IL-27-induced, MSC-derived Exosomes Promote MMP3 Expression Through the miR-206/L3MBTL4 Axis in Synovial Fibroblasts.

Context: In rheumatoid arthritis (RA), hyperproliferative fibroblast-like synoviocytes (FLS) can secrete a variety of tissue hydrolases, such as matrix metalloproteinases (MMPs), causing the destruction of chondrocytes. Mesenchymal stem cells (MSCs) can directly affect FLS through extracellular vesicles (EVs). Interleukin-27 (IL-27) is a pleiotropic immune regulator frequently overexpressed in RA. Objective: The study intended to examine the effects of IL-27-induced exosomes from bone-marrow mesenchymal stem cells (BM-MSCs) and to determine if they promote the secretion of MMP3 in synovial cells. Design: The research team performed a genetic study. Setting: The study took place at the First Affiliated Hospital of Hainan Medical University in Haikou City, Hainan, China. Outcome Measures: The research team: (1) determined if IL-27 expression had occurred in the synovial fluid; (2) co-cultured IL-27-induced MSCs with FLS to detect the expression of MMP3 in the FLS; (3) Under IL-27 induction, MSC-derived exosomes with IL-27R knockdown were collected to detect the expression of microRNAs(miRNAs) associated with RA; (4) screened the miRNAs to determine the most significant differences in expression; (5) determined the miRNA target genes in arthritis, using Western blot (WB) and qRT-PCR; and (6) Dual luciferase and ChIP experiments confirm regulation of MMP3 by L3MBTL4. Results: IL-27 was highly expressed in RA, and the IL-27-induced, MSC-derived exosomes promoted the expression of MMP3 in FLS. The IL-27-induced MSC-derived exosomes significantly upregulated the expression of miR-206-3p, and the miR-206-3p target, miR-206/ lethal(3) malignant brain tumor-like protein 4 (L3MBTL4), regulated the MMP3 transcription. The IL-27-induced, MSC-derived exosomes promoted MMP3 expression in the FLS through the miR-206-3p/L3MBTL4 axis, thereby promoting chondrocyte degradation and aggravating RA. Conclusions: IL-27 can induce the expression of miR-206 in MSCs, and miR-206 can be transported into FLS through MSC-EVs to promote FLS migration and MMP3 expression and aggravate articular cartilage damage. Patients with RA who have a high IL-27 expression may not be suitable to receive treatment with MSCs, and clinicians can use MSCs that knock down or delete IL-27R to treat RA patients who have a high IL-27 expression.

SS31 Confers Cerebral Protection by Reversing Mitochondrial Dysfunction in Early Brain Injury Following Subarachnoid Hemorrhage, via the Nrf2- and PGC-1α-Dependent Pathways.

In early brain injury (EBI), oxidative stress occurs following subarachnoid hemorrhage (SAH), and mitochondria are intricately linked to this process. SS31, a mitochondria-targeting antioxidative peptide, has been demonstrated to be beneficial for multiple diseases because of its powerful antioxidant and neuroprotective properties. Although our previous study revealed that SS31 was involved in the powerful antioxidant effect following SAH, the underlying molecular mechanisms remained unclear. Thus, our study aimed to investigate the neuroprotective effects of SS31 by reversing mitochondrial dysfunction in EBI following SAH, via activating the Nrf2 signaling and PGC-1α pathways. Our findings confirmed that SS31 ameliorated SAH-triggered oxidative insult. SS31 administration decreased redundant reactive oxygen species, alleviated lipid peroxidation, and elevated the activities of antioxidant enzymes. Concomitant with the inhibited oxidative insult, SS31 dramatically attenuated neurological deficits, cerebral edema, neural apoptosis, and blood-brain barrier disruption following SAH. Moreover, SS31 remarkably promoted nuclear factor-erythroid 2 related factor 2 (Nrf2) nuclear shuttle and upregulated the expression levels of heme oxygenase-1 and NADPH: quinine oxidoreductase1. Additionally, SS31 enhanced the expression levels of PGC-1α and its target genes, and increased the mtDNA copy number, promoting mitochondrial function. However, PGC-1α-specific inhibitor SR-18292 pretreatment dramatically suppressed SS31-induced Nrf2 expression and PGC-1α activation. Furthermore, pretreatment with SR-18292 reversed the neuroprotective and antioxidant roles of SS31. These significant beneficial effects were associated with the activation of the Nrf2 signaling and PGC-1α pathways and were antagonized by SR-18292 administration. Our findings reveal that SS31 exhibits its neuroprotective activity by reversing mitochondrial dysfunction via activating the Nrf2 signaling pathway, which could be mediated through PGC-1α activation.

Resveratrol Improves Mitochondrial Biogenesis Function and Activates PGC-1α Pathway in a Preclinical Model of Early Brain Injury Following Subarachnoid Hemorrhage.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) has been shown to play a pivotal role in the regulation of mitochondrial biogenesis in diseases. Resveratrol (RSV), a natural polyphenolic reagent, has powerful antioxidant properties and the ability to scavenge mitochondrial reactive oxygen species (ROS) in a variety of central nervous system diseases. However, the underlying molecular mechanisms of RSV on mitochondrial biogenesis in early brain injury (EBI) following subarachnoid hemorrhage (SAH) remain poorly understood. This study aimed to explore the potential neuroprotective effects of RSV on mitochondrial biogenesis and function by activation of the PGC-1α signaling pathway in a prechiasmatic cistern SAH model. PGC-1α expression and related mitochondrial biogenesis were detected. Amounts of nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) were determined to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis after SAH were observed in the temporal cortex. Resveratrol increased the expression of PGC-1α, NRF1, and TFAM, and promoted PGC-1α nuclear translocation. Moreover, RSV could scavenge excess ROS, increase the activity of superoxide dismutase (SOD), enhance the potential of mitochondrial membrane and ATP levels, reduce the number of mitochondrial DNA copy, and decrease the level of malondialdehyde (MDA). RSV significantly ameliorated the release of apoptosis-related cytokines, namely P53, cleaved caspase-3, cytochrome c, and BAX, leading to the amelioration of neuronal apoptosis, brain edema, and neurological impairment 24 h after SAH. These results indicate that resveratrol promotes mitochondrial biogenesis and function by activation of the PGC-1α signaling pathway in EBI following SAH.

Anti-inflammatory effects of luteolin on acute gouty arthritis rats via TLR/MyD88/NF-κB pathway. / æœ¨çŠ€è‰ç´ é€šè¿‡TLR/MyD88/NF-κBé€šè·¯å‚ä¸Žæ€¥æ€§ç—›é£Žæ€§å ³èŠ‚ç‚Žå¤§é¼ çš„æŠ—ç‚Žä½œç”¨.

OBJECTIVES: To investigate the anti-inflammatory effect of luteolin on the acute gouty arthritis (AGA) rats and the underlying mechanisms. METHODS: A total of sixty rats were chosen and randomly divided into 5 groups:A control group, a monosodium urate (MSU) group, a colchicine group, 2 luteolin groups (50 mg/kg, 150 mg/kg). The AGA model of rats was established by injecting monosodium urate (MSU) at the concentration of 25 mg/mL into the ankle joint cavity. Changes of joint swelling index at different time points and the levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in serum and synovial were measured. The mRNA expression of TLR2, TLR4, and MyD88 in synovial tissue was detected by real-time PCR, and the protein expression of TLR2, TLR4, MyD88, and NF-κB in synovial tissues was determined by Western blotting. The inflammatory cells of the ankle joint and its surrounding soft tissues were observed after HE staining, and the expression of NF-κB was determined by immunohistochemistry. RESULTS: Compared with the MSU group, the joint swelling indexes of the luteolin group and the colchicine group were significantly decreased (P<0.05), and the levels of IL-1ß, IL-6 and TNF-α were also significantly decreased (P<0.01). The mRNA levels of TLR2, TLR4, and MyD88 and the protein levels of TLR2, TLR4, MyD88, and NF-κB were significantly decreased (P<0.01). CONCLUSIONS: Luteolin can reduce the inflammatory response of acute gouty arthritis via down-regulating the TLR/MyD88/NF-κB pathway, and it is expected to be an effective drug for the treatment of acute gouty arthritis.

SS31 attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage possibly by the mitochondrial pathway.

BACKGROUND: SS31 has been shown to have neuroprotective effects in a number of neurological degenerative diseases. However, the mechanisms and its role of neuroprotection after subarachnoid hemorrhage (SAH) remain unexplored. The aim of the present study is to evaluate the neuroprotective effects of SS31 on early brain injury (EBI) induced by SAH in rats and the potential mechanisms of the protective effects of SS31. METHODS: Sprague-Dawley rats were randomly divided into four groups: Sham, SAH, SAH + vehicle, and SAH + SS31 groups. The SAH-induced prechiasmatic cistern rat model was established in this study. Neurological scores were evaluated at 24 h and 72 h after SAH. The brain edema, blood-brain barrier (BBB) permeability, neuronal apoptosis, malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, as well as the expression of mitochondrial and cytosolic cytochrome C (Cyt C), and Bax were analyzed at 24 h after SAH. RESULTS: When compared with the vehicle-treated group, treatment with SS31 significantly reduced MDA levels and restored the activities of GPx and SOD in the temporal cortex following SAH when compared with the vehicle-treated group. In addition, the levels of mitochondrial Cyt C and Bax respectively increased and decreased by SS31 treatment. Moreover, SS31 treatment ameliorated brain edema and Evans blue dye extravasation, improved neurological deficits, and decreased neuronal apoptosis at 24 h after SAH. CONCLUSION: Our data provides initial evidence that SS31 could alleviate EBI after SAH through its antioxidant property and ability in inhibiting neuronal apoptosis, likely by modulating the mitochondrial apoptotic pathway.

Mitochondrial-targeted antioxidant MitoQ provides neuroprotection and reduces neuronal apoptosis in experimental traumatic brain injury possibly via the Nrf2-ARE pathway.

Mitoquinone (MitoQ) is a powerful mitochondrial-targeted antioxidant whose neuroprotective effects have been shown in a variety of animal models of neurological diseases. However, its roles in traumatic brain injury (TBI) remain unexplored. The primary objective of this study was to investigate the neuroprotection afforded by MitoQ in a mouse model of TBI, and the involvement of the Nrf2-ARE signaling pathway in the putative neuroprotective mechanism. Mice were randomly divided into four groups: sham group, TBI group, TBI + vehicle group, and TBI + MitoQ group. MitoQ (4 mg/kg, administered intraperitoneally) or an equal volume of vehicle was given at 30 min after TBI. After 24 h, brain samples were harvested for analysis. The results demonstrated that treatment with MitoQ significantly improved neurological deficits, alleviated brain edema and inhibited cortical neuronal apoptosis. Furthermore, MitoQ administration increased the activity of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), whereas it decreased the malondialdehyde (MDA) content. In addition, MitoQ treatment reduced Bax protein translocation to mitochondria and cytochrome c release into the cytosol. Moreover, MitoQ greatly accelerated the Nrf2 nuclear translocation and subsequently upregulated the expression of Nrf2 downstream proteins, including heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (Nqo1). In conclusion, the results in the study demonstrate that MitoQ exerts neuroprotective effects in the mouse model of TBI, possibly by activating the Nrf2-ARE pathway.

Global exponential convergence of Cohen-Grossberg neural networks with time delays.

In this paper, we derive a general sufficient condition ensuring global exponential convergence of Cohen-Grossberg neural networks with time delays by constructing a novel Lyapunov functional and smartly estimating its derivative. The proposed condition is related to the convex combinations of the column-sum and the row-sum of the connection matrices and also relaxes the constraints on the network coefficients. Therefore, the proposed condition generalizes some previous results in the literature.