Osteostatin Mitigates Gouty Arthritis through the Inhibition of Caspase-1 Activation and Upregulation of Nrf2 Expression.

Gouty arthritis results from monosodium urate (MSU) crystal deposition in joints, initiating (pro)-interleukin (IL)-1ß maturation, inflammatory mediator release, and neutrophil infiltration, leading to joint swelling and pain. Parathyroid hormone-related protein (107-111) C-terminal peptide (osteostatin) has shown anti-inflammatory properties in osteoblasts and collagen-induced arthritis in mice, but its impact in gouty arthritis models remains unexplored. We investigated the effect of osteostatin on pyroptosis, inflammation, and oxidation in macrophages, as well as its role in the formation of calcium pyrophosphate dihydrate crystals and MSU-induced gouty arthritis in mice models. Osteostatin ameliorated pyroptosis induced by lipopolysaccharide and adenosine 5'-triphosphate (LPS + ATP) in mice peritoneal macrophages by reducing the expression of caspase-1, lactate dehydrogenase release, and IL-1ß and IL-18 secretion. Additionally, IL-6 and tumor necrosis factor-α (TNF-α) were also decreased due to the reduced activation of the NF-κB pathway. Furthermore, osteostatin displayed antioxidant properties in LPS + ATP-stimulated macrophages, resulting in reduced production of mitochondrial and extracellular reactive oxygen species and enhanced Nrf2 translocation to the nuclei. In both models of gouty arthritis, osteostatin administration resulted in reduced pro-inflammatory cytokine production, decreased leukocyte migration, and reduced caspase-1 and NF-κB activation. These results highlight the potential of osteostatin as a therapeutic option for gouty arthritis.

Systemic and local effect of oxidative stress on recurrent aphthous stomatitis: systematic review.

Recurrent aphthous stomatitis (RAS) is a chronic and recurrent inflammatory disease of the mouth. It is characterised by the appearance of painful ulcers in the oral mucosa. RAS is believed to be a multifactorial disease with genetic predisposition, environmental factors and alterations in the immune system. Oxidative stress, caused by an imbalance between free radicals and the antioxidant system, also appears to be involved in the pathogenesis of RAS. Several risk factors, such as smoking, iron and vitamin deficiency and anxiety, may contribute to the development of the disease. Understanding the underlying mechanisms may help in the prevention and treatment of RAS. We searched PubMed, Scopus and Web of Science databases for articles on oxidative stress in patients with RAS from 2000 to 2023. Studies analysing oxidant and antioxidant levels in the blood and saliva of RAS patients and healthy controls were selected. Of 170 potentially eligible articles, 24 met the inclusion criteria: 11 studies on blood samples, 6 on salivary samples and 7 on both blood and salivary samples. Multiple oxidative and antioxidant markers were assessed in blood and saliva samples. Overall, statistically significant differences were found between RAS patients and healthy controls for most markers. In addition, increased oxidative DNA damage was observed in patients with RAS. Patients with RAS show elevated levels of oxidative stress compared to healthy controls, with a significant increase in oxidative markers and a significant decrease in antioxidant defences in saliva and blood samples.

Antioxidant treatments in patients with oral submucous fibrosis: A systematic review.

INTRODUCTION: Oral submucous fibrosis (OSMF) is a well-known precancerous oral lesion, characterized by scarring, tissue fibrosis, and premalignant lesions. The goal of clinical treatment is to reduce inflammation and improve patients' quality of life by enhancing mouth opening among others. Antioxidant treatment has shown promising results in inducing regression of lesions and preventing OSMF in high-risk individuals. This study investigates the effectiveness of various antioxidant agents against OSMF. MATERIALS AND METHODS: The study followed PRISMA guidelines and searched three scientific databases: PubMed, Web of Science, and Scopus, using specific algorithms related to "antioxidant treatment," "burning sensation," and "mouth opening." The quality assessment of controlled clinical studies adhered to Cochrane guidelines. RESULTS: The analysis included 19 clinical trials comparing different treatments, including various antioxidants. Aloe vera, curcumin, and lycopene, among others, showed positive outcomes in treating OSMF by improving burning sensation, mouth opening, tongue protrusion, and cheek flexibility. CONCLUSION: Antioxidant therapies are found to be effective in treating OSMF, even when compared to conventional treatments such as corticosteroids. The study highlights the need for further research and standardization of clinical protocols.

Efficacy of stem cells in bone rehabilitation in patients with alveolar bone atrophy: a systematic review

Background: Biomedical engineering proposes the use of stem cells as a bone rehabilitation treatment in patients with alveolar bone defects. Many authors suggest that this innovative technique could represent the future of bone regeneration in dentistry. The present study systematically reviewed the efficacy of stem cells in bone regeneration in patients with alveolar bone atrophy. Material and methods: The study was developed following the criteria of the PRISMA guideline (2020). The literature review was conducted in Pubmed, Medline Complete, and Scopus. The search algorithms used the following key words: stem cells, bone regeneration, and alveolar ridge augmentation. To assess the risk of bias, the CASPe methodology was used. Results: Seven clinical trials in humans were included in this systematic review. In all the studies, the proposed objective of bone regeneration by using stem cells was achieved, although in a different way with different results. Although the authors of the analysed clinical trials achieved favourable results, they highlighted the presence of multiple limitations throughout bone regeneration treatments, such as scarce scientific literature on stem cells, a reduced number of follow-up studies, and a lack of a standardized international protocol. Conclusions: Based on the analysed studies, it is concluded that the therapy proposed by tissue engineering through the use of stem cells to rehabilitate patients with bone atrophies can be considered effective. In addition, the need for further studies and standardization of protocols is highlighted. (AU)

Extracellular Vesicles Do Not Mediate the Anti-Inflammatory Actions of Mouse-Derived Adipose Tissue Mesenchymal Stem Cells Secretome.

Adipose tissue represents an abundant source of mesenchymal stem cells (MSC) for therapeutic purposes. Previous studies have demonstrated the anti-inflammatory potential of adipose tissue-derived MSC (ASC). Extracellular vesicles (EV) present in the conditioned medium (CM) have been shown to mediate the cytoprotective effects of human ASC secretome. Nevertheless, the role of EV in the anti-inflammatory effects of mouse-derived ASC is not known. The current study has investigated the influence of mouse-derived ASC CM and its fractions on the response of mouse-derived peritoneal macrophages against lipopolysaccharide (LPS). CM and its soluble fraction reduced the release of pro-inflammatory cytokines, adenosine triphosphate and nitric oxide in stimulated cells. They also enhanced the migration of neutrophils or monocytes, in the absence or presence of LPS, respectively, which is likely related to the presence of chemokines, and reduced the phagocytic response. The anti-inflammatory effect of CM may be dependent on the regulation of toll-like receptor 4 expression and nuclear factor-κB activation. Our results demonstrate the anti-inflammatory effects of mouse-derived ASC secretome in mouse-derived peritoneal macrophages stimulated with LPS and show that they are not mediated by EV.

Chondroprotective effects of the combination chondroitin sulfate-glucosamine in a model of osteoarthritis induced by anterior cruciate ligament transection in ovariectomised rats.

CONTEXT: The efficacy of the combination chondroitin sulfate-glucosamine (CS-GlcN) in the treatment of knee osteoarthritis (OA) has been suggested in recent clinical studies. In vitro reports have also suggested anti-inflammatory and anti-resorptive effects of this combination. OBJECTIVE: The aim of this study was to characterize the effects of CS-GlcN on joint degradation in vivo including the assessment of inflammation and bone metabolism in a model of OA. MATERIALS AND METHODS: We have used the OA model induced by anterior cruciate ligament transection (ACLT) in ovariectomised rats. CS-GlcN was administered daily (oral gavage) from week 0 until week 12 after ovariectomy at the dose of 140 (CS)+175 (GlcN)(HCl) mg/kg. Histochemical analyses were performed, the levels of biomarkers and inflammatory mediators were measured by luminex or ELISA and bone microstructure was determined by µCT. RESULTS: CS-GlcN protected against cartilage degradation and reduced the levels of inflammatory mediators such as interleukin-1ß and tumor necrosis factor-α in the affected knee. In addition, serum biomarkers of inflammation and cartilage and bone degradation including matrix metalloproteinase-3, C-telopeptide of type II collagen and the ratio receptor activator of nuclear factor κB ligand/osteoprotegerin were significantly decreased by CS-GlcN. This treatment also tended to improve some bone microstructural parameters without reaching statistical significance. DISCUSSION AND CONCLUSIONS: These results demonstrate the chondroprotective effects of CS-GlcN in vivo, in the experimental model of ACLT in ovariectomised rats, and suggest that this combination may be useful to control the joint catabolic effects of inflammatory stress. These findings could have clinical relevance related to the prevention of joint degradation by CS-GlcN and support the potential development of OA treatments based on this combination.

Paracrine in vivo inhibitory effects of adipose tissue-derived mesenchymal stromal cells in the early stages of the acute inflammatory response.

BACKGROUND AIMS: Excessive or unresolved inflammation leads to tissue lesions. Adipose tissue-derived mesenchymal stromal cells (AMSCs) have shown protective effects that may be dependent on the modulation of inflammation by secreted factors. METHODS: We used the zymosan-induced mouse air pouch model at two time points (4 h and 18 h) to evaluate the in vivo effects of AMSCs and their conditioned medium (CM) on key steps of the early inflammatory response. We assessed the effects of AMSCs and CM on leukocyte migration and myeloperoxidase activity. The levels of chemokines, cytokines and eicosanoids in exudates were measured by use of enzyme-linked immunoassay or radio-immunoassay. In addition, the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1) was studied by use of Western blotting and the phosphorylation of p65 nuclear factor-κB (NF-κB) by immunofluorescence. RESULTS: All inflammatory parameters were significantly reduced by CM and AMSCs to a similar extent at 4 h after zymosan injection with lower effects at 18 h. The observed inhibition of leukocyte migration was associated with reduced levels of chemokines and leukotriene B4. Interleukin-1ß, interleukin-6, tumor necrosis factor-α and tumor necrosis factor-stimulated gene 6 levels were significantly decreased. The downregulation of mPGES-1 was associated with inhibition of prostaglandin E2 production. Our results suggest that these anti-inflammatory effects are related, in part, to the inhibition of NF-κB activation. CONCLUSIONS: AMSCs dampen the early process of inflammation in the zymosan-induced mouse air pouch model through paracrine mechanisms. These results support the potential utility of these cells as a source of novel treatment approaches for inflammatory pathologies.

Effects of BIS076 in a model of osteoarthritis induced by anterior cruciate ligament transection in ovariectomised rats.

BACKGROUND: Osteoarthritis (OA) is the most frequent articular disease and a leading cause of disability. There is a need for effective treatments able to slow the progression of disease. Some of the available treatments are dietary supplements providing natural components. Recent studies have shown that estrogen deficiency contributes to the pathophysiological events of OA progression. METHODS: We have used the anterior cruciate ligament transection model of OA in ovariectomised rats to study the effects of BIS076, a new formulation of a natural porcine cartilage extract associated with hydroxyapatite (as a source of calcium) and vitamin D3. Cartilage degradation, proteoglycan depletion and synovitis were followed by histochemistry. Effects on bone microstructure were determined by µCT. The levels of biomarkers in serum and inflammatory mediators in knee homogenates were measured by luminex or ELISA. RESULTS: Oral administration of BIS076 reduced articular cartilage damage and serum levels of cartilage degradation markers C-telopeptide of type II collagen and cartilage oligomeric matrix protein, as well as matrix metalloproteinase-3. The local inflammatory response was down-regulated by BIS076 with lower production of pro-inflammatory cytokines and prostaglandin E2 in joint tissues. In addition, BIS076 was effective on metaphyseal bone alterations as this formulation increased volumetric bone mineral density and improved bone micro-architecture. These effects were related to the modification of bone metabolism reflected by changes in bone biomarkers with reductions in the ratio receptor activator of nuclear factor κB ligand/osteoprotegerin and the levels of tartrate-resistant acid phosphatase-5b, suggesting an inhibitory activity of BIS076 on trabecular bone resorption. CONCLUSIONS: We have demonstrated the protective properties of a new formulation (BIS076) on joint lesion and bone alterations in an experimental model of OA in ovariectomised rats. This study supports the interest of BIS076 in OA treatments.