beryllium, silica and zirconium was also studied in 105 of the sarcoidosis patients and in 24 of the controls. A significantly higher percentage of sarcoidosis patients (27·6%) than controls (4·2%) had an immunological response to metals or silica (P = 0·014). A higher percentage of these sarcoidosis patients showed fibrosis on chest X-ray 5 years after the diagnosis (69·2 versus 30·3%, P = 0·016). No significant differences in mycobacterial or vimentin enzyme-linked immunospot (ELISPOT) assay results were observed between sarcoidosis and control patients. A significantly lower percentage of sarcoidosis patients (3·5%) than control patients (15·7%) had a positive ELISPOT for P. acnes catalase (P = 0·003). However, sarcoidosis patients sensitized to P. acnes catalase were more likely to have skin involvement, while sarcoidosis patients sensitized to mycobacterial antigens were more likely to have cardiac involvement. Our study suggests a more prominent role for inorganic triggers in sarcoidosis pathogenesis than previously thought. Immunological sensitization to inorganic antigens was associated with development of fibrotic sarcoidosis. No association was found between sensitization to bacterial antigens or vimentin and sarcoidosis in Dutch patients. However, our data suggest that trigger-related phenotypes can exist in the heterogeneous population of sarcoidosis patients.