Evaluating the Anti-Osteoarthritis Potential of Standardized Boswellia serrata Gum Resin Extract in Alleviating Knee Joint Pathology and Inflammation in Osteoarthritis-Induced Models.

Osteoarthritis is a widespread chronic degenerative disease marked by the deterioration of articular cartilage, modifications in subchondral bone, and a spectrum of symptoms, including pain, stiffness, and disability. Ultimately, this condition impairs the patient's quality of life. This study aimed to evaluate the therapeutic efficacy of standardized Boswellia serrata gum resin extract (BSRE) in a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis. A total of 60 rats were allocated into six groups: normal control group (NC), osteoarthritis control (injected with MIA, OC), O + B50 (injected with MIA and treated with 50 mg/kg body weight (BW) BSRE), O + B75 (injected with MIA and treated with 75 mg/kg BW BSRE), O + B100 (injected with MIA and treated with 100 mg/kg BW BSRE), and O + M (injected with MIA and treated with 150 mg/kg BW methyl sulfonyl methane). Several parameters, including knee joint swelling, histopathological changes, and the expression of collagen type II alpha 1 (COL2A1) and aggrecan, were comprehensively assessed. Concurrently, the serum levels and mRNA expression of inflammatory mediators, cytokines, and matrix metalloproteinases (MMPs) were analyzed in both the serum and knee joint synovium. The results demonstrated that BSRE significantly mitigated knee joint swelling, cartilage destruction, and tissue deformation. Notably, BSRE administration markedly upregulated the expression of COL2A1 and aggrecan while concurrently reducing levels of nitric oxide, prostaglandin E2, leukotriene B4, interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Furthermore, a substantial decrease was observed in the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, 5-lipoxygenase, IL-6, TNF-α and MMP-3 and -13, thereby indicating promising therapeutic implications for osteoarthritis. In conclusion, BSRE exhibited anti-inflammatory properties and inhibited cartilage matrix degradation in a rat model of MIA-induced osteoarthritis, with the O + B100 group showing significant reductions in swelling and notable improvements in joint cartilage damage. These findings illuminate the preventive and therapeutic potential of BSRE for osteoarthritis treatment, emphasizing the criticality of exhaustive evaluation of novel compounds.

Bone protective effect of sinomenine against monosodium iodoacetate induced knee and hip injury in rat model: an inflammatory pathway.

PURPOSE: Osteoarthritis (OA) is a degenerative joint disease which is categorized via destruction of joint cartilage and it also affects the various joints, especially knees and hips. Sinomenine active phytoconstituents isolated from the stem of Sinomenium acutum and already proof anti-inflammatory effect against the arthritis model of rodent. In this experimental protocol, we scrutinized the anti-osteoarthritis effect of sinomenine against monosodium iodoacetate (MIA) induced OA in rats. METHODS: MIA (3 mg/50 µL) was used for inducing the OA in the rats, and rats received the oral administration of sinomenine (2.5, 5 and 7.5 mg/kg body weight) up to the end of the experimental study (four weeks). The body and organs weight were estimated. Aggrecan, C-terminal cross-linked telopeptide of type II collagen (CTX-II), glycosaminoglycans (GCGs), monocyte chemoattractant protein-1 (MCP-1), Interferon gamma (IFN-γ), antioxidant, inflammatory cytokines, inflammatory mediators and matrix metalloproteinases (MMP) were analyzed. RESULTS: Sinomenine significantly (P < 0.001) boosted the body weight and reduced the heart weight, but the weight of spleen and kidney remain unchanged. Sinomenine significantly (P < 0.001) reduced the level of nitric oxide, MCP-1 and improved the level of aggrecan, IFN-γ and GCGs. Sinomenine remarkably upregulated the level of glutathione, superoxide dismutase and suppressed the level of malonaldehyde. It effectually modulated the level of inflammatory cytokines and inflammatory mediators and significantly (P < 0.001) reduced the level of MMPs, like MMP-1, 2, 3, 9 and 13. CONCLUSIONS: Sinomenine is a beneficial active agent for the treatment of OA disease.

Enhanced detection of monoiodoacetic acid at ng/L level by ion chromatography with novel derivatization-free pretreatment.

Concerns have recently arisen regarding the formation of carcinogenic and genotoxic iodinated haloacetic acids (HAAs), such as monoiodoacetic acid (MIAA), during the disinfection of iodine-containing water with chloramine. Existing detection methods for MIAA rely on either labor-intensive derivatization operations or expensive instruments, making analysis challenging. To bypass these issues, this study proposed a novel two-step liquid-liquid extraction strategy to enrich MIAA and then pioneered the integration of common ion chromatography (IC) with an ultraviolet detector to measure trace MIAA precisely. This novel approach achieved a remarkable 155.6-fold enrichment of MIAA and significantly reduced the need for water and chemicals, hence enhancing its efficiency and environmental friendliness. Besides, this method effectively removed coexisting anions and separated MIAA from other interferents by adjusting IC column and eluent conditions. The method detection limit of MIAA is an impressive 21.44 ng/L, and the recoveries in synthetic and real water samples ranged from 85 to 113%, with maximum deviations of 7.59%. We validated the reliability of our approach by comparing it with the USEPA 552.3 method. In conclusion, this IC-based method proves to be a robust and environment-benign solution for detecting trace MIAA in complex water components.

Ginkgolide C inhibits ROS-mediated activation of NLRP3 inflammasome in chondrocytes to ameliorate osteoarthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba, as the most widely available medicinal plant worldwide, has been frequently utilized for treat cardiovascular, cerebrovascular, diabetic and other diseases. Due to its distinct pharmacological effects, it has been broadly applications in pharmaceuticals, health products, dietary supplements, and so on. Ginkgolide C (GC), a prominent extract of Ginkgo biloba, possesses potential in anti-inflammatory and anti-oxidant efficacy. AIMS OF THE STUDY: To determine whether GC mitigated the progressive degeneration of articular cartilage in a Monosodium Iodoacetate (MIA)-induced osteoarthritis (OA) rat model by inhibiting the activation of the NLRP3 inflammasome, and the specific underlying mechanisms. MATERIALS AND METHODS: In vivo, an OA rat model was established by intra-articular injection of MIA. The protective effect of GC (10 mg/kg) on articular cartilage was evaluated. Application of ATDC5 cells to elucidate the mechanism of the protective effect of GC on articular cartilage. Specifically, the expression levels of molecules associated with cartilage ECM degrading enzymes, OS, ERS, and NLRP3 inflammasome activation were analyzed. RESULTS: In vivo, GC ameliorated MIA-induced OA rat joint pain, and exhibited remarkable anti-inflammatory and anti- ECM degradation effects via inhibition of the activation of NLRP3 inflammasome, the release of inflammatory factors, and the expression of matrix-degrading enzymes in cartilage. Mechanically, GC inhibited the activation of NLRP3 inflammasome by restraining ROS-mediated p-IRE1α and activating Nrf2/NQO1 signal path, thereby alleviating OA. The ROS scavenger NAC was as effective as GC in reducing ROS production and inhibiting the activation of NLRP3 inflammasome. CONCLUSIONS: GC have exerted chondroprotective effects by inhibiting the activation of NLRP3 inflammasome.

Anti-osteoarthritis, Bone Protective and Antiinflammatory Effect of Lusianthridin against Monosodium Iodoacetate Induced Osteoarthritis via Suppression of Inflammatory Pathway.

Osteoarthritis (OA) is characterized by the gradual deterioration and worsening of the knee joint, leading to both pain and deformity. The current research exhibited the anti-osteoarthritis effect of lusianthridin against monosodium iodoacetate (MIA) induced OA in rats. RAW cells were used for the cell viability. The inflammatory cytokines and mediators were estimated in the cell lines after the lipopolysaccharide (LPS) treatment. For the in vivo study, the rats were received the intraperitoneal administration of MIA (3 mg/kg) for the induction of OA. The rats were received the oral administration of lusianthridin (5, 10 and 20 mg/kg) and the body and organ weight estimated. Antioxidant, cytokines, inflammatory and matrix metalloproteinases (MMP) level were also estimated. The mRNA expression of MMP were also estimated. The lusianthridin treatment remarkably suppressed the cell viability. LPS induced RAW cell suppressed the level of nitrate, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), MMP-2 and MMP-9 level. Lusianthridin remarkably altered the level of body weight and organ weight (liver, spleen, renal and heart weight). lusianthridin suppressed the oxidative stress via altered the level of antioxidant parameters. Lusianthridin significantly (p < 0.001) decreased the level of cartilage oligometrix matrix protein (COMP) and c-reactive protein (CRP); cytokines such as TNF-α, IL-1ß, IL-6, IL-10; inflammatory parameters include 5- Lipoxygenase (5-LOX), COX-2, leukotriene B4 (LTB4), PGE2; transforming growth factor beta (TGF-ß); MMP level like MMP-1, 3, 9, 13, respectively. Lusianthridin significantly suppressed the mRNA expression of MMP. Collectively, the result of the study showed that antiosteoarthritis effect of lusianthridin via suppression of inflammatory parameters.

Integrated Analysis of DNA Methylation and Gene Expression Profiles in a Rat Model of Osteoarthritis.

Osteoarthritis (OA) is common and affected by several factors, such as age, weight, sex, and genetics. The pathogenesis of OA remains unclear. Therefore, using a rat model of monosodium iodoacetate (MIA)-induced OA, we examined genomic-wide DNA methylation using methyl-seq and characterized the transcriptome using RNA-seq in the articular cartilage tissue from a negative control (NC) and MIA-induced rats. We identified 170 genes (100 hypomethylated and upregulated genes and 70 hypermethylated and downregulated genes) regulated by DNA methylation in OA. DNA methylation-regulated genes were enriched in functions related to focal adhesion, extracellular matrix (ECM)-receptor interaction and the PI3K-Akt and Hippo signaling pathways. Functions related to extracellular matrix organization, extracellular matrix proteoglycans, and collagen formation were involved in OA. A molecular and protein-protein network was constructed using methylated expression-correlated genes. Erk1/2 was a downstream target of OA-induced changes in DNA methylation and RNA expression. We found that the integrin subunit alpha 2 (ITGA2) gene is important in focal adhesion, alpha6-beta4 integrin signaling, and the inflammatory response pathway in OA. Overall, gene expression changes because DNA methylation influences OA pathogenesis. ITGA2, whose gene expression changes are regulated by DNA methylation during OA onset, is a candidate gene. Our findings provide insights into the epigenetic targets of OA processes in rats.

The Combined Intraosseous Administration of Orthobiologics Outperformed Isolated Intra-articular Injections in Alleviating Pain and Cartilage Degeneration in a Rat Model of MIA-Induced Knee Osteoarthritis.

BACKGROUND: Intra-articular (IA) platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) injections have shown efficacy and safety in treating osteoarthritis (OA). However, the effectiveness and mechanisms of combined intraosseous (IO) administration of these orthobiologics have yet to be explored. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate the effect on pain, cartilage, synovium/infrapatellar fat pad (IFP), and subchondral bone in rat knee OA, comparing isolated IA with combined IA and IO (IA+IO) injections of PRP or BMAC. It was hypothesized that combined injections would be superior to sole IA injections. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 48 rats were divided into 6 groups: sham (only joint puncture during OA induction with IA+IO saline injection treatment) and 5 groups with OA induction, control (IA+IO saline injection), PRP (IA PRP+IO saline injection), BMAC IA (IA BMAC+IO saline injection), PRP IA+IO (IA+IO PRP injection), and BMAC IA+IO (IA+IO BMAC injection). OA was induced by IA injection of monosodium iodoacetate (MIA). Rats were administered different orthobiologics according to their grouping 3 weeks after the MIA injection. Pain changes were evaluated using the weightbearing ratio assay at weeks 3, 4, 5, 7, and 9 after OA induction. Rats were euthanized at week 9 for gross, radiological, histological, immunohistochemical, and immunofluorescence assessments of cartilage, synovium, and subchondral bone. RESULTS: Compared with the control group, all orthobiologics injection groups had reduced joint pain. Compared with IA injection, IA+IO injections provided superior pain relief by suppressing calcitonin gene-related peptide and substance P in both the synovium/IFP and subchondral bone. IA+IO injections slowed the progression of subchondral bone lesions by inhibiting CD31hiEmcnhi vessel formation and excessive osteoclast and osteoblast turnover while preserving subchondral bone microarchitecture, slowing cartilage degeneration. However, IA+IO injections did not outperform isolated IA injections in reducing synovitis and synovium/IFP fibrosis. Compared with PRP, BMAC exhibited superior inhibition of pain-related mediators, but no significant differences were observed in synovitis suppression, infrapatellar fat pad fibrosis, and subchondral bone protection. CONCLUSION: IA+IO injections of orthobiologics were more effective in relieving pain, slowing cartilage degeneration, and inhibiting abnormal vascularization and remodeling compared with isolated IA injections. BMAC showed superior pain relief in the synovium/IFP and subchondral bone compared with PRP. Further research is needed to optimize PRP and BMAC components for enhanced efficacy in OA management. CLINICAL RELEVANCE: Our findings contribute to advancing the understanding of pain relief mechanisms and support the endorsement of IO injection of orthobiologics for the treatment of OA and joint pain.

Reversible SAHH inhibitor ameliorates MIA-induced osteoarthritis of rats through suppressing MEK/ERK pathway.

Osteoarthritis (OA) is characterized by gradual articular cartilage degradation, accompanied by persistent low-grade joint inflammation, correlating with radiographic and pain-related progression. The latent therapeutic potential of DZ2002, a reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH), holds promise for OA intervention. This study endeavored to examine the therapeutic efficacy of DZ2002 within the milieu of OA. The cytotoxicity of DZ2002 was evaluated using the MTT assay on bone marrow-derived macrophages. The inhibitory impact of DZ2002 during the process of osteoclastogenesis was assessed using TRAP staining, analysis of bone resorption pits, and F-actin ring formation. Mechanistic insights were derived from qPCR and Western blot analyses. Through the intra-articular injection of monosodium iodoacetate (MIA), an experimental rat model of OA was successfully instituted. This was subsequently accompanied by a series of assessments including Von Frey filament testing, analysis of weight-bearing behaviors, and micro-CT imaging, all aimed at assessing the effectiveness of DZ2002. The findings emphasized the effectiveness of DZ2002 in mitigating osteoclastogenesis induced by M-CSF/RANKL, evident through a reduction in TRAP-positive OCs and bone resorption. Moreover, DZ2002 modulated bone resorption-associated gene and protein expression (CTSK, CTR, Integrin ß3) via the MEK/ERK pathway. Encouragingly, DZ2002 also alleviates MIA-induced pain, cartilage degradation, and bone loss. In conclusion, DZ2002 emerges as a potential therapeutic contender for OA, as evidenced by its capacity to hinder in vitro M-CSF/RANKL-induced osteoclastogenesis and mitigate in vivo osteoarthritis progression. This newfound perspective provides substantial support for considering DZ2002 as a compelling agent for osteoarthritis intervention.

A Blend of Tamarindus Indica and Curcuma Longa Extracts Alleviates Monosodium Iodoacetate (MIA)-Induced Osteoarthritic Pain and Joint Inflammation in Rats.

BACKGROUND AND OBJECTIVE: NXT15906F6 (TamaFlexTM) is a proprietary herbal composition containing Tamarindus indica seeds and Curcuma longa rhizome extracts. NXT15906F6 supplementation has been shown clinically effective in reducing knee joint pain and improving musculoskeletal functions in healthy and knee osteoarthritis (OA) subjects. The objective of the present study was to assess the possible molecular basis of the anti-OA efficacy of NXT15906F6 in a monosodium iodoacetate (MIA)-induced model of OA in rats. METHODS: Healthy male Sprague Dawley rats (age: 8-9 wk body weight, B.W.: 225-308 g (n = 12) were randomly assigned to one of the six groups, (a) vehicle control, (b) MIA control, (c) Celecoxib (10 mg/kg B.W.), (d) TF-30 (30 mg/kg B.W.), (e) TF-60 (60 mg/kg B.W.), and (f) TF-100 (100 mg/kg B.W.). OA was induced by an intra-articular injection of 3 mg MIA into the right hind knee joint. The animals received either Celecoxib or TF through oral gavage over 28 days. The vehicle control animals received intra-articular sterile normal saline. RESULTS: Post-treatment, NXT15906F6 groups showed significant (p < 0.05) dose-dependent pain relief as evidenced by improved body weight-bearing capacity on the right hind limb. NXT15906F6 treatment also significantly reduced the serum tumor necrosis factor-α (TNF-α, p < 0.05) and nitrite (p < 0.05) levels in a dose-dependent manner. mRNA expression analyses revealed the up-regulation of collagen type-II (COL2A1) and down-regulation of matrix metalloproteinases (MMP-3, MMP-9 and MMP-13) in the cartilage tissues of NXT15906F6-supplemented rats. Cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) protein expressions were down-regulated. Decreased immunolocalization of NF-κß (p65) was observed in the joint tissues of NXT15906F6-supplemented rats. Furthermore, microscopic observations revealed that NXT15906F6 preserved MIA-induced rats' joint architecture and integrity. CONCLUSION: NXT15906F6 reduces MIA-induced joint pain, inflammation, and cartilage degradation in rats.

Effects of emulsified and non-emulsified palm tocotrienol on bone and joint health in ovariectomised rats with monosodium iodoacetate-induced osteoarthritis.

Postmenopausal women are susceptible to osteoporosis and osteoarthritis. Tocotrienol, a bone-protective nutraceutical, is reported to prevent osteoarthritis in male rats. However, its efficacy on joint health in oestrogen deficiency has not been validated. Besides, data on the use of emulsification systems in enhancing bioavailability and protective effects of tocotrienol are limited. Ovariectomised adult female Sprague-Dawley rats (3 months old) were treated with refined olive oil, emulsified (EPT, 100 mg/kg/day with 25% vitamin E content), non-emulsified palm tocotrienol (NEPT, 100 mg/kg/day with 50% vitamin E content) and calcium carbonate (1% w/v in drinking water) plus glucosamine sulphate (250 mg/kg/day) for 10 weeks. Osteoarthritis was induced with monosodium iodoacetate four weeks after ovariectomy. Baseline control was sacrificed upon receipt, while the sham group was not ovariectomised and treated with refined olive oil. EPT and NEPT prevented femoral metaphyseal and subchondral bone volume decline caused by ovariectomy. EPT decreased subchondral trabecular separation compared to the negative control. EPT preserved stiffness and Young's Modulus at the femoral mid-shaft of the rats. Circulating RANKL was reduced post-treatment in the EPT group. Joint width was reduced in all the treatment groups vs the negative control. The EPT group's grip strength was significantly improved over the negative control and NEPT group. EPT also preserved cartilage histology based on several Mankin's subscores. EPT performed as effectively as NEPT in preventing osteoporosis and osteoarthritis in ovariectomised rats despite containing less vitamin E content. This study justifies clinical trials for the use of EPT in postmenopausal women with both conditions.

Stimulation of nuclear receptor REV-ERBs alleviates monosodium iodoacetate-induced osteoarthritis pathology of mice and the induction of inflammatory molecules expression in primary cultured chondrocytes.

Because inflammation in chondrocytes contributes to the induction of osteoarthritis (OA), regulation of their activity is essential. A previous study showed that stimulation of the reverse erythroblastosis virus (REV-ERB) nuclear receptors in spinal glial cells elicits anti-inflammatory and antinociception effects in animal models of chronic pain. However, the involvement of REV-ERBs in chondrocyte functions and OA pathologies remains to be elucidated. In the current study, we found that pretreatment with the REV-ERB agonist SR9009 significantly blocked the increases in inflammatory molecules [(matrix metalloproteinase (MMP) 3, MMP9, and MMP13] and cytokines (interleukin-1ß and tumor necrosis factor) in primary cultured chondrocytes following treatment with lipopolysaccharide. Furthermore, repeated intra-articular treatment with SR9009 significantly prevented monosodium iodoacetate-induced mechanical hypersensitivity and tended to partially reduce knee joint damage in mice. In conclusion, our findings suggest that REV-ERBs have a critical role in alleviating nociceptive hypersensitivity in OA pathologies by negatively regulating inflammation in chondrocytes.

Bone protective effect of sinomenine against monosodium iodoacetate induced knee and hip injury in rat model: an inflammatory pathway

Purpose: Osteoarthritis (OA) is a degenerative joint disease which is categorized via destruction of joint cartilage and it also affects the various joints, especially knees and hips. Sinomenine active phytoconstituents isolated from the stem of Sinomenium acutum and already proof anti-inflammatory effect against the arthritis model of rodent. In this experimental protocol, we scrutinized the anti-osteoarthritis effect of sinomenine against monosodium iodoacetate (MIA) induced OA in rats. Methods: MIA (3 mg/50 µL) was used for inducing the OA in the rats, and rats received the oral administration of sinomenine (2.5, 5 and 7.5 mg/kg body weight) up to the end of the experimental study (four weeks). The body and organs weight were estimated. Aggrecan, C-terminal cross-linked telopeptide of type II collagen (CTX-II), glycosaminoglycans (GCGs), monocyte chemoattractant protein-1 (MCP-1), Interferon gamma (IFN-γ), antioxidant, inflammatory cytokines, inflammatory mediators and matrix metalloproteinases (MMP) were analyzed. Results: Sinomenine significantly (P < 0.001) boosted the body weight and reduced the heart weight, but the weight of spleen and kidney remain unchanged. Sinomenine significantly (P < 0.001) reduced the level of nitric oxide, MCP-1 and improved the level of aggrecan, IFN-γ and GCGs. Sinomenine remarkably upregulated the level of glutathione, superoxide dismutase and suppressed the level of malonaldehyde. It effectually modulated the level of inflammatory cytokines and inflammatory mediators and significantly (P < 0.001) reduced the level of MMPs, like MMP-1, 2, 3, 9 and 13. Conclusions: Sinomenine is a beneficial active agent for the treatment of OA disease.

Novel evidence on iodoacetic acid-induced immune protein functional and conformational changes: Focusing on cellular and molecular aspects.

Elevated levels of iodide occur in raw water in certain regions, where iodination disinfection byproducts are formed during chloramine-assisted disinfection of naturally iodide-containing water. Iodoacetic acid (IAA) is one of the typical harmful products. The mechanisms underlying IAA-induced immunotoxicity and its direct effects on biomolecules remained unclear in the past. Cellular, biochemical, and molecular methods were used to investigate the mechanism of IAA-induced immunotoxicity and its binding to lysozyme. In the presence of IAA, the cell viability of coelomocytes was significantly reduced to 70.8 %, as was the intracellular lysozyme activity. Upon binding to IAA, lysozyme underwent structural and conformational changes, causing elongation and unfolding of the protein due to loosening of the backbone and polypeptide chains. IAA effectively quenched the fluorescence of lysozyme and induced a reduction in particle sizes. Molecular docking revealed that the catalytic residue, Glu 35, which is crucial for lysozyme activity, resided within the docking range, suggesting the preferential binding of IAA to the active site of lysozyme. Moreover, electrostatic interaction emerged as the primary driving force behind the interaction between IAA and lysozyme. In conclusion, the structural and conformational changes induced by IAA in lysozyme resulted in impaired immune protein function in coelomocytes, leading to cellular dysfunction.

Transcranial Direct Current Stimulation Attenuates the Chronic Pain of Osteoarthritis in Rats via Reducing NMDAR2B Expressions in the Spinal Cord.

OBJECTIVES: Osteoarthritis (OA) has been the common cause to lead to chronic pain. Transcranial direct current stimulation (tDCS) is effective in the treatment of chronic pain, but its analgesic mechanism is still unclear. This study observed the analgesic effects of tDCS in rats to explore the top-down analgesic modulation mechanism of tDCS. METHODS: Monosodium iodoacetate (MIA) was used to establish OA chronic pain model. After 21 days, the rats received tDCS for 14 consecutive days (20 min/day). We assessed the pain-related behaviors of rats at different time points. Western blot and Immunohistochemistry were performed to observe the expression level of NMDAR2B in the spinal cord after tDCS treatment. RESULTS: After MIA injection, rats developed apparent mechanical hyperalgesia and thermal hyperalgesia. However, the pain-related behaviors of rats were significantly improved after tDCS treatment. In addition, the expression of NMDAR2B and the proportion of positive stained cells of NMDAR2B were reversed by tDCS treatment. CONCLUSIONS: The results demonstrated that tDCS can attenuate OA-induced chronic pain in rats via reducing NMDAR2B expressions in the spinal cord. We believe that this may be the result of tDCS participating in the top-down modulation of pain pathway in the endogenous analgesic system.

Potentiating TRPA1 by Sea Anemone Peptide Ms 9a-1 Reduces Pain and Inflammation in a Model of Osteoarthritis.

Progressive articular surface degradation during arthritis causes ongoing pain and hyperalgesia that lead to the development of functional disability. TRPA1 channel significantly contributes to the activation of sensory neurons that initiate neurogenic inflammation and mediates pain signal transduction to the central nervous system. Peptide Ms 9a-1 from the sea anemone Metridium senile is a positive allosteric modulator of TRPA1 and shows significant anti-inflammatory and analgesic activity in different models of pain. We used a model of monosodium iodoacetate (MIA)-induced osteoarthritis to evaluate the anti-inflammatory properties of Ms 9a-1 in comparison with APHC3 (a polypeptide modulator of TRPV1 channel) and non-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam and ibuprofen. Administration of Ms 9a-1 (0.1 mg/kg, subcutaneously) significantly reversed joint swelling, disability, thermal and mechanical hypersensitivity, and grip strength impairment. The effect of Ms 9a-1 was equal to or better than that of reference drugs. Post-treatment histological analysis revealed that long-term administration of Ms9a-1 could reduce inflammatory changes in joints and prevent the progression of cartilage and bone destruction at the same level as meloxicam. Peptide Ms 9a-1 showed significant analgesic and anti-inflammatory effects in the model of MIA-induced OA, and therefore positive allosteric modulators could be considered for the alleviation of OA symptoms.

Therapeutic Nanodiamonds Containing Icariin Ameliorate the Progression of Osteoarthritis in Rats.

In present study, icariin (ICA)/tannic acid (TA)-nanodiamonds (NDs) were prepared as follows. ICA was anchored to ND surfaces with absorbed TA (ICA/TA-NDs) and we evaluated their in vitro anti-inflammatory effects on lipopolysaccharide (LPS)-activated macrophages and in vivo cartilage protective effects on a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis (OA). The ICA/TA-NDs showed prolonged release of ICA from the NDs for up to 28 days in a sustained manner. ICA/TA-NDs inhibited the mRNA levels of pro-inflammatory elements, including matrix metalloproteinases-3 (MMP-3), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and increased the mRNA levels of anti-inflammatory factors (i.e., IL-4 and IL-10) in LPS-activated RAW 264.7 macrophages. Animal studies exhibited that intra-articular injection of ICA/TA-NDs notably suppressed levels of IL-6, MMP-3, and TNF-α and induced level of IL-10 in serum of MIA-induced OA rat models in a dose-dependent manner. Furthermore, these noticeable anti-inflammatory effects of ICA/TA-NDs remarkably contributed to the protection of the progression of MIA-induced OA and cartilage degradation, as exhibited by micro-computed tomography (micro-CT), gross findings, and histological investigations. Accordingly, in vitro and in vivo findings suggest that the prolonged ICA delivery of ICA/TA-NDs possesses an excellent latent to improve inflammation as well as defend against cartilage disorder in OA.

Low Glycolysis Is Neuroprotective during Anoxic Spreading Depolarization (SD) and Reoxygenation in Locusts.

Migratory locusts enter a reversible hypometabolic coma to survive environmental anoxia, wherein the cessation of CNS activity is driven by spreading depolarization (SD). While glycolysis is recognized as a crucial anaerobic energy source contributing to animal anoxia tolerance, its influence on the anoxic SD trajectory and recovery outcomes remains poorly understood. We investigated the effects of varying glycolytic capacity on adult female locust anoxic SD parameters, using glucose or the glycolytic inhibitors 2-deoxy-d-glucose (2DG) or monosodium iodoacetate (MIA). Surprisingly, 2DG treatment shared similarities with glucose yet had opposite effects compared with MIA. Specifically, although SD onset was not affected, both glucose and 2DG expedited the recovery of CNS electrical activity during reoxygenation, whereas MIA delayed it. Additionally, glucose and MIA, but not 2DG, increased tissue damage and neural cell death following anoxia-reoxygenation. Notably, glucose-induced injuries were associated with heightened CO2 output during the early phase of reoxygenation. Conversely, 2DG resulted in a bimodal response, initially dampening CO2 output and gradually increasing it throughout the recovery period. Given the discrepancies between effects of 2DG and MIA, the current results require cautious interpretations. Nonetheless, our findings present evidence that glycolysis is not a critical metabolic component in either anoxic SD onset or recovery and that heightened glycolysis during reoxygenation may exacerbate CNS injuries. Furthermore, we suggest that locust anoxic recovery is not solely dependent on energy availability, and the regulation of metabolic flux during early reoxygenation may constitute a strategy to mitigate damage.

Bixa orellana ethyl acetate fraction and its isolated compound ellagic acid attenuate the progression of MIA-induced osteoarthritis in rat knees.

Osteoarthritis (OA) is a pathology that is characterized by progressive erosion of articular cartilage. In this context, medicinal plants have become relevant tools regarding their potential role in the prevention and treatment of OA, being safe and effective. The aim of this work was investigate the therapeutic efficacy of the ethyl acetate fraction of Bixa orellana leaves (BoEA) and ellagic acid (ElAc) for the therapeutic treatment of OA induced by monosodium iodoacetate (MIA) in rats. The plant material was extracted via maceration with 70 % hydroalcoholic solvent (BoHE). The ethyl acetate (BoEA) fraction was by solvents in increasing order of polarity. The ElAc was identified and isolated in BoEA using high performance liquid chromatography (HPLC-DAD) and analytical curve. The OA was induced using MIA in the right knee at the knee joint. Doses of BoEA and ElAc were administered daily (every 24 h, orally) at concentrations of 50, 100 and 50 mg/kg, respectively, for 28 days after induced OA. We evaluated the animals through clinical and radiological examinations every 7 days and, on the 29th day, the animals were euthanized, the joints being removed for histopathological analysis and the serum for cytokine analysis. BoEA and ElAc compounds reduced inflammation and nociception in OA and were as effective as indomethacin in clinical parameters of joint discomfort and allodynia in rats, in addition to showing improvements in radiological and histopathological images, acting on the progress of cartilage deterioration, proving properties related to anti-inflammatory and analgesic processes, being important allies for new therapeutic interventions for the treatment of OA.

Regular walking exercise prior to knee osteoarthritis reduces joint pain in an animal model.

We investigated the effect of regular walking exercise prior to knee osteoarthritis (OA) on pain and synovitis in a rat monoiodoacetic acid (MIA)-induced knee OA model. Seventy-one male Wistar rats were divided into three groups: (i) Sedentary + OA, (ii) Exercise + OA, and (iii) Sedentary + Sham groups. The Exercise + OA group underwent a regular treadmill walking exercise at 10 m/min (60 min/day, 5 days/week) for 6 weeks, followed by a 2-mg MIA injection in the right knee. The right knee joint was removed from rats in this group at the end of the 6-week exercise period and at 1 and 6 weeks after the MIA injection. After the 6 weeks of treadmill exercise but before MIA injection, there were no significant differences among the three groups in the pressure pain threshold, whereas at 1 week post-injection, the Exercise + OA group's pressure pain threshold was significantly higher than that in the Sedentary + OA group, and this difference persisted until the end of the experimental period. The histological changes in articular cartilage and subchondral bone revealed by toluidine blue staining showed no difference between the Sedentary + OA and EX + OA groups. The expression levels of interleukin (IL)-4 and IL-10 mRNA in the infrapatellar fat pad and synovium were significantly increased by the treadmill exercise. Significant reductions in the number of CD68-, CD11c-positive cells and IL-1ß mRNA expression and an increase in the number of CD206-positive cells were observed at 1 week after the MIA injection in the Exercise + OA group compared to the Sedentary + OA group. These results suggest that regular walking exercise prior to the development of OA could alleviate joint pain through increases in the expressions of anti-inflammatory cytokines in the rat infrapatellar fat pad and synovium.

Therapeutic effects of combining curcumin and swimming in osteoarthritis using a rat model.

Osteoarthritis (OA) is a common debilitating degenerative disease of the elderly. We aimed to study the therapeutic effects of combining curcumin and swimming in monosodium iodoacetate (MIA)-induced OA in a rat model. The rats were divided into 5 groups (n = 9). Group 1 received saline and served as a control group. Groups 2-5 were injected intra-articularly in the right knee with 100 µL MIA. One week later, groups 3 and 5 were started on daily swimming sessions that gradually increased to 20-mins per session, and for groups 4 and 5, oral curcumin was administered at a dose of 200 mg/kg for 4 weeks. The combination therapy (curcumin + swimming) showed the most effective results in alleviating pain and joint stiffness as well as improving histological and radiological osteoarthritis manifestations in the knee joints. The combination modality also reduced serum C-reactive protein and tissue cartilage oligomeric matrix protein levels. Mechanistically, rats received dual treatment exhibited restoration of miR-130a and HDAC3 expression. The dual treatment also upregulated PPAR-γ alongside downregulation of NF-κB and its inflammatory cytokine targets TNF-α and IL-1ß. Additionally, there was downregulation of MMP1 and MMP13 in the treated rats. In conclusion, our data showed that there is a therapeutic potential for combining curcumin with swimming in OA, which is attributed, at least in part, to the modulation of miR-130a/HDAC3/PPAR-γ signaling axis.