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Eleven triterpenoid saponins, including five new compounds, which were named densiflorasides A - E (1 - 5), were isolated from aerial parts of Mussaenda densiflora (Rubiaceae). Their structures were elucidated based on spectroscopic and single-crystal X-ray diffraction analyses and chemical methods. All the isolated compounds and the aglycone heinsiagenin A were evaluated for their immunosuppressive and antiosteoclastogenic activities in vitro. Compounds 6 - 8 and heinsiagenin A inhibited osteoclastogenesis, with IC50 values ranging from 8.24 to 17.7 µM. Furthermore, compounds 3, 6 - 8, and heinsiagenin A significantly inhibited T-cell proliferation, with IC50 values ranging from 2.56 to 8.60 µM, and compounds 3 - 5 and 11 inhibited the proliferation of B lymphocytes, with IC50 values ranging from 1.29 to 8.49 µM. Further in vivo experiments indicated that heinsiagenin A could significantly attenuate IMQ-induced psoriasis and DSS-induced colitis in mice.
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Proliferación Celular , Relación Dosis-Respuesta a Droga , Inmunosupresores , Saponinas , Triterpenos , Saponinas/farmacología , Saponinas/química , Saponinas/aislamiento & purificación , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Inmunosupresores/farmacología , Inmunosupresores/química , Inmunosupresores/aislamiento & purificación , Relación Estructura-Actividad , Triterpenos/química , Triterpenos/farmacología , Triterpenos/aislamiento & purificación , Estructura Molecular , Linfocitos T/efectos de los fármacos , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Masculino , Osteoclastos/efectos de los fármacosAsunto(s)
Antígeno CTLA-4 , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Animales , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Microbioma Gastrointestinal/inmunologíaRESUMEN
Enteric IL-17RA deficiency leads to gut dysbiosis, consequently initiating the proliferation of tumors at remote locations. The deficiency or blockade of enteric IL-17RA induces the secretion of IL-17A by B cells and Th17 cells in response to microbial signals, resulting in a systemic elevation of IL-17A and fostering the growth of remote tumors. This figure was created with BioRender.com.
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Cephalotanes are a rare class of diterpenoids occurring exclusively in Cephalotaxus plants. The intriguing structures and promising biological activities for this unique compound class prompt us to investigate C. fortunei var. alpina and C. sinensis, leading to the isolation of six undescribed cephalotane-type diterpenoids and/or norditerpenoids, ceforloids A-F (1-6). Their structures were elucidated by comprehensive analysis of spectroscopic data, including ECD and single-crystal X-ray diffraction studies, as well as quantum chemical calculations. Compound 1 possesses an unprecedented norditerpenoid skeleton featuring an unusual acetophenone moiety, and originated putatively from a disparate biogenetic pathway. Compounds 4 and 5 incorporate a unique 12,13-p-hydroxybenzylidene acetal motif. Compound 6 is a rare cephalotane-type diterpenoid glycoside. Immunosuppressive assays showed that compounds 2 and 6 exhibited mild suppressive activity against the activated T and B lymphocytes proliferation. These findings not only expanded the structural diversity of this small group of diterpenoids, but also explored their potential as novel structures for the development of immunosuppressive agents.
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Cephalotaxus , Diterpenos , Estructura Molecular , Cephalotaxus/química , Diterpenos/farmacología , Diterpenos/química , Inmunosupresores , Cristalografía por Rayos XRESUMEN
Osteoarthritis (OA) is characterized by gradual articular cartilage degradation, accompanied by persistent low-grade joint inflammation, correlating with radiographic and pain-related progression. The latent therapeutic potential of DZ2002, a reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH), holds promise for OA intervention. This study endeavored to examine the therapeutic efficacy of DZ2002 within the milieu of OA. The cytotoxicity of DZ2002 was evaluated using the MTT assay on bone marrow-derived macrophages. The inhibitory impact of DZ2002 during the process of osteoclastogenesis was assessed using TRAP staining, analysis of bone resorption pits, and F-actin ring formation. Mechanistic insights were derived from qPCR and Western blot analyses. Through the intra-articular injection of monosodium iodoacetate (MIA), an experimental rat model of OA was successfully instituted. This was subsequently accompanied by a series of assessments including Von Frey filament testing, analysis of weight-bearing behaviors, and micro-CT imaging, all aimed at assessing the effectiveness of DZ2002. The findings emphasized the effectiveness of DZ2002 in mitigating osteoclastogenesis induced by M-CSF/RANKL, evident through a reduction in TRAP-positive OCs and bone resorption. Moreover, DZ2002 modulated bone resorption-associated gene and protein expression (CTSK, CTR, Integrin ß3) via the MEK/ERK pathway. Encouragingly, DZ2002 also alleviates MIA-induced pain, cartilage degradation, and bone loss. In conclusion, DZ2002 emerges as a potential therapeutic contender for OA, as evidenced by its capacity to hinder in vitro M-CSF/RANKL-induced osteoclastogenesis and mitigate in vivo osteoarthritis progression. This newfound perspective provides substantial support for considering DZ2002 as a compelling agent for osteoarthritis intervention.
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Resorción Ósea , Cartílago Articular , Osteoartritis , Ratas , Animales , Ácido Yodoacético/efectos adversos , Ácido Yodoacético/metabolismo , Factor Estimulante de Colonias de Macrófagos/metabolismo , Sistema de Señalización de MAP Quinasas , Osteoartritis/inducido químicamente , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Dolor/tratamiento farmacológico , Cartílago Articular/metabolismo , Resorción Ósea/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Modelos Animales de EnfermedadRESUMEN
Dry eye disease (DED) is a prevalent ocular disorder with a multifactorial etiology. The pre-angiogenic and pre-inflammatory milieu of the ocular surface plays a critical role in its pathogenesis. DZ2002 is a reversible type III S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, which has shown excellent anti-inflammatory and immunosuppressive activities in vivo and in vitro. In this study, we evaluated the therapeutic potential of DZ2002 in rodent models of DED. SCOP-induced dry eye models were established in female rats and mice, while BAC-induced dry eye model was established in female rats. DZ2002 was administered as eye drops (0.25%, 1%) four times daily (20 µL per eye) for 7 or 14 consecutive days. We showed that topical application of DZ2002 concentration-dependently reduced corneal neovascularization and corneal opacity, as well as alleviated conjunctival irritation in both DED models. Furthermore, we observed that DZ2002 treatment decreased the expression of genes associated with angiogenesis and the levels of inflammation in the cornea and conjunctiva. Moreover, DZ2002 treatment in the BAC-induced DED model abolished the activation of the STAT3-PI3K-Akt-NF-κB pathways in corneal tissues. We also found that DZ2002 significantly inhibited the proliferation, migration, and tube formation of human umbilical endothelial cells (HUVECs) while downregulating the activation of the STAT3-PI3K-Akt-NF-κB pathway. These results suggest that DZ2002 exerts a therapeutic effect on corneal angiogenesis in DED, potentially by preventing the upregulation of the STAT3-PI3K-Akt-NF-κB pathways. Collectively, DZ2002 is a promising candidate for ophthalmic therapy, particularly in treating DED.
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Neovascularización de la Córnea , Síndromes de Ojo Seco , Ratas , Humanos , Ratones , Animales , Femenino , Neovascularización de la Córnea/tratamiento farmacológico , Neovascularización de la Córnea/metabolismo , Neovascularización de la Córnea/patología , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Roedores/metabolismo , Células Endoteliales/metabolismo , Angiogénesis , Inflamación/tratamiento farmacológico , Síndromes de Ojo Seco/tratamiento farmacológico , Síndromes de Ojo Seco/inducido químicamente , Factor de Transcripción STAT3/metabolismoRESUMEN
BACKGROUND: Ulcerative colitis (UC), a chronic inflammatory disease, is caused by abnormal immune system reactions resulting in inflammation and ulcers in the large intestine. Phillygenin (PHI) is a natural compound found in Forsythia suspensa (Thunb.) Vahl, which is known for its antipyretic, anti-inflammatory, antiobesity, and other biological activities. However, the therapeutic role and molecular mechanisms of PHI on UC are still insufficiently researched. METHODS: In this study, dextran sulfate sodium (DSS) and 2.5% 2,4,6-trinitro-Benzenesulfonic acid (TNBS)-induced acute UC were used to investigate the therapeutic effects of PHI. We evaluated the effects of PHI on disease activity index (DAI), body weight, mortality, intestinal mucosal barrier, cytokine secretion, and macrophage infiltration into colon tissue using various techniques such as flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), RT-qPCR, and Western blot analysis. RESULTS: Our findings revealed that PHI has therapeutic properties in UC treatment. PHI was able to maintain body weight, reduce DAI and mortality, restore the intestinal mucosal barrier, and inhibit cytokine secretion. Flow cytometry assay and immunofluorescence indicated that PHI reduces macrophage infiltration into colon tissue. Mechanistically, PHI may exert anti-inflammatory effects by downregulating the TLR4/MyD88/NF-κB pathway and inhibiting the activation of NLRP3 inflammasome. CONCLUSION: In conclusion, PHI possesses significant anti-inflammatory properties and is expected to be a potential drug for UC treatment. Our study delves into the underlying mechanisms of PHI therapy and highlights the potential for further research in developing PHI-based treatments for UC.
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Colitis Ulcerosa , Forsythia , FN-kappa B/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Inflamasomas/efectos adversos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/farmacología , Receptor Toll-Like 4/metabolismo , Forsythia/metabolismo , Transducción de Señal , Antiinflamatorios/efectos adversos , Citocinas/metabolismo , Peso CorporalRESUMEN
Intestinal barrier disruption due to the intestinal epithelial cells' (IECs) death is one of the critical pathological features of inflammatory bowel diseases (IBDs). SM934, an artemisinin analog, has previously been proven to ameliorate colitis induced by dextran sulfate sodium (DSS) in mice by suppressing inflammation response. In this study, we investigated the protective effects of SM934 on the epithelial barrier and the underlying mechanism in trinitrobenzene sulfonic acid (TNBS)-induced colitis mice. We demonstrated that SM934 restored the body weight and colon length, and improved the intestine pathology. Furthermore, SM934 treatment preserved the intestinal barrier function via decreasing the intestinal permeability, maintaining epithelial tight junction (TJ) protein expressions, and preventing apoptosis of epithelial cells, which were observed both in the colon tissue and the tumor necrosis factor-α (TNF-α)-induced human colonic epithelial cell line HT-29. Specifically, SM934 reduced the pyroptosis of IECs exposed to pathogenic signaling and inhibited pyroptosis-related factors such as NOD-like receptor family pyrin domain containing 3 (NLRP3), adapter apoptosis-associated speck-like protein (ASC), cysteine protease-1 (caspase-1), gasdermin (GSDMD), interleukin-18 (IL-18), and high-mobility group box 1 (HMGB1) both in colon tissue and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) co-stimulated HT-29 cells in vitro. Moreover, SM934 interdicted pyroptosis via blocking the transduction of mitogen-activated protein kinase (MAPK) and nuclear factor-kB (NF-kB) signaling pathways. In conclusion, SM934 protected TNBS-induced colitis against intestinal barrier disruption by inhibiting the apoptosis and pyroptosis of epithelial cells via the NLRP3/NF-κB/MAPK signal axis, and intestinal barrier protection in company with an anti-inflammatory strategy might yield greater benefits in IBD treatment.
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Although disrupted bile acid (BA) homeostasis is implicated in inflammatory bowel disease (IBD), the role of hepatic BA metabolism in the pathogenesis of colitis is poorly understood. Here, we found that cholic acid (CA) levels were increased in patients and mice. Cytochrome P450 8B1 (CYP8B1), which synthesizes CA, was induced in livers of colitic mice. CA-treated or liver Cyp8b1-overexpressing mice developed more severe colitis with compromised repair of the mucosal barrier, whereas Cyp8b1-knockout mice were resistant to colitis. Mechanistically, CA inhibited peroxisome proliferator-activated receptor alpha (PPARα), resulting in impeded fatty acid oxidation (FAO) and impaired Lgr5+ intestinal stem cell (ISC) renewal. A PPARα agonist restored FAO and improved Lgr5+ ISC function. Activation of the farnesoid X receptor (FXR) suppressed liver CYP8B1 expression and ameliorated colitis in mice. This study reveals a connection between the hepatic CYP8B1-CA axis and colitis via regulating intestinal epithelial regeneration, suggesting that BA-based strategies might be beneficial in IBD treatment.
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Colitis , Enfermedades Inflamatorias del Intestino , Animales , Ácidos y Sales Biliares , Autorrenovación de las Células , Ácido Cólico/metabolismo , Ácido Cólico/farmacología , Colitis/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR alfa/genética , PPAR alfa/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Esteroide 12-alfa-Hidroxilasa/genética , Esteroide 12-alfa-Hidroxilasa/metabolismoRESUMEN
Aberrant microbe-immune cell interaction is a predisposing factor in inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Cortex Periplocae is a famous traditional Chinese medicine with putative anti-rheumatoid arthritis and anti-dyspepsia effects. Here, we show that the Periploca sepium periplosides (PePs), a cardiac glycosides-free pregnane glycosides extract from root bark of Cortex Periplocae, alleviates colon inflammation, improves intestinal epithelial barrier function, and prevents colitis-associated tumorigenesis in mice with colitis and CAC. Mechanistically, PePs treatment modulates abnormal gut microbiota composition in model mice, especially enriches an anti-inflammatory commensal bacterium A. muciniphila BAA-835. We further demonstrate that the altered gut microbiota following PePs treatment plays an important role in modulation of intestinal Type 17 immunity in both colitis and CAC mouse model. Our results indicate that PePs may be used as a potential gut microbiota modulator to treat IBD and CAC.
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Neoplasias Asociadas a Colitis , Colitis , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Animales , Colitis/complicaciones , Colitis/tratamiento farmacológico , Colitis/microbiología , Sulfato de Dextran , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Células Th17/patologíaRESUMEN
Autoimmune diseases are chronic immune diseases characterized by dysregulation of immune system, which ultimately results in a disruption in self-antigen tolerance. Cumulative data show that nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) play essential roles in various autoimmune diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, multiple sclerosis (MS), etc. NLR proteins, consisting of a C-terminal leucine-rich repeat (LRR), a central nucleotide-binding domain, and an N-terminal effector domain, form a group of pattern recognition receptors (PRRs) that mediate the immune response by specifically recognizing cellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and triggering numerous signaling pathways, including RIP2 kinase, caspase-1, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and so on. Based on their N-terminal domain, NLRs are divided into five subfamilies: NLRA, NLRB, NLRC, NLRP, and NLRX1. In this review, we briefly describe the structures and signaling pathways of NLRs, summarize the recent progress on NLR signaling in the occurrence and development of autoimmune diseases, as well as highlight numerous natural products and synthetic compounds targeting NLRs for the treatment of autoimmune diseases.
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Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/metabolismo , Proteínas NLR/antagonistas & inhibidores , Proteínas NLR/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Furanos/administración & dosificación , Furanos/inmunología , Furanos/metabolismo , Humanos , Indenos/administración & dosificación , Indenos/inmunología , Indenos/metabolismo , Proteínas NLR/inmunología , Piridinas/administración & dosificación , Piridinas/inmunología , Piridinas/metabolismo , Sulfonamidas/administración & dosificación , Sulfonamidas/inmunología , Sulfonamidas/metabolismoRESUMEN
Rheumatoid arthritis (RA) is characterized by joint leukocyte infiltration, synovial inflammation and bone damage result from osteoclastogenesis. Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor (BCR) and Fc gamma receptor (FcγR) signaling involved in the pathobiology of RA and other autoimmune disorders. SOMCL-17-016 is a potent and selective tricyclic BTK inhibitor, structurally distinct from other known BTK inhibitors. In present study we investigated the therapeutic efficacy of SOMCL-17-016 in a mouse collagen-induced arthritis (CIA) model and underlying mechanisms. CIA mice were administered SOMCL-17-016 (6.25, 12.5, 25 mg·kg-1·d-1, ig), or ibrutinib (25 mg·kg-1·d-1, ig) or acalabrutinib (25 mg·kg-1·d-1, ig) for 15 days. We showed that oral administration of SOMCL-17-016 dose-dependently ameliorated arthritis severity and bone damage in CIA mice; it displayed a higher in vivo efficacy than ibrutinib and acalabrutinib at the corresponding dosage. We found that SOMCL-17-016 administration dose-dependently inhibited anti-IgM-induced proliferation and activation of B cells from CIA mice, and significantly decreased anti-IgM/anti-CD40-stimulated RANKL expression in memory B cells from RA patients. In RANKL/M-CSF-stimulated RAW264.7 cells, SOMCL-17-016 prevented osteoclast differentiation and abolished RANK-BTK-PLCγ2-NFATc1 signaling. In summary, this study demonstrates that SOMCL-17-016 presents distinguished therapeutic effects in the CIA model. SOMCL-17-016 exerts a dual inhibition of B cell function and osteoclastogenesis, suggesting that it to be a promising drug candidate for RA treatment.
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Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Células B de Memoria/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Autoanticuerpos/metabolismo , Inflamación/tratamiento farmacológico , Activación de Linfocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos DBA , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Pirimidinas/uso terapéutico , Alcaloides de Pirrolicidina/uso terapéutico , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Kidney is a major target organ in both antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). The etiology of antiphospholipid syndrome nephropathy associated lupus nephritis (APSN-LN) is intricate and remains largely unrevealed. We proposed in present work, that generation of antiphospholipid antibodies (aPLs), especially those directed towards the oxidized neoepitopes, are largely linked with the redox status along with disease progression. Moreover, we observed that compromised antioxidative capacity coincided with turbulence of inflammatory cytokine profile in the kidney of male NZW×BXSB F1 mice suffered from APSN-LN. SM934 is an artemisinin derivative that has been proved to have potent immunosuppressive properties. In current study, we elaborated the therapeutic benefits of SM934 in male NZW×BXSB F1 mice, a murine model develops syndrome resembled human APS associated with SLE, for the first time. SM934 treatment comprehensively impeded autoantibodies production, inflammatory cytokine accumulation and excessive oxidative stress in kidney. Among others, we interpreted in present work that both anti-inflammatory and antioxidative effects of SM934 is closely correlated with the enhancement of Nrf2 signaling and expression of its targets. Collectively, our finding confirmed that therapeutic strategy simultaneously exerting antioxidant and anti-inflammatory efficacy provide a novel feasible remedy for treating APSN-LN.
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Antiinflamatorios/uso terapéutico , Síndrome Antifosfolípido/tratamiento farmacológico , Artemisininas/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Anticuerpos Antifosfolípidos/metabolismo , Síndrome Antifosfolípido/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Inflamación , Riñón/efectos de los fármacos , Riñón/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Nefritis Lúpica/metabolismo , Nefritis Lúpica/prevención & control , Masculino , Ratones , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Psoriasis is the most prevalent inflammatory skin disorders, affecting 1-3% of the worldwide population. We previously reported that topical application of methyl 4-(adenin-9-yl)-2-hydroxybutanoate (DZ2002), a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, was a viable treatment in murine psoriatic skin inflammation. In current study, we further explored the mechanisms of DZ2002 on keratinocyte dysfunction and skin infiltration, the key pathogenic events in psoriasis. We conducted genome-wide DNA methylation analysis in skin tissue from imiquimod (IMQ)-induced psoriatic and normal mice, demonstrated that topical administration of DZ2002 directly rectified aberrant DNA methylation pattern in epidermis and dermis of psoriatic skin lesion. Especially, DZ2002 differentially regulated DNA methylation of GATA3 and LCN2 promoters, which maintained keratinocytes differentiation and reduced inflammatory infiltration in psoriatic skin respectively. In vitro studies in TNF-α/IFN-γ-elicited HaCaT manifested that DZ2002 treatment rectified compromised keratinocyte differentiation via GATA3 enhancement and abated chemokine expression by reducing LCN2 production under inflammatory stimulation. Chemotaxis assays conducted on dHL-60 cells confirmed that suppression of LCN2 expression by DZ2002 was accompanied by CXCR1 and CXCR2 downregulation, and contributed to the inhibition of CXCL8-driven neutrophils migration. In conclusion, therapeutic benefits of DZ2002 are achieved through differentially regulating DNA methylation of GATA3 and LCN2 promoters in psoriatic skin lesion, which efficiently interrupt the pathogenic interplay between keratinocytes and infiltrating immune cells, thus maintains epidermal keratinocytes differentiation and prevents dermal immune infiltration in psoriatic skin.
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Adenina/análogos & derivados , Antiinflamatorios/farmacología , Butiratos/farmacología , Metilación de ADN/efectos de los fármacos , Factor de Transcripción GATA3/genética , Queratinocitos/efectos de los fármacos , Lipocalina 2/genética , Regiones Promotoras Genéticas/efectos de los fármacos , Psoriasis/prevención & control , Piel/efectos de los fármacos , Adenina/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Factor de Transcripción GATA3/metabolismo , Células HL-60 , Células HaCaT , Humanos , Queratinocitos/metabolismo , Queratinocitos/patología , Lipocalina 2/metabolismo , Ratones Endogámicos BALB C , Infiltración Neutrófila/efectos de los fármacos , Psoriasis/genética , Psoriasis/metabolismo , Psoriasis/patología , Piel/metabolismo , Piel/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Periploca sepium Bunge (P. sepium) is used in traditional Chinese medicine (TCM) for the treatment of autoimmune diseases, particularly rheumatoid arthritis. Periploca sepium periplosides (PePs), isolated from the root bark of P. sepium, characterized as the cardiac glycosides-free pregnane glycosides fraction, is expected to possess therapeutic potential on inflammatory arthritis. AIM OF THE STUDY: The current study is designed to evaluate the anti-nociceptive, anti-inflammatory and anti-arthritic activities effects of the PePs. MATERIALS AND METHODS: The anti-nociceptive activity of PePs was examined in the writhing test and hot-plate test in mice. The anti-inflammatory activity of PePs was determined by the 2, 4-dinitro-1-fluorobenzene (DNFB)-induced ear edema model and the carrageenan induced paw edema model in mice. The anti-arthritic activity of PePs was investigated by evaluating the joint inflammation and arthritis pathology in rat adjuvant induced arthritis (AIA) and murine collagen induced arthritis (CIA). Phytohaemagglutinin M (PHA-M) -elicited human peripheral blood mononuclear cells (PBMCs) were further applied to assess the suppressive activity of PePs on IFN-γ and IL-17 production. RESULTS: PePs treatment markedly decreased the acetic acid-induced visceral nociceptive response and increased the hot-plate pain threshold. Further, oral administration of PePs exhibited anti-inflammatory activity by decreasing DNFB-induced ear edema in mice and carrageenan-induced paw edema in rats. Moreover, oral treatment of PePs ameliorated joint swelling and attenuated bone erosion in rodent arthritis, and the therapeutic benefits were partially attributed to the suppression of proinflammatory cytokines such IFN-γ and IL-17. Moreover, PePs suppressed the proliferation as well as IFN-γ and IL-17 secretion in PHA-M-elicited human PBMCs in a concentration dependent manner. CONCLUSIONS: Taken together, our results justified the traditional use of Periploca sepium Bunge for the treatment of diseases associated with inflammation and pain.