Treatment Of Inflammation-related Disorders Research Articles

Control of CD4+ T cells to restrain inflammatory diseases via eukaryotic elongation factor 2 kinase

CD4+ T cells, particularly IL-17-secreting helper CD4+ T cells, play a central role in the inflammatory processes underlying autoimmune disorders. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is pivotal in CD8+ T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension. However, its specific immunological role in CD4+ T cell activities and related inflammatory diseases remains elusive. Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4+ T cells, impairs their ability to secrete cytokines. Notably, this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17, fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4+ T cells. Furthermore, the absence of eEF2K in CD4+ T cells is linked to increased metabolic activity and mitochondrial bioenergetics. We have shown that eEF2K regulates mitochondrial function and CD4+ T cell activity through the upregulation of the transcription factor, signal transducer and activator of transcription 3 (STAT3). Crucially, the deficiency of eEF2K exacerbates the severity of inflammation-related diseases, including rheumatoid arthritis, multiple sclerosis, and ulcerative colitis. Strikingly, the use of C188-9, a small molecule targeting STAT3, mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout (KO) CD4+ T cells. These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4+ T cells and its indispensable involvement in inflammation-related diseases. Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders.

Anti-Inflammatory Activity of Oxyresveratrol Tetraacetate, an Ester Prodrug of Oxyresveratrol, on Lipopolysaccharide-Stimulated RAW264.7 Macrophage Cells

Oxyresveratrol (OXY) has been reported for its anti-inflammatory activity; however, the pharmaceutical applications of this compound are limited by its physicochemical properties and poor pharmacokinetic profiles. The use of an ester prodrug is a promising strategy to overcome these obstacles. In previous researches, several carboxylate esters of OXY were synthesized and oxyresveratrol tetraacetate (OXY-TAc) was reported to possess anti-melanogenic and anti-skin-aging properties. In this study, in addition to OXY-TAc, two novel ester prodrugs of OXY, oxyresveratrol tetrapropionate (OXY-TPr), and oxyresveratrol tetrabutyrate (OXY-TBu), were synthesized. Results from the Caco-2-permeation assay suggested that synthesized ester prodrugs can improve the membrane-permeation ability of OXY. The OXY-TAc exhibited the most significant profile, then this prodrug was chosen to observe anti-inflammatory activities with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Our results showed that OXY-Tac significantly alleviated secretion of several pro-inflammatory mediators (nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), mitigated expression of enzyme-regulated inflammation (inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)), and suppressed the MAPK cascades. Interestingly, the observed anti-inflammatory activities of OXY-TAc were more remarkable than those of its parent compound OXY. Taken together, we demonstrated that OXY-TAc improved physicochemical and pharmacokinetic profiles and enhanced the pharmacological effects of OXY. Hence, the results in the present study would strongly support the clinical utilities of OXY-TAc for the treatment of inflammation-related disorders.

Preventive effect of oligonol on nitric oxide and reactive oxygen species production through regulation of nuclear factor kappa B signaling pathway in RAW 264.7 macrophage cells against sodium nitroprusside.

Oligonol, a low-molecular weight polyphenol isolated from lychee fruit, has been shown to possess beneficial properties, including anti-oxidative, anti-diabetic, and hepatoprotective properties in vitro and in vivo. This study was performed to investigate the anti-inflammatory effects of oligonol using sodium nitroprusside (SNP)-stimulated RAW 264.7 macrophage cells. Our results demonstrated that exposure of SNP to RAW 264.7 cells significantly decreased cell viability, and increased nitric oxide (NO) and reactive oxygen species (ROS) production. However, treatment with oligonol inhibited cell death and suppressed the over-production of NO and ROS induced by SNP in a dose-dependent manner. Consistent with these findings, oligonol significantly downregulated the mRNA levels of pro-inflammatory mediators, inducible nitric oxide synthase and cyclooxygenase-2, when compared with the SNP-treated control group. Furthermore, suppression of nuclear factor-κB (NF-κB) activation was also observed after treatment with oligonol in RAW 264.7 macrophage cells. These results suggest that oligonol attenuated SNP-induced oxidative stress and inflammatory responses via regulation of the NF-κB signalling pathway. On the basis of such potent anti-oxidant and anti-inflammatory properties, we propose that oligonol may contribute in the prevention and treatment of inflammation-related disorders.

Medicinal plants of northern Angola and their anti-inflammatory properties

Ethnopharmacological relevance32 plants, from which 30 are used in local traditional medicine – identified by interviews with the resident population – in the province of Uíge in northern Angola for the treatment of inflammation related disorders, were screened on different anti-inflammatory parameters. Three extracts were selected for a detailed ethnobotanical, pharmacological and phytochemical investigation based on their in vitro activity. Aim of the studyWe aimed to assess the in vitro anti-inflammatory activity of these plants and highlight the active principles of the three most promising candidates. Materials and methodsPlant material was collected in northern Angola during eight field trips from 2013 to 2015 based on data documented in 61 interviews with 142 local informants. 36 methanol (MeOH) extracts were prepared and tested at different concentrations (100, 50, 10µg/mL) to evaluate their inhibition on cyclooxygenase (COX)−2 expression and on nitric oxide (NO) release in lipopolysaccharide (LPS)-stimulated J774A.1 macrophages. Five selected extracts were additionally tested at the lower concentrations of 5, 2.5, and 1.25µg/mL and for their potential on inhibition of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) release. The major compounds of three of those five extracts were either identified by HPLC coupled with (tandem) mass spectrometry and comparison with data from literature or isolated from the respective extracts and confirmed by NMR experiments (one and two dimensional). Results30 plant species with in total 161 citations were mentioned by the informants to have anti-inflammatory properties. The predominantly used plant part is the leaf (39%), followed by underground organs like roots and rhizomes (25%), bark (18%) as well as fruits and seeds with 15%. With 47%, decoction is the most frequent preparation form. A large number of the MeOH extracts showed promising activities in our preliminary screening for the inhibition of COX-2 expression and NO release. Five extracts with high activities in both assays showed also concentration dependent inhibition at lower concentrations and a decreased release of two additional pro-inflammatory mediators (IL-6 and TNF-α) vs. LPS. Three leaf extracts where chosen for a detailed investigation, which lead to the identification of several constituents: verbascoside and isoverbascoside (Acanthus montanus), geraniin, chebulagic acid and a large flavonoid fraction (Alchornea cordifolia) as well as the four flavonoids astilbin, isovitexin, isoorientin and swertisin (Chaetocarpus africanus). Their implication in the observed biological activity was proved by comparison with published data of these compounds in identical or similar pharmacological models. ConclusionsThe indigenous use of these plants against inflammation related ailments could be – at least partly – verified by our in vitro models for many of the investigated extracts. Acanthus montanus and Alchornea cordifolia particularly stood out with their high activity in all four performed assays, which was in accordance with pharmacological studies of their major constituents in literature. In addition, this study was the first phytochemical investigation of Chaetocarpus africanus and first description of the occurrence of the ellagitannins geraniin and chebulagic acid in Alchornea cordifolia. These results support the traditional use and should encourage further investigations of medicinal plants of northern Angola.

Eucalyptus globulus Inhibits Inflammasome-Activated Pro-Inflammatory Responses and Ameliorate Monosodium Urate-Induced Peritonitis in Murine Experimental Model.

Eucalyptus globulus Labill. (E. globulus, Myrtaceae) is used in Europe as a traditional folk remedy for inflammation-related disorders such as arthritis, diabetes, asthma, and gout. We investigated this study to evaluate the protective effects of E. globulus extract (EG) on inflammatory responses, and provide scientific and mechanistic evidence in in vitro and in vivo experimental models. LPS-stimulated murine bone marrow-derived macrophages (BMDMs) were used to study the regulatory effect of EG on inflammasome activation in vitro. Monosodium urate (MSU)-induced peritonitis was used to study the effect of EG in an in vivo murine model. EG suppressed IL-[Formula: see text] secretion via the regulation of apoptosis-associated speck-like proteins containing a CARD (ASC) oligomerization and caspase-1 maturation, leading to the inhibition of inflammasome activation. In the in vivo study, EG suppressed the MSU-induced peritonitis by attenuating interleukin (IL)-1[Formula: see text], providing scientific support for its traditional use in the treatment of inflammation-related disorders.

Protective effects of Cinnamomum cassia (Lamaceae) against gout and septic responses via attenuation of inflammasome activation in experimental models

Ethnopharmacological relevanceCinnamomum cassia (C. cassia, Lauraceae family), commonly used for treating dyspepsia, gastritis, blood circulation, and inflammatory diseases is considered as one of the 50 fundamental herbs in traditional Chinese medicine. Aim of the studyThe anti-inflammatory action of an ethanol extract of C. cassia (CA), and its underlying mechanisms were explored in both in vitro cellular and in vivo murine models. Materials and methodsBone marrow-derived macrophages (BMDMs) were used to study the regulatory effect of CA on inflammasome activation. A lipopolysaccharide (LPS)-induced sepsis mouse model and a monosodium urate (MSU)-induced gout model were employed to study the effect of CA on in vivo efficacy. ResultsCA improved the survival rate in the LPS-induced septic shock mouse model and inhibited inflammasome activation including NLRP3, NLRC4, and AIM2, leading to suppression of interleukin-1β secretion. Further, ASC oligomerization and its speck formation in cytosol were attenuated by CA treatment. Furthermore, CA improved both survival rate of LPS-induced septic shock and gout murine model. ConclusionsCA treatment significantly attenuated danger signals-induced inflammatory responses via regulation of inflammasome activation, substantiating the traditional claims of its use in the treatment of inflammation-related disorders.

3, 3′-Neolignans from Pithecellobium clypearia Benth and their anti-inflammatory activity

The twigs and leaves of Pithecellobium clypearia Benth have been used as a folk medicine for the treatment of diseases related to inflammation in southern China for many years. To search for novel bioactive constituents as lead structures for anti-inflammatory drug development, seven new 3, 3′-neolignans (1–7), together with four known ones (8–11) were isolated from the 70% EtOH extract of the twigs and leaves of P. clypearia. Their structures were determined by spectroscopic analyses, especially the 1D, 2D NMR and CD spectra. The antioxidant and anti-inflammatory activities of all the isolated compounds were investigated. Among them, compound 11 showed promising activity against nitric oxide (NO) and considerable antioxidant activity. These findings will help in the effective use of P. clypearia as a valuable source of novel compounds for the prevention and treatment of inflammation-related disorders.

Evaluation of Anti-inflammatory and Antioxidant Properties of Crude Extract and Forskolin from Solena amplexicaulis Leaf

Leaves of Solena amplexicaulis are traditionally used as a remedy for the treatment of inflammation related disorders in the form of decoction by the Paliyar tribal community of Theni district, Tamil Nadu, India. This study was designed to investigate the antiinflammatory and antioxidant potential of crude methanol leaf extract and the isolated compound, forskolin from S. amplexicaulis. Their effects were evaluated by carrageenan-induced paw edema in experimental rats for 4 h. In vivo antioxidant and histopathological studies were also performed. Therapeutic potential of forskolin was further substantiated using PASS software. The oral administration of forskolin (10 mg/kg) exerted potent antiinflammatory activity by reducing paw edema (87.79%) than the crude extract (150 and 300 mg/kg) and it was comparable with the standard drug, indomethacin (10 mg/kg, 93.89%). Consistent with these findings, antioxidant, histopathological architecture and PASS software also reflected its prominent curative property. The obtained results therefore suggest that the compound, forskolin obtained from S. amplexicaulis is considered to be a valuable source of remedy for inflammation.

Anti-inflammatory properties of Morus bombycis Koidzumi via inhibiting IFN-β signaling and NLRP3 inflammasome activation

Ethnopharmacological relevanceMorus bombycis Koidzumi (M. bombycis, Moraceae) has been used in Asian countries as a traditional medicine for the treatment of hypertension, diabetes, and inflammation-related disorders. Aim of studyAlthough its anti-inflammatory actions have been partly documented, scientific evidence involving its molecular mechanisms related to inflammasome activation signaling pathways remains unknown. Materials and methodsLipopolysaccharide-stimulated RAW 264.7 cells and bone marrow-derived murine macrophages were used to study the in vitro effect of methanolic extract of M. bombycis (MB) on inflammatory responses. A monosodium urate crystal (MSU)-induced peritonitis murine model was used to study the in vivo effects. ResultsMB attenuated the production of nitric oxide and interleukin-6, through the regulation of the interferon-β receptor signaling pathway. MB also inhibited IL-1β secretion via attenuation of NLRP3 inflammasome activation. Furthermore, MB inhibited MSU-induced peritonitis in the in vivo murine model. ConclusionsThis study provides the key molecular mechanisms involved in the anti-inflammatory effects of M. bombycis, substantiating the traditional claims of its use in the treatment of inflammation-related disorders.

Anti-inflammatory effect of emodin via attenuation of NLRP3 inflammasome activation.

Emodin, an active constituent of oriental herbs, is widely used to treat allergy, inflammation, and other symptoms. This study provides the scientific basis for the anti-inflammasome effects of emodin on both in vitro and in vivo experimental models. Bone marrow-derived macrophages were used to study the effects of emodin on inflammasome activation by using inflammasome inducers such as ATP, nigericin, and silica crystals. The lipopolysaccharide (LPS)-induced endotoxin shock model was employed to study the effect of emodin on in vivo efficacy. Emodin treatment attenuated interleukin (IL)-1β secretion via the inhibition of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation induced by ATP, nigericin, and silica crystals. Further, emodin ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin mouse models. This study is the first to reveal mechanism-based evidence, especially with respect to regulation of inflammasome activation, substantiating traditional claims of emodin in the treatment of inflammation-related disorders.

Syneilesis palmata (Thunb.) Maxim. extract attenuates inflammatory responses via the regulation of TRIF-dependent signaling and inflammasome activation

Ethnopharmacological relevanceSyneilesis palmata (Thunb.) Maxim. (S. palmata, Asteraceae) is a traditional Korean therapeutic herb widely used to treat pain, arthritis, and other symptoms. This study provides the scientific basis for the anti-inflammatory effects of S. palmata extract (SP) in both in vitro and in vivo experimental models. Materials and methodsLipopolysaccharide (LPS)-stimulated murine macrophages were used to study the regulatory effect of SP on the inflammatory mediators in vitro. Bone marrow-derived macrophages were used to study the effects of SP on inflammasome activation. Escherichia coli-induced sepsis mouse model and LPS-induced endotoxin shock model were employed to study the effect of SP on in vivo efficacy. ResultsSP inhibited the LPS-stimulated release of proinflammatory mediators, such as nitric oxide and interleukin (IL)-6 in RAW 264.7 cells. SP treatment also attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation induced by monosodium urate, ATP, and nigericin. Further, SP ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin and E. coli-induced sepsis mouse models. Mechanistic studies revealed that inhibitory effects of SP were mediated through the regulation of TRIF-dependent signaling and inflammasome activation. ConclusionThis study was the first to reveal mechanistic-based evidence substantiating the traditional claims of SP in the treatment of inflammation-related disorders, such as pain and arthritis.

Diosgenin inhibits superoxide generation in FMLP-activated mouse neutrophils via multiple pathways

Diosgenin possesses anti-inflammatory and anticancer properties. Activated neutrophils produce high concentrations of the superoxide anion which is involved in the pathophysiology of inflammation-related diseases and cancer. In the present study, the inhibitory effect and possible mechanisms of diosgenin on superoxide generation were investigated in mouse bone marrow neutrophils. Diosgenin potently and concentration-dependently inhibited the extracellular and intracellular superoxide anion generation in Formyl-Met-Leu-Phe (FMLP)- activated neutrophils, with IC50 values of 0.50 ± 0.08 μM and 0.66 ± 0.13 μM, respectively. Such inhibition was not mediated by scavenging the superoxide anion or by a cytotoxic effect. Diosgenin inhibited the phosphorylation of p47phox and membrane translocation of p47phox and p67phox, and thus blocking the assembly of nicotinamide adenine dinucleotide phosphate oxidase. Moreover, cellular cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) expression were also effectively increased by diosgenin. It attenuated FMLP-induced increase of phosphorylation of cytosolic phospholipase A (cPLA2), p21-activated kinase (PAK), Akt, p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK). Our data indicate that diosgenin exhibits inhibitory effects on superoxide anion production through the blockade of cAMP, PKA, cPLA2, PAK, Akt and MAPKs signaling pathways. The results may explain the clinical implications of diosgenin in the treatment of inflammation-related disorders.

Andrographolide, a major component of Andrographis paniculata leaves, has the neuroprotective effects on glutamate-induced HT22 cell death

Andrographis paniculata (AP) is a traditional herbal medicine that is used for the treatment of inflammation-related disorders, dyspepsia, and diarrhea. Recently, the biological effects of AP on cancer, microbial infections, cardiovascular disease, and inflammation were reported. However, neuroprotective actions of AP during glutamate-induced oxidative stress have not been investigated. In this study, we isolated andrographolide (AG) as an active compound from the ethanolic extract of AP leaves, and evaluated its neuroprotective mechanisms using glutamate-treated HT22 mouse hippocampal neuronal cells. Five mM glutamate reduced cell survival significantly to 55.90 ± 2.16%. However, 5 μM AG restored cell viability to 102.19 ± 13.98%. AG decreased the early apoptosis by inhibiting Ca2+ influx, intracellular reactive oxygen species production, and lipid peroxidation. Moreover, AG regulated the levels of Bcl-2, Bid, Bax, and apoptosis-inducing factor. AG also inhibited the phosphorylation of mitogen activated protein kinases including p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase.