Osteoarthritis (OA) is a complicated degenerative disease that affects whole joint tissue. Currently, apart from surgical approaches to treat late stage OA, effective treatments to reverse OA are not available. Thus, the mechanisms leading to OA, and more effective approaches to treat OA should be investigated. According to available evidence, the PI3K/AKT/mTOR signaling pathway is essential for normal metabolism of joint tissues, but is also involved in development of OA. To provide a wide viewpoint to roles of PI3K/ AKT/mTOR signaling pathway in osteoarthritis, a comprehensive literature search was performed using PubMed terms 'PI3K OR AKT OR mTOR' and 'osteoarthritis'. This review highlights the role of PI3K/AKT/ mTOR signaling in cartilage degradation, subchondral bone dysfunction, and synovial inflammation, and discusses how this signaling pathway affects development of the disease. We also summarize recent evidences of therapeutic approaches to treat OA by targeting the PI3K/AKT/mTOR pathway, and discuss potential challenges in developing these strategies for clinical treatment of OA.
Light has been widely used for cancer therapeutics such as photodynamic therapy (PDT) and photothermal therapy. This paper describes a strategy called enzyme-enhanced phototherapy (EEPT) for cancer treatment. We constructed a nanoparticle platform by covalent conjugation of glucose oxidase (GOx) to small polymer dots, which could be persistently immobilized into a tumor. While the malignant tumors have high glucose uptake, the GOx efficiently catalyzes the glucose oxidation with simultaneous generation of HO. Under light irradiation, the in situ generated HO was photolyzed to produce hydroxyl radical, the most reactive oxygen species, for killing cancer cells. In vitro assays indicated that the cancer cells were destroyed by using a nanoparticle concentration at 0.2 μg/mL and a light dose of ∼120 J/cm, indicating the significantly enhanced efficiency of the EEPT method when compared to typical PDT that requires a photosensitizer of >10 μg/mL for effective cell killing under the same light dose. Furthermore, remarkable inhibition of tumor growth was observed in xenograft-bearing mice, indicating the promise of the EEPT approach for cancer therapeutics.
Small molecules participate extensively in various life processes. However, specific and sensitive detection of small molecules in a living system is highly challenging. Here, we describe in vivo real-time dynamic monitoring of small molecules by a luminescent polymer-dot oxygen transducer. The optical transducer combined with an oxygen-consuming enzyme can sensitively detect small-molecule substrates as the enzyme-catalyzed reaction depletes its internal oxygen reservoir in the presence of small molecules. We exemplify this detection strategy by using glucose-oxidase-functionalized polymer dots, yielding high selectivity, large dynamic range, and reversible glucose detection in cell and tissue environments. The transducer-enzyme assembly after subcutaneous implantation provides a strong luminescence signal that is transdermally detectable and continuously responsive to blood glucose fluctuations for up to 30 days. In view of a large library of oxygen-consuming enzymes, this strategy is promising for in vivo detection and quantitative determination of a variety of small molecules.
We realized white light-emitting diodes with high color rendering index (85-96) and widely variable color temperatures (2805-7786 K) by combining three phosphors based on carbon dots and polymer dots, whose solid-state photoluminescence self-quenching was efficiently suppressed within a polyvinyl pyrrolidone matrix. All three phosphors exhibited dominant absorption in the UV spectral region, which ensured the weak reabsorption and no energy transfer crosstalk. The WLEDs showed excellent color stability against the increasing current because of the similar response of the tricolor phosphors to the UV light variation.
Summary Background Osteoarthritis (OA) is a complex process comprised of mechanical load, inflammation, and metabolic factors. It is still unknown that if chondrocytes undergo ferroptosis during OA and if ferroptosis contribute to the progression of OA. Materials and methods In our study, we use Interleukin-1 Beta (IL-1β) to simulate inflammation and ferric ammonium citrate (FAC) to simulate the iron overload in vitro . Also, we used the surgery-induced destabilized medial meniscus (DMM) mouse model to induce OA in vivo . We verify ferroptosis by its definition that defined by the Nomenclature Committee on Cell Death with both in vitro and in vivo model. Results We observed that both IL-1β and FAC induced reactive oxygen species (ROS), and lipid ROS accumulation and ferroptosis related protein expression changes in chondrocytes. Ferrostatin-1, a ferroptosis specific inhibitor, attenuated the cytotoxicity, ROS and lipid-ROS accumulation and ferroptosis related protein expression changes induced by IL-1β and FAC and facilitated the activation of Nrf2 antioxidant system. Moreover, erastin, the most classic inducer of ferroptosis, promoted matrix metalloproteinase 13 (MMP13) expression while inhibited type II collagen (collagen II) expression in chondrocytes. At last, we proved that intraarticular injection of ferrostatin-1 rescued the collagen II expression and attenuated the cartilage degradation and OA progression in mice OA model. Conclusions In summary, our study firstly proved that chondrocytes underwent ferroptosis under inflammation and iron overload condition. Induction of ferroptosis caused increased MMP13 expression and decreased collagen II expression in chondrocytes. Furthermore, inhibition of ferroptosis, by intraarticular injection of ferrostatin-1, in our case, seems to be a novel and promising option for the prevention of OA. The translational potential of this article The translation potential of this article is that we first indicated that chondrocyte ferroptosis contribute to the progression of osteoarthritis which provides a novel strategy in the prevention of OA.
This paper described the energy-transfer amplified singlet oxygen generation in semiconductor polymer dots (Pdots) for in vitro and in vivo photodynamic therapy. Hydrophobic photosensitizer tetraphenylporphyrin was facilely doped in the nanoparticles consisting of densely packed semiconductor polymers. Optical characterizations indicated that the fluorescence of Pdots was completely quenched by the photosensitizer, yielding an energy transfer efficiency of nearly 100% and singlet-oxygen generation quantum yield of ∼50%. We evaluated the cellular uptake, dark toxicity, and photodynamic therapy of the Pdot photosensizer in human gastric adenocarcinoma cells. The in vitro studies indicated that cancer cells were efficiently destroyed at very low dose of the Pdots such as 1 μg/mL by using the light dose of 90 J/cm(2), which is considerably less than that in clinical practice. The antitumor effect of the Pdots was further evaluated in vivo with human gastric adenocarcinoma xenografts in Balb/c nude mice, which show that the xenograft tumors were significantly inhibited and eradicated in some cases. Our results indicate the energy transfer amplified Pdot platforms have great therapeutic potential for treating malignant cancers.
Mitochondrial dysfunction is involved in aging and multiple degenerative diseases, including intervertebral disc degeneration (IVDD) and osteoarthritis (OA). Thus, the maintenance of mitochondria homeostasis and function is important. Mitophagy, a process that selectively clears damaged or dysfunctional mitochondria through autophagic machinery, functions to maintain mitochondrial quality control and homeostasis. IVDD and OA are similar joint diseases involving the degradation of cartilaginous tissues that are mainly caused by oxidative stress, cell apoptosis and extracellular matrix (ECM) degradation. Over the past decade, accumulating evidence indicates the essential role of mitophagy in the pathogenesis of IVDD and OA. Importantly, strategies by the regulation of mitophagy exert beneficial effects in the pre-clinical experiments. Given the importance and novelty of mitophagy, we provide an overview of mitophagy pathways and discuss the roles of mitophagy in IVDD and OA. We also highlight the potential of targeting mitophagy for the treatment of degenerative joint diseases.
Optical methods such as absorptiometry, fluorescence, and surface plasmon resonance have long been explored for sensing glucose. However, these schemes have not had the clinical success of electrochemical methods for point-of-care testing because of the limited performance of optical sensors and the bulky instruments they require. Here, we show that an ultrasensitive optical transducer can be used for wireless glucose monitoring via a smartphone. The optical transducer combines oxygen-sensitive polymer dots (Pdots) with glucose oxidase that sensitively detect glucose when oxygen is consumed in the glucose oxidation reaction. By judicious design of the Pdots with ultralong phosphorescence lifetime, the transducer exhibited a significantly enhanced sensitivity by 1 order of magnitude as compared to the one in a previous study. As a result, the optical images of subcutaneous glucose level obtained with the smartphone camera could be utilized to clearly distinguish between euglycemia and hyperglycemia. We further developed an image processing algorithm and a software application that was installed on a smartphone. Real-time dynamic glucose monitoring in live mice was demonstrated with the smartphone and the implanted Pdot transducer.
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