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Animal contextual fear conditioning (CFC) models are the most-studied forms used to explore the neural substances of posttraumatic stress disorder (PTSD). In addition to the well-recognized hippocampal–amygdalar system, the retrosplenial cortex (RSC) is getting more and more attention due to substantial involvement in CFC, but with a poor understanding of the specific roles of its two major constituents—dysgranular (RSCd) and granular (RSCg). The current study sought to identify their roles and underlying brain network mechanisms during the encoding processing of the rat CFC model. Rats with pharmacologically inactivated RSCd, RSCg, and corresponding controls underwent contextual fear conditioning. [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scanning was performed for each animal. The 5-h and 24-h retrieval were followed to test the formation of contextual memory. Graph theoretic tools were used to identify the brain metabolic network involved in encoding phase, and changes of nodal (brain region) properties linked, respectively, to disturbed RSCd and RSCg were analyzed. Impaired retrieval occurred in disturbed RSCd animals, not in RSCg ones. The RSC, hippocampus (Hip), amygdala (Amy), piriform cortex (Pir), and visual cortex (VC) are hub nodes of the brain-wide network for contextual fear memory encoding in rats. Nodal degree and efficiency of hippocampus and its connectivity with amygdala, Pir, and VC were decreased in rats with disturbed RSCd, while not in those with suppressed RSCg. The RSC plays its role in contextual fear memory encoding mainly relying on its RSCd part, whose condition would influence the activity of the hippocampal–amygdalar system. [ABSTRACT FROM AUTHOR]

Migraine, characterized by hyperalgesia of the trigeminovascular system, is a severe condition that leads to severe reductions in the quality of life. Upon external stimulation, the levels of various neurotransmitters, including aspartic acid (Asp), glutamic acid (Glu), γ-amino butyric acid (GABA), norepinephrine (NE) and 5-hydroxytryptamine (5-HT), are significantly altered; this directly or indirectly promotes trigeminal hypersensitivity. Fructus Viticis is a Traditional Chinese Medicine with analgesic properties to provide efficient relief of migraine. In the present study, the underlying mechanisms of the analgesic effect of Fructus Viticis methanolic extract were assessed in rats with nitroglycerin-induced migraine. The plasma levels of the neurotransmitters calcitonin gene-related peptide (CGRP) and substance P (SP), as well as the amount of c-fos immunoreactive cells (c-fos IR cells) in the brain, were detected. The analgesic effect was obvious, as Fructus Viticis methanolic extract ameliorated migraine-like behaviours in nitroglycerin-induced rats. The levels of 5-HT, GABA and NE in the brain of migraine model rats was lower compared with that of control rats, whereas opposite observations were made in the contents of excitatory amino acids. Pre-treatment with Fructus Viticis methanolic extract elevated the levels of 5-HT, GABA and NE, and also lowered the levels of excitatory amino acids, including Glu and Asp. In addition, treatment with Fructus Viticis methanolic extract lowered the plasma levels of CGRP and SP and decreased the c-fos IR cells in the brainstem. The present study provided a further scientific basis for the anti-migraine effects of Fructus Viticis. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis. Succinate is an inflammatory metabolic signal that exacerbates RA synovitis by activating succinate receptor 1 (SUCNR1) to amplify the release of IL-1β. Thus, inhibition of succinate activation of SUCRN1 could be an effective method to inhibit the inflammation of RA. Baihu Jia Guizhi decoction (BHGZ), which is composed of Gypsum Fibrosum, Anemarrhena asphodeloides Bge., Cinnamomum cassia Presl., Glycyrrhiza uralensis Fisch., and Oryza sativa L., is a Traditional Chinese Medicine (TCM) prescription used to treat RA in clinic. In addition, TCM believes that damp and heat environment is one of the causes of RA. In this study, we tested the role of damp and heat environments in exacerbating RA inflammation and the anti-inflammatory effect of BHGZ, based on succinate/SUCNR1/IL-1β pathway in the adjuvant arthritis (AA) model with damp and heat environment (AA + DHE). Results showed that paw swelling and synovial pathology were significantly increased in AA rats, and these results were aggravated by stimulation in damp and heat environment. BHGZ improved AA + DHE rats' paw swelling, synovial hyperplasia, and inflammatory cell infiltration and reduced IL-1β. In addition, AA rats significantly increased the expression of SUCNR1, and the stimulation of damp and heat environment not only increased the expression of SUCNR1 but also promoted the accumulation of succinate. BHGZ simultaneously reduced the concentration of succinate and the expression of SUCNR1. Finally, SDH activity was decreased in AA rats and AA + DHE rats, while BHGZ increased SDH activity and then reduced succinate concentration. Therefore, we prove that damp and heat environment deteriorated the inflammation of RA which is the activation of succinate/SUCNR1 pathway, while BHGZ regulates SDH activity to reduce the accumulation of succinate and inhibit the activation of SUCNR1 that is the underlying mechanism of its treatment of RA. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Clematis chinensis Osbeck / Notopterygium incisum Ting ex H, T-Chang (CN) is a traditional Chinese herb couple with prominent efficacy. The herb couple has been commonly used for clinical treatment of arthralgia syndrome (“Bi Zheng” in Chinese) for centuries in China, including rheumatic arthritis, osteoarthritis and gout in modern medicine. Aim of the study To evaluate the anti-arthritic effect of CN herb couple in a rat model of rheumatoid arthritis (RA). Materials and methods Rats were divided randomly into six groups with eight each. Adjuvant-induced arthritis (AIA) model was established by intradermal injection of complete Freund's adjuvant (CFA). Rats were treated orally with different dosages of CN (0.7 g/kg, 2.1 g/kg, 6.3 g/kg) from day 16 till day 40. Ibuprofen (50.4 mg/kg) served as a positive control. Spontaneous activity, body weight, paw swelling, and arthritis index (AI) were monitored throughout drug treatment. Then serum levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) were determined by enzyme linked immunosorbent assay (ELISA) kits. In addition, histopathological examination and immunohistochemistry were used to assess the severity of arthritis. Results Three dosage of CN significantly ameliorated symptoms of RA via increasing body weight as well as reducing paw swelling (at dose of 6.3 g/kg, p <0.01) in AIA rats. An extremely significant reduction of AI ( p <0.001) was also observed with treatment of CN (6.3 g/kg) compared with model group. In parallel, treatment of CN significantly down-regulated levels of TNF-α, IL-6, and VEGF both in serum ( p <0.01) and in joint synovial compared with model rats. And histopathology revealed noticeable reduction in synovial hyperplasia, cartilage damage, and inflammatory infiltration by CN treatment, especially at dose of 6.3 g/kg. Conclusions To conclude, all results suggest that CN possesses evident anti-arthritic effects in AIA rats. [ABSTRACT FROM AUTHOR]

Clematidis Radix et Rhizoma, a kind of traditional Chinese medicine, is derived from Clematis chinensis Osbeck, Clematis hexapetala Pall. and Clematis manshurica Rupr. This herb shows great effects on expelling wind and dispelling dampness in ancient and it has anti-inflammatory and analgesic activity in modern clinical application. This experiment aimed to research anti-rheumatoid arthritis effect of crude and wine processed RC based on glycolysis metabolism to provide new ideas treating RA. Network pharmacology was applied to preliminarily forecast the potential pathways of common targets of RC and RA. RAW264.7 macrophages were induced by LPS, NO production, glucose uptake, lactate production, ROS and MMP were detected as instructions in vitro. ELISA was used to measure the content of HK2, PKM2 and LDHA involving in glycolysis process. Gut microbiota was analyzed by 16S rRNA gene amplicon sequencing in CIA rats. Crude and wine processed RC had good anti-inflammatory effect by reducing NO in RAW264.7 macrophages and ameliorating inflammatory infiltration and cartilage surface erosion in CIA rats. Whether in LPS-induced macrophages or CIA rats, crude and wine processed RC could inhibit glycolysis by down-regulating the expression of PKM2, causing less glucose uptake and lactic acid, which lead to less ROS and higher MMP to normal. PI3K-AKT and HIF-1α pathways were deduced to possibly play a crucial part in controlling glycolysis metabolism by network pharmacology analysis. Besides, it was displayed that Firmicutes and Bacteroidetes were prominent gut microbiota in CIA rats feces. CC-H and PZ-H groups could both increase the relative abundance of Firmicutes and decrease Bacteroidetes. These microbiota also played a role in RA pathological process via involving in energy metabolism, carbohydrate metabolism and immune system. Crude and wine processed RC have a good influence in ameliorating rheumatoid arthritis by inhibiting glycolysis and modulating gut microbiota together. [Display omitted] • Thermal and wine processed RC had good anti-inflammatory effects to ameliorate RA in vitro and vivo. • Thermal and wine processed RC inhibited glycolysis via mainly decreasing PKM2 in vitro and vivo. • The gut microbiota Roseburia and Prevotella were related with glycolytic enzyme PKM2 and LDHA. • PI3K-AKT pathway and HIF-1α pathway were deduced to be closed with glycolysis metabolism by network pharmacology analysis. • Thermal and wine processed RC may treat RA through inhibiting glycolysis combined with modulating gut microbiota. [ABSTRACT FROM AUTHOR]

Alleviating rheumatism by inhibiting synovitis is a routine treatment for rheumatoid arthritis (RA). Baihu Jia Guizhi Decoction (BHJGZ) is a classic prescription and has a long history of application for treating RA with a good anti-inflammatory action. However, the underlying molecular mechanisms have not been fully elucidated. This work aimed to decipher the potential mechanism of BHJGZ against RA focusing on Ras/MEK/ERK pathway. Based on the prediction of network pharmacology, the inhibition action of BHJGZ on Ras/MEK/ERK pathway was firstly validated in vivo and in vitro. Moreover, the affinity with the ingredients of BHJGZ in serum and the targets of Ras/MEK/ERK pathway were evaluated. Finally, the efficacy of BHJGZ for relieving RA was assessed in AA rats. The Ras/MEK/ERK pathway was predicted by network pharmacology as one of important mechanisms of BHJGZ to treat RA. The high expression of Ras protein in synovitis of AA rats was significantly reduced by the treatment with BHJGZ, and the activation of Ras/MEK/ERK pathway in vivo and in vitro was also markedly inhibited (p < 0.05 or p < 0.01). Moreover, the level of p-ERK/ERK, IL-6 and TNF-α in vitro were further suppressed after Ras or MEK was inhibited by mirdametinib or lonafarnib respectively (p < 0.01). Furthermore, the results of molecular docking showed a good affinity and stable binding with the ingredients of BHJGZ in serum and multiple key proteins of the Ras/MEK/ERK pathway. Finally, paw swelling, paw circumference and pathological changes of joint synovitis were significantly reduced by BHJGZ in AA rats (p < 0.05). The inhibition of Ras/MEK/ERK pathway is one of crucial mechanisms of BHJGZ for ameliorating synovitis of RA. [Display omitted] • The therapeutic effect of BHJGZ on rheumatoid arthritis was proved. • It was demonstrated that BHJGZ can alleviate synovitis of rheumatoid arthritis. • It was proved that BHJGZ could inhibit Ras/MEK/ERK signal pathway. • This study provided a new idea for the treatment of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Si Shen Wan is a traditional Chinese herbal medicine formula for the treatment of diseases with diarrhea, such as ulcerative colitis, allergic colitis and chronic colitis. To investigate the protective and healing effects of Si Shen Wan in the experimental colitis induced by trinitrobenzene sulphonic acid, and to furture explore its mechanism of action. Materials and methods: Rats with colitis treated with Si Shen Wan for 10 days. Colon wet weight, colon organ coefficient, colonic damage score and pathological change after trinitrobenzene sulphonic acid challenge were determined. The levels of MPO, MDA, GSH-PX, SOD and the expression of IL-4 and IL-10 mRNA in the colon were also measured. Results: After treatment, colon wet weight, colon organ coefficient and colonic damage score were lower than that in the control group (p<0.05). MDA and MPO concentrations in the inflamed colonic tissues were decreased remarkably in the treated groups compared with that in the control group (p<0.05). But SOD level, IL-4 and IL-10 mRNA expression in the inflamed colonic tissues were obviously increased. Conclusions: It is a potential path that protective effect of Si Shen Wan on impaired colonic mucosa rats with experimental colitis was accomplished by down-regulating the level of MDA and MPO, and up-regulating the level of SOD and the IL-4 and IL-10 mRNA expression in the colon mucosa. [Copyright &y& Elsevier]

• CA alleviated inflammation of rheumatoid arthritis in rats by suppressing IL-1β. • CA reduced HIF-1α expression by limiting succinate aggregation and GPR91 activation. • CA inhibited NLRP3 expression through Succinate/GPR91&HIF-1α for IL-1β suppression. Cinnamaldehyde (CA) is an essential component of cinnamon (Cinnamomum cassia Presland), which is often used as a flavoring condiment in beverages, pastries, perfumes, etc. Cinnamon is also used as herbal medicine in China and Southeast Asia to treat rheumatoid arthritis. However, the molecular mechanism is unclear. In this study, we aim to investigate its anti-inflammatory effects against Rheumatoid arthritis (RA) using activated macrophages (Raw246.7) in vitro and adjuvant arthritis rats (AA) in vivo. The results demonstrated that CA significantly reduced synovial inflammation in AA rats, possibly due to suppression of the expressions of pro-inflammatory cytokines, especially the IL-1β. Further investigation found that CA also suppressed the activity of HIF-1α by inhibiting the accumulation of succinate in cytoplasm. As we know, the reduction of HIF-1α nucleation slows down IL-1β production, because HIF-1α activates the expression of NLRP3, which is involved in the assembly of inflammasome and processing of IL-1β. In addition, CA also inhibited the expression of the succinate receptor GPR91, which in turn inhibited the activation of HIF-1α. In conclusions, our results suggested that CA might be a potential therapeutic compound to relieve rheumatoid arthritis progress by suppressing IL-1β through modulating succinate/HIF-1α axis and inhibition of NLRP3. [ABSTRACT FROM AUTHOR]