Qifu-yin activates the Keap1/Nrf2/ARE signaling and ameliorates synaptic injury and oxidative stress in APP/PS1 mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms through which QFY mitigates AD pathology remain to be fully delineated. AIM OF THE STUDY: This study aimed to explore the therapeutic implications of QFY on the synaptic injury and oxidative stress in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice, with a concerted effort to elucidate the molecular mechanisms related to synaptic preservation and memory improvement. MATERIALS AND METHODS: The components of QFY were identified by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The neuroprotective effects of QFY was evaluated using six-month-old male APP/PS1 mice. Subsequent to a 15 days of QFY regimen, spatial memory was assessed utilizing the Morris water maze (MWM) test. Amyloid-beta (Aß) aggregation was detected via immunostaining, while the quantification of Aß1-40 and Aß1-42 was achieved through enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy (TEM) was used to investigate the synaptic structure and mitochondrial morphology. Golgi staining was applied to examine dendritic spine density. Reactive oxygen species (ROS), 3-nitrotyrosine (3-NT) and 4-hydroxy-nonenal (4-HNE) assays were employed to assess oxidative stress. The expression profiles of Aß metabolism-associated enzymes and the Keap1/Nrf2/ARE signaling pathway were determined by Western blot. RESULTS: A total of 20 principal compounds in QFY were identified. QFY mitigated memory deficits of APP/PS1 mice, including reducing escape latency and search distance and increasing the time and distance spent in the target quadrant. In addition, QFY increased platform crossings of APP/PS1 mice in the probe trial of MWM tests. TEM analysis showed that QFY increased synapse number in the CA1 region of APP/PS1 mice. Further studies indicated that QFY elevated the expression levels of Post synaptic density protein 95 (PSD95) and synaptophysin, and mitigated the loss of dendritic spine density in the hippocampus of APP/PS1 mice. QFY has been shown to ameliorated the structural abnormalities of mitochondria, including mitochondrial dissolution and degradation, up-regulate ATP synthesis and membrane potential in the hippocampus of APP/PS1 mice. Moreover, QFY activated the Keap1/Nrf2/ARE signaling pathway in the hippocampus of APP/PS1 mice, which might contribute to the neuroprotective effects of QFY. CONCLUSION: QFY activates the Keap1/Nrf2/ARE signaling, and protects against synaptic and mitochondrial dysfunction in APP/PS1 mice, proposing a potential alternative therapeutic strategy for AD management.

AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.

AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.

Neuroprotective effects of Aucubin against cerebral ischemia-reperfusion injury.

AIMS: To study the role of Aucubin (AU) in cerebral ischemia-reperfusion injury and investigate the potential mechanisms. METHODS: For the in vitro experiment, primary microglia were cultured and stimulated by Lipopolysaccharides (LPS) and treated with AU. Male C57/BL6J mice were used and middle cerebral artery occlusion (MCAO) model was performed to induce cerebral ischemia-reperfusion injury. For the short-term effects, mice administrated with AU (40 mg/kg) for 3 days after MCAO were evaluated for the infarct volume and neurological deficits. The neuroinflammatory factors and microglia activation were determined by Real-time PCR, western blot and immunofluorescence staining. For the long-term effects, MCAO mice were injected daily with AU (5 mg/kg or 10 mg/kg) for 28 days. Behavior tests were used to assess the neurological deficits of MCAO mice, and white matter integrity was determined by myelin basic protein (MBP) staining and black-gold staining. RESULTS: AU suppressed LPS-induced activation of microglia and pro-inflammatory cytokines release, and downregulated the NF-κB and MAPK pathways in primary microglia. In addition, AU attenuated ischemic injury and inhibited the neuro-inflammatory response in MCAO mice. Moreover, AU induced prolonged improvements in sensorimotor function and memory function following MCAO, and preserved white matter integrity in the long-term experiments. CONCLUSIONS: AU protected against ischemic injury, which might be correlated with the downregulation of NF-κB and MAPK signaling pathways. Furthermore, AU alleviated cognitive impairment after stroke and restored white matter integrity. Our data indicated that AU might be a potential compound for the treatment of stroke and post-stroke cognitive impairment.

Insight into the Alkali Resistance Mechanism of FeMoTiOx Catalysts for NH3 Selective Catalytic Reduction of NO: Self-Defense Effects of MoOx for Alkali Capture.

The deactivation of selective catalytic reduction (SCR) catalysts caused by alkali metal poisoning remains an insurmountable challenge. In this study, we examined the impact of Na poisoning on the performance of Fe and Mo co-doped TiO2 (FeaMobTiOx) catalysts in the SCR reaction and revealed the related alkali resistance mechanism. On the obtained Fe1Mo2.6TiOx catalyst, the synergistic catalytic effect of uniformly dispersed FeOx and MoOx species leads to remarkable catalytic activity, with over 90% NO conversion achieved in a wide temperature range of 210-410 °C. During the Na poisoning process, Na ions predominantly adsorb on the MoOx species, which exhibit stronger alkali resistance, effectively safeguarding the FeOx species. This preferential adsorption minimizes the negative effect of Na poisoning on Fe1Mo2.6TiOx. Moreover, Na poisoning has little influence on the Eley-Rideal reaction pathway involving adsorbed NHx reacting with gaseous NOx. After Na poisoning, the Lewis acid sites were deteriorated, while the abundant Brønsted acid sites ensured sufficient NHx adsorption. As a benefit from the self-defense effects of active MoOx species for alkali capture, FeaMobTiOx exhibits exceptional alkali resistance in the SCR reaction. This research provides valuable insights for the design of highly efficient and alkali-resistant SCR catalysts.

Biosynthesis of gold nanoparticles, characterization and their loading with zonisamide as a novel drug delivery system for the treatment of acute spinal cord injury.

In the present work, a facile biosynthetic approach for the synthesis of AuNPs using bark extract of Juglans regia (J. regia) is reported. Ultra-violet visible (UV-vis) absorption spectroscopic studies exhibited and narrow SPR absorption band at 540 nm, represented the isotropy in particle size. The transmission electron microscopy (TEM) and X-ray diffraction (XRD) analysis, confirmed the fabrication of spherical and crystalline nanoparticles of average size of about 14 nm. Also, typical characteristic selected area electron diffraction (SAED) pattern showed the crystalline nature of AuNPs. The prepared AuNPs were loaded with zonisamide which can be used for future spinal cord injury repair applications. The fourier transform infrared spectroscopy (FTIR) analysis represented the zonisamide loading onto AuNPs. The biological preparation of AuNPs using the bark extract of J. regia is prominent approach because of its eco friendly nature without using any toxic chemicals. The controlled-release of zonisamide-AuNPs was about 43.0 ±â€¯2.2 nm with high stability and solubility under room temperature conditions. Further, the cytotoxicity results showed the comparatively higher toxicity of zonisamide-AuNPs towards CTX TNA2 cells than free zonisamide. Hence, zonisamide-AuNPs may act as very good clinical drug for future therapeutic treatment of spinal cord injury.

Acupuncture for balance dysfunction in patients with stroke: A systematic review protocol.

BACKGROUND: Balance dysfunctions in stroke survivors are common and have significant impact on functional independence and rehabilitation. As a crucial technique of Traditional Chinese Medicine, acupuncture has been used widely for balance dysfunctions after stroke, although its effective evidence is not clear. Hence, we plan this systematic review protocol to evaluate the value of its efficacy and safety for balance dysfunctions after stroke. METHODS: We will search the databases from the publishment to April 2018: Web of Science, PubMed, Medline, Cochrane Library, EBASE, WHO International Clinical Trials Registry Platform, Wanfang, Chinese Biomedical Literature Database, Chinese Scientific Journal Database (VIP), and China National Knowledge Infrastructure. The clinical efficacy will be accepted as the primary outcomes. RevMan V.5.3 software will be used to compute the data synthesis when a meta-analysis is allowed. RESULTS: This systematic review and meta-analysis will provide a high-quality synthesis of current evidence of acupuncture for balance dysfunctions after stroke including clinical efficacy, balance ability, walking ability, and activity of daily life etcetera. CONCLUSION: This protocol will determine whether acupuncture is an effective and safety intervention for balance dysfunctions after stroke.

miR-340 alleviates chemoresistance of osteosarcoma cells by targeting ZEB1.

Chemoresistance during treatment of osteosarcoma (OS) is attracting more and more attention as the main clinical obstacle. The purpose of this study was to elucidate the role of miR-340 in chemoresistance of OS. Plasmid construction and transfection, miRNA arrays, PCR analyses, and western blot analysis, as well as MTT, apoptosis, and luciferase assays were carried out in MG-63 cells and MG-63/cisplatin (DDP)-resistant cells. The results showed that miR-340 was downregulated in OS tissues and drug-resistant OS cells. Moreover, a negative correlation was observed between miR-340 and ZEB1 expression in OS tissues. Forced expression of miR-340 in drug-resistant OS cells significantly reduced multidrug resistance-1 and P-gp expression. Overexpression of miR-340 enhanced sensitivity to DDP by inhibiting viability and promoting apoptosis. The luciferase assay and western blot analysis identified ZEB1 as a direct target of miR-340, and miR-340 negatively regulated ZEB1 expression. Ectopic expression of ZEB1 reversed the effects of miR-340 on P-gp expression, cell viability, and apoptosis. miR-340 alleviated chemoresistance of OS cells by targeting ZEB1. Our results indicate that targeting miR-340 may be a potential therapeutic approach to treat drug-resistant OS.

Transcription Factor 21 (TCF21) rs12190287 Polymorphism is Associated with Osteosarcoma Risk and Outcomes in East Chinese Population.

BACKGROUND The transcription factor 21 (TCF21) gene is believed to be a tumor suppressor gene. TCF21 gene polymorphisms were found to play a role in the tumorigenesis of some solid malignancies. We raised a hypothesis that genetic polymorphisms of TCF21 were correlated with risk and prognosis of osteosarcoma. MATERIAL AND METHODS We recruited 225 young osteosarcoma individuals and 250 cancer-free controls. Five tagging SNPs (TCF21 rs2327429 T>C, rs2327433 A>G, rs2327433 A>G, rs12190287 C>G, and rs4896011 T>A) were genotyped. Preserved DNA samples from blood underwent PCR analysis for genotyping. RESULTS rs12190287 C>G is a good predictor of osteosarcoma risk and outcomes. The CG and GG genotypes of rs12190287 predict elevated risk of osteosarcoma. Besides, rs12190287 CG and GG genotypes are associated with Enneking stage and potential in forming metastasis of osteosarcoma. CONCLUSIONS Genetic polymorphisms of TCF21 are potentially predictive for osteosarcoma risk and outcomes.

The correlation between the high-intensity zone on a T2-weighted MRI and positive outcomes of discography: a meta-analysis.

BACKGROUND: This meta-analysis aimed to assess the correlation between the high-intensity zone (HIZ) of a lumbar MRI and discography. METHODS: We conducted an electronic search of the PubMed, MEDLINE, Embase, and ScienceDirect databases from their respective inceptions to October 2016 using the following search terms: "low back pain," "discogenic low back pain," "HIZ or high-intensity zone," and "discography". Relevant journals and conference proceedings were manually searched. Two reviewers independently assessed the quality of the studies, extracted data from the included studies, and analyzed the data. RESULTS: Eleven studies were included. The results of the meta-analysis indicated that outstanding relativity and statistically significant correlations were observed between the HIZ and abnormal disc morphology (OR = 47.79; 95% CI: 17.07 to 133.77; P < 0.00001), HIZ and pain reproduction (OR = 8.65, 95% CI: 6.01 to 15.23, P < 0.00001), and HIZ and abnormal morphology pain reproduction (OR = 11.74, 95% CI: 1.99 to 69.36, P = 0.007). CONCLUSIONS: The presence of an HIZ on a lumbar MRI T2-weighted image indicates abnormal disc morphology. There is a strong relationship between the HIZ and pain reproduction. The HIZ can be an effective index for prediction of discogenic low back pain.

[Case-control studies on therapeutic effects of combined methods of minimally invasive percutaneous proximal humerus locked osteosynthesis plate with injectable bone for the treatment of proximal humerus fractures in elderly patients].

OBJECTIVE: To evaluate the clinical effects of combined methods of minimally invasive percutaneous proximal humeral internal locking system (PHILOS) and injectable bone for the treatment of proximal humerus fractures in elderly patients. METHODS: From January 2006 to January 2012, 80 patients with proximal humerus fractures were randomly divided into two groups (n = 40). The patients in the research group were treated with minimally invasive PHILOS fixation combined with injectable bone, including 20 males and 20 females, with an average age of (68.4 +/- 11.9) years; according to AO classification, 2 cases of type A1, 3 cases of type A2, 6 cases of type B1, 7 cases of type B2, 9 cases of type B3, 6 cases of type C1, 7 cases of type C2. The patients in the control group were treated with PHILOS fixation, including 18 males and 22 females, with an average age of (65.4 +/- 10.7) years; according to AO classification, 3 cases of type A1, 4 cases of type A2, 5 cases of type B1, 8 cases of type B2, 10 cases of type B3, 5 cases of type C, and 5 cases of type C2. The BMD, satisfactory rate, postoperative complications,bone healing time, Constant-Murley score in the two groups were reviewed and compared. RESULTS: In the research group, no patients had necrosis of femoral head, 1 patient had shoulder varus, 1 patient had internal fixation loosening, 36 patients were satisfactory with the treatment results, BMD was (1.013 +/- 0.109) g/cm2, bone healing time averaged (12.00 +/- 3.79) weeks, and the Constant-Murley score was 97.2 +/- 4.6. In the control group, 3 patients had necrosis of femoral head, 5 patients had shoulder varus, 6 patients had internal fixation loosening, 32 patients were satisfactory with the treatment results, BMD was (0.812 +/- 0.089) g/cm2, bone healing time averaged (20.00 +/- 8.67) weeks,and the Constant-Murley score was 78.5 +/- 3.2. The results of BMD, satisfactory rate, postoperative complications, bone healing time, and Constant-Murley score in the research group were better than those of control group (P < 0.05). CONCLUSION: PHILOS combined with injectable bone for the treatment of proximal humerus fractures in elderly patients has advantages of minimal wound, stable fixation, and earlier rehabilitation.

[Case-control study of influence factors analysis on short-term recovery after total knee arthroplasty in old patients with osteoarehritis].

OBJECTIVE: To investigate the relationship between variable influence factors and postoperative 2 week hospital special surgery (HSS) of knee joint, thus offer the treatment suggestion to patients with osteoarthritis, and judge the comprehensive effective prognosis to the clinical patient. METHODS: From March 2008 to August 2010, 72 patients with 72 knees were treated with TKA (treatment group), including 30 males and 42 females with a mean age of (71.9 +/- 6.2) years (ranged, 60 to 86 years). Twenty-two patients with HoldenIV OA treated by arthroscopy were in the control group, including 10 males and 12 females with a mean age of (70.5 +/- 5.9) years. The index including height, weight, BMI, muscle strength,knee joint HSS score and ROM were evaluated before operation and at 1st, 2nd weeks after operation. RESULTS: The HSS knee score and ROMs of patients in the treatment group improved. The pre-operative ROM, HSS score, knee pain, continous passive motion (CPM) at different level (i.e.CPM initial angle) had a prominent positive correlation with HSS score in postoperative 2 weeks. The factors such as patients' age, height, weight, BMI, muscular strength, etc. had no obvious relevant to HSS score in postoperative 2 weeks. CONCLUSION: The pre-operative HSS score, knee pain, knee ROM, perioperative severe complications, and postoperative CPM initial angle have a positive correlation with the postoperative effects.