Diabetic hyperglycemia has been suggested to play a role in osteoarthritis. Peroxisome proliferator-activated receptor-g (PPARg) was implicated in several pathological conditions including diabetes and inflammation. The detailed effects and mechanisms of hyperglycemia on cartilage damage still need to be clarified. Here, we investigated the role of PPARg in hyperglycemia-triggered chondrocyte/cartilage damages using a human chondrocyte culture model and a diabetic mouse model. Human chondrocytes were cultured and treated with high concentration of glucose (30 mM) to mimic hyperglycemia in the presence or absence of pioglitazone, a PPARg agonist. Streptozotocin (STZ) was used to induce mouse diabetes. Our data showed that high glucose induced the protein expressions of cyclooxygenase-2 (COX-2) and production of prostaglandin-E 2 (PGE 2 ), interleukin-6 (IL-6), and metalloproteinase-13 (MMP-13), but decreased the protein expression of collagen II and PPARg in human chondrocytes. These alterations in high glucosetreated human chondrocytes could be reversed by pioglitazone in a dose-dependent manner. Moreover, pioglitazone administration could also significantly reverse the hyperglycemia, formation of AGEs, productions of IL-6 and MMP-13, and cartilage damage in STZinduced diabetic mice. Taken together, these findings suggest that hyperglycemia down-regulates PPARg expression and induces inflammatory and catabolic responses in human chondrocytes and diabetic mouse cartilages. Keywords: PPARg; diabetes; osteoarthritis; chondrocyte; collagen Chondrocytes, which are the only cellular components of cartilage, are embedded in extensive extracellular matrix (ECM) and maintain equilibrium between anabolic and catabolic activities under normal physiological circumstances. 1,2 Cartilage damage is caused by the imbalance between catabolic and anabolic capacities of chondrocytes. Catabolic activities of chondrocytes are related to the elevated release of cartilage degrading enzymes, such as matrix metalloproteinases (MMPs), while anabolic activities result in the productions of type II collagen and aggrecan. 3 MMPs are usually minimally expressed in normal physiological conditions while are highly induced under special pathological conditions, such as inflammation or arthritis. [4][5][6] In the joint cartilage, MMPs, synthesized and secreted by the residing chondrocytes, play a role in degrading ECM. 6 MMP-13 (collagenase-3) actively degrades type II collagen, which is a major collagen type related to build up the structural backbone of ECM in the cartilage. 7,8 Osteoarthritis (OA), one of the most common forms of arthritis diseases, is a progressive degenerative joint disease with signs and symptoms of inflammation, leading to significant functional impairment and disability in older adults. Growing evidence indicates that metabolic factors play a key role in the progression of arthritis diseases. 9 OA has recently been suggested to have a positive correlation with glucose imbalance, metabolic dysfunction, and diabe...
Honokiol, a component of the herb Magnolia officinalis , exhibits antioxidant, anti-inflammatory and anxiolytic properties, increases seizure threshold, and promotes neurite outgrowth. Because stroke has become the second leading cause of death in industrialized countries, an effective neuroprotectant is urgently required. In this study, we attempted to elucidate in a mouse cerebral ischaemia model whether honokiol could be a neuroprotectant. Adult male Institute of Cancer Research (ICR) mice were subjected to middle cerebral artery occlusion for 45 min. Honokiol (10 µ g/kg in 0.2 ml of saline) or control vehicle was intraperitoneally administered twice, 15 min. before and 60 min. after the induction of ischaemia. Cerebral ischaemia induced by this method was associated with an increase in synaptosomal production of reactive oxygen species, with decreases in synaptosomal mitochondrial membrane potential ( ∆Ψ m) and synaptosomal mitochondrial metabolic function, and with reductions in Na + , K + -ATPase activities of tissues isolated from selected brain regions. Administration of honokiol resulted in significant reductions in brain infarct volume and in synaptosomal production of reactive oxygen species. The decreases in synaptosomal mitochondrial membrane potential, synaptosomal mitochondrial metabolic function and tissue Na + , K + -ATPase activities observed in the ischaemic brains were also attenuated by honokiol treatments. It is concluded that honokiol can protect brain against ischaemic reperfusion injury and preserve mitochondrial function from oxidative stress. Regarding therapeutic application, further studies are needed to assess the efficacy and safety of honokiol in clinical situations. Therefore, honokiol appears to exert a broad spectrum of effects with potential clinical relevance to brain ischaemia, brain trauma, seizures, neurodegenerative diseases, neuroregeneration and anxiety. However, few studies have been conducted to evaluate the possible therapeutic effects of this agent in the diseased brain.With an incidence approximating 250 -400 per 100,000 individuals and a mortality rate approximating 30%, stroke has become the second leading cause of death in industrialized countries [7]. During cerebral ischaemia, the substrates required for energy production are rapidly depleted and mitochondrial dysfunction is observed. Mitochondrial ATP depletion is a critical factor in determining neuronal cell death. The production of ATP is critical for the maintenance of the ion pumping activity of Na + , K + -ATPase. This enzyme regulates the ionic concentration gradients in neurones for stimulating the generation of action potentials. Evidence accumulated indicates that this enzyme is most sensitive to reactive oxygen species (ROS) and thus changes of ATP production [8]. Therefore, we monitored this enzymic activity as an indicator of the degree of brain injury after ischaemic insult.An initial event generated during cerebral ischaemia is the production of ROS, which induces oxidation of cellula...
Titanium dioxide nanoparticles (Nano-TiO2) are gradually being used extensively in clinical settings, industry, and daily life. Accumulation studies showed that Nano-TiO2 exposure is able to cause injuries in various animal organs, including the lung, liver, spleen, and kidney. However, it remains unclear whether exposure of Nano-TiO2 by inhalation causes renal fibrosis. Here, we investigated the role of reactive oxygen species (ROS)/reactive nitrogen species (RNS) related signaling molecules in chronic renal damage after Nano-TiO2 inhalation in mice. Mice were treated with Nano-TiO2 (0.1, 0.25, and 0.5 mg/week) or microparticle-TiO2 (0.5 mg/week) by nonsurgical intratracheal instillation for 4 weeks. The results showed that Nano-TiO2 inhalation increased renal pathological changes in a dose-dependent manner. No renal pathological changes were observed in microparticle-TiO2-instilled mice. Nano-TiO2 (0.5 mg/week) possessed the ability to precipitate in the kidneys, determined by transmission electron microscopy and increased serum levels of blood urea nitrogen. The expressions of markers of ROS/RNS and renal fibrosis markers, including nitrotyrosine, inducible nitric oxide synthase, hypoxia inducible factor-1α (HIF-1α), heme oxygenase 1, transforming growth factor-β (TGFβ), and collagen I, determined by immunohistochemical staining were increased in the kidneys. Furthermore, Nano-TiO2-induced renal injury could be mitigated by iNOS inhibitor aminoguanidine and ROS scavenger N-acetylcysteine treatment in transcription level. The in vitro experiments showed that Nano-TiO2 significantly and dose-dependently increased the ROS production and the expressions of HIF-1α and TGFβ in human renal proximal tubular cells, which could be reversed by N-acetylcysteine treatment. Taken together, these results suggest Nano-TiO2 inhalation might induce renal fibrosis through a ROS/RNS-related HIF-1α-upregulated TGF-β signaling pathway.
NMDA receptors are abundant, ubiquitously distributed throughout the brain, fundamental to excitatory neurotransmission, and critical for normal CNS function. However, excessive glutamate overstimulates NMDA receptors, leading to increased intracellular calcium and excitotoxicity. Mitochondrial dysfunction associated with loss of Ca(2+)homeostasis and enhanced cellular oxidative stress has long been recognized to play a major role in cell damage associated with excitotoxicity. In this experiment, we attempted to explore whether treatment with memantine (an NMDA receptor antagonist) and tea polyphenol (an antioxidant and anti-inflammatory agent), either alone or in combination, is effective in neuroprotection in a mouse excitotoxic injury model. Memantine (10 mg/kg/day), tea polyphenol (60 mg/kg/day), or a combination (memantine 5 mg/kg/day plus tea polyphenol 30 mg/kg/day) was administered by oral gavage for 2 consecutive days before causing excitotoxic injury. Mice received a 0.3-microL NMDA [335 mM (pH 7.2)] injection into the left striatum. Locomotor activity was assessed 24 hr before and after excitotoxic injury. Brain synaptosomes were harvested 24 hr after excitotoxic injury for assessment of Na(+), K(+)-ATPase and Mg(2+)-ATPase activity, reactive oxygen species production, mitochondrial membrane potential (Delta Psi m), mitochondrial reductase activity (MTT test), and Ca(2+)concentration. The results showed that treatment with memantine could significantly rescue mitochondrial function by attenuating the decreased mitochondrial membrane potential (Delta Psi m) and mitochondrial reductase activity in mouse excitotoxic injury. Treatment with tea polyphenol could significantly decrease the increased production of synaptosomal reactive oxygen species (ROS) and thus reduced the deteriorative ROS-sensitive Na(+), K(+)-ATPase and Mg(2+)-ATPase activity. However, neither memantine nor tea polyphenol alone could significantly improve the impaired locomotor activity unless treatment was combined. Combined treatment with memantine and tea polyphenol could significantly protect mice against excitotoxic injury by reducing the increased synaptosomal ROS production, attenuating the decreased Na(+), K(+)-ATPase and Mg(2+)-ATPase activity, the mitochondrial membrane potential (Delta Psi m), the mitochondrial reductase activity, and the increased synaptosomal Ca(2+)concentration. In addition, the impairment in locomotor activity was also significantly improved. Therefore, the combined treatment of memantine and tea polyphenol is more effective in neuroprotection than either memantine or tea polyphenol alone in mouse excitotoxic injury. These findings provide useful information about the potential application of memantine and tea polyphenols in preventing clinical excitotoxic injury such as brain trauma, brain ischemia, epilepsy, and Alzheimer's disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.