Correction to: TREM2 Attenuates Aß1-42-Mediated Neuroinflammation in BV-2 Cells by Downregulating TLR Signaling.

The article titled "TREM2 Attenuates Aß1­42­Mediated Neuroinflammation in BV­2 Cells by Downregulating TLR Signaling", written by Huiping Long, Gang Zhong, Chengzhi Wang, Jian Zhang, Yueling Zhang, Jinglian Luo, Shengliang Shi, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 27 May 2019 with open access.

TREM2 Attenuates Aß1-42-Mediated Neuroinflammation in BV-2 Cells by Downregulating TLR Signaling.

The pathogenesis of late-onset Alzheimer's disease (LOAD) mainly involves abnormal accumulation of extracellular ß-amyloid (Aß) and the consequent neurotoxic effects. The triggering receptor expressed on myeloid cells 2 (TREM2) gene is associated with the pathogenesis of LOAD and plays important roles in mediating the phagocytosis of Aß by microglia and regulating inflammation in central nervous system. However, the exact mechanisms of these processes have not yet been clarified. In this study, we investigated the mechanism by which TREM2 regulates neuroinflammation and promotes Aß1-42 clearance by BV-2 cells and further elucidated the underlying molecular mechanisms. We either silenced or overexpressed TREM2 in BV-2 cells and evaluated the cell viability, Aß1-42 content, and expression of inflammatory markers (IL-1ß, IL-6, and TNF-α). TREM2 overexpression up-regulated cell activity, promoted clearance of Aß1-42 by BV-2 cells, and down-regulated expression of the inflammatory factors. In addition, TREM2 overexpression downregulation the expression of the TLR family (TLR2, TLR4 and TLR6) in BV-2 cells. Moreover, LPS, as an agonist of the TLR family, up-regulated the expression of inflammatory cytokines (IL-1ß, TNF-α, and IL-6) in BV-2 cells overexpressing TREM2. In conclusion, TREM2 promoted clearance of Aß1-42 by BV-2 cells and restored BV-2 cell viability from Aß1-42-mediated neuroinflammation by downregulating TLRs. These findings suggest that TREM2 may be a target for LOAD therapy.

Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/ß-Catenin Signaling Pathway.

BACKGROUND/AIMS: Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/ß-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. METHODS: The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1ß)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. RESULTS: ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1ß, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/ß-catenin signaling pathway, suggesting that it might serve as a Wnt/ß-catenin antagonist to reduce inflammation and prevent cartilage degradation. CONCLUSION: In conclusion, ART alleviates IL-1ß-mediated inflammatory response and OA progression by regulating the Wnt/ß-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA.

Blood-brain barrier Permeable nanoparticles for Alzheimer's disease treatment by selective mitophagy of microglia.

Current treatments for Alzheimer's disease (AD) that focus on inhibition of Aß aggregation failed to show effectiveness in people who already had Alzheimer's symptoms. Strategies that synergistically exert neuroprotection and alleviation of oxidative stress could be a promising approach to correct the pathological brain microenvironment. Based on the key roles of microglia in modulation of AD microenvironment, we describe here the development of Prussian blue/polyamidoamine (PAMAM) dendrimer/Angiopep-2 (PPA) nanoparticles that can regulate the mitophagy of microglia as a potential AD treatment. PPA nanoparticles exhibit superior blood-brain barrier (BBB) permeability and exert synergistic effects of ROS scavenging and restoration of mitochondrial function of microglia. PPA nanoparticles effectively reduce neurotoxic Aß aggregate and rescue the cognitive functions in APP/PS1 model mice. Together, our data suggest that these multifunctional dendrimer nanoparticles exhibit efficient neuroprotection and microglia modulation and can be exploited as a promising approach for the treatment of AD.

Oxoglaucine mediates Ca2+ influx and activates autophagy to alleviate osteoarthritis through the TRPV5/calmodulin/CAMK-II pathway.

BACKGROUND AND PURPOSE: Stimulation of calcium influx and suppression of autophagy play important roles in the pathogenesis of osteoarthritis (OA). In this study, we used a novel inhibitor of TRPV5 cation channels - oxoglaucine to attenuate progression of deterioration and pathological changes in OA patient-derived chondrocytes and OA animal model, by activating autophagy. EXPERIMENTAL APPROACH: Inhibition by oxoglaucine of calcium influx was assessed in cells.. Analyses were also carried out to investigate the effect of oxoglaucine on OA by detection of anti-inflammatory response, TRPV5/CAMK-II/calmodulin pathway, autophagy, and cartilage protection both in vitro and in vivo. demonstrated by macroscopic evaluation and histological findings. KEY RESULTS: Oxoglaucine suppressed expression of proinflammatory and apoptosis-related proteins, including TNF-α, IL-6, IL-1ß, MMP-13, CASP-3, and BAX, and prevented matrix degradation in OA chondrocytes. It also successfully blocked Ca2+ influx, activating autophagy dose-dependently asshown by up-regulated expression of LC-3II/I, Beclin-1, ATG5, ATG7, higher autophagic influx and formation of autophagic vesicles. It also decreased expression of mRNA and protein of TRPV5, CAMK-II, and calmodulin. Conversely, 1,25-dihydroxyvitamin D3, anagonist of TRPV5 channels, reversed the oxoglaucine-induced calcium influx inhibition and autophagy activation, demonstrating the association of oxoglaucine with TRPV5. Further, oxoglaucine prevented the apoptosis and matrix degradation of articular cartilage in a rat model of OA. CONCLUSION AND IMPLICATIONS: Oxoglaucine protects against cartilage damage by blocking the TRPV5/CAMK-II/calmodulin pathway to inhibit Ca2+ influx and activate autophagy. Our results indicate that oxoglaucine has the potential to become a candidate drug for treatment of OA.

Nifedipine inhibits oxidative stress and ameliorates osteoarthritis by activating the nuclear factor erythroid-2-related factor 2 pathway.

Nifedipine is a voltage-gated calcium channel inhibitor widely used in the treatment of hypertension. Nifedipine has been reported to have antioxidant and anti-apoptotic effects and promotes cell proliferation. However, the effects of nifedipine on oxidative stress and apoptosis in osteoarthritic (OA) chondrocytes are still unclear. In this study, we sought to investigate whether nifedipine alleviates oxidative stress and apoptosis in OA through nuclear factor erythroid-2-related factor 2 (Nrf2) activation. The cytotoxicity of nifedipine against human chondrocytes was detected using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) kit, whereas mRNA and protein expression levels were measured using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. The oxidative stress level was analyzed by measuring reactive oxygen species (ROS), glutathione peroxidase (GSH-px), catalase (CAT) and superoxide dismutase (SOD) activities. The role of Nrf2 in the effect of nifedipine on OA was analyzed using an Nrf2 inhibitor brusatol (BR). The result showed that nifedipine inhibited the expression of matrix metalloprotein(MMP)-13, interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, inducible nitric oxide (NO) synthase (iNOS), and prostaglandin E2 (PGE2), as well as reduced ROS production in human OA chondrocytes, which was partially reversed by BR. Nifedipine prevented cartilage degeneration and contributed to the expression of Nrf-2 in chondrocytes. These results indicate that nifedipine inhibited inflammation and oxidative stress in chondrocytes via activation of Nrf-2/HO-1 signaling.

miRNA-335-5p relieves chondrocyte inflammation by activating autophagy in osteoarthritis.

AIMS: Osteoarthritis (OA) is a chronic and degenerative joint disease prevalent in the elderly, which is characterized by hypertrophy and reactive hyperplasia of articular cartilage. Autophagy has been reported to inhibit inflammation and reduce chondrocyte apoptosis in OA. As the microRNA (miRNA)-335-5p has been linked to both inflammation and autophagy, this study aimed to investigate its potential role in regulating autophagy during the pathogenesis of OA. MAIN METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect miRNA-335-5p expression in normal and OA human chondrocytes. Following transfection of human OA chondrocytes with double-stranded miRNA-335-5p mimic/inhibitor, qRT-PCR, western blotting, and immunofluorescence were used to determine expression levels of the inflammatory mediators IL-1ß, IL-6, and TNF-α, and the autophagic markers Beclin-1, autophagy-related protein 5 (ATG5), and ATG7. The autophagy inhibitor 3-methyladenine (3-MA) was used to link the anti-inflammatory effects of miRNA-335-5p to autophagy. KEY FINDINGS: The expression of miRNA-335-5p was significantly lower in OA chondrocytes than in normal chondrocytes. Transfection of human OA chondrocytes with the miRNA-335-5p mimic led to a remarkable increase in viability, a significant increase in autophagy-related factors, and a reduction in inflammatory mediators. Importantly, treatment of miRNA-335-5p-overexpressing OA chondrocytes with the autophagy inhibitor 3-MA restored the expression of inflammatory mediators. SIGNIFICANCE: We conclude that miRNA-335-5p can significantly alleviate inflammation in human OA chondrocytes by activating autophagy. Therefore, miRNA-335-5p has potential for future use in the clinical diagnosis and treatment of OA.

Dopamine-melanin nanoparticles scavenge reactive oxygen and nitrogen species and activate autophagy for osteoarthritis therapy.

Anti-oxidative agents hold great potential in osteoarthritis (OA) therapy. However, most radical scavengers have poor biocompatibility and potential cytotoxicity, which limit their applications. Herein we explore dopamine melanin (DM) nanoparticles as a novel scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS). DM nanoparticles show low cytotoxicity and a strong ability to sequester a broad range of ROS and RNS, including superoxides, hydroxyl radicals, and peroxynitrite. This translates to excellent anti-inflammatory and chondro-protective effects by inhibiting intracellular ROS and RNS and promoting antioxidant enzyme activities. With an average diameter of 112.5 nm, DM nanoparticles can be intra-articularly (i.a.) injected into an affected joint and retained at the injection site. When tested in vivo in rodent OA models, DM nanoparticles showed diminished inflammatory cytokine release and reduced proteoglycan loss, which in turn slowed down cartilage degradation. Mechanistic studies suggest that DM nanoparticles also enhance autophagy that benefits OA control. In summary, our study suggests DM nanoparticles as a safe and promising therapeutic for OA.

Correction: Dopamine-melanin nanoparticles scavenge reactive oxygen and nitrogen species and activate autophagy for osteoarthritis therapy.

Correction for 'Dopamine-melanin nanoparticles scavenge reactive oxygen and nitrogen species and activate autophagy for osteoarthritis therapy' by Gang Zhong et al., Nanoscale, 2019, 11, 11605-11616.