A novel phthalein component ameliorates neuroinflammation and cognitive dysfunction by suppressing the CXCL12/CXCR4 axis in rats with vascular dementia.

ETHNOPHARMACOLOGICAL RELEVANCE: Chuanxiong, a plant of the Umbelliferae family, is a genuine medicinal herb from Sichuan Province. Phthalides are one of its main active components and exhibit good protective effect against cerebrovascular diseases. However, the mechanism by which phthalides exert neuroprotective effects is still largely unclear. AIM OF THE STUDY: In this study, we extracted a phthalein component (named as QBT) from Ligusticum Chuanxiong, and investigated its neuroprotective effects against vascular dementia (VaD) rats and the underlying mechanism, focusing on the chemokine 12 (CXCL12)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis. METHODS: A rat model of VaD was established, and treated with QBT. Cognitive dysfunction in VaD rats was assessed using the Y-maze, new object recognition, and Morris water maze tests. Neuronal damage and inflammatory response in VaD rats were examined through Nissl staining, immunofluorescence, enzyme-linked immunospecific assay, and western blotting analysis. Furthermore, the effects of QBT on CXCL12/CXCR4 axis and its downstream signaling pathways, Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/nuclear factor-κB (NF-κB), were investigated in VaD rats and BV2 microglial cells exposed to oxygen glucose deprivation. RESULTS: QBT significantly alleviated cognitive dysfunction and neuronal damage in VaD rats, along with inhibition of VaD-induced over-activation of microglia and astrocytes and inflammatory response. Moreover, QBT exhibited anti-inflammatory effects by inhibiting the CXCL12/CXCR4 axis and its downstream JAK2/STAT3 and PI3K/AKT/NF-κB pathways, thereby attenuating the neuroinflammatory response both in vivo and in vitro. CONCLUSION: QBT effectively mitigated neuronal damage and cognitive dysfunction in VaD rats, exerting neuroprotective effects by suppressing neuroinflammatory response through inhibition of the CXCL12/CXCR4 axis.

Modulation of Xiongdanjiuxin pills on the gut-liver axis in high-fat diet rats.

AIM: Xiongdanjiuxin pill (XP) is a traditional Chinese medicine formula for the prevention and treatment of hyperlipidemia (HLP) and related complications. In this study, the gut-liver axis was used as the breakthrough point to analyze the therapeutic effect and potential mechanism of XP on HLP model rats and related complications. MAIN METHODS: We used high-fat diet (HFD) to establish the HLP model of rats and treated them with XP. The 16S rRNA sequencing method was used to explore the effect of XP on the gut microbiota of HFD rats, and the effects of XP on ileum pathology, intestinal barrier and circulatory inflammation in HFD rats were also investigated. We further explored the molecular mechanism of XP treating liver inflammation in rats with HFD by regulating toll-like receptor 4 (TLR4) signaling. KEY FINDINGS: We found that XP could regulate the imbalance of gut microbiota in HFD rats, and up-regulate the expression of tight junction protein in intestinal epithelium of HFD rats, thereby improving the intestinal barrier damage and intestinal inflammatory response. In addition, XP could significantly reduce the levels of inflammatory cytokines in HFD rats, and inhibit TLR4 signaling pathway, thereby reducing liver inflammation in HFD rats. SIGNIFICANCE: XP can effectively improve the imbalance of gut-liver axis in hyperlipidemic rats and alleviate the inflammatory damage of liver. Its mechanism may be related to regulating the disorder of gut microbiota and inhibiting TLR4 signal pathway, so as to achieve the therapeutic effect on hyperlipidemic fatty liver in rats.

The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication.

Obviously, immune cells like T cells and macrophages play a major role in rheumatoid arthritis (RA). On one hand, the breakdown of immune homeostasis directly induces systemic inflammation; on the other hand, these cells initiate and perpetuate synovitis and tissue damages through the interaction with fibroblast-like synoviocytes (FLS). In recent years, the pathological link between metabolic disorders and immune imbalance has received increasing attention. High energy demand of immune cells leads to the accumulation of metabolic byproducts and inflammatory mediators. They act on various metabolism-sensitive signal pathways as well as relevant transcription factors, such as HIF-1α, and STATs. These molecular events will impact RA-related effectors like circulating immune cells and joint-resident cells in return, allowing the continuous progression of systemic inflammation, arthritic manifestations, and life-threatening complications. In other words, metabolic complications are secondary pathological factors for the progression of RA. Therefore, the status of energy metabolism may be an important indicator to evaluate RA severity, and in-depth explorations of the mechanisms underlying the mystery of how RA-related metabolic disorders develop will provide useful clues to further clarify the etiology of RA, and inspire the discovery of new anti-rheumatic targets. This article reviews the latest research progress on the interactions between immune and metabolism systems in the context of RA. Great importance is attached to the changes in certain pathways controlling both immune and metabolism functions during RA progression.

α-Mangostin Inhibited M1 Polarization of Macrophages/Monocytes in Antigen-Induced Arthritis Mice by Up-Regulating Silent Information Regulator 1 and Peroxisome Proliferators-Activated Receptor γ Simultaneously.

Background: α-Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor γ (PPAR-γ) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties. Methods: Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-γ inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-γ proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-γ were validated by experiments in vitro. Results: SIRT1 and PPAR-γ inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-γ and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-γ, and MG promoted the co-expression of SIRT1 and PPAR-γ in joints. Synchronously activating SIRT1 and PPAR-γ was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes. Conclusion: MG binds PPAR-γ and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.

Pt Nanoparticles Confined in a 3D Porous FeNC Matrix as Efficient Catalysts for Rechargeable Li-CO2/O2 Batteries.

The cathodic product Li2CO3, due to its high decomposition potential, has hindered the practical application of rechargeable Li-CO2/O2 batteries. To overcome this bottleneck, a Pt/FeNC cathodic catalyst is fabricated by dispersing Pt nanoparticles (NPs) with a uniform size of 2.4 nm and 8.3 wt % loading amount into a porous microcube FeNC support for high-performance rechargeable Li-CO2/O2 batteries. The FeNC matrix is composed of numerous two-dimensional (2D) carbon nanosheets, which is derived from an Fe-doping zinc metal-organic framework (Zn-MOF). Importantly, using Pt/FeNC as the cathodic catalyst, the Li-CO2/O2 (VCO2/VO2 = 4:1) battery displays the lowest overpotential of 0.54 V and a long-term stability of 142 cycles, which is superior to batteries with FeNC (1.67 V, 47 cycles) and NC (1.87 V, 23 cycles) catalysts. The FeNC matrix and Pt NPs can exert a synergetic effect to decrease the decomposition potential of Li2CO3 and thus enhance the battery performance. In situ Fourier transform infrared (FTIR) spectroscopy further confirms that Li2CO3 can be completely decomposed under a low potential of 3.3 V using the Pt/FeNC catalyst. Impressively, Li2CO3 exhibits a film structure on the surface of the Pt/FeNC catalysts by scanning electron microscopy (SEM), and its size can be limited by the confined space between the carbon sheets in Pt/FeNC, which enlarges the better contacting interface. In addition, density functional theory (DFT) calculations reveal that the Pt and FeNC catalysts show a higher adsorption energy for Li2CO3 and Li2CO4 intermediates compared to the NC catalyst, and the possible discharge pathways are deeply investigated. The synergetic effect between the FeNC support and Pt active sites makes the Li-CO2/O2 battery achieve optimal performance.

Consumption of Saturated Fatty Acids-Rich Lard Benefits Recovery of Experimental Arthritis by Activating PPAR-γ.

SCOPE: This study investigates the impacts of lard and related fatty acids intake on rheumatoid arthritis (RA) animal models. METHOD AND RESULTS: Collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) are induced in SD rats and C57 BL/6 mice respectively, which are fed by lard-rich diet (LRD) for 42 days with intake restriction or not. AIA SD rats are treated by representative fatty acids for 30 days. Body weight, arthritis score, and metabolic profile are periodically recorded. Monocyte distribution, cytokine/metabolites levels, gene expression, and tissue damages are investigated by flow cytometry, ELISA, colorimetry, PCR, and histological methods. After being treated by fatty acids in vitro, THP-1 monocytes and the corresponding medium are collected for ELISA, PCR, immunoblotting, and reporter gene assays. Irrespective of intake amounts, LRD decreases inflammatory cytokines and inhibits glycolysis in all rheumatic rodents. Furthermore, it alters monocyte distribution and promotes PPAR-γ expression in AIA mice. Overall evidences show that both saturated (SF) and unsaturated fatty acids (USF) from lard can attenuate inflammation by activating PPAR-γ. Silencing PPAR-γ abrogates their anti-inflammatory effects in vitro. Besides, SF can stimulate TLR4/NF-κB pathway. CONCLUSION: Lard consumption is beneficial for active inflammatory arthritis recovery. Even SF can activate PPAR-γ and consequently attenuate inflammation.

CP-25 enhances OAT1-mediated absorption of methotrexate in synoviocytes of collagen-induced arthritis rats.

Organic anion transporter 1 (OAT1) plays a major role in mediating the absorption, distribution and excretion of drugs and other xenobiotics in the human body. In this study we explored the OAT1 status in rheumatoid arthritis (RA) patients and arthritic animals and its role in regulating the anti-arthritic activity of methotrexate (MTX). We showed that OAT1 expression was significantly downregulated in synovial tissues from RA patients compared with that in the control patients. In collagen-induced arthritis (CIA) rats, synovial OAT1 expression was significantly decreased compared with the control rats. In synoviocytes isolated from CIA rats, PGE2 (0.003-1.75 µM) dose-dependently downregulated OAT1 expression, resulting in decreased absorption of MTX. Silencing OAT1 in synoviocytes caused a 43.7% reduction in the uptake of MTX. Furthermore, knockdown of OAT1 impaired MTX-induced inhibitory effects on the viability and migration of synoviocytes isolated from CIA rats. Moreover, injection of OAT1-shRNA into articular cavity of CIA rats significantly decreased synovial OAT1 expression and impaired the anti-arthritic action of MTX, while injection of lentivirus containing OAT1 sequences led to the opposite results. Interestingly, we found that paeoniflorin-6'-O-benzene sulfonate (CP-25) upregulated OAT1 expression both in vitro and in vivo and promoted MTX uptake by synoviocytes via regulating OAT1 expression and function. Taken together, OAT1 plays a major role in regulating MTX uptake by synoviocytes and the anti-arthritic activity of MTX. OAT1 is downregulated in RA and CIA rats, which can be improved by CP-25.

Xanthones from securidaca inappendiculata antagonizes the anti-rheumatic effect of methotrexate by inhibiting reduced folate carrier 1.

BACKGROUND: The first-line anti-rheumatic drug methotrexate (MTX) is used in the combination. Because of the unpredictable adverse reactions, optimization of relevant regimens is necessary and meaningful. This study aimed to study the possible interaction between Securidaca inappendiculate Hassk. Derived xanthones and MTX. METHODS: We established adjuvant-induced arthritis (AIA) model, which was treated with MTX and MTX + xanthone-rich fraction (XRF). The clinical efficacy was evaluated by histopathological examination, and LC-MS was used to monitor the blood concentration of MTX. Western blotting and immunohistochemistry were used to detect protein expression. In vitro, we assessed the activity of related transporters by cellular uptake assay based on HEK-293T cells. RESULTS: Compared with MTX-treated rats, inflammation in the immunized rats in the MTX + XRF group was obvious, indicating that XRF antagonized the anti-rheumatic effect of MTX. Meanwhile, XRF reduced liver and kidney injuries caused by MTX in addition to MTX. Results from immunohistochemical and nappendiculat assays suggested that XRF may reduce uptake of MTX by down-regulating reduced folate carrier 1 (RFC1). CONCLUSION: This study indicated that XRF could reduce the plasma concentration of MTX by inhibiting the expression of RFC1, antagonize the therapeutic effect of MTX on AIA rats, and reduce its oral bioavailability. The combination of S. inappendiculate and MTX should be further optimized to achieve the goal of increasing efficiency and reducing toxicity.

AMPK/SIRT1 Deficiency Drives Adjuvant-Induced Arthritis in Rats by Promoting Glycolysis-Mediated Monocytes Inflammatory Polarization.

Background: Exact roles of many metabolic regulators in rheumatoid arthritis (RA) are to be clarified. This study aimed to further characterize the impacts of silent information regulator 1 (SIRT1) status changes on this disease. Methods: Fluctuation pattern of SIRT1 expression in adjuvant-induced arthritis (AIA) rats was monitored using periodically collected white blood cells. Another bath of AIA rats were treated by SIRT1 agonist resveratrol. Blood from these rats was used to separate monocytes and plasma, which were subjected to polymerase chain reaction (PCR), enzyme linked immunosorbent assay (ELISA), and biochemical analyses. Clinical implication of SIRT1 activation was verified by treating AIA rat monocytes with SIRT1 agonist and overexpression vector in vitro. Results: SIRT1 deficiency occurred in AIA rats, which was accompanied with down-regulation of interleukin 10 (IL-10) and arginase-1 (ARG-1). Resveratrol eased oxidative stress and increased IL-10 production in vivo. Results of ELISA analysis demonstrated that resveratrol attenuated AIA severity in rats. Furthermore, it restored the altered levels of triglyceride, lactate and pyruvate in blood. Resveratrol promoted IL-10 production, and suppressed glycolysis of AIA monocytes cultured in vitro. SIRT1 overexpression similarly reshaped differentiation profile of AIA monocytes, evidenced by changes in metabolism indicators, IL-10 production and AMP-activated protein kinase (AMPK) pathway status. Although overexpressing SIRT1 in normal cells did not affect glycolysis significantly, it attenuated AMPK antagonist-caused abnormality. Conclusion: SIRT1 deficiency is implicated in AIA-related immune abnormality and metabolism alteration. Activating this signaling with resveratrol would impair the inflammatory polarization of monocytes, and consequently ease the severity of RA.

Glycolysis aggravates methotrexate toxicity by fueling RFC1-controlled intestinal absorption in rheumatic rats.

Methotrexate (MTX) is a first line anti-rheumatic drug. This study was designed to investigate the impact of rheumatoid arthritis (RA) conditions on its oral absorption, and clarify the relevance with changes of MTX absorption-related transporters in rheumatic models. MTX was orally administered to healthy, collagen-induced arthritis (CIA), and adjuvant-induced arthritis (AIA) rats. MTX plasma concentrations were determined by a validated liquid chromatography-mass spectrometry method. We found that intestinal MTX absorption was significantly increased in CIA/AIA rats versus healthy controls. This finding was supported by small intestine-based MTX uptake assay in vitro. Meanwhile, intestinal expression of both reduced folate carrier 1 (RCF1) and proton-coupled folate transporter (PCFT) remained unchanged. The everted intestinal sac assay confirms RFC1 is the key transporter accounting for intestinal MTX absorption, as its antagonist salicylazosulfapyridine showed potent capacity in reducing MTX uptake. No correlation between RA-related cytokines and RCF1 expression was observed in clinical samples. We further revealed that when cultured with AIA rat or RA patient serum, lactate and adenosine triphosphate (ATP) production as well as MTX uptake in MDCKII cells were significantly increased, and this increase was completely abrogated by ATP production-related metabolic inhibitors. Thanks to its inhibitory effects on MTX bioavailability, the glycolysis inhibitor shikonin diminished MTX-induced injuries of kidney and liver in AIA rats. These data demonstrate that glycolysis-driven high energy metabolism increases MTX absorption in rheumatic subjects, leading to the exacerbated toxicity. These findings will have important implications in optimizing MTX regimens for RA treatment with better efficacy and lower toxicity.

Research progress of clinical intervention and nursing for patients with post-stroke dysphagia.

Post-stroke dysphagia (PSD) is a common and costly complication of stroke and is associated with increased mortality, morbidity, and hospitalization. Although most patients can spontaneously resume swallowing, there are still many patients who do not recover and even die. Despite multiple advances in the acute treatment and secondary prevention of stroke, the effective treatment of PSD remains a neglected area. Studies have shown that repair mechanisms of neurostimulation techniques and increased cortical activity play an important role in the treatment of PSD. In addition, nutritional interventions are also crucial for the treatment of malnutrition in PSD patients. Therefore, this article reviews the effects of the current main clinical treatment methods and nutritional interventions on the treatment and rehabilitation of PSD patients. It also emphasized the necessity of developing an individualized care plan for PSD patients, which is of great significance to promote the clinical treatment, nutritional status, prognosis, and quality of life of PSD patients.

Xiaoyao-Qingluoyin Cure Adjuvant-Induced Arthritis by Easing LPS Response-Related Pathway-Mediated Immune Abnormality.

Qingluoyin (QLY) is a representative herbal formula prescribed for hot symptom-related rheumatoid arthritis treatment. Among its derivatives, Xiaoyao-Qingluoyin (XYQLY) attracts increasing attention due to the notable clinical efficacy. In this study, we compared its effects with QLY on adjuvant-induced arthritis (AIA) in rats and partially elucidated the antirheumatic mechanism using a network pharmacology-based strategy. After continuous oral treatments, clinical outcomes were systematically evaluated by radiographic, histological, immunohistochemical, and serological analyses. Possibly altered pathways were predicted based on reported interactions between the related chemicals and proteins/genes. The obtained conclusion was further validated by experiments in vitro. QLY and XYQLY eased polyarthritis in AIA rats after repeated doses, which reflected in reduced inflammation and bone degradation and downregulated p-p65, MMP3, and TLR4 expressions in joints. Meanwhile, they restored oxidative stress (MDA, SOD, GSH, T-AOC, and NO) and inflammatory indicators (TNF-α and CO) in serum. Synovium-based immunoblotting assay revealed that QLY and XYQLY were similarly effective in downregulating MMP3 and COX-2, but XYQLY treatment exhibited notable merit in suppressing p-p65 expression. Network pharmacology analysis hinted that XYQLY should exert greater impacts on LPS signaling and the downstream. Based on results from LC-MS analysis, we treated AIA rat-derived peripheral blood mononuclear cells with either QLY or XYQLY-based chemical combinations and confirmed that XYQLY had the better potential in inhibiting TLR4/NF-κB-controlled IL-6 production. Consequently, it led to a more profound decrease in Th17 cells counts. Overall evidence demonstrated that XYQLY was especially effective in regulating innate immunity and, therefore, improved immune environment in AIA rats as a whole.

α-Mangostin Treats Early-Stage Adjuvant-Induced Arthritis of Rat by Regulating the CAP-SIRT1 Pathway in Macrophages.

BACKGROUND: Studies have found that α-mangostin (MG) can relieve experimental arthritis by activating cholinergic anti-inflammatory pathway (CAP). It affects the polarization of macrophages and the balance of related immune cell subpopulations, but the specific mechanism is still unclear. It has been found that silent information regulator 1 (SIRT1) is closely related to macrophage activity. The purpose of this study is to explore the mechanism of MG intervening in macrophage polarization during treatment of early adjuvant-induced (AIA) rats through the CAP-SIRT1 pathway. METHODS: We investigated the polarization of M1 macrophages and the differentiation of Th1 in AIA rats by flow cytometry. Activity of acetylcholinesterase (AChE) and the level of nicotinic adenine dinucleotide (NAD+) in serum were also detected, and immunohistochemical was used to detect the levels of α7 nicotinic cholinergic receptor (α7nAChR) and SIRT1. Then in macrophages, the molecular mechanism of MG regulating the abnormal activation of macrophages in rats with early AIA through the CAP-SIRT1 pathway was studied. RESULTS: MG can significantly inhibit the polarization of M1 macrophages and the differentiation of Th1 in AIA rats in the acute phase of inflammation. MG can significantly inhibit the activity of AChE and increase the level of NAD+, thereby further up-regulated the expression levels of α7nAChR and SIRT1. Meanwhile, MG inhibited nuclear factor-κB (NF-κB)-mediated inflammation by activating the CAP-SIRT1 pathway in macrophages. CONCLUSION: In summary, the stimulation of MG induced CAP activation, which up-regulated SIRT1 signal, and thereby inhibited M1 polarization through the NF-κB pathway, and improved the pathological immune environment of early-stage AIA rats.

The Effect of α7nAChR Signaling on T Cells and Macrophages and Their Clinical Implication in the Treatment of Rheumatic Diseases.

Rheumatoid arthritis (RA) is one of the most common autoimmune disease and until now, the etiology and pathogenesis of RA is not fully understood, although dysregulation of immune cells is one of the leading cause of RA-related pathological changes. Based on current understanding, the priority of anti-rheumatic treatments is to restore immune homeostasis. There are several anti-rheumatic drugs with immunomodulatory effects available nowadays, but most of them have obvious safety or efficacy shortcomings. Therefore, the development of novel anti-rheumatic drugs is still in urgently needed. Cholinergic anti-inflammatory pathway (CAP) has been identified as an important aspect of the so-called neuro-immune regulation feedback, and the interaction between acetylcholine and alpha 7 nicotinic acetylcholine receptor (α7nAChR) serves as the foundation for this signaling. Consistent to its immunomodulatory functions, α7nAChR is extensively expressed by immune cells. Accordingly, CAP activation greatly affects the differentiation and function of α7nAChR-expressing immune cells. As a result, targeting α7nAChR will bring profound therapeutic impacts on the treatment of inflammatory diseases like RA. RA is widely recognized as a CD4+ T cells-driven disease. As a major component of innate immunity, macrophages also significantly contribute to RA-related immune abnormalities. Theoretically, manipulation of CAP in immune cells is a feasible way to treat RA. In this review, we summarized the roles of different T cells and macrophages subsets in the occurrence and progression of RA, and highlighted the immune consequences of CAP activation in these cells under RA circumstances. The in-depth discussion is supposed to inspire the development of novel cell-specific CAP-targeting anti-rheumatic regimens.

Evolution of Cationic Vacancy Defects: A Motif for Surface Restructuration of OER Precatalyst.

Defects have been found to enhance the electrocatalytic performance of NiFe-LDH for oxygen evolution reaction (OER). Nevertheless, their specific configuration and the role played in regulating the surface reconstruction of electrocatalysts remain ambiguous. Herein, cationic vacancy defects are generated via aprotic-solvent-solvation-induced leaking of metal cations from NiFe-LDH nanosheets. DFT calculation and in situ Raman spectroscopic observation both reveal that the as-generated cationic vacancy defects tend to exist as VM (M=Ni/Fe); under increasing applied voltage, they tend to assume the configuration VMOH , and eventually transform into VMOH-H which is the most active yet most difficult to form thermodynamically. Meanwhile, with increasing voltage the surface crystalline Ni(OH)x in the NiFe-LDH is gradually converted into disordered status; under sufficiently high voltage when oxygen bubbles start to evolve, local NiOOH species become appearing, which is the residual product from the formation of vacancy VMOH-H . Thus, we demonstrate that the cationic defects evolve along with increasing applied voltage (VM → VMOH → VMOH-H ), and reveal the essential motif for the surface restructuration process of NiFe-LDH (crystalline Ni(OH)x → disordered Ni(OH)x → NiOOH). Our work provides insight into defect-induced surface restructuration behaviors of NiFe-LDH as a typical precatalyst for efficient OER electrocatalysis.

Regulation of Sirt1 on energy metabolism and immune response in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease. Synovial hyperplasia and persistent inflammation serve as its typical pathological manifestations, which ultimately lead to joint destruction and function loss. Both clinical observations and metabolomics studies have revealed the prevalence of metabolic disorders in RA. In inflammatory immune microenvironments, energy metabolism is profoundly changed. Increasingly evidences suggest that this abnormality is involved in the occurrence and development of RA-related inflammation. Unsurprisingly, many energy metabolism sensors have been confirmed with immunoregulatory properties. As a representative, silent information regulator type 1 (Sirt1) controls many aspects of immune cells, such as cell lifespan, polarization, and secretion by functioning as a transcriptional regulator. Because of the profound clinical implication, researches on Sirt1 in the regulation of energy metabolism and immune functions under RA conditions have gradually gained momentum. This signaling balances glycolysis, lipid metabolism and insulin secretion orchestrating with other metabolism sensors, and consequently affects immune milieu through a so-called metabolism-immune feedback mechanism. This article reviews the involvement of Sirt1 in RA by discussing its impacts on energy metabolism and immune functions, and specially highlights the potential of Sirt1-targeting anti-rheumatic regimens. It also provides a theoretical basis for clarifying the mystery about the high incidence of metabolic complications in RA patients and identifying new anti-rheumatic reagents.

The Role of α7nAChR-Mediated Cholinergic Anti-inflammatory Pathway in Immune Cells.

Alpha 7 nicotinic acetylcholine receptor (α7nAChR) is widely distributed in the nervous and non-cholinergic immune systems. It is necessary for the cholinergic transmitter to participate in the regulation of inflammatory response and is the key element of cholinergic anti-inflammatory pathway (CAP). Because of the profound impact of CAP on the immune system, α7nAChR is considered as a potential therapeutic target for the treatment of inflammatory diseases. Available evidences confirmed that manipulation of CAP by activating α7nAChR with either endogenous acetylcholine (ACh) or cholinergic agonists can substantially alleviate inflammatory responses both in vivo and in vitro. However, the mechanism through which CAP curbs the excessive pro-inflammatory responses and maintains immune homeostasis is not fully understood. Obtained clues suggest that the crosstalk between CAP and classical inflammatory pathways is the key to elucidate the anti-inflammatory mechanism, and the impacts of CAP activation in α7nAChR-expressing immune cells are the foundation of the immunoregulatory property. In this article, we review and update the knowledge concerning the progresses of α7nAChR-based CAP, including α7nAChR properties, signal transductions, interactions with classic immune pathways, and immunoregulatory functions in different immune cells. Certain critical issues to be addressed are also highlighted. By providing a panoramic view of α7nAChR, the summarized evidences will pave the way for the development of novel anti-inflammatory reagents and strategy and inspire further researches.

Metabolic Enzyme Triosephosphate Isomerase 1 and Nicotinamide Phosphoribosyltransferase, Two Independent Inflammatory Indicators in Rheumatoid Arthritis: Evidences From Collagen-Induced Arthritis and Clinical Samples.

Metabolic intervention is a novel anti-rheumatic approach. The glycolytic regulator NAMPT has been identified as a therapeutic target of rheumatoid arthritis (RA), while other metabolic regulators coordinating NAMPT to perpetuate inflammation are yet to be investigated. We continuously monitored and validated expression changes of Nampt and inflammatory indicators in peripheral while blood cells from rats with collagen-induced arthritis (CIA). Gene transcriptional profiles of Nampt+ and Nampt++ samples from identical CIA rats were compared by RNA-sequencing. Observed gene expression changes were validated in another batch of CIA rats, and typical metabolic regulators with persistent changes during inflammatory courses were further investigated in human subjects. According to expression differences of identified genes, RA patients were assigned into different subsets. Clinical manifestation and cytokine profiles among them were compared afterwards. Nampt overexpression typically occurred in CIA rats during early stages, when iNos and Il-1ß started to be up-regulated. Among differentially expressed genes between Nampt+ and Nampt++ CIA rat samples, changes of Tpi1, the only glycolytic enzyme identified were sustained in the aftermath of acute inflammation. Similar to NAMPT, TPI1 expression in RA patients was higher than general population, which was synchronized with increase in RFn as well as inflammatory monocytes-related cytokines like Eotaxin. Meanwhile, RANTES levels were relatively low when NAMPT and TPI1 were overexpressed. Reciprocal interactions between TPI1 and HIF-1α were observed. HIF-1α promoted TPI1 expression, while TPI1 co-localized with HIF-1α in nucleus of inflammatory monocytes. In short, although NAMPT and TPI1 dominate different stages of CIA, they similarly provoke monocyte-mediated inflammation.

Xanthones from Securidaca inappendiculata antagonized the antirheumatic effects of methotrexate in vivo by promoting its secretion into urine.

BACKGROUND: This study was designed to characterize the interaction between Securidaca inappendiculata Hassk. derived xanthones and methotrexate (MTX). METHODS: Collagen-induced arthritis (CIA) was induced in rats, which were treated with MTX, a xanthone-rich fraction (XRF), or MTX+XRF by gavage for 30 days. Clinical efficacy was assessed based on arthritis scores, serological analysis, and histological examination. Protein expression was investigated by either immunohistochemical or immunoblotting methods. MTX concentrations were determined by HPLC or LC-MS methods. Obtained results were further validated by in vitro assays using 1,7-dihydroxy-3,4-dimethoxyxanthone and HEK 293 T cells. RESULTS: XRF antagonized the antirheumatic effects of MTX in vivo, suggested by higher levels of proinflammatory cytokines, and severer swelling and deformation of joints in CIA rats in the MTX+XRF group compared with MTX monotherapy. XRF reduced MTX concentration in plasma and promoted its excretion into urine. As a result, XRF attenuated MTX-induced edema of the proximal tubule. Furthermore, XRF restored the decreased expression of organic anion transporter three (OAT3), which accounts for MTX secretion in the kidney. Consistently, 1,7-dihydroxy-3,4-dimethoxyxanthone promoted the cellular intake of MTX by increasing OTA3 expression. CONCLUSION: It is suggested that the combined use of S. inappendulata with MTX should be optimized to avoid the antagonistic effects and improve the safety of the MTX regimen.

Activation of Cholinergic Anti-Inflammatory Pathway in Peripheral Immune Cells Involved in Therapeutic Actions of α-Mangostin on Collagen-Induced Arthritis in Rats.

BACKGROUND: Studies have shown that α-mangostin (MG) could exert anti-rheumatic effects in vivo by restoring immunity homeostasis, and have indicated that activation of the choline anti-inflammatory pathway (CAP) may contribute to this immunomodulatory property. The current study was designed to further investigate the effects of MG on the CAP in peripheral immune cells and clarify its relevance to the potential anti-rheumatic actions. METHODS: The catalytic activity of acetylcholinesterase (AChE) and expression of α7-nicotinic cholinergic receptor (α7nAChR) in peripheral blood mononuclear cells (PBMCs) from rats with collagen-induced arthritis (CIA) or human volunteers were evaluated after MG treatment. Consequent influences on the immune environment were assessed by flow cytometry and ELISA analyses. Indirect effects on joints resulting from these immune changes were studied in a co-culture system comprised of fibroblast-like synoviocytes (FLSs) and PBMCs. RESULTS: MG promoted α7nAChR expression in PBMCs both in vivo and in vitro, and inhibited the enzymatic activity of AChE simultaneously. Activation of the CAP was accompanied by a significant decrease in Th17 cells (CD4+IL-17A+), while no obvious changes concerning the distribution of other T-cell subsets were noticed upon MG treatment. Meanwhile, MG decreased the secretion of TNF-α and IL-1ß under inflammatory conditions. PBMCs from MG-treated CIA rats lost the potential to stimulate NF-κB activation and pro-inflammatory cytokine production of FLSs in the co-culture system. CONCLUSION: Overall, the evidence suggested that MG can improve the peripheral immune milieu in CIA rats by suppressing Th17-cell differentiation through CAP activation, and achieve remission of inflammation mediated by FLSs.