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Okanin attenuated cognitive impairment in BCCAO mice. Okanin inhibited microglial activation, decreased NLRP3 inflammasome activation and increased miR-7 expression in vivo and in vitro, and inhibited microglia-induced neuronal injury.

Although berberine (BBR) is considered to be of therapeutic value in treating various disorders; however, its low bioavailability hinders its further development on clinical application. To evaluate the effects of BBR against chondrocyte damage, we synthesized liposomal nanoparticles loaded with BBR (BBR@LNPs) with an average particle size of 137 nm using microfluidic technology. The CCK8 assay was used to determine the cytotoxicity of the BBR@LNPs in C28/I2. Additionally, flow cytometry and western blotting were used to investigate the mechanism of its protect chondrocytes from H2O2-induced oxidative damage in C28/I2. Our findings showed that BBR@LNPs had stable nanoscale structure and low cytotoxicity. Importantly, administration of BBR@LNPs significantly inhibited ROS release and cell apoptosis in H2O2-induced C28/I2, BBR@LNPs enhanced mitochondrial autophagy by up-regulating PINK1 and Parkin expression. Our findings may provide some guidance BBR-loaded lipid nanoparticle delivery system in cartilage injury.

We aimed to assess the regulatory effects of miR-28 on the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMMSCs). HBMMSCs isolated, cultured and induced (at P3) to undergo osteogenic induction. The expressions of miRNAs were detected by gene microarray, and differentially expressed miRNAs in hBMMSCs compared with induced cells were obtained by significance analysis of microarrays. The microarray findings were confirmed by RT-PCR. TargetScan showed that signal transducer and activator of transcription 1 (STAT1) was the downstream target gene of miR-28. The relationship between miR-28 and STAT1 was validated using dual-luciferase reporter gene assay. HBMMSCs were transfected with miR-28 mimics and STAT1 siRNA, respectively. Samples were collected on day 10 after osteogenic differentiation, and the alkaline phosphatase (AKP) activity, Runt-related transcription factor 2 (RUNX2, a key regulator of osteogenic differentiation) and STAT1 expressions were determined using kits, PCR and Western blotting, respectively. Cell proliferation and migration were detected through CCK-8 and Transwell assays, respectively. During the osteogenic differentiation of hBMMSCs, the expression level of miR-28 increased. MiR-28 specifically bound the 3’-untranslated region (3’UTR) of STAT1 mRNA. It inhibited STAT1 expression in a targeted manner during osteogenic differentiation. Interference with STAT1 partially mimicked the regulatory effects of miR-28 overexpression on the osteogenic differentiation of hBMMSCs. Interference with STAT1 or overexpression of miR-28 did not affect proliferation or migration. MiR-28 has gradually increased expression during the osteogenic differentiation of hBMMSCs, which can directly bind STAT1 3’UTR and inhibit its expression, thereby up-regulating AKP and RUNX2, and promoting osteogenic differentiation.

Cognitive impairment is the main clinical feature following stroke, and microglia-mediated inflammatory response is a major contributor to it.

Tumoral calcinosis (TC) is a rare disease characterized by periarticular soft tissue calcification. Some cases were reported in Africa and the Middle East. We report an 11-year-old Chinese girl presenting with recurrent multiple subcutaneous masses around the right elbow and hip regions. Although we found abnormalities in FGF23, a protein associated with phosphate metabolism, no positive results were observed in gene sequencing and analysis. The imaging features, laboratory examination, and pathology results confirmed our diagnosis. By using oral phosphorus-lowering drugs (acetazolamide) combined with complete surgical excision, good results were achieved, and no recurrence was reported during the follow-up of 18 months. We report a case of primary hyperphosphatemic TC. The combined use of oral phosphorus-lowering drugs (acetazolamide) and complete surgical excision produced good results, and no recurrence was reported during the follow-up of 18 months.

Pterostilbene, a methylated stilbene derived from many plant foods, has significant anti-inflammatory activity. Meanwhile, vascular dementia (VaD) is the second most common subtype of dementia, in which inflammation is one of the major pathogenic contributors. However, the protective effect of pterostilbene on VaD is not well understood. In this work, we investigated the effect of pterostilbene on VaD and explored its underlying mechanisms using in vivo and in vitro models. Y-maze and Morris water maze tests showed pterostilbene-attenuated cognitive impairment in mice with bilateral common carotid artery occlusion (BCCAO). The hippocampal neuronal death and microglial activation in BCCAO mice were also reduced by pterostilbene treatment. Further, pterostilbene inhibited the expression of TLR4 and downstream inflammatory cytokines in these mice, with similar results observed in an oxygen-glucose deprivation and reperfusion (OGD/R) BV-2 cell model. In addition, its anti-inflammatory effect on OGD/R BV-2 cells was partially blocked by TLR4 overexpression. Moreover, Triad3A-TLR4 interactions were increased by pterostilbene following enhanced ubiquitination and degradation of TLR4, and the inhibitory effect of pterostilbene on inflammation was blocked by Triad3A knockdown in OGD/R-stimulated BV-2 cells. Together, these results reveal that pterostilbene could reduce vascular cognitive impairment and that Triad3A-mediated TLR4 degradation might be the key target.

Worldwide, ovarian cancer (OC) is the seventh common cancer and the second most common cause of cancer death in women. Due to high rates of relapse, there is an urgent need for the identification of new targets for OC treatment. The far-upstream element binding protein 1 (FBP1) and enhancer of zeste homolog 2 (EZH2) are emerging proto-oncogenes that regulate cell proliferation and metastasis. In the present study, Oncomine data analysis demonstrated that FBP1 was closely associated with the development of OC, and The Cancer Genome Atlas (TCGA) data analysis indicated that there was a positive correlation between FBP1 and EZH2 in ovarian tissues. Moreover, we found that FBP1 knockdown suppressed tumor formation in nude mice and cisplatin resistance of OC cells, but the role of FBP1 in the cisplatin resistance of OC cells remained unclear. In addition, we verified physical binding between FBP1 and EZH2 in OC cells, and we demonstrated that FBP1 knockdown enhanced cisplatin cytotoxicity in OC cells and down-regulated EZH2 expression and trimethylation of H3K27. These results suggested that FBP1 increases cisplatin resistance of OC cells by up-regulating EZH2/H3K27me3. Thus, FBP1 is a prospective novel target for the development of OC treatment.

BACKGROUND AND OBJECTIVE: Cartilage defects and degeneration have a major impact on daily mobility and quality of life for millions of people worldwide. As the most effective seed cells for tissue engineering applications in regenerative medicine, mesenchymal stem cells (MSCs) are pluripotent cells with mesoderm and neural crest origin. The combination of biomaterial scaffolds with stem cells and drugs for cartilage damage repair has brought much hope to the medical field. METHODS: We searched and compared the literature on cartilage damage repaired by stem cells through PubMed and Web of Science method, this review summarizes the research progress of mesenchymal stem cells from various tissue sources in repairing articular cartilage injury. KEY CONTENT AND FINDINGS: We found that peripheral blood, bone marrow, umbilical cord blood, adipose tissue, and umbilical cord are classic stem cell sources. Stem cells can be stimulated by various growth factors, recombinant proteins, or important monomers to generate cartilage in vitro. At the same time, MSCs obtained from various sources can secrete different growth factors to further regulate their own cartilage formation. These stem cells may promote the cartilage damage repair by promoting differentiation and fighting inflammation. CONCLUSIONS: This review summarizes and discusses the advantages and disadvantages of the ability of MSCs from different sources to treat cartilage injury, and provides help and identification for the subsequent in-depth research and preclinical application of various MSCs.

Radiation-induced acute intestinal injury is a common and serious occurrence following abdominal and pelvic irradiation. The Nod-like receptor protein 3 (NLRP3)-dependant inflammasome and inflammation activation is crucial in this process. In a pre-experimental design of radiation-induced intestinal injury, we found that rosiglitazone inhibited caspase-1 which is a key marker of inflammasome activation. The purpose of the present study was to clarify the inhibitory effect of rosiglitazone on the NLRP3 inflammasome both in vivo and in vitro. Radiation-induced intestinal injury after rosiglitazone treatment, and the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), caspase-1 and NLRP3 in a radiation-induced intestinal injury model in a rat and macrophages were observed. We found that rosiglitazone ameliorated radiation-induced intestinal injury in rats by suppressing the expression of caspase-1, NLRP3, IL-1β and TNF-α. Treatment with rosiglitazone in vitro reduced the expression of NLRP3, and the NLRP3 activator monosodium urate (MSU) reversed the inhibition of IL-1β and TNF-α by rosiglitazone in macrophages. MSU reversed the protective effect of rosiglitazone on radiation-induced intestinal injury in rats by reversing the rosiglitazone-induced inhibition of IL-1β and TNF-α. Taken together, these findings indicate that the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates radiation-induced intestine inflammation in rats via inhibiting the induction of the NLRP3-dependent inflammasome in macrophages.

Structurally diverse biflavonoids have attracted significant research interest for drug discovery over past decades. Biflavonoid oriented phytochemistry research on the stems of

Background. Neurodegenerative diseases, such as Alzheimer’s disease, and traumatic brain and spinal cord injury (SCI) are prevalent in clinical practice. Inhibition of hyperactive inflammation and proliferation of endogenous neural stem cells (NSCs) is a promising treatment strategy for SCI. Our previous studies demonstrated the beneficial effects of rosiglitazone (Rosi) on SCI, but its roles in inflammation inhibition and proliferation of NSCs are unknown. Methods. SCI in a rat model was established, and the effects of Rosi on motor functions were assessed. The effects of Rosi on NSC proliferation and the underlying mechanisms were explored in details. Results. We showed that Rosi ameliorated impairment of moto functions in SCI rats, inhibited inflammation, and promoted proliferation of NSCs in vivo. Rosi increased ATP production through enhancing glycolysis but not oxidative phosphorylation. Rosi reduced mitophagy by downregulating PTEN-induced putative kinase 1 (PINK1) transcription to promote NSC proliferation, which was effectively reversed by an overexpression of PINK1 in vitro. Through KEGG analysis and experimental validations, we discovered that Rosi reduced the expression of forkhead box protein O1 (FOXO1) which was a critical transcription factor of PINK1. Three FOXO1 consensus sequences (FCSs) were found in the first intron of the PINK1 gene, which could be potentially binding to FOXO1. The proximal FCS (chr 5: 156680169–156680185) from the translation start site exerted a more significant influence on PINK1 transcription than the other two FCSs. The overexpression of FOXO1 entirely relieved the inhibition of PINK1 transcription in the presence of Rosi. Conclusions. Besides inflammation inhibition, Rosi suppressed mitophagy by reducing FOXO1 to decrease the transcription of PINK1, which played a pivotal role in accelerating the NSC proliferation.

POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome is a rare and complicated disease related to multiple organs and systems. Here, we report a case of systemic mastocytosis (SM) that was misdiagnosed as a POEMS syndrome.A 42-year-old man presented with skin changes, diarrhea, and limb numbness.Positron emission tomography/computed tomography revealed extravascular volume overload, organomegaly, lymphadenopathy, and bone lesions with mixed lesions of osteosclerosis and osteolysis. Therefore, POEMS syndrome was suspected. Further histopathological and immunohistochemical examination of the bone marrow, lymph nodes, and gastric mucosa suggested a diagnosis of mastocytosis. The c-Kit D816V mutation confirmed the diagnosis of SM.The patient received the treatment of pegylated interferon-alpha weekly and glucocorticoid daily.The symptoms relieved significantly.There are many similar features between POEMS syndrome and SM, probably leading to misdiagnosis. This study analyzed the different points between them which can provide help for differentiation.

The ethyl acetate extract of the stems of Jatropha curcas (ESJ) exerted prominent anti-neuroinflammatory effect through inhibiting microglial overactivation, and reducing mRNA expression of inflammatory factors, including nitric oxide (NO), inducible nitric oxide synthase, and interleukin-1β in the cortex and the formation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes in C57BL/6 mice. Phytochemical research afforded twenty-three major constituents, including five undescribed components (diterpenes 1-3, 7 and a triterpene 18) and a new natural product [a diterpene, (3S,5S,10R)-3-hydroxy-12-methoxy-13-methylpodopcarpa-8,11,13-trien-7-one (8)], by comprehensive analysis of spectroscopic data. Bioassay showed that ESJ (IC

This is the first study to profile natural sesquiterpene coumarins (SCs) in Ferula bungeana, a medicinal plant of the genus Ferula in China. Eight undescribed sesquiterpene coumarins (1-8), along with six known ones (9-14) were obtained from the whole plant of F. bungeana. These unreported SCs (1-8) enriched the structural diversity of natural SCs, especially these with the hydroxy or carbonyl group at C-7' and a hydroperoxy group at C-7' or C-8'. Compounds (9-14) were reported for the first time from this plant. The in vitro anti-neuroinflammatory activity assay showed that compounds 2 and 9 showed stronger inhibitory effect on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced BV-2 microglia, compared with positive control minocycline, and compounds 5 and 10 showed moderate inhibitory effects.

During our continuous investigation of natural, herbal inhibitors of microglial over-activation in the Euphorbiaceae family, two plants of the Vernicia genus showed remarkable inhibitory effects on nitric oxide (NO) production in over-activated microglia. In this study, bioactivity-guided phytochemical research on the active fraction of the roots of V. montana was carried out. As a result, seven undescribed terpenoids and lignans, together with thirty-one known components, were isolated and identified using comprehensive spectral analysis. All the identified compounds were evaluated for their inhibitory effects on NO production in lipopolysaccharide-stimulated BV-2 cells. Combined with our previous research on the Vernicia genus, the effective material basis of different plants and medicinal components was analyzed systematically.

BACKGROUND: Osteoarthritis (OA) is characterized by erosion and degradation of articular cartilage. This study assessed the effects of curcumin on mouse knee cartilage chondrocytes. METHODS: Chondrocytes were treated for 24 hours with interleukin IL-1β (10 ng/mL) alone, or the combination of curcumin (10, 20, and 50 µM) and IL-1β. The proliferation, viability, and cytotoxicity of the chondrocytes were evaluated by the MTS assay. Expression of SOX9, AGG, Col2α, MMP9, ADAMTS5, COX2, iNOS, pIκB-α, pNF-κB, and hypoxia-inducible factor-2α (HIF-2α) were detected by western blotting or quantitative polymerase chain reaction (q-PCR). Nuclear translocation of NF-κB and HIF-2α were investigated by immunofluorescence and immunohistochemistry. In in vivo experiments, mice were subjected to destabilization of the medial meniscus (DMM) and given curcumin orally for 6 weeks. Cartilage integrity was evaluated by OARSI (Osteoarthritic Research Society International) scores. RESULTS: Curcumin significantly inhibited the IL-1β-induced reduction of cell viability, degradation of ECM, and the expression of SOX9, Col2α, and AGG (P

Background:Multiple studies have focused on stem cell-based treatments for rotator cuff disorders; however, the outcomes are not consistent.Objective:This systematic review and meta-analysis were performed to evaluate the effects of stem cells on rotator cuff healing.Methods:A detailed search of relevant studies was conducted in three databases including Pubmed/ Medline, Cochrane library, and Embase databases, using the following keywords: “rotator cuff” or “Tissue Engineering” AND “stem cell” from inception to January 01, 2019. The standard mean difference (SMD) and 95% confidence interval (CI) for each individual study were extracted from the original studies or calculated based on relevant data and pooled to obtain integrated estimates using random effects modeling.Results:A total of 22 studies were identified. The results demonstrated that the ultimate strain in the stem cell group was significantly higher than that in the control group at 4 and 8 weeks. Muscle weight in the stem cell group was higher than the control group at 8 weeks, while no significant differences were detected at 16 weeks. The stem cell group had lower visual analog scale scores (VAS) at 1, 3, and 6 months, and higher American shoulder and elbow surgeons score (ASES) at 3 months. In addition, the walking distance, time, and speed in the stem cell group were significantly superior to those in the control group.Conclusion:This meta-analysis confirms that stem cells improved the rehabilitation of rotator cuff disorders. However, larger-scale studies are needed to further support these findings.

Particulate matter with a diameter of less than 2.5 μm (PM2.5) easily deposits on lung alveoli and degrades human health. Surfactant protein A (SP-A) is the most abundant pulmonary surfactant protein stored in lamellar bodies (LBs) of alveolar epithelial type II cells. The impacts of PM2.5 on SP-A are multifaceted and intractable, and the underlying mechanism remains unclear. In this study, the expression and distribution of SP-A in Balb/c mice and A549 cells under PM2.5 exposure were investigated. The results showed that the low and medium concentration of PM2.5 gradually enhanced SP-A protein and mRNA expression, whereas the high concentration of PM2.5 conspicuously decreased SP-A protein but not its mRNA compared with the control. The trafficking of SP-A to LBs was gradually disturbed, and concomitantly, the lesions of LBs responsible for the transport and storage of SP-A protein were exacerbated with increased PM2.5 concentration. Reactive oxygen species production abundantly increased upon PM2.5 exposure, and it was antagonized by the oxidant inhibitor N-acetylcysteine. Subsequently, the injured LBs and the decrease in SP-A expression under exposure to the high concentration of PM2.5 were well rescued. The present study provides a new perspective to investigate the adverse effects of PM2.5 or diesel exhaust particles on other proteins transported to and stored in LBs.

The effects of eight oral anti-coronavirus drugs (lopinavir, ritonavir, chloroquine, darunavir, ribavirin, arbidol, favipiravir, oseltamivir) on the metabolism of four specific glycosides (polydatin, geniposide, quercitrin, glycyrrhizin) and on the activities of three major glycosidases (β-glucosidase, α-rhamnosidase, β-glucuronidase) from gut microflora were explored

Background Through a comprehensive analysis of the joint synovial fluid produced in the process of rabbit articular cartilage regeneration, the role and characteristics of knee synovial fluid in the process of decalcified bone transplantation-induced articular cartilage regeneration were explored. Methods Twenty New Zealand white rabbits (approximately 2.5 kg in weight) were selected, and bilateral distal femoral bones from two randomly selected rabbits were extracted. After decalcification, the bones were cut into 2 mm × 4 cm long decalcified bone strips. Meanwhile, the other 18 rabbits were randomly divided into three groups: the test group (8 rabbits), the positive control group (6 rabbits), and the blank group (4 rabbits). In the test group, the decalcified bone joint was transplanted into the rabbits at the articular cartilage defect; in the positive control group, the articular cartilage defect of the rabbits were treated and put aside; in the blank group, no rabbits were treated. On the day of transplantation, and on the 4th, 8th, 12th, and 16th weeks after transplantation, the joint synovial fluid of each group was taken for two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) analysis, and related database verification and identification, and compared with the positive control group and the blank group. Results Using 2D-PAGE to separate various proteins in the synovial fluid of the rabbit knee joints, it was found that there were differential protein spots in the test group compared with the blank group and the positive control group. After conducting a comparative search and query in the UniProt database, through comprehensive analysis, it was finally found that three proteins with molecular weights of 23,429.4, 57,431.4, and 26,071.1 that may be related to the regeneration of articular cartilage appeared in the test group. Conclusions In the process of inducing the regeneration of articular cartilage using decalcified bone transplantation, knee joint synovial fluid produced specific proteins, which may play an important role in the regeneration of articular cartilage. These findings may offer novel ideas in laying a foundation for the in-depth study of articular cartilage regeneration.

Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.

Articular cartilage injury or defect is a common disease and is mainly characterized by cartilage degradation because of chondrocyte inflammation. By now, there are no effective drugs and methods to protect articular cartilage from degradation. Icariin (ICA) is a typical flavonoid compound extracted from Epimedii Folium with anti-inflammatory and bone-protective effects. Our previous studies demonstrate that ICA up-regulates HIF-1α expression and glycolysis in chondrocytes and maintains chondrocyte phenotype. As another member of HIFs family, HIF-2α always plays a key role in inflammation. The effect of ICA on HIF-2α is unclear by now. In the present study, we confirmed the findings in our previous study that ICA promoted not only chondrocyte vitality and extracellular matrix (ECM) synthesis, but also the anti-inflammatory effect of ICA. In bone defect mice, ICA inhibited the expressions of NF-κB and HIF-2α. In TNF-α-treated ADTC5 chondrocytes, ICA neutralized the activation of IKK (IKK phosphorylation), the phosphorylation of IkB and NF-κB and the expression of HIF-2α. Furthermore, ICA inhibited the nucleus transfer of NF-κB and the expressions of MMP9 and ADAMTS5, two key targets of NF-κB/HIF-2α signal pathway. Taken together, the present study demonstrated that ICA may increase the vitality of chondrocytes by suppressing the inflammatory injury through the inhibition on NF-κB/HIF-2α signaling pathway. ICA is one effective candidate drug for the treatment of articular cartilage injury.

In the present study, effect of pterostilbene on β-amyloid 1-42 (AβThe behavior results show that pterostilbene alleviated AβThe present study reports that pterostilbene alleviated Aβ

Increasing evidence proposes that inflammation play a vital role in the pathogenesis of osteoarthritis (OA).The nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome has been found to be involved in OA pathogenesis by activation of Toll-like receptors (TLR) and NF-κB signal pathway, thus enhancing the production of proinflammatory cytokines and subsequently resulting in cartilage degeneration and synovial inflammation. Here, we provide an overview of the molecular mechanism and regulation of the NLRP3 inflammasome and its role in the pathogenesis of OA. Finally, we contemplate the potential of therapeutic targeting to the NLRP3 inflammasome and its associated signaling pathways as a promising way for OA treatment.

Ethnopharmacological relevance Ferula sinkiangensis K. M. Shen is a traditional Chinese medicine that has a variety of pharmacological properties relevant to neurological disorders and inflammations. Kellerin, a novel compound extracted from Ferula sinkiangensis, exerts a strong anti-neuroinflammatory effect by inhibiting microglial activation. Microglial activation plays a vital role in ischemia-induced brain injury. However, the potential therapeutic effect of kellerin on focal cerebral ischemia is still unknown. Aim of the study To explore the effect of kellerin on cerebral ischemia and clarify its possible mechanisms, we applied the middle cerebral artery occlusion (MCAO) model and the LPS-activated microglia model in our study. Materials and methods Neurological outcome was examined according to a 4-tiered grading system. Brain infarct size was measured using TTC staining. Brain edema was calculated using the wet weight minus dry weight method. Neuron damage and microglial activation were observed by immunofluorescence in MCAO model in rats. In in vitro studies, microglial activation was examined by flow cytometry and the viability of neuronal cells cultured in microglia-conditioned medium was measured using MTT assay. The levels of pro-inflammatory cytokines were measured by qRT-PCR and ELISA. The proteins involved in NF-κB signaling pathway were determined by western blot. Intracellular ROS was examined using DCFH-DA method and NADPH oxidase activity was measured using the NBT assay. Results We found that kellerin improved neurological outcome, reduced brain infarct size and decreased brain edema in MCAO model in rats. Under the pathologic conditions of focal cerebral ischemia, kellerin alleviated neuron damage and inhibited microglial activation. Moreover, in in vitro studies of LPS-stimulated BV2 cells kellerin protected neuronal cells from being damaged by inhibiting microglial activation. Kellerin also reduced the levels of pro-inflammatory cytokines, suppressed the NF-κB signaling pathway, and decreased ROS generation and NADPH oxidase activity. Conclusions Our discoveries reveal that the neuroprotective effects of kellerin may largely depend on its inhibitory effect on microglial activation. This suggests that kellerin could serve as a novel anti-inflammatory agent which may have therapeutic effects in ischemic stroke.

The aryl hydrocarbon receptor (AhR) is a ligand‑activated transcription factor originally isolated and characterized as the dioxin or xenobiotic receptor. With the discovery of endogenous ligands and studies of AhR knockout mice, AhR has been found to serve an important role in several biological processes, including immune responses and developmental and pathological regulation. In particular, it has been considered as a new major player in cardiovascular diseases. Recent studies have revealed that the development of atherosclerosis is closely associated with AhR function. However, the roles of the AhR in the pathological development of atherosclerosis and atherosclerosis‑associated diseases remain unclear. The current review presents the molecular mechanisms involved in the regulation of AhR expression during inflammation, oxidative stress and lipid deposition. Additionally, the role of the AhR in atherosclerosis and atherosclerosis‑associated diseases is reviewed.

Persistent inflammation disrupts functional recovery after spinal cord injury (SCI). Peroxisome proliferator-activated receptor gamma (PPAR-γ) activation promotes functional recovery in SCI rats by inhibiting inflammatory cascades and increasing neuronal survival. We sought to clarify the relationship between PPAR-γ activation and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome suppression, and the role of NF-κB in activating the NLRP3 inflammasome in neurons. In SCI rats, we found that rosiglitazone (PPAR-γ agonist) inhibited the expression of caspase-1. In in vitro neurons, G3335 (PPAR-γ antagonist) reversed the rosiglitazone-induced inhibition of caspase-1, interleukin 1 (IL-1β), and interleukin 6 (IL-6). Rosiglitazone inhibited the expression of NLRP3, caspase-1, IL-1β, and IL-6. However, the activator of NLRP3 could counteract this inhibition induced by PPAR-γ activation. NF-κB did not participate in the process of rosiglitazone-induced inhibition of NLRP3. Consistent with our in vitro results, we verified that locomotor recovery of SCI rats in vivo was regulated via PPAR-γ, NLRP3, and NF-κB. These results suggest that PPAR-γ activation exerts an anti-inflammatory effect by suppressing the NLRP3 inflammasome—but not NF-κB—in neurons and that PPAR-γ activation is a promising therapeutic target for SCI.

SCOPE In the present study, effect of pterostilbene on β-amyloid 1-42 (Aβ1-42 ) induced cognitive impairment in mice is investigated and explored its possible mechanism of action. METHODS AND RESULTS The behavior results show that pterostilbene alleviated Aβ1-42 -induces cognitive dysfunction assessed using the Y-maze test, novel object recognition task, Morris water maze test, and passive avoidance test. Pterostilbene alleviates neuron loss and accumulation of reactive oxygen species in Aβ1-42 treated mouse brain. Additionally, pterostilbene promotes nuclear factor-E2 p45-related factor 2 (Nrf2) nuclear translocation and enhance the transcription and expression of antioxidant genes such as heme oxygenase-1 and superoxide dismutase both in vivo and in vitro. Nrf2 inhibitor ML385 reverses the antioxidant function of pterostilbene in SH-SY5Y cells. Nrf2 is the master regulator of oxidative homeostasis and can be activated by substrate adaptor sequestosome-1 (also named p62). Pterostilbene promotes the binding of Kelch-like ECH-associated protein 1 and p62, which enhanced activation of Nrf2. CONCLUSION The present study reports that pterostilbene alleviated Aβ1-42 -induces cognitive dysfunction in mice. The mechanism of pterostilbene can be associated to the inhibition of oxidative stress through the Nrf2 signaling pathway.

Chinese herbal extracts are being used increasingly to treat osteoarthritis (OA) in recent years. Baicalin (BA) is an active component of Scutellaria baicalensis Georgi extracts and protects chondrocytes against damage. The aim of the present study was to examine the mechanism of action of BA on chondrocytes from mouse articular cartilage. In total, 44 µM BA and 10 µM hypoxia-inducible-factor-1α (HIF-1α) inhibitor BAY-87-2243 were screened by the [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] method. Alcian blue and Safran O staining were used to investigate the synthesis of extracellular matrix (ECM) in chondrocytes treated with BA. The expression of HIF-1α and chondrogenic marker genes including SOX9, AGG and Col2α was detected by western blotting or reverse-transcription quantitative (RT-qPCR), the expression of PHD1,2,3 and catabolic genes including ADAMTS5, MMP9 and MMP13 were detected by RT-qPCR. To investigate the effect of BA on the ECM synthesis of chondrocytes, 44 µM BA and 10 µM BAY were chosen for further experimentation. It was confirmed that BA at a concentration of 44 µM could significantly promote the secretion of ECM. The expressions of genes including HIF-1α, SOX9, collagen type 2 (Col2α) and aggrecan (AGG) were elevated following BA pretreatment and decreased by subsequent BAY-87-2243 stimulation for 24 h. Compared with untreated chondrocytes, the expressions of genes including ADAMTS5, MMP9, MMP13, PHD1, PHD2 and PHD3 in chondrocytes treated by BA were downregulated, however, BAY-87-2243 reversed the effect of BA on the genes including ADAMTS5, MMP9, MMP13, PHD1, PHD2 and PHD3 in chondrocytes. The findings of the present study suggest that BA may promote ECM synthesis and marker gene expression in chondrocytes by activating HIF-1α. Therefore, BA may represent a novel clinical drug for OA.

Background: Proliferation of neural stem cells (NSCs) is crucial for recovery from spinal cord injury (SCI). The effect of PPAR-γ agonist on SCI recovery and the way it regulating NSCs proliferation are both unknown. Methods: The effects of PPAR-γ agonist (rosiglitazone) treatment on recovery from SCI and proliferation of NSCs were confirmed. The roles of mitophagy and PTEN induced putative kinase 1 (PINK1) in rosiglitazoneinduced proliferation of NSCs were explored. Details mechanisms on the transcription regulation of PINK1 by rosiglitazone were addressed. Findings: Rosiglitazone independently increased the proportion of Nestin /Brdu cells in the spinal cord and motor function of SCI rats. It reduced mitophagy and expression of PTEN induced putative kinase 1 (PINK1) in NSCs. The forkhead box protein O1 (FOXO1) was identified as the transcription factor mostly altered by rosiglitazone. Restoration of FOXO1 expression antagonized the effects of rosiglitazone on mitophagy and PINK1 expression. The FOXO1 consensus sequence (FCS) was not identified upstream of the PINK1 transcription start site, but three FCSs were found in the first intron of the PINK1 gene. All of the FCSs participated in the regulation of PINK1 transcription upon treatment with rosiglitazone and expression of FOXO1 but the proximal FCS (chr 5: 156680169-156680185, 3022 bp counting from the translation start site) exerted greater influence. Conclusions: PPAR-γ agonist could be a promising therapeutic strategy for spinal cord injury. Funding Statement:This work was supported by the National Natural Science Foundation of China (Grant No. 81870334, 81301038, 81300071, 81300279 and 81741067); the Science and Technology Program of Guangdong (Grant No. 2015A020212029); and the Science and Technology Program of Guangzhou City (Grant No. 201510010048, 201607010009, 201607010010 and 201804010050). Declaration of Interests: All authors declare no potential conflict of interest. Ethics Approval Statement: All of the animal experiments complied with the ARRIVE guidelines, and they were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 8023, revised 1978)

Objective: Epidemiological studies have shown that elevated concentrations of ambient particulate matter (aerodynamic diameter ≤2.5 μm; PM2.5) correlates with increased incidence of asthma. The aim of this study was to determine whether PM2.5 participates in the exacerbation of asthma. Methods: Effects of 1, 10 and 100 μg PM2.5 instilled intratracheally in ovalbumin (OVA)-sensitized or asthmatic mice were compared. Results: PM2.5 exposure in the OVA-sensitized and especially asthmatic groups increased Mch responsiveness in a dose-dependent manner. In OVA-sensitized groups, exposure to 1 μg of PM2.5 caused no detectable lung inflammation, while 10 and 100 μg of PM2.5 resulted in a slightly increased trend in numbers of neutrophils and macrophages. Compared with the asthmatic control group, both 10 and 100 μg of PM2.5 provoked a significant increase in eosnophils and neutrophils whereas only 100 μg of PM2.5 noticeably enhanced lymphocytes. In asthmatic groups, administration of 100 μg of PM2.5 greatly increased levels of the pro-inflammatory cytokine TNF-α and Th2-related cytokines IL-4 and IL-10 in bronchoalveolar lavage fluid, but it decreased Th1-related INF-γ. In addition, 10 and 100 μg of PM2.5 exacerbated inflammatory infiltration, goblet cell metaplasia and lung ultrastructure lesions in asthmatic mice. Conclusions: Our results suggested that acute exposure of PM2.5 could synergize with allergens in the subsequent challenge to aggravate the severity of asthma in sensitized mice, possibly by promoting a Th2-biased immune response.