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.

Protective effects of Pudilan Tablets against osteoarthritis in mice induced by monosodium iodoacetate.

Osteoarthritis (OA) is a complicated disorder that is the most prevalent chronic degenerative joint disease nowadays. Pudilan Tablets (PDL) is a prominent traditional Chinese medicine formula used in clinical settings to treat chronic inflammatory illnesses. However, there is currently minimal fundamental research on PDL in the therapy of joint diseases. As a result, this study looked at the anti-inflammatory and anti-OA properties of PDL in vitro and in vivo, as well as the mechanism of PDL in the treatment of OA. We investigated the anti-OA properties of PDL in OA mice that were generated by monosodium iodoacetate (MIA). All animals were administered PDL (2 g/kg or 4 g/kg) or the positive control drug, indomethacin (150 mg/kg), once daily for a total of 28 days starting on the day of MIA injection. The CCK-8 assay was used to test the vitality of PDL-treated RAW264.7 cells in vitro. RAW264.7 cells that had been activated with lipopolysaccharide (LPS) were used to assess the anti-inflammatory properties of PDL. In the MIA-induced OA model mice, PDL reduced pain, decreased OA-induced cartilage damages and degradation, decreased production of pro-inflammatory cytokines in serum, and suppressed IL-1ß, IL-6, and TNF-α mRNA expression levels in tibiofemoral joint. In RAW264.7 cells, PDL treatment prevented LPS-induced activation of the ERK/Akt signaling pathway and significantly decreased the levels of inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α. In conclusion, these results suggest that PDL is involved in combating the development and progression of OA, exerts a powerful anti-inflammatory effect on the knee joint, and may be a promising candidate for the treatment of OA.

Pathological Characteristics of Monosodium Iodoacetate-Induced Osteoarthritis in Rats.

BACKGROUND: This study aimed to identify pain-related behavior and pathological characteristics of the knee joint in rats with monosodium iodoacetate (MIA)-induced osteoarthritis (OA). METHODS: Knee joint inflammation was induced by intra-articular injection of MIA (4 mg/50 µL, n = 14) in 6-week-old male rats. Knee joint diameter, weight-bearing percentage on the hind limb during walking, the knee bending score, and paw withdrawal to mechanical stimuli were measured to evaluate edema and pain-related behavior for 28 d after MIA injection. Histological changes in the knee joints were evaluated using safranin O fast green staining on days 1, 3, 5, 7, 14, and 28 after OA induction (n = 3, respectively). Changes in bone structure and bone mineral density (BMD) were examined 14 and 28 d after OA (n = 3, respectively) using micro-computed tomography (CT). RESULTS: The knee joint diameter and knee bending scores of the ipsilateral joint significantly increased 1 d after MIA injection, and the increased knee joint diameter and knee bending score persisted for 28 d. Weight-bearing during walking and paw withdrawal threshold (PWT) decreased from 1 and 5 d, respectively, and were maintained up to 28 d after MIA. Cartilage destruction started on day 1, and Mankin scores for bone destruction significantly increased for 14 d, as shown by micro-CT imaging. CONCLUSION: The present study demonstrated that histopathological structural changes in the knee joint due to inflammation started soon after MIA injection, which induced OA pain from inflammation-related acute pain to spontaneous and evoked associated chronic pain.

Astragaloside IV as a novel CXCR4 antagonist alleviates osteoarthritis in the knee of monosodium iodoacetate-induced rats.

BACKGROUND AND PURPOSE: C-X-C chemokine receptor type 4 (CXCR4) inhibition protects cartilage in osteoarthritis (OA) animal models. Therefore, CXCR4 has becoming a novel target for OA drug development. Since dietary and herbal supplements have been widely used for joint health, we hypothesized that some supplements exhibit protective effects on OA cartilage through inhibiting CXCR4 signaling. METHODS: The single-cell RNA sequencing data of OA patients (GSE152805) was re-analyzed by Scanpy 1.9.0. The docking screening of CXCR4 antagonists was conducted by Autodock Vina 1.2.0. The CXCR4 antagonistic activity was evaluated by calcium response in THP-1 cells. Signaling pathway study was conducted by bulk RNA sequencing and western blot analysis in human C28/I2 chondrocytes. The anti-OA activity was evaluated in monosodium iodoacetate (MIA)-induced rats. RESULTS: Astragaloside IV (ASN IV), the predominate phytochemical in Astragalus membranaceus, has been identified as a novel CXCR4 antagonist. ASN IV reduced CXCL12-induced ADAMTS4,5 overexpression in chondrocytes through blocking Akt signaling pathway. Furthermore, ASN IV administration significantly repaired the damaged cartilage and subchondral bone in MIA-induced rats. CONCLUSION: The blockade of CXCR4 signaling by ASN IV could explain anti-OA activities of Astragalus membranaceus by protection of cartilage degradation in OA patients. Since ASN IV as an antiviral has been approved by China National Medical Products Administration for testing in people, repurposing of ASN IV as a joint protective agent might be a promising strategy for OA drug development.

Anti-Inflammatory and Analgesic Effects of Schisandra chinensis Leaf Extracts and Monosodium Iodoacetate-Induced Osteoarthritis in Rats and Acetic Acid-Induced Writhing in Mice.

In this study, we aimed to determine the anti-inflammatory and antinociceptive activities of Schisandra chinensis leaf extracts (SCLE) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, an acetic acid-induced mouse model of writhing, and a monosodium iodoacetate (MIA)-induced rat model of osteoarthritis (OA). In LPS-stimulated RAW264.7 cells, a 100 µg/mL dose of SCLE significantly reduced the production of nitric oxide (NO), interleukin-1ß (IL-1ß), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and prostaglandin E2 (PGE2). Acetic acid-induced writhing responses in mice that quantitatively determine pain were significantly inhibited by SCLE treatment. In addition, SCLE significantly decreased the MIA-induced elevation in OA symptoms, the expression levels of pro-inflammatory mediators/cytokines and matrix metalloproteinases, and cartilage damage in the serum and joint tissues. Our data demonstrated that SCLE exerts anti-osteoarthritic effects by regulating inflammation and pain and can be a useful therapeutic candidate against OA.

The Xiaogu San Attenuates Pain and Cartilage Damage in Rats with Monosodium Iodoacetate Induced Osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease with an increasing incidence associated with increased life expectancy. The application of traditional Chinese medicine in the treatment of OA has become a research hotspot. OBJECTIVE: This study investigated the effects of XGS externally applied to osteoarthritic joints and analyze its effect on pain in monosodium iodoacetate (MIA)-induced OA rats. This study also evaluates potential mechanisms behind the anti-osteoarthritic effects of XGS. METHODS: A total of 24 Sprague Dawley rats were evenly and randomly divided into three separate groups, including the normal control (NC), OA and XGS groups. MIA (50 µL, 10 mg/mL) was injected into the left knee joints of the rats to induce OA. After 7 days, The rats of XGS group were given XGS (0.45 g) that was externally applied to the left knee joint, were fixed with gauze, and continuously administered XGS for 28 days. Morphological changes in tissues and organs were examined using H&E staining. Biochemical indicators were measured using an automatic biochemical analyzer. Inflammatory cytokines were detected using ELISA kits and immunohistochemistry. RNA-based high-throughput sequencing (RNA-seq) was performed to detect differential expression of mRNAs in normal and MIA-induced OA rats. RESULTS: Stride of the left leg was extended in rats, matrix increased on cartilage tissue surfaces, and inflammatory cytokines were reduced when treated with XGS. RNA-seq results revealed that the PI3K-Akt signaling pathway is activated in the OA model. The qRT-PCR showed that the expression levels of Tnn, Col6a6, Igf1 and Lamb1 were up-regulated by XGS. CONCLUSION: Altogether, this work demonstrated the potential therapeutic effects of XGS in rats with OA induced by MIA. The XGS may be considered an alternative therapy to manage OA.

Iodoacetic Acid, a Water Disinfection Byproduct, Disrupts Hypothalamic, and Pituitary Reproductive Regulatory Factors and Induces Toxicity in the Female Pituitary.

Iodoacetic acid (IAA) is a water disinfection byproduct (DBP) formed by reactions between oxidizing disinfectants and iodide. In vitro studies have indicated that IAA is one of the most cyto- and genotoxic DBPs. In humans, DBPs have been epidemiologically associated with reproductive dysfunction. In mouse ovarian culture, IAA exposure significantly inhibits antral follicle growth and reduces estradiol production. Despite this evidence, little is known about the effects of IAA on the other components of the reproductive axis: the hypothalamus and pituitary. We tested the hypothesis that IAA disrupts expression of key neuroendocrine factors and directly induces cell damage in the mouse pituitary. We exposed adult female mice to IAA in drinking water in vivo and found 0.5 and 10 mg/l IAA concentrations lead to significantly increased mRNA levels of kisspeptin (Kiss1) in the arcuate nucleus although not affecting Kiss1 in the anteroventral periventricular nucleus. Both 10 mg/l IAA exposure in vivo and 20 µM IAA in vitro reduced follicle stimulating hormone (FSHß)-positive cell number and Fshb mRNA expression. IAA did not alter luteinizing hormone (LHß) expression in vivo although exposure to 20 µM IAA decreased expression of Lhb and glycoprotein hormones, alpha subunit (Cga) mRNA in vitro. IAA also had toxic effects in the pituitary, inducing DNA damage and P21/Cdkn1a expression in vitro (20 µM IAA) and DNA damage and Cdkn1a expression in vivo (500 mg/l). These data implicate IAA as a hypothalamic-pituitary-gonadal axis toxicant and suggest the pituitary is directly affected by IAA exposure.

Biosynthesis of gold nanoparticles for the treatment of osteoarthritis alone or in combination with Diacerein® in a rat model.

Gold (Au) compounds were used as an effective therapeutic agent for various inflammatory diseases; however, the use of Au compounds becomes limited because of its association with several side effects. Hence, gold nanoparticles (AuNPs) were developed as a new option for the medical proposes. However, the safety evaluation of gold nanoparticles (AuNPs) in osteoarthritis (OA) treatment remains vague. This study aimed to biosynthesize, characterize and evaluate the therapeutic effects of biosynthesized AuNPs and/or Diacerein® (DIA) in experimental OA. OA was induced by a single injection of monosodium iodoacetate (3 mg/joint) in the intra-articular knee of female rats. Normal rats (N-rats) and OA-rats were treated orally for 5 weeks as follow: untreated N-rats; untreated OA-rats; N-rats received DIA (50 mg/kg b.w); N-rats received AuNPs (30 µg/kg b.w.); N-rats received AuNPs plus DIA; OA-rats received DIA; OA-rats received AuNPs, and OA-rats received AuNPs plus DIA. Blood, knee cartilage, liver and kidney samples were collected for biochemical and histological analysis. The synthesized AuNPs were nearly spherical with average size of 20 nm and zeta potential of 33 mV. AuNPs and DIA induced a significant improvement in serum inflammatory cytokines, biochemical parameters, estrogen level, hepatic and renal oxidative markers, hepatic DNA fragmentation, genomic template stability and cartilage joint histology of OA-rats. AuNPs were more effective than DIA and the combined treatment was more effective than the single treatment. It could be concluded that AuNPs are promising for the treatment of OA alone or in combination with DIA.

Inhibition effect of Caragana sinica root extracts on Osteoarthritis through MAPKs, NF-κB signaling pathway.

Osteoarthritis (OA) is a common joint disease characterized by degradation and inflammation of cartilage extracellular matrix. We aimed to evaluate the protective effect of Caragana sinica root (CSR) on interleukin (IL)-1ß-stimulated rat chondrocytes and a monosodium iodoacetate (MIA)-induced model of OA. In vitro, cell viability of CSR-treated chondrocytes was measured by MTT assay. The mRNA expression of Matrix metallopeptidases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) and extracellular matrix (ECM) were analyzed by quantitative real-time PCR (qRT-PCR). Moreover, the protein expression of MAPK (phosphorylation of EKR, JNK, p38), inhibitory kappa B (IκBα) and nuclear factor-kappa B (NF-κB p65) was detected by western blot analysis. In vivo, the production of nitric oxide (NO) was detected by Griess reagent, while those of inflammatory mediators, MMPs and ECM were detected by ELISA. The degree of OA was evaluated by histopathological analyses, Osteoarthritis Research Society International (OARSI) score and micro-CT analysis. CSR significantly inhibited the expression of MMPs, ADAMTSs and the degradation of ECM in IL-1ß-stimulated chondrocytes. Furthermore, CSR significantly suppressed IL-1ß-stimulated of MAPKs, NF-κB signaling pathway. In vivo, CSR and Indomethacin inhibited the production of inflammatory mediators, MMPs and degradation of ECM in MIA-induced model of OA. In addition, CSR improved the severity of OA. Taken together, these results suggest CSR is a potential therapeutic active agent in the treatment of OA.

Molecular Targets of Natural Products for Chondroprotection in Destructive Joint Diseases.

Osteoarthritis (OA) is the most common type of arthritis that occurs in an aged population. It affects any joints in the body and degenerates the articular cartilage and the subchondral bone. Despite the pathophysiology of OA being different, cartilage resorption is still a symbol of osteoarthritis. Matrix metalloproteinases (MMPs) are important proteolytic enzymes that degrade extra-cellular matrix proteins (ECM) in the body. MMPs contribute to the turnover of cartilage and its break down; their levels have increased in the joint tissues of OA patients. Application of chondroprotective drugs neutralize the activities of MMPs. Natural products derived from herbs and plants developed as traditional medicine have been paid attention to, due to their potential biological effects. The therapeutic value of natural products in OA has increased in reputation due to their clinical impact and insignificant side effects. Several MMPs inhibitor have been used as therapeutic drugs, for a long time. Recently, different types of compounds were reviewed for their biological activities. In this review, we summarize numerous natural products for the development of MMPs inhibitors in arthritic diseases and describe the major signaling targets that were involved for the treatments of these destructive joint diseases.

Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity In Vivo.

The hallmark of joint diseases, such as osteoarthritis (OA), is pain, originating from both inflammatory and neuropathic components, and compounds able to modulate the signal transduction pathways of the cannabinoid type-2 receptor (CB2R) can represent a helpful option in the treatment of OA. In this perspective, a set of 18 cannabinoid type-2 receptor (CB2R) ligands was developed based on an unprecedented structure. With the aim of improving the physicochemical properties of previously reported 4-hydroxy-2-quinolone-3-carboxamides, a structural optimization program led to the discovery of isosteric 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide derivatives. These new compounds are endowed with high affinity for the CB2R and moderate to good selectivity over the cannabinoid type-1 receptor (CB1R), associated with good physicochemical characteristics. As to the functional activity at the CB2R, compounds able to act either as agonists or as inverse agonists/antagonists were discovered. Among them, compound 51 emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA).

Reduction of osteoarthritis severity in the temporomandibular joint of rabbits treated with chondroitin sulfate and glucosamine.

Osteoarthritis is a degenerative disease that causes substantial changes in joint tissues, such as cartilage degeneration and subchondral bone sclerosis. Chondroitin sulfate and glucosamine are commonly used products for the symptomatic treatment of osteoarthritis. The aim of the present study was to investigate the effects of these products when used as structure-modifying drugs on the progression of osteoarthritis in the rabbit temporomandibular joint. Thirty-six New Zealand rabbits were divided into 3 groups (n = 12/group): control (no disease); osteoarthritis (disease induction); and treatment (disease induction and administration of chondroitin sulfate and glucosamine). Osteoarthritis was induced by intra-articular injection of monosodium iodoacetate. Animals were killed at 30 and 90 days after initiation of therapy. The treatment was effective in reducing disease severity, with late effects and changes in the concentration of glycosaminoglycans in the articular disc. The results indicate that chondroitin sulfate and glucosamine may have a structure-modifying effect on the tissues of rabbit temporomandibular joints altered by osteoarthritis.

Thermoresponsive Hyalomer intra-articular hydrogels improve monoiodoacetate-induced osteoarthritis in rats.

Osteoarthritis (OA) is characterized by degenerative knees, fingers and hip joints. In OA joints, the concentration and polymerization of hyaluronic acid (HA) are changed; affecting the viscosity of the synovial fluid. Replenishing HA synovial fluid content, along with an anti-inflammatory drug could be a cost-effective strategy. As free drugs are rapidly cleared out of the synovial fluid, we aimed to prepare Hyalomer in situ forming gel for intra-articular (IA) injection. Hyalomer contains poloxamer 407 (PX) as thermogelling agent, HA, and diclofenac potassium (DK) as an anti-inflammatory. Hyalomer formulations were prepared and characterized in terms of sol-gel transition, gelation time, in vitro release and 3-month stability. The selected Hyalomer formula was injected IA in OA rat model, in comparison to its individual components. The optimized Hyalomer formulation showed 25% DK release after 24 h and 40% after 4 days. The gelation time was 40 ± 2.08 s and gelation temperature was 26 ± 1.87 °C. Hyalomer maintained the percentage drug release and DK content after 3-months storage. In OA rats, Hyalomer showed the highest anti-nociceptive and anti-edematous effect. Both radiography and histopathology revealed regenerated cartilage profile in Hyalomer-treated group. combining IA HA and diclofenac in thermoresponsive gel represents a promising therapeutic alternative for OA.

Osthole ameliorates cartilage degradation by downregulation of NF-κB and HIF-2α pathways in an osteoarthritis murine model.

Osteoarthritis (OA) is a common and disabling joint disease mainly characterized by cartilage degradation, with the knees most commonly affected. No effective treatment for the cartilage degradation of OA exists. Preliminary studies have revealed the protective and osteogenic effects of osthole, a natural coumarin first isolated from Cnidium monnieri (Fructus Cnidii); however, no evidence of osthole in an OA-related model has been published to date. This study further explored the effects of osthole in a monoiodoacetate (MIA)-induced OA-related animal model and focused on the molecular mechanism(s) behind the anti-inflammatory and cartilage protective effects of osthole. This study revealed that the cartilage protective effect of osthole in a MIA-induced osteoarthritis (OA) murine model can be explained by downregulation of COX-2 and RUNX2 by inhibition of NF-κB and HIF-2α up-regulated by OA induction, resulting in downregulation of MMP-13, Syndecan IV and ADAMTS-5. In addition, osthole might have anti-inflammatory and analgesic effects due to COX-2 inhibition. Osthole can be considered as a potential component of the treatment of OA, for it possesses a cartilage protective effect, as well as anti-inflammation, analgesic, and movement improving effects. Further preclinical and human clinical studies are needed to examine the efficacy and safety profile of long-term therapy.

Protectin DX attenuates IL-1ß-induced inflammation via the AMPK/NF-κB pathway in chondrocytes and ameliorates osteoarthritis progression in a rat model.

Protectin DX (PDX) has been reported to have extensive anti-inflammatory effects. However, it is unknown whether PDX acts as an anti-inflammatory agent in the context of osteoarthritis (OA). This study aimed to evaluate the anti-inflammatory activity of PDX in vitro and in vivo in a model of OA. Primary rat chondrocytes were preincubated with PDX 1 h prior to IL-1ß treatment for 24 h. We found that PDX was nontoxic, and pretreatment with PDX increased cell viability in IL-1ß-induced chondrocytes. Preincubation with PDX also efficiently inhibited the degradation of type II collagen dose-dependently. Additionally, the expression of MMP-3, MMP-13, ADAMTS4, iNOS, COX-2, NO, and PGE2 decreased after IL-1ß stimulation when cells were preincubated with PDX. Moreover, PDX inhibited the increase in phosphorylated NF-κB p65 and IκBα upon IL-1ß stimulation, and the negative effects of IL-1ß on chondrocytes were partially blocked by treatment with pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor. In addition, we found that PDX increased AMPK phosphorylation in IL-1ß-mediated chondrocytes. The phosphorylation of AMPK could be inhibited by compound C, a classic AMPK inhibitor. Compound C also remarkably reversed the decrease in p65 phosphorylation and MMP-13 expression caused by PDX. Furthermore, nuclear translocation of NF-κB was visible by immunofluorescence after PDX-induced AMPK activation. Additionally, we verified that PDX ameliorated cartilage degradation in monosodium iodoacetate (MIA)-induced OA rats through histological evaluation and ELISA of TNF-α in the serum and intra-articular lavage fluid. In conclusion, we have shown that PDX suppresses inflammation in chondrocytes in vitro and in vivo, likely through the AMPK/NF-κB signaling pathway. Our results suggest that PDX could be a useful novel therapeutic agent for OA treatment.

KLF2 Protects against Osteoarthritis by Repressing Oxidative Response through Activation of Nrf2/ARE Signaling In Vitro and In Vivo.

Osteoarthritis (OA) is a multifactorial and inflammatory disease characterized by cartilage destruction that can cause disability among aging patients. There is currently no effective treatment that can arrest or reverse OA progression. Kruppel-like factor 2 (KLF2), a member of the zinc finger family, has emerged as a transcription factor involved in a wide variety of inflammatory diseases. Here, we identified that KLF2 expression is downregulated in IL-1ß-treated human chondrocytes and OA cartilage. Genetic and pharmacological overexpression of KLF2 suppressed IL-1ß-induced apoptosis and matrix degradation through the suppression of reactive oxygen species (ROS) production. In addition, KLF2 overexpression resulted in increased expression of heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1) through the enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Further, Nrf2 inhibition abrogated the chondroprotective effects of KLF2. Safranin O/fast green and TUNEL staining demonstrated that adenovirus-mediated overexpression of KLF2 in joint cartilage protects rats against experimental OA by inhibiting cartilage degradation and chondrocyte apoptosis. Immunohistochemical staining revealed that KLF2 overexpression significantly decreases MMP13 expression caused by OA progression in vivo. This in vitro and in vivo study is the first to investigate the antioxidative effect and mechanisms of KLF2 in OA pathogenesis. Our results collectively provide new insights into OA pathogenesis regulated by KLF2 and a rationale for the development of effective OA intervention strategies.

Effects of Extract of Arrabidaea chica Verlot on an Experimental Model of Osteoarthritis.

The aim of this study was to analyze the analgesic potential of Arrabidaea chica extract (EHA) as an alternative to osteoarthritis (OA) treatment. Thus, the extract was initially evaluated by the cyclooxygenase inhibition test. The analgesic effect of the extract, in vivo, was also verified in a model of OA induced by sodium monoiodoacetate (2 mg). EHA was administered to rats at doses of 50, 150, and 450 mg/kg between 3 and 25 days after OA induction. The animals were clinically evaluated every 7 days, euthanized at 29 days, and the liver, spleen, kidney and knee collected for histopathological analysis. The chemical composition of EHA was identified by HPLC-MS and the identified compounds submitted to molecular docking study. The results showed that the extract promoted cyclooxygenase inhibition and produced significant improvements in disability, motor activity, hyperalgesia, and OA-induced allodynia parameters, in addition to improvements in the radiological condition of the knees (but not observed in the histopathological study). Chemically the extract is rich in flavonoids. Among them, we evidence that amentoflavone showed very favorable interactions with the enzyme COX-2 in the in silico analysis. Thus, it is concluded that A. chica has important analgesic properties for the treatment of OA.

The influence of probiotic diet and chondroitin sulfate administration on Ptgs2, Tgfb1 and Col2a1 expression in rat knee cartilage during monoiodoacetate-induced osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a common worldwide disease induced by a wide range of biochemical processes, mainly inflammation and degradation of collagen. The aim of this study, was to describe the effect of a multistrain probiotic (PB) and chondroitin sulfate (CS), administered separately or in combination, on the expression of Ptgs2, Tgfb1 and Col2a1 during monoiodoacetate-induced OA in male rats. METHODS: OA was induced in male rats by injecting monoiodoacetate in right hind knee. Therapeutic groups received 3 mg/kg of CS for 28 days and/or 1.4 g/kg of multistrain PB for 14 days. Knee cartilage were taken 30 days after monoiodoacetate injection. RNA was extracted and the expression of Ptgs2, Tgfb1 and Col2a1 were analyzed using SYBR Green 1-step real-time quantitative polymerase chain reaction. RESULTS: Induction of OA caused an upregulation in Ptgs2, Tgfb1 expression, and downregulation of Col2a1. Separate administration of PB and CS reduced Ptgs2 and Tgfb1 expressions. Their combined administration significantly decreased the expression of these pro-inflammatory cytokines, comparable to controls. Expression of Col2a1 showed similar behavior, with upregulation in therapeutic group with separate administration and the cumulative effects in case of co-administration. CONCLUSIONS: The multistrain PB diet may offer a perspective to improve the standard treatment of OA and, necessitates further investigation with clinical trials.

Lactobacillus acidophilus ameliorates pain and cartilage degradation in experimental osteoarthritis.

Osteoarthritis (OA) is a chronic and degenerative disease that causes pain, cartilage deformation, and joint inflammation. Lactobacillus species have been used as dietary supplements to induce the production of antimicrobial and anti-inflammatory factors. The goal of this study was to determine whether Lactobacillus acidophilus ameliorates monosodium iodoacetate-induced OA. L. acidophilus showed anti-nociceptive properties and protected against cartilage destruction. It also downregulated the levels of proinflammatory cytokines and increased the levels of anti-inflammatory cytokines in the joints of OA rats. L. acidophilus additionally restored the balance between anabolic and catabolic factors in chondrocytes from OA patients. These results suggest that L. acidophilus can alleviate OA-associated pain and delay the progression of the disease by inhibiting proinflammatory cytokine production and reducing cartilage damage.

Avocado soybean unsaponifiables ameliorates cartilage and subchondral bone degeneration in mono-iodoacetate-induced knee osteoarthritis in rats.

Osteoarthritis (OA), the most common type of arthritis, is a disabling progressive disease mainly affecting the elderly and is becoming a major public health problem. Current therapies for OA provide only palliative pain relief and therapeutic candidates that are able to slow the progression of structural deterioration is a major unmet need for this disorder. Avocado soybean unsaponifiables (ASU) has proven its safety and effectiveness in clinical studies of knee osteoarthritis (OA); however, whether ASU exerts structure-modifying effects is still to be elucidated. There are limited studies that have explored the underlying mechanisms of ASU's beneficial effects in animal models of OA. To this end, this study is the first to evaluate the effects of ASU in a rat model of mono-iodoacetate (MIA)-induced knee OA. OA was induced in rats by knee intra-patellar injection of MIA. Oral administration of ASU (27.5 mg/kg per day for 3 weeks) was initiated 3 weeks after MIA injection. We analysed the knee samples using light and electron microscopy. In addition, we used immunohistochemistry to investigate the expression of inducible nitric oxide synthase (iNOS), tumour necrosis factor-α (TNF-α), and matrix metalloproteinase-13 (MMP-13) in OA cartilage and subchondral bone. ASU significantly attenuated the synovium, cartilage, and subchondral degeneration. In addition, it reduced the expression of TNF-α and MMP-13 in OA cartilage and the expression of iNOS in both OA cartilage and subchondral bone. These results provide evidence of the structure-modifying abilities of ASU via its anti-oxidative and anti-inflammatory properties, in addition to its ability to modulate MMP-13 activity. This work suggests that ASU can be used as a potential disease-modifying treatment for OA.