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Background: Morinda citrifolia (Noni) is a plant that has long been used in various products such as foods and cosmetics. Although noni has been known to have immunostimulatory activity, detailed mechanism at the cellular level has not been fully elucidated yet. In this study, we focused on understanding as to how noni fruit can positively stimulate body's immune responses. Methods: To do this, an ethanol extract of noni fruit (Mc-fEE) was prepared and administered for 30 days to male C57BL/6 mice for in vivo experiment. NK cell activity and cytokine production level from Mc-fEE-treated mice were analyzed by flowcytometry, real-time PCR, and ELISA. Mc-fEE-triggered molecular events were detected from RAW264.7 cells and splenocytes using Western blotting and real-time PCR analyses. Results: The mRNA expression levels of cytokines such as interleukin families, interferon (IFN)-β, and tumor necrosis factor (TNF)-α were increased by Mc-fEE treatment in vitro and in vivo. Western blotting analysis showed that the phosphorylation levels of nuclear factor (NF)-κB and activator protein (AP)-1 subunits these were enhanced in Mc-fEE-treated RAW264.7 cells. In addition, according to in vivo experiments, it was considered that Mc-fEE can increase the population of splenic NK cells and subsequent upregulation of their cytotoxic activity against YAC-1 cells, a T- cell lymphoma. Conclusion: In this paper, we could confirm that Mc-fEE has remarkable immunostimulatory effects by activation and increase of the NK cell population. [ABSTRACT FROM AUTHOR]

Background. Depression is a major cause of disability and most antidepressant medicines are ineffective owing to their high toxicity and numerous adverse effects. As a result, there is an urgent need to find new effective treatment methods. This paper aims to investigate the effect and mechanism of total saikosaponins (TSS) on depression-like behaviors induced by chronic unpredictable mild stress (CUMS) in rats. Methods. Twenty-four male SD rats were randomly divided into 4 groups: control group, CUMS group, TSS group, and fluoxetine (Flu) group. Then, the following tests were conducted: sucrose preference test, open field test, and elevated plus maze test. Additionally, ELISA was used to detect the levels of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) in the serum of the rats as well as the levels of inflammatory cytokines IL-1β, IL-6, and TNF-α in the hippocampus, and Western blot was used for measuring the expression of brain-derived neurotrophic factor (BDNF) protein and related proteins of the PI3K/AKT/NF-κB signaling pathway in the hippocampus. Results. TSS could significantly improve rat behaviors, specifically indicated by increases in sucrose preference, total movement distance, stay time in the central area, number of entries into open arms, time spent in open arms, and a decrease in stay time in the peripheral area. TSS acted to significantly reduce BDNF protein expression and increase the contents of ACTH and CORT in serum as well as the levels of IL-1β, IL-6, and TNF-α in the hippocampal tissue in rats. In addition, it was able to raise the ratios of p-PI3K/PI3K and p-AKT/AKT and decrease the ratio of p-p65/p65 in tissues, which in turn regulated the PI3K/AKT/NF-κB signaling pathway. Conclusions. TSS, through regulating PI3K/AKT/NF-κB signaling axis, can alleviate depression-like behaviors and elevate neuroendocrine hormone levels and inflammatory factor levels. [ABSTRACT FROM AUTHOR]

Background: The Pro-inflammatory mediators such as prostaglandin E2, nitric oxide and TNF-α are the key players in the stimulation of the inflammatory responses. Thus, the pro-inflammatory mediators are considered to be potential targets for screening nutraceutical with anti-inflammatory activity. Methods: In this context, we explored the anti-inflammatory potency of seagrass extract with western blot (Bio-Rad) analysis by using LPS induced RAW macrophages as in-vitro models, western blot analysis, In-silico methods using Mastero 13.0 software. Results: The anti-inflammatory activity of Seagrass was demonstrated through down regulation of Pro-inflammatory markers such as Cyclooxygenase-2, induced Nitric oxide synthase and prostaglandin E synthase-1. The results were validated by docking the phytochemical constituents of seagrass namely Isocoumarin, Hexadecanoic acid, and Cis-9 Octadecenoic acid, 1,2 Benzene dicarboxylic acid and beta-sitosterol with TNF-alpha, COX-2, iNOS and PGES-1. Conclusion: The methanolic extract of seagrass Halophila beccarii is a potential nutraceutical agent for combating against inflammation with a significant anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Background. Angelica Yinzi (AYZ) is a Chinese traditional herbal formula reported to attenuate itches and inflammation caused by atopic dermatitis (AD). However, the underlying mechanism of AYZ in the attenuation of itchiness and inflammation remains unknown. Objective. This study investigated the mechanism of AYZ in reducing itchiness in mice with 1-chloro-2,4-dinitrobenzene- (DNCB-)-induced atopic dermatitis. Methods. Hematoxylin and eosin (H&E) and toluidine blue staining were used to evaluate pathological changes in skin tissue, while an enzyme‐linked immunosorbent assay (ELISA) was used to assess the cytokine levels in the skin. After that, qRT-PCR was performed to determine the mRNA levels of cytokines in the skin. Immunofluorescence and western blotting analysis were further used to assess µ-opioid receptor (MOR) expression and immunohistochemistry to assess the p-ERK, p-AKT, and κ-opioid receptor (KOR). Results. The AYZ treatment alleviated the AD clinical symptoms, including decreasing the scratching frequency, the ear thickness, and the infiltration of mast cells, lymphocytes, inflammatory cells, and mononuclear cells. In addition, AYZ inhibited the expression of interleukin (IL)-13, thymic stromal lymphopoietin (TSLP), and reduced neuraminidase (NA), corticotropin-releasing factor (CRF), and reactive oxygen species (ROS) expression. Markers involved in itches, such as p-ERK and p-AKT, were significantly downregulated following AYZ treatment. Besides, AYZ significantly increased MOR expression and downregulated KOR in the epidermis and spinal cord. Conclusion. Our findings imply that AYZ ameliorates pruritus-related AD through skin repair, antioxidation, and balancing peripheral MOR and KOR. The findings in this study lay a theoretical foundation for the control mechanism of peripheral itch. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is the second commonest microvascular complication of diabetes mellitus. It is characterized by chronic inflammation and angiogenesis. Palm oil-derived tocotrienol-rich fraction (TRF), a substance with anti-inflammatory and anti-angiogenic properties, may provide protection against DR development. Therefore, in this study, we investigated the effect of TRF on retinal vascular and morphological changes in diabetic rats. The effects of TRF on the retinal expression of inflammatory and angiogenic markers were also studied in the streptozotocin (STZ)-induced diabetic rats. Methods: Male Sprague Dawley rats weighing 200–250 g were grouped into normal rats (N) and diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (55 mg/kg body weight) whereas N similarly received citrate buffer. STZ-injected rats with blood glucose of more than 20 mmol/L were considered diabetic and were divided into vehicle-treated (DV) and TRF-treated (DT) groups. N and DV received vehicle, whereas DT received TRF (100 mg/kg body weight) via oral gavage once daily for 12 weeks. Fundus images were captured at week 0 (baseline), week 6 and week 12 post-STZ induction to estimate vascular diameters. At the end of experimental period, rats were euthanized, and retinal tissues were collected for morphometric analysis and measurement of NFκB, phospho-NFκB (Ser536), HIF-1α using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Retinal inflammatory and angiogenic cytokines expression were measured by ELISA and real-time quantitative PCR. Results: TRF preserved the retinal layer thickness (GCL, IPL, INL and OR; p < 0.05) and retinal venous diameter (p < 0.001). TRF also lowered the retinal NFκB activation (p < 0.05) as well as expressions of IL-1β, IL-6, TNF-α, IFN-γ, iNOS and MCP-1 (p < 0.05) compared to vehicle-treated diabetic rats. Moreover, TRF also reduced retinal expression of VEGF (p < 0.001), IGF-1 (p < 0.001) and HIF-1α (p < 0.05) compared to vehicle-treated rats with diabetes. Conclusion: Oral TRF provided protection against retinal inflammation and angiogenesis in rats with STZ-induced diabetes by suppressing the expression of the markers of retinal inflammation and angiogenesis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the therapeutic effects of total glucosides of paeony (TGP) on psoriasis based on the immunomodulatory effect of dermal mesenchymal stem cells (DMSCs). Methods: A total of 30 male BALB/c mice were divided into 6 groups (n=5 in each) by a random number table method, including control, psoriasis model (model, 5% imiquimod cream 42 mg/d), low-, medium- and high-dose TGP (50, 100, and 200 mg/kg, L, M-, and H-TGP, respectively), and positive control group (2.5 mg/kg acitretin). After 14 days of continuous administration, the skin's histopathological changes, apoptosis, secretion of inflammatory cytokines, and proportion of regulatory T cells (Treg) and T helper cell 17 (Th17) were evaluated using hematoxylin-eosin (HE) staining, TdT-mediated dUTP nick end labeling staining, enzyme-linked immunosorbent assay, and flow cytometry, respectively. DMSCs were further isolated from the skin tissues of normal and psoriatic mice, and the cell morphology, phenotype, and cycle were observed. Furthermore, TGP was used to treat psoriatic DMSCs to analyze the effects on the DMSCs immune regulation. Results: TGP alleviated skin pathological injury, reduced epidermis layer thickness, inhibited apoptosis, and regulated the secretion of inflammatory cytokines and the proportion of Treg and Th17 in the skin tissues of psoriatic mice (P<0.05 or P<0.01). There was no significant difference in cell morphology and phenotype between control and psoriatic DMSCs (P>0.05), however, more psoriatic DMSCs remained in G0/G1 phase compared with the normal DMSCs (P<0.01). TGP treatment of psoriatic DMSCs significantly increased cell viability, decreased apoptosis, relieved inflammatory response, and inhibited the expression of toll-like receptor 4 and P65 (P<0.05 or P<0.01). Conclusion: TGP may exert a good therapeutic effect on psoriasis by regulating the immune imbalance of DMSCs. [ABSTRACT FROM AUTHOR]

Background. Clinacanthus nutans (Burm.f.) Lindau (C. nutans) has been used in the therapy of hepatitis B (HB) and is effective; however, the mechanism of action has not been elucidated. Objective. To investigate the protective effects of C. nutans aqueous extract on the hepatitis B virus (HBV) mouse model based on correlation analysis between gut microbiota and liver metabolomics. Materials and Methods. We firstly constructed the animal model by high-pressure injection of pcDNA3.1(+)/HBV plasmid into the tail vein and treated it with C. nutans. The biomarkers and inflammatory cytokines of HB were detected by enzyme-linked immunosorbent assay and quantitative PCR; the Illumina-MiSeq platform was used for investigating gut microbiota; the LC-MS/MS method was utilized on screening liver tissue metabolites; multiomics joint analysis was performed using the R program. Results. Compared with the modeling group, C. nutans significantly decreased the expression levels of HBsAg, IL-1β, TNF-α P < 0.05 in the serum, and cccDNA P < 0.05 in the liver tissues of mice. C. nutans dramatically reduced the ratio of Firmicutes and Bacteroidetes P < 0.05 and significantly declined the proportion of Lactobacillaceae and Lactobacillus P < 0.05 , dramatically increasing the relative abundance of Bacteroidales_S24-7_group, Rikenellaceae, and Alistipes P < 0.05 ; LC-MS/MS analysis results showed that C. nutans dramatically upregulate hippuric acid, L-histidine, trehalose, D-threitol, and stachyose and downregulate uridine 5′-diphosphate, cholic acid, trimethylamine N-oxide, CDP-ethanolamine, and phosphorylcholine P < 0.05 . The correlation analysis revealed that C. nutans affects the related metabolite levels of hippuric acid and cholic acid through the modulation of crucial bacteria (Alistipes) P < 0.01 , exerting specific anti-inflammatory effects. Conclusion. These results suggest that C. nutans exerts protective effects in HBV model mice, showing the therapeutic potential for anti-HBV infection. [ABSTRACT FROM AUTHOR]

Introduction: Osteoarthritis is a public health concern that leads to disability due to chronic pain, stiffness, sleep disturbance, and depression. D-limonene is a racemic mixture of limonene, a natural cyclic monoterpene, and the major component of the oil extracted from the citrus rind with chemo-preventive and anti-inflammatory activities. The purpose of this study was to investigate the anti-inflammatory properties of Dlimonene compared with dexamethasone and ibuprofen in bovine fibroblast-like synoviocyte cells (BFLSc) as well as Human THP-1 monocyte/macrophage-like cells. Materials and Methods: BFLSc was isolated from the synovial membrane of the metacarpal joint cartilage of an 8-month-old Holstein. THP-1 cells were prepared by the Pasteur Institute of Iran. Cells were cultivated and exposed to 20 ng/ml lipopolysaccharide (LPS) stimulation without, or in the presence of, ibuprofen, dexamethasone, or D-limonene (7.5µg/ml). The gene expressions of cyclooxygenase-2 (COX-2), Interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and Tumor necrosis factor alpha (TNF-α) were evaluated by real-time PCR. Concentrations of Nitric Oxide (NO), and Prostaglandin-E2 (PGE2) were measured by ELISA methods. Results: The inhibitory effects of D-limonene included dose-dependent decreases in the expression of iNOS and COX-2 proteins (P < 0.05). The treated cells secreted increased amounts of COX-2, IL-1β, iNOS, TNF-α, NO, and PGE2 in response to LPS stimulation in all conditions. D-limonene quenched the gene expression of COX-2, iL-1β, iNOS, and TNF-α, in BFLSc, and the production of PGE2 and NO in monocyte/macrophage cells alike dexamethasone, and ibuprofen. Conclusion: The results obtained in this study show that D-limonene probably exerts anti-inflammatory effects through the suppression of TNF- α, IL-1β, COX-2, and iNOS and NO, PGE2 production. [ABSTRACT FROM AUTHOR]

Background. Allergic rhinitis (AR) is a type I allergic disease induced by IgE. Traditional Chinese medicine Saposhnikovia divaricata (Turcz.) Schischk (SD) has anti-inflammatory and antiallergic effects. Materials and Methods. AR model mice were constructed with ovalbumin (OVA) sensitization to observe the improving effect of SD treatment on AR by counting the number of sneezing and rubbing the nose, hematoxylin-eosin, periodic acid-Schiff, and toluidine blue stains. In addition, the allergy and inflammatory cytokines levels and inflammatory cells were observed by ELISA and Wright's-Giemsa stain. The protein levels of the TLR4/TRAF6/NF-κB and IL-6/ROR-γt/STAT3 pathways were measured by immunohistochemistry, quantitative real-time PCR, and western blot. The intestinal microflora abundance in mice was observed by 16S rDNA high-throughput sequencing. Results. SD treatment inhibited the sneezing and rubbing times of the nose, decreased the degree of a dense arrangement of cells and mucosal swelling and the number of goblet and mast cells of nasal lavage fluid, reduced the levels of IgE, histamine, Leukotriene B4, IL-4, IL-5, TNF-α, IL-6, and IL-17, the eosinophils, neutrophils, and lymphocytes number, the LR4, TRAF6, IL-6, ROR-γt, and STAT3 mRNA levels, respectively, while, it increased the IL-2, IL-10, IFN-γ, and TGF-β1 proteins. SD treatment inhibited the NF-κB, p-STAT3, TLR4, TRAF6, and p-IκBα/IκBα proteins. Besides, the effects of OVA and SD treatments were significantly correlated with the abundance of intestinal microflora. The abundances of Cytophagales, Burkholderia, Alteromonadales, Lactococcus, and Clostridiaceae were changed in SD treatment on AR mice. Conclusions. This study provides a possibility that the improvement effect of SD treatment on allergies and inflammation in AR mice may be related to the TLR4/TRAF6/NF-κB and IL-6/ROR-γt/STAT3 pathways and intestinal microflora modulation. [ABSTRACT FROM AUTHOR]

Juglans regia has been used to treat inflammatory and arthritic disorders in traditional medicine. The present study aimed to investigate the antiarthritic and anti-inflammatory potential of ethanolic leaves extract of J. regia. Arthritis was induced in rodents with Freund's complete adjuvant. J. regia treatment was started on 8th day of arthritis induction and sustained for 20 days. Acute inflammatory models were developed using carrageenan, histamine, serotonin, and dextran. Qualitative and GC-MS analyses were also performed. Arthritis was determined using an arthritis scoring index and histopathological examination of ankle joints. RT-PCR was performed to determine the expression of pro-inflammatory markers (TNF-α, NF-κB, IL-6, IL-1β, and COX-2) and anti-inflammatory IL-4. PGE2 levels were evaluated using an ELISA. Blood and biochemical parameters were also determined. Paw edema was measured using a digital plethysmometer. Treatment with extracts inhibited arthritic development and attenuated paw edema along with all histopathological parameters. The expression levels of pro-inflammatory cytokines and COX-2 were downregulated, while IL-4 was upregulated. PGE2 levels were also reduced in extract-treated groups. Blood and biochemical parameters were nearly normalized in the treatment groups. Both extracts significantly inhibited carrageenan, histamine, serotonin, and dextran-induced paw edema. Qualitative phytochemical screening and GC-MS analysis confirmed that extracts possessed potential medicinal compounds. In conclusion, ethanol and n-hexane extracts of J. regia leaves have immunomodulatory and anti-inflammatory effects that ameliorate experimentally induced arthritis and edema. The inhibition of autacoids may also be one of the mechanisms inducing the immunomodulatory effect. [ABSTRACT FROM AUTHOR]

Acute pharyngitis is an inflammation of the pharyngeal mucous membrane and submucous lymphoid tissues. Unsatisfactory treatment and repeated occurrences might cause chronic pharyngitis and other complications. Syringa oblata L. (S. oblata) is a traditional Chinese medicine that exhibited a significant therapeutic effect on various inflammatory diseases. Its commercial drug Yan Li Xiao (YLX) capsule is used as a cure for the treatment of inflammatory diseases, such as bacillary dysentery, tonsillitis, bronchitis, and acute gastroenteritis. However, studies about S. oblata relieving acute pharyngitis are rare. In this study, high-performance liquid chromatography (HPLC) was used to analyze the chemical profile of S. oblata, and the bioactive phytoconstituents were isolated and identified by nuclear magnetic resonance (NMR) and mass spectrometry. An ammonia-induced acute pharyngitis rat model was established to estimate the protective effect of S. oblata in vivo for the first time. The severity of pharyngitis was observed by appearance index and HE staining. The cytokines expression was performed by ELISA. Crucial proteins expression associated with TLR4/NF-κB/MAPK and NLRP3 inflammasome signaling pathways were analyzed by western blotting and immunohistochemistry. Furthermore, the anti-inflammatory effect of isolated compounds was evaluated by suppressing lipopolysaccharide- (LPS-) induced NO generation and regulating the cytokines levels in RAW 264.7 cells. The results showed that S. oblata exhibited a protective effect in the ammonia-induced acute pharyngitis rat model, and the compounds exert potential anti-inflammatory properties against LPS-activated RAW 254.7 cells. [ABSTRACT FROM AUTHOR]

Background. Traditional Chinese medicine Smilax is the rhizome of liliaceous plant Smilax china L., which is used to treat pelvic inflammatory disease and anxieties. Purpose. To investigate the mechanism of anti-inflammatory activity of the extract from Smilax china L. (ES). Methods. The components of ES were identified by UPLC-QTOF-MS/MS. The anti-inflammatory activities were evaluated in xylene-induced ear oedema and egg white-induced plantar swelling test. Cell viability was examined by CCK-8 assay. The inflammatory mediators, proinflammatory cytokines, and MAPK and NF-κB signals in LPS-stimulated THP-1 cells were determined using ELISA, real-time PCR, and Western blot, respectively. Results. 20 compounds of ES were confirmed by comparing with the reference substance. ES displayed more prominent anti-inflammatory activity than the positive control "Jin Gang Teng" capsule in the in vivo acute inflammatory model. ES suppressed the expression of PGE2 and 6-Keot-PGF1α, and the ratio of IC50 (COX-1)/IC50 (COX-2) of ES was 3.15, which indicated that ES could selectively inhibit COX-2. ES dose-dependently (12.5, 25, and 50 mg/L) decreased the production and mRNA levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Furthermore, ES significantly decreased LPS-induced phosphorylation of p38, JNK, ERK1/2, and p65, inhibiting the expression of IKKα and the degradation of IκBα. Conclusion. The results suggested that ES could selectively inhibit the activity of COX-2, and the anti-inflammatory effect of ES was associated with the inhibition of IL-1β, IL-6, and TNF-α via negative regulation of MAPK and NF-κB signaling pathways in LPS-induced THP-1 cells. [ABSTRACT FROM AUTHOR]