Anti-rheumatoid Arthritis Effects Research Articles

Uncovering the mechanisms of Zhubi decoction against rheumatoid arthritis through an integrated study of network pharmacology, metabolomics, and intestinal flora

Ethnopharmacological relevanceZhubi Decoction (ZBD) is a modified formulation derived from the classic traditional Chinese medicine prescription “Er-Xian Decoction” documented in the esteemed “Clinical Manual of Chinese Medical Prescription”. While the utilization of ZBD has exhibited promising clinical outcomes in treating rheumatoid arthritis (RA), the precise bioactive chemical constituents and the underlying mechanisms involved in its therapeutic efficacy remain to be comprehensively determined. Aim of the studyThis study aims to systematically examine ZBD's pharmacological effects and molecular mechanisms for RA alleviation. Materials and methodsUtilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of ZBD in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. The UPLC-MS/MS technique was utilized to analyze the compounds of ZBD. The potential therapeutic targets and signaling pathways of ZBD in the management of RA were predicted using network pharmacology. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. Key targets and predicted pathways were further validated using immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16 S rDNA sequencing and investigated the effects of ZBD on the microbiota of CIA rats through bioinformatics and statistical methods. ResultsZBD exhibited remarkable efficacy in alleviating RA symptoms in CIA rats without notable side effects. This included reduced paw redness and swelling, minimized joint damage, improved the histopathology of cartilage and synovium, mitigated the inflammatory state, and lowered serum concentrations of cytokines TNF-α, IL-1β and IL-6. Notably, the effectiveness of ZBD was comparable to MTX. Network pharmacology analysis revealed inflammation and immunity-related signaling pathways, such as PI3K/AKT, MAPK, IL-17, and TNF signaling pathways, as vital mediators in the effectual mechanisms of ZBD. Immunofluorescence analysis validated ZBD's ability to inhibit PI3K/AKT pathway proteins. Serum metabolomics studies revealed that ZBD modulates 170 differential metabolites, partially restored disrupted metabolic profiles in CIA rats. With a notable impact on amino acids and their metabolites, and lipids and lipid-like molecules. Integrated analysis of metabolomics and network pharmacology identified 6 pivotal metabolite pathways and 3 crucial targets: PTGS2, GSTP1, and ALDH2. Additionally, 16 S rDNA sequencing illuminated that ZBD mitigated gut microbiota dysbiosis in the CIA group, highlighting key genera such as Ligilactobacillus, Prevotella_9, unclassified_Bacilli, and unclassified_rumen_bacterium_JW32. Correlation analysis disclosed a significant link between 47 distinct metabolites and specific bacterial species. ConclusionZBD is a safe and efficacious TCM formulation, demonstrates efficacy in treating RA through its multi-component, multi-target, and multi-pathway mechanisms. The regulation of inflammation and immunity-related signaling pathways constitutes a crucial mechanism of ZBD's efficacy. Furthermore, ZBD modulates host metabolism and intestinal flora. The integrated analysis presents experimental evidence of ZBD for the management of RA.

Combining network pharmacology, molecular docking, and experimental verification to investigate the anti-rheumatoid arthritis effect and mechanism of Baeckea frutescens leaves

Combining network pharmacology, molecular docking, and experimental verification to investigate the anti-rheumatoid arthritis effect and mechanism of <em>Baeckea frutescens</em> leaves

Chinese medicine Di-long (Pheretima vulgaris) and its active fraction exhibit anti-rheumatoid arthritis effects by inhibiting CXCL10/CXCR3 chemotaxis in synovium

Ethnopharmacological relevanceDi-Long (Pheretima vulgaris) is a classic animal sourced traditional Chinese medicine. It has been used for the treatment of joint inflammation and arthralgia for over two thousand years due to its effects of Tong-Luo-Zhi-Tong (dredging collaterals and alleviating pain). Our previous study showed that Chinese medicine Di-Long has significant anti-rheumatoid arthritis (RA) effects. Aim of the studyConsidering Di-Long as a potential source of active compounds with specific anti-RA therapeutic effects, this research was to obtain the anti-RA target-specific active fraction from Di-Long extracts (DL), and to further explore the chemical basis and verify the anti-RA mechanism of this active fraction. Materials and methodsTranscriptomic was applied to obtain the main anti-RA targets of DL on human RA fibroblast-like synoviocytes (FLS) and validated by qPCR. The target-corresponding active fraction was isolated from DL by ethanol precipitation and gel chromatography, and analyzed by nanoliter chromatography-mass spectrometry. Anti-RA effects of this active fraction was investigated by collagen-induced arthritis (CIA) in mice, and anti-RA mechanisms were verified in cocultured model of rat FLS and peripheral blood lymphocytes. ResultsWe confirmed that CXCL10/CXCR3 was the main anti-RA target of DL. The active fraction - A (2182 - 890 Da) was isolated from DL based on its CXCL10 inhibiting effects in RA-FLS. Fraction A contains 195 peptides (192 were newly discovered), 26 of which might be bioactive and were considered to be the chemical basis of its anti-RA effects. Fraction A significantly ameliorated the joint destruction and overall inflammation in CIA mice, and downregulated CXCR3 expression in mice joint. Fraction A inhibited the chemotaxis of Th-cells in rat peripheral blood lymphocytes towards the TNF-α-induced rat FLS through CXCL10/CXCR3 pathway. ConclusionsOur work indicated that active fraction from DL containing small peptides exhibits promising therapeutic effects for RA through inhibiting CXCL10/CXCR3 chemotaxis.

Anti-rheumatoid arthritis effects of traditional Chinese medicine Fufang Xiaohuoluo pill on collagen-induced arthritis rats and MH7A cells.

Fufang Xiaohuoluo pill (FFXHL) is a commonly used prescription in clinical practice for treating rheumatoid arthritis in China, yet its specific mechanism remains unclear. This study aims to elucidate the pharmacological mechanisms of FFXHL using both in vivo and in vitro experiments. The collagen-induced arthritis (CIA) rat model was established to evaluate FFXHL's therapeutic impact. Parameters that include paw swelling, arthritis scores, and inflammatory markers were examined to assess the anti-inflammatory and analgesic effects of FFXHL. Human fibroblast-like synoviocytes (MH7A cells) is activated by tumour necrosis factor-alpha (TNF-α) were used to explore the anti-inflammatory mechanism on FFXHL. Our findings indicate that FFXHL effectively reduced paw swelling, joint pain, arthritis scores, and synovial pannus hyperplasia. It also lowered serum levels of TNF-α, interleukin-1β (IL1β), and interleukin-6 (IL-6). Immunohistochemical analysis revealed decreased expression of nuclear factor-kappa B (NF-κB) p65 in FFXHL-treated CIA rat joints. In vitro experiments demonstrated FFXHL's ability to decrease protein secretion of IL-1β and IL-6, suppress mRNA expression of matrix metalloproteinases (MMP) -3, -9, and -13, reduce reactive oxygen species (ROS) levels, and inhibit NF-κB p65 translocation in TNF-α stimulated MH7Acells. FFXHL also suppressed protein levels of extracellular signal-regulated kinase (ERK), c-Jun Nterminal kinase (JNK), p38 MAP kinase (p38), protein kinase B (Akt), p65, inhibitor of kappa B kinase α/β (IKKα/β), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) induced by TNF-α in MH7A cells. The findings imply that FFXHL exhibits significant anti-inflammatory and antiarthritic effects in both CIA rat models and TNF-α-induced MH7A cells. The potential mechanism involves the inactivation of TLR4/MyD88, mitogen-activated protein kinases (MAPKs), NF-κB, and Akt pathways by FFXHL.

Biomimetic nanoparticles for effective Celastrol delivery to targeted treatment of rheumatoid arthritis through the ROS-NF-κB inflammasome axis

Previous study has indicated that Celastrol (Cel) has various physiological and pharmacological effects, including antibacterial, antioxidant, pro-apoptotic, anticancer and anti-rheumatoid arthritis (RA) effects. However, low water solubility, low oral bioavailability, narrow treatment window, and high incidence of systemic adverse reactions still limit the further clinical application of Cel. Here, aiming at effectively overcome those shortcomings of Cel to boost its beneficial effects for treating RA, we developed the leukosome (LEUKO) coated biomimetic nanoparticles (NPs) for the targeted delivery of Cel to arthritis injury area in RA. LEUKO were synthesized using membrane proteins purified from activated J774 macrophage. LEUKO and Cel-loaded LEUKO (Cel@LEUKO) were characterized using dynamic light scattering and transmission electron microscopy. Our results demonstrated that Cel@LEUKO can inhibit the inflammatory response of lipopolysaccharide (LPS) induced mouse monocyte macrophage leukemia cells (RAW264.7 cells) and human rheumatoid arthritis synovial fibroblasts (MH7A) cells through the inhibition of reactive oxygen species (ROS)-NF-κB pathway. In addition, research has shown that LEUKO effectively targets and transports Cel to the inflammatory site of RA, increased drug concentration in affected areas, reduced systemic toxicity of Cel, and reduced clinical symptoms, inflammatory infiltration, bone erosion, and serum inflammatory factors in collagen-induced arthritis (CIA) rats.

Anti-rheumatoid arthritis potential of Halodule pinifolia: development, characterization and in vivo evaluation of H. pinifolia-based oral suspension and lipid nano-emulsion.

For treating chronic diseases like rheumatoid arthritis, herbal medicines are preferred due to their evident therapeutic effects and lesser side effects as compared to the long-term used conventional drugs. In this study, the anti-rheumatoid arthritis effect of an unexplored marine grass Halodule pinifolia (HP), and a combination of it with Glycyrrhiza glabra (liquorice; LQ), prepared as a conventional suspension (C1) and a lipid nano-emulsion (C1-N) was evaluated in Freund's complete adjuvant (FCA)- and collagen-induced arthritis (CIA) models. Formulations C1 and C1-N contained standardized extract HP (100mg/kg) as major active ingredient and liquorice LQ (50mg/kg) as both active ingredient (anti-inflammatory and anti-ulcer) and sweetening agent. Oral administration of HP and C1 to FCA-induced Sprague-Dawley rats significantly reduced the paw oedema, spleen index, controlled the haematological parameters, cytokine levels (IL-1β, IL-6, TNF-α estimated by ELISA), mRNA expression of cytokines and osteoclast markers (RANK, TRAP and cathepsin K measured by RTPCR). Histopathology and radiological scanning demonstrated lesser joint deterioration in sample-treated rats, as evident phenotypically. The downregulation of CD51 and MMP-3 (western blot) corroborated the anti-arthritic effect of HP and C1. HP showed better results among all. Further, under the CIA model, both C1 and C1-N were found to be potentially active as evidenced by their effect on rat paw oedema, spleen index, haematological parameters, rheumatoid factor, cytokines, osteoclast markers, histology and X-rays. The results proved the anti-arthritic effect of HP and the formulations, particularly the lipid nano-emulsion that showed improved stability as well as activity.

Cayratia albifolia C.L.Li exerts anti-rheumatoid arthritis effect by inhibiting macrophage activation and neutrophil extracellular traps (NETs)

BackgroundCayratia albifolia C.L.Li (CAC), commonly known as “Jiao-Mei-Gu” in China, has been extensively utilized by the Dong minority for several millennia to effectively alleviate symptoms associated with autoimmune diseases. CAC extract is believed to possess significant anti-inflammatory properties within the context of Dong medicine. However, an in-depth understanding of the specific pharmaceutical effects and underlying mechanisms through which CAC extract acts against rheumatoid arthritis (RA) has yet to be established.MethodsTwenty-four Sprague–Dawley rats were divided into four groups, with six rats in each group. To induce the collagen-induced arthritis (CIA) model, the rats underwent a process of double immunization with collagen and adjuvant. CAC extract (100 mg/kg) was orally administered to rats. The anti-RA effects were evaluated in CIA rats by arthritis score, hind paw volume and histopathology analysis. Pull-down assay was conducted to identify the potential targets of CAC extract from RAW264.7 macrophage lysates. Moreover, mechanism studies of CAC extract were performed by immunofluorescence assays, real-time PCR and Western blot.ResultsCAC extract was found to obviously down-regulate hind paw volume of CIA rats, with diminished inflammation response and damage. 177 targets were identified from CAC extract by MS-based pull-down assay. Bioinformatics analysis found that these targets were mainly enriched in macrophage activation and neutrophils extracellular traps (NETs). Additionally, we reported that CAC extract owned significant anti-inflammatory activity by regulating PI3K-Akt-mTOR signal pathway, and inhibited NETosis in response to PMA.ConclusionsWe clarified that CAC extract significantly attenuated RA by inactivating macrophage and reducing NETosis via a multi-targets regulation.Graphical

Abelmoschus manihot (L.) medik. seeds alleviate rheumatoid arthritis by modulating JAK2/STAT3 signaling pathway

Ethnopharmacological relevanceAbelmoschus manihot (L.) Medik. Seeds (AMS, སོ་མ་ར་ཛ།), a Tibetan classical herbal in China, are rich in flavonoids and phenolic glycosides compounds, such as quercetin and its derivatives. Moreover, it has been found to possess anti-rheumatoid arthritis (RA) effects. Nonetheless, its anti-RA mechanism is yet unknown. Aim of the studyThis research aimed to examine the active ingredients of AMS as well as potential pharmacological mechanisms in AMS on RA. Materials and methodsThe ultra-performance liquid chromatography-electrospray ionization-tandem multistage mass spectrometry (UPLC-ESI-IT-MSn) technique was used to determine the primary chemical components of AMS that were responsible for the therapeutic effects on RA. In addition, 36 male Wistar rats weighing between 200 and 220 g were classified at random into six groups [normal control group, collagen-induced arthritis (CIA) group, methotrexate group (positive control, 1.05 mg/kg), AMS group (157.5 mg/kg, 315 mg/kg, 630 mg/kg)]. CIA rats were given AMS extract by intragastric administration for 28 days, and their ankles were photographed to observe the degree of swelling. Further, the arthritis score, paws swelling, and body weight changes of CIA rats were determined to observe whether AMS has any effect on RA, and synovial and cartilage tissue injuries were identified by histopathology. Besides, the levels of IL-10, TNF-α, IL-1β, INF-γ, etc. in serum were estimated by ELISA. Western blot experiments were implemented to identify the expression levels of protein involved in the JAK2/STAT3 signaling pathway in the CIA rats’ synovial tissues. Moreover, the mechanisms and targets of active ingredient therapy of AMS for RA were predicted using network pharmacology and then verified using molecular docking. ResultIn the present study, 12 compounds were detected by UPLC-ESI-IT-MSn, such as quercetin and its derivative which could be potential active ingredients that contribute to the anti-RA properties of AMS. Our in vivo studies on CIA rats revealed that an AMS-H dose of 630 mg/kg significantly improved joint damage while decreasing the arthritic index and paw swelling. Furthermore, AMS inhibited the INF-γ, IL-6, IL-17, IL-1β, and TNF-α, levels while upregulating the expression of anti-inflammatory cytokines IL-10 and IL-4 in serum. Besides, AMS inhibited the protein Bcl-2/Bax, STAT3, and JAK2 levels, and promoted the expression of Caspase3, SOCS1, and SOCS3 in the JAK2/STAT3 pathway. Additionally, the JAK/STAT signaling pathway was found to perform a remarkable function in the AMS therapy of RA as evidenced by enrichment in GO terms and KEGG pathways. Meanwhile, data from molecular docking experiments indicated that the core targets of PIK3CA, JAK2, and SRC bound stably to the active ingredients of mimuone, 4′-methoxy-bavachromanol, and quercetin. ConclusionAccording to these findings, the AMS could improve joint inflammation in CIA rats, and its underlying mechanism could be linked to the regulation of the JAK2/STAT3 pathway. Therefore, AMS might become a promising agent for alleviating inflammation in RA patients.

Plants Used in the Treatment of Rheumatoid Arthritis

Chronic, persistent and incapacitating autoimmune ailments known as Rheumatoid Arthritis (RA) are marked by cartilage and bone damage surrounding the joints as well as systemic inflammation of the joints. The fact that 75% of RA patients are female points to the significance of hormones in the etiology of the condition. Synovial membrane inflammation involves mechanisms in the form of genetic, environmental, including immunologic variables that are believed to have a role in its pathogenic mechanism. When it comes to treating RA, the focus has shifted from relieving symptoms to implementing therapeutic regimens that affect the disease’s activity and eventually have been found to halt or stop structural joint destruction. Salicylates, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), corticosteroids, and Disease Modifying Anti-Rheumatic Drugs (DMARDs), Methotrexate (MTX), as well as biologic response enhancers, are some examples of drugs. However, it has negative effects which need to be overcome. It is required to employ herbs and a variety of plants to treat joint pain and inflammation. There are numerous plants with medicinal properties that have been clinically demonstrated to have anti-rheumatoid arthritis effects. As a result, plants and their derivatives with significant benefits are being used for the management of rheumatoid arthritis. The current assessment focuses on medicinal plants that have anti-rheumatoid arthritis efficacy.

Pharmacokinetics, anti-rheumatoid arthritis activity, and active ingredient contents of Eucommia ulmoides Oliv

Eucommia ulmoides Oliv. is a deciduous tree which contains various chemical ingredients. The main objective was to document the active chemical ingredients of Eucommia ulmoides Oliv. and their metabolic profiles in vivo, with a view to providing an experimental and theoretical basis for clarifying the mechanisms underlying the pharmacological activity of Eucommia ulmoides Oliv. against rheumatoid arthritis. Eight main active constituents of Eucommia ulmoides Oliv. bark (pinoresinol glucopyranoside, aucubin, geniposidic acid, geniposide, genipin, chlorogenic acid, quercetin and betulinic acid) were quantified using high-performance liquid chromatography (HPLC). This paper additionally identified and characterized prototype metabolites via ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with the Human Metabolome Database (HMDB) and literature comparisons. Ultra pressure liquid chromatography-mass spectrometry/ mass spectrometry (UPLC-MS/MS) was subsequently employed to quantify these components in blood over time and evaluate their pharmacokinetic characteristics. The anti-rheumatoid arthritis effects of genipin, pinoresinol glucopyranoside and their combinations were assessed using in vitro cellular assays. We identified and characterized a total of 53 ingredients from Eucommia ulmoides Oliv. bark and plasma samples, among which 20 were confirmed as prototype metabolites. Meanwhile, this paper derived and analyzed the metabolic cleavage pathway of 8 index ingredients. Six of these compounds displayed rapid entry into blood, with high plasma exposure and fast elimination rates. Data from the in vitro cellular assay showed that aucubin, pinoresinol glucopyranoside, genipin, and combinations of these compounds effectively inhibit MH7A cell proliferation, reduce NO release, and decrease inflammatory factor levels.

Anti-rheumatoid arthritis effects of total saponins from Rhizoma Panacis Majoris on adjuvant-induced arthritis in rats and rheumatoid arthritis fibroblast-like synoviocytes

BackgroundTotal saponins from Rhizoma Panacis Majoris (RPMTG) showed significant antitumour activity in our previous studies. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) with tumour-like characteristics have received attention as a therapeutic target for RA. However, the potential effect and mechanism of action of RPMTG against RA-FLS remain unclear. ObjectiveThe study investigated the therapeutic effect of RPMTG on adjuvant-induced arthritis (AIA) in rats, and the regulation effect and underlying mechanism on apoptosis, autophagy of RA-FLS. MethodsThe therapeutic effect of RPMTG was determined by the symptoms and signs of AIA rats. The production of inflammatory cytokines was detected by ELISA. Histopathological change of the ankle and synovial tissues were detected by HE staining. Flow cytometry, Hoechst 33342/PI staining, MDC staining, and TEM were used to determine the effects of RPMTG on apoptosis and autophagy. Western blotting was applied to detect the expression levels of proteins. ResultsIn AIA rats, RPMTG treatment ameliorated paw swelling, and arthritis score, restored synovial histopathological changes, inhibited the expression of IL-6 and IL-1β, exhibiting its potent anti-arthritis effect. In vitro, RPMTG depressed the proliferation of RA-FLS, arrested cell cycle in G0/G1 phase, and induced mitochondria-mediated apoptosis. Moreover, RPMTG significantly inhibited the autophagy in vivo and in vitro, proved by decreasing the expression of autophagy-related indicators (LC3II/LC3I, Beclin-1). Mechanistically, the study demonstrated that the activation of p38 MAPK and PI3K/Akt/mTOR pathways was mainly involved in the therapeutic effects of RPMTG. Interestingly, the effect of RPMTG on apoptosis was reversed after Rapamycin treatment, which preliminarily demonstrated that the inhibitory effect of RPMTG on autophagy was beneficial to the effect on inducing apoptosis. The regulation effect of RPMTG concurrently on apoptosis and autophagy revealed its unique advantages in RA treatment. ConclusionRPMTG showed potent therapeutic effects on AIA rats and induced apoptosis, inhibited autophagy mainly through activating the p38 MAPK and PI3K/Akt/mTOR pathways in RA-FLS.

Triptolide nanoemulsion gel as a transdermal drug delivery system: preparation, pharmacokinetics, and rheumatoid arthritis evaluation.

This study aimed to develop and evaluate triptolide nanoemulsion gels (TP-NE gels) as a transdermal drug delivery system. TP-NE was prepared and optimized via emulsification and the central composite design response surface method. The optimized TP-NE gel was evaluated in vitro and in vivo. TP-NE gel microstructure, in vitro and in vivo pharmacokinetics, and anti-rheumatoid arthritis effects were studied to evaluate the feasibility of its percutaneous administration. The Optimized TP-NE was observed using a Malvern Autosizer Nano ZS 90 inspection system and a transmission electron microscope (TEM). The nanoemulsion had an average size of 162.9 ± 0.281 nm, a polydispersity index of 0.272 ± 0.024, a zeta potential of -30.03 ± 2.01 mV, and mostly spherical and uniform morphology. In addition, the TP-NE gel pharmacokinetics, assessed via a skin-blood two-site synchronous microdialysis, revealed that TP was higher in the skin than in the blood. TP-NE gel is crucial in reducing knee edema, inhibiting inflammation, and treating rheumatoid arthritis by regulating tumor necrosis factor-alpha, interleukin-1β, and -6 levels. The TP-NE gel is a promising local delivery method for rheumatoid arthritis (RA)-associated edema and inflammation and can serve as a prospective platform for percutaneous TP administration.

Lonicerin alleviates the progression of experimental rheumatoid arthritis by downregulating M1 macrophages through the NF-κB signaling pathway.

The present study aimed to evaluate anti-rheumatoid arthritis (RA) effect of Lonicerin (LON), a safe compound with anti-inflammatory and immunomodulatory properties. Nevertheless, the exact role of LON in RA remains elusive. In this test, the anti-RA effect of LON was evaluated in collagen-induced arthritis (CIA) mouse model. Relevant parameters were measured during the experiment; ankle tissue and serum were collected at the end of the experiment for radiology, histopathology, and inflammation analysis. ELISA, qRT-PCR, immunofluorescence, and western blot were used to explore the effect of LON on the polarization of macrophages and related signal pathways. It was discovered that LON treatment attenuated the disease progression of CIA mice with lower paw swelling, clinical score, mobility, and inflammatory response. LON treatment significantly decreased M1 marker levels in CIA mice and LPS/IFN-γ-induced RAW264.7 cells, while slightly increasing M2 marker levels in CIA mice and IL-4-induced RAW264.7 cells. Mechanistically, LON attenuated the activation of the NF-κB signaling pathway, which contributes to M1 macrophage polarization and inflammasome activation. In addition, LON inhibited NLRP3 inflammasome activation in M1 macrophages, thereby reducing inflammation by inhibiting IL-1β and IL-18 release. These results indicated that LON might exert anti-RA effects by regulating the polarization of M1/M2 macrophage, especially by inhibiting macrophage polarization toward M1.

Dissolving microneedle patches-mediated percutaneous delivery of tetramethylpyrazine for rheumatoid arthritis treatment

Recently, transdermal treatment of rheumatoid arthritis (RA) has received increasing attention due to the advantages of improving patient compliance and avoiding gastrointestinal side effects. However, the stratum corneum (SC) barrier limits the transdermal delivery of most substances. Therefore, we constructed tetramethylpyrazine-loaded dissolving microneedle patches (TMP-DMNPs) and investigated its anti-rheumatoid arthritis effect. The cone-shaped dissolving microneedle patch had complete, neatly arranged needles and great mechanical strength. It could effectively penetrate the stratum corneum when applied to the skin. In vitro transdermal experiment showed that DMNPs could significantly promote the transdermal penetration of TMP compared with TMP-cream. The needles were completely dissolved within 18 min and the applied skin recovered completely within 3 h. The excipients and blank DMNP had good safety and biocompatibility to human rheumatoid arthritis fibroblast synovial cells. To compare the therapeutic effects, the animal model was established. The experiments of paw swelling, histopathology and X-ray examination showed that dissolving microneedles significantly alleviated paw condition, reduced the serum concentrations of proinflammatory cytokines, and inhibited synovial tissue damage in AIA rats. These results indicate that the DMNPs we prepared can deliver TMP safely, effectively and conveniently, providing a basis for the percutaneous treatment of RA.

Anti-Rheumatoid Arthritis Effects of Dangshen Ejiao Pill Mediated through Nuclear Factor-κB Pathway

Dangshen Ejiao (DE) pill, a traditional Chinese hospital preparation, has been used for the treatment of rheumatoid arthritis (RA) in China for decades with an unknown mechanism. This study aims to investigate the anti-RA and anti-inflammatory effect of DE using a Collagen-Induced Arthritis (CIA) model and explore its underlying mechanism of action. The quality control analysis of DE was performed by the phytochemical determination of 9 main monomers. The anti-RA effect of DE was validated by its reduction of inflammatory responses and CCP level in the CIA model. DE inhibited the production of pro-inflammatory cytokines IL-1β and IL-6 both in vivo and in vitro. Further mechanism study revealed that DE might alleviate inflammatory responses in the treatment of RA by blocking both canonical and noncanonical NF-κB pathways, and thus provided a powerful scientific foundation for its expanded application and approval as an anti-RA drug.

Messenger Nanozyme for Reprogramming the Microenvironment of Rheumatoid Arthritis.

Dysregulation of superoxide anion (O2-) and hydrogen peroxide (H2O2) metabolism in the microenvironment of rheumatoid arthritis (RA) drives the feedback loops of TNF-α and IL-1β thereby inducing an inflammatory storm between immune cells and joint tissue cells. Here, we combine nanoscale manganese dioxide (MnO2) with microvesicles derived from macrophage (MMV). The former possesses superoxide dismutase (SOD) and catalase (CAT)-like activities that can modulate this imbalance, and we amplify the enzyme-like activities by using the amorphous hollow mesoporous structure and surface modification. The latter is a natural endogenous component with the parent cell-like inflammatory homing ability and a unique function of transmitting information to surrounding and distant cells (″messenger function″), which helps amorphous hollow MnO2 (H-MnO2) nanozymes to cloak in the blood and reach the site of inflammation, where they can not only accumulate in activated macrophages but also pretend to be ″messengers″ that are utilized by fibroblast-like synoviocytes (FLS) and chondrocytes. In addition, we also load dexamethasone sodium phosphate (DSP) for helping the nanozymes work. Messenger nanozyme (MMV-MnO2@DSP) inherits the natural properties of MMV and mimics the enzymatic activity of SOD and CAT. It accumulates in activated macrophages to restore the metabolism of O2- and H2O2 while promoting repolarization and inhibits the feedback loops of TNF-α and IL-1β among macrophages, fibroblast-like synoviocytes, and chondrocytes, leading to anti-rheumatoid arthritis effects in vitro and in vivo.

Hezi inhibits Tiebangchui-induced cardiotoxicity and preserves its anti-rheumatoid arthritis effects by regulating the pharmacokinetics of aconitine and deoxyaconitine

Ethnopharmacological relevanceTiebangchui (TBC, dried roots of Aconitum pendulum Busch. and Aconitum flavum Hand.-Mazz.) is a well-known Tibetan medicine for dispelling cold and relieving pain. In China, it is widely used in prevention and treatment of various diseases, such as rheumatoid arthritis (RA), traumatic injury, and fracture. However, its cardiotoxicity and neurotoxicity seriously restrict its clinical application. Traditionally, Hezi (HZ, dry ripe fruit of Terminalia chebula Retz. and Terminalia chebula Retz. var. tomentella Kurt.) is generally used in combination with TBC for the purpose of toxicity reducing and efficacy enhancing, but so far we still can’t clearly elucidate the compatibility effect and mechanism of the classical herbal pair. Aim of studyTo investigate the compatibility effect and mechanism of TBC co-administered with HZ. MethodsIn the present study, we clarified the cardioprotective role of HZ on the cardiotoxicity induced by TBC. The electrocardiogram, the levels of serum cardiac troponin T (cTnT), the activities of cardiac superoxide dismutase (SOD), malonaldehyde (MDA), and histopathology of heart tissue have been determined in each group. Meanwhile, the anti-RA effect of each group was investigated by paw swelling measurement and histopathological examination of synovial. To explore the underlying mechanism, we performed the pharmacokinetic studies of aconitine (AC) and deoxyaconitine (DE) in TBC group and TBC + HZ group by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) system. ResultsTBC co-administered with HZ could significantly inhibit the increased heart rate and the prolonged QTc interval induced by TBC (p < 0.01). And TBC + HZ group had lower levels of serum cTnT, cardiac MDA, and higher levels of cardiac SOD compared with TBC group (p < 0.01). In addition, the combination of TBC and HZ could preserve the anti-RA effect of TBC. Both TBC administration alone and TBC + HZ combination administration could effectively alleviate the paw swelling (p < 0.01). Furthermore, TBC co-administered with HZ could significantly decrease the area under the concentration-time curve (AUC(0-∞)) and maximum concentration (Cmax) of AC and DE comapred with TBC administration alone (p < 0.01 or p < 0.05). Meanwhile, it was observed that the time to reach the peak concentration (Tmax), elimination half-life (t1/2), mean retention time (MRT) of AC and DE in TBC group were significantly higher than those in TBC + HZ group (p < 0.01 or p < 0.05). ConclusionsTBC co-administered with HZ could reduce TBC-induced cardiotoxicty and preserve its anti-RA efficacy. The underlying mechanism is associated with the change of pharmacokinetic process of AC and DE.

Anti-rheumatoid arthritis effects of Xanthii Fructus by affecting the PI3K-AKT signaling pathway based on TMT-labeled quantitative proteomics.

Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic symmetrical multiple arthritis. Current traditional counter-therapies are expensive and have side effects. Xanthii Fructus has effects in expelling wind and cold, draining the nasal orifice, and removing wind and dampness. However, its mechanism of action against rheumatoid arthritis is unknown. In this paper, the mechanism of the anti- rheumatoid arthritis effect of Xanthii Fructus is studied by proteomics. The experimental results show that it could significantly reduce serum inflammatory factor levels, alleviate joint edema, improve vasodilation and congestion, and significantly reduce the number of inflammatory cells. Proteomics results show that the PI3K-AKT signaling pathway is the key pathway for Xanthii Fructus to treat rheumatoid arthritis. In this study, we obtained a new understanding of the mechanism of Xanthii Fructus in the treatment of rheumatoid arthritis, which provided a theoretical basis for its prevention and treatment and laid the foundation for further research.

Potential pharmacodynamic substances of Laportea bulbifera in treatment of rheumatoid arthritis based on serum pharmacochemistry and pharmacology

The present study investigated the pharmacodynamic material basis of Laportea bulbifera in the treatment of rheumatoid arthritis. Firstly, human rheumatoid arthritis fibroblast-like synoviocyte line MH7A was cultured in vitro and treated with tumor necrosis factor alpha(TNF-α, 50 ng·mL~(-1)). The proliferation and the levels of inflammatory cytokines such as prostaglandin E2(PGE2), interleukin-1β(IL-1β), and interleukin-6(IL-6) of the MH7A cells exposed to the serum containing L. bulbifera were determined to evaluate the anti-rheumatoid arthritis effects of the serum. Furthermore, the ultra-performance liquid chromatography tandem mass spectrometry fingerprints of the L. bulbifera crude extract, the drug-containing serum, and the drug-free serum were compared to identify the compounds newly generated in the serum after oral administration of the extract. According to the peak areas of common peaks and the results of anti-rheumatoid arthritis effect test, the active components were identified. The serum containing L. bulbifera significantly inhibited the proliferation of the MH7A cells activated by TNF-α and the expression of PGE2, IL-6, and IL-1β. Thirty newly generated compounds were detected in the drug-containing serum. Among them, neochlorogenic acid, cryptochlorogenic acid, chlorogenic acid, rutin, isoquercitrin, luteoloside, kaempferol-3-O-rutinoside, and quercitrin were also present in the crude extract. Twelve characteristic peaks(3, 7, 8, 14, 18, 19, 21, 23, 24, m6, m7, and m15) were significantly correlated with the pharmaceutical effect. According to the correlations, neochlorogenic acid, cryptochlorogenic acid, and chlorogenic acid had great contributions to the anti-rheumatoid arthritis activity. This study preliminarily clarified the potential pharmacodynamic substances of L. bulbifera in the treatment of rheumatoid arthritis, which laid a theoretical and experimental foundation for further development and application of the medicinal plant.

Cortex periplocae modulates the gut microbiota to restrict colitis and colitis-associated colorectal cancer via suppression of pathogenic Th17 cells

Aberrant microbe-immune cell interaction is a predisposing factor in inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Cortex Periplocae is a famous traditional Chinese medicine with putative anti-rheumatoid arthritis and anti-dyspepsia effects. Here, we show that the Periploca sepium periplosides (PePs), a cardiac glycosides-free pregnane glycosides extract from root bark of Cortex Periplocae, alleviates colon inflammation, improves intestinal epithelial barrier function, and prevents colitis-associated tumorigenesis in mice with colitis and CAC. Mechanistically, PePs treatment modulates abnormal gut microbiota composition in model mice, especially enriches an anti-inflammatory commensal bacterium A. muciniphila BAA-835. We further demonstrate that the altered gut microbiota following PePs treatment plays an important role in modulation of intestinal Type 17 immunity in both colitis and CAC mouse model. Our results indicate that PePs may be used as a potential gut microbiota modulator to treat IBD and CAC.