RÉSUMÉ
The most common neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD), are the seventh leading cause of mortality and morbidity in developed countries. Clinical observations of NDD patients are characterized by a progressive loss of neurons in the brain along with memory decline. The common pathological hallmarks of NDDs include oxidative stress, the dysregulation of calcium, protein aggregation, a defective protein clearance system, mitochondrial dysfunction, neuroinflammation, neuronal apoptosis, and damage to cholinergic neurons. Therefore, managing this pathology requires screening drugs with different pathological targets, and suitable drugs for slowing the progression or prevention of NDDs remain to be discovered. Among the pharmacological strategies used to manage NDDs, natural drugs represent a promising therapeutic strategy. This review discusses the neuroprotective potential of seaweed and its bioactive compounds, and safety issues, which may provide several beneficial insights that warrant further investigation.
Sujet(s)
Maladie d'Alzheimer , Maladie de Parkinson , Algue marine , Humains , Maladie de Parkinson/traitement médicamenteux , Maladie d'Alzheimer/traitement médicamenteux , Stress oxydatif/physiologieRÉSUMÉ
A series of thalidomide analogues, where the fused benzene ring in the phthalimide moiety was converted into two separated diphenyl rings in maleimide moiety and N-aminoglutarimide moiety was replaced by substituted phenyl moiety, were synthesized and evaluated for their NO inhibitory activities on BV2 cells stimulated with lipopolysaccharide (LPS). Among the synthesized compounds, the dimethylaminophenyl analogue 1s (IC50 = 7.1 µM) showed significantly higher inhibitory activity than the glutarimide analogue 1a (IC50 > 50 µM) and suppressed NO production dose-dependently without cytotoxicity. In addition, 1s inhibited the production of pro-inflammatory cytokines and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by blocking nuclear factor-kappa B (NF-κB) and p38 MAPK pathways. These results demonstrated that 1s showed good anti-inflammatory activity and could become a leading compound for the treatment of neuroinflammatory diseases.
Sujet(s)
Lipopolysaccharides , Pyrroles , Lipopolysaccharides/pharmacologie , Pyrroles/métabolisme , Anti-inflammatoires , Facteur de transcription NF-kappa B/métabolisme , Monoxyde d'azote/métabolisme , Nitric oxide synthase type II/métabolisme , Microglie/métabolisme , Cyclooxygenase 2/métabolismeRÉSUMÉ
A series of rimonabant analogues, where the N-aminopiperidine moiety was replaced by various amines and an additional carbonyl group, were synthesized and their inhibition of nitric oxide (NO) production was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells. Among the synthesized compounds, the morpholine analogue 7y (IC50â¯=â¯4.71⯱â¯0.11⯵M) showed significantly higher inhibitory activity than rimonabant (IC50â¯=â¯16.17⯱â¯0.56⯵M), and suppressed NO production dose-dependently without cytotoxicity. In addition, 7y inhibited the expression of iNOS, COX-2 and pro-inflammatory cytokines and attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB) and ERK MAPK phosphorylation in BV2 cells. These results demonstrated that 7y exerted anti-inflammatory effects by ERK pathway in BV2 cells, which can be used for the prevention and treatment of neuroinflammatory diseases.
Sujet(s)
Anti-inflammatoires , Lipopolysaccharides , Rimonabant , Anti-inflammatoires/pharmacologie , Cyclooxygenase 2/métabolisme , Lipopolysaccharides/pharmacologie , Microglie , Facteur de transcription NF-kappa B/métabolisme , Monoxyde d'azote , Nitric oxide synthase type II/métabolisme , Rimonabant/analogues et dérivés , Rimonabant/composition chimique , Rimonabant/pharmacologieRÉSUMÉ
Caspase-8 has been classified as an apoptotic caspase, and its initial definition was an initiator of extrinsic cell death. During the past decade, the concept of caspase-8 functioning has been changed by findings of its additional roles in diverse biological processes. Although caspase-8 was not originally thought to be involved in the inflammation process, many recent works have determined that caspase-8 plays an important role in the regulatory functions of inflammatory processes. In this review, we describe the recent advances in knowledge regarding the manner in which caspase-8 modulates the inflammatory responses concerning inflammasome activation, cell death, and cytokine induction.
Sujet(s)
Apoptose , Caspase 8/métabolisme , Inflammation , Animaux , Anti-inflammatoires/pharmacologie , Mort cellulaire , Cytokines/métabolisme , Humains , Inflammasomes/métabolisme , Interleukine-1 bêta/métabolisme , Souris , Facteur de transcription NF-kappa B/métabolisme , Nécroptose , PyroptoseRÉSUMÉ
Macrophages play a major role in innate immune responses by producing a variety of immune mediators and cytokines. The stimulation of macrophages by natural products may lead to an enhanced innate immune system. This study evaluated the immunostimulatory effects of a polysaccharide-rich crude fraction of Celosia cristata L. flowers (CCP) on murine macrophages. CCP treatment induced the production of inducible nitric oxide synthase, cyclooxygenase-2, and cytokines by macrophages. Mechanistically, the activation of mitogen-activated protein kinases, NF-κB and toll-like receptor 4 were found to be associated with the stimulatory functions of CCP. CCP was found to be primarily composed of galacturonic acid and glucose in addition to small amounts of arabinose and galactose. This study demonstrated that CCP may enhance the innate immune responses and potentially improve the immune functions in the body.
Sujet(s)
Celosia/composition chimique , Fleurs/composition chimique , Facteurs immunologiques/pharmacologie , Macrophages/effets des médicaments et des substances chimiques , Polyosides/pharmacologie , Animaux , Cellules cultivées , Cytokines/analyse , Cytokines/immunologie , Femelle , Facteurs immunologiques/composition chimique , Facteurs immunologiques/isolement et purification , Macrophages/immunologie , Souris , Souris de lignée C3H , Polyosides/composition chimique , Polyosides/isolement et purification , Cellules RAW 264.7RÉSUMÉ
ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C.A. Meyer (Araliaceae), has been used in traditional medicine for preventive and therapeutic purposes in Asian countries. One of the active ginsenoside metabolites, 20(S)-Protopanaxatriol (PPT), has been associated with diverse pharmacological effects, including anti-inflammatory properties. AIM OF THE STUDY: Although the capacity of PPT as an anti-inflammatory agent has been studied, this study aimed to explore the intrinsic mechanism of PPT in regulating inflammasome activation-mediated inflammatory responses in experimental models. MATERIALS AND METHODS: Lipopolysaccharide (LPS)-primed peritoneal macrophages in vitro was used to study the role of PPT on inflammasome activation. LPS-induced septic shock and monosodium urate (MSU)-induced murine peritonitis models were employed for in vivo evaluations. RESULTS: PPT attenuated NLRP3 inflammasome activation and also reduced ASC oligomerization, leading to attenuation of interleukin (IL)-1ß secretion. Further, PPT inhibited IL-1ß secretion in both LPS-induced septic shock and MSU-induced mouse peritonitis models. CONCLUSIONS: This study revealed that ginsenoside metabolite PPT, inhibits inflammation-mediated inflammasome activation and supported the traditional use of ginseng in treating various inflammatory disorders.
Sujet(s)
Anti-inflammatoires/usage thérapeutique , Inflammasomes/immunologie , Protéine-3 de la famille des NLR contenant un domaine pyrine/immunologie , Panax , Péritonite/traitement médicamenteux , Sapogénines/usage thérapeutique , Choc septique/traitement médicamenteux , Animaux , Anti-inflammatoires/pharmacologie , Ginsénosides/métabolisme , Interleukine-1 bêta/immunologie , Lipopolysaccharides/pharmacologie , Macrophages péritonéaux/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Péritonite/induit chimiquement , Péritonite/immunologie , Sapogénines/pharmacologie , Choc septique/immunologie , Acide uriqueRÉSUMÉ
ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum indicum (C. indicum), a perennial plant, has long been used to treat inflammation-related disorders, such as pneumonia, hypertension, gastritis, and gastroenteritis. AIM OF THE STUDY: The inhibitory effect of C. indicum extract (C.I) on inflammasome activation was investigated to validate its potential in treating inflammation related disorders. MATERIALS AND METHODS: LPS-primed bone marrow-derived macrophages (BMDMs) were used to confirm the inhibitory effect of C.I on selective inflammasome activation in vitro. A monosodium urate (MSU)-induced murine peritonitis model was employed to study the effect of C.I in vivo. RESULTS: C.I inhibited activation of NLRP3 and AIM2 inflammasomes, leading to suppression of interleukin-1ß secretion in vitro. Further, C.I regulates the phosphorylation of apoptosis-associated speck-like protein containing a CARD (ASC), which could be the main contribution to attenuate these inflammasomes activation. C.I also suppressed secretion of pro-inflammatory cytokines and neutrophils recruitment in MSU-induced murine peritonitis model. CONCLUSIONS: This study provides scientific evidence substantiating the traditional use of C. indicum in the treatment of inflammatory diseases, including gout, which is induced by physiologically analogous cause to MSU-induced peritonitis.
Sujet(s)
Anti-inflammatoires/pharmacologie , Protéines adaptatrices de signalisation CARD/métabolisme , Chrysanthemum , Protéines de liaison à l'ADN/métabolisme , Inflammasomes/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Péritonite/métabolisme , Extraits de plantes/pharmacologie , Animaux , Anti-inflammatoires/usage thérapeutique , Femelle , Goutte/traitement médicamenteux , Goutte/métabolisme , Antigoutteux/pharmacologie , Antigoutteux/usage thérapeutique , MAP Kinase Kinase 4/métabolisme , Souris de lignée C57BL , Péritonite/induit chimiquement , Péritonite/traitement médicamenteux , Phosphorylation/effets des médicaments et des substances chimiques , Parties aériennes de plante , Extraits de plantes/usage thérapeutique , Acide uriqueRÉSUMÉ
Necroptosis, or caspase-independent programmed cell death, is known to be involved in various pathological conditions, such as ischemia/reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. Although several inhibitors of necroptosis have been identified, none of them are currently in clinical use. In the present study, we identified a new compound, 4-({[5-(4-aminophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-N-(1,3-thiazol-2-yl) benzamide (NTB451), with significant inhibitory activity on the necroptosis induced by various triggers, such as tumor necrosis factor-α (TNF-α) and toll-like receptor (TLR) agonists. Mechanistic studies revealed that NTB451 inhibited phosphorylation and oligomerization of mixed lineage kinase domain like (MLKL), and this activity was linked to its inhibitory effect on the formation of the receptor interacting serine/threonine-protein kinase 1 (RIPK1)-RIPK3 complex. Small interfering RNA (siRNA)-mediated RIPK1 knockdown, drug affinity responsive target stability assay, and molecular dynamics (MD) simulation study illustrated that RIPK1 is a specific target of NTB451. Moreover, MD simulation showed a direct interaction of NTB451 and RIPK1. Further experiments to ensure that the inhibitory effect of NTB451 was restricted to necroptosis and NTB451 had no effect on nuclear factor-κB (NF-κB) activation or apoptotic cell death upon triggering with TNF-α were also performed. Considering the data obtained, our study confirmed the potential of NTB451 as a new necroptosis inhibitor, suggesting its therapeutic implications for pathological conditions induced by necroptotic cell death.
Sujet(s)
Apoptose/effets des médicaments et des substances chimiques , Imidazoles/pharmacologie , Nécrose/métabolisme , Relation dose-effet des médicaments , Humains , Imidazoles/composition chimique , Modèles moléculaires , Structure moléculaire , Facteur de transcription NF-kappa B/métabolisme , Nécrose/traitement médicamenteux , Phosphorylation/effets des médicaments et des substances chimiques , Conformation des protéines , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Receptor-Interacting Protein Serine-Threonine Kinases/antagonistes et inhibiteurs , Transduction du signal/effets des médicaments et des substances chimiques , Relation structure-activité , Récepteur de type Toll-3/composition chimique , Récepteur de type Toll-3/métabolisme , Facteur de nécrose tumorale alpha/métabolismeRÉSUMÉ
Ginseng (the root of Panax ginseng Meyer) fermented by Lactobacillus plantarum has been found to attenuate allergic responses in in vitro and in vivo experimental models. Ginseng has been reported to also possess various biological functions including anti-inflammatory activity. The present study was aimed at comparing the anti-allergic effect of ginseng and fermented ginseng extracts on IgE-mediated passive cutaneous anaphylaxis in vitro in a murine cell line and in vivo in mice. Fermented ginseng extract (FPG) showed higher inhibitory effect against in vitro and in vivo allergic responses when compared with ginseng extract (PG). The secretion of ß-hexosaminidase and interleukin (IL)-4 from the IgE-DNP-stimulated RBH-2H3 mast cells were significantly (p < 0.05) inhibited by FPG treatment, and this effect was concentration-dependent. Further, MKK4 activation and subsequent JNK phosphorylation were attenuated by FPG treatment. The inhibitory effect of FPG on the in vitro allergic response was verified in vivo against IgE-DNP-induced passive cutaneous anaphylaxis in a mouse model. These data indicated that the fermentation of ginseng with L. plantarum enhanced its anti-allergic effects both in vitro and in vivo. We predict that compositional changes in the ginsenosides caused by the fermentation may contribute to the change in the anti-allergic effects of ginseng. The results of our study highlight the potential of the use of FPG as a potential anti-allergic agent.