Copper-mediated cascade radical cyclization of olefins with naphthalenyl iododifluoromethyl ketones.

Copper-mediated radical cyclization of naphthalenyl iododifluoromethyl ketones with olefins was successfully developed to generate a series of unprecedented gem-difluorodihydrophenanthrenones, especially 2,2-difluoro-3,4-dihydrophenanthren-1(2H)-one derivatives. This strategy features the use of cheap copper powder and excellent regioselectivity and diastereoselectivity, thus providing a facile approach for application in drug discovery and development. Preliminary mechanistic studies indicate the involvement of difluorinated radical intermediates. Density functional theory (DFT) calculation was performed to provide further evidence for regioselectivity.

Bone marrow mesenchymal stem cell-derived microvesicles protect rat pheochromocytoma PC12 cells from glutamate-induced injury via a PI3K/Akt dependent pathway.

Studies have suggested that mesenchymal stem cells (MSCs) can protect neuronal cells from excitotoxicity, but the underlying mechanisms are still remaining elusive. In the study, we show that microvesicles released by rat bone marrow-derived MSCs (rBMSC-MVs) protect rat pheochromocytoma PC12 cells from glutamate-induced excitotoxicity. BMSC-MVs upregulate Akt phosphorylation and Bcl-2 expression, downregulate Bax expression, and reduce the cleavage of caspase-3 in glutamate-treated PC12 cells. Such protective effects are partially abrogated by inhibiting PI3K, indicating that rBMSC-MVs act via the PI3K/Akt pathway. Transplantation of rBMSC-MVs may, therefore, be a promising strategy to treat cerebral injury or some other neuronal diseases involving excitotoxicity.

Altered regional homogeneity in experimentally induced low back pain: a resting-state fMRI study.

BACKGROUND: Functional imaging studies have indicated that patients with low back pain can have significant reductions in cerebral cortex grey matter. However, the mechanisms governing the nociceptive pathways in the human brain are unclear. The aim of this study was to use functional magnetic resonance imaging (fMRI) and regional homogeneity (ReHo) to investigate changes in resting-state brain activity in subjects that experienced experimentally induced low back pain. METHODS: Healthy subjects (n = 15) underwent fMRI (3.0 T) at baseline and during painful stimulation (intramuscular injection of 3% hypertonic saline). RESULTS: Compared to the scans conducted at baseline, scans conducted during experimentally induced low back pain showed increased ReHo on the right side in the medial prefrontal cortex, precuneus, insula, parahippocampal gyrus and cerebellum (posterior lobe), but decreased ReHo in the primary somatosensory cortex, anterior cingulate cortex and parahippocampal gyrus on the left side. The right inferior parietal lobule also showed a decreased ReHo (P < 0.05, cluster threshold ≥10). CONCLUSIONS: These findings suggest that abnormally spontaneous resting-state activity in some brain regions may be associated with pain processing. These changes in neural activity may contribute to the recognition, execution, memory and emotional processing of acute low back pain.

Pain-Related Risk Factors Among Radiologic Stages of Knee Osteoarthritis: Data From the Osteoarthritis Initiative.

OBJECTIVE: To investigate whether risk factors related to pain vary at different stages of knee osteoarthritis (OA). METHODS: Individuals from the Osteoarthritis Initiative with available Kellgren/Lawrence (K/L) grade and numerical rating scale (NRS) data at baseline were included in this study. Pain severity was classified into 3 categories based on NRS scores: no pain, mild pain, and moderate/severe pain. Knee OA severity was stratified into 4 categories according to the K/L system. Pain risk factors were evaluated using generalized ordinal logistic regression analysis, and a heatmap was created to compare differences in standardized regression coefficients between subgroups of patients with different knee OA severities. RESULTS: A total of 4,446 subjects were included in this study: 1,574 individuals without pain (35.4%), 1,138 individuals with mild pain (25.6%), and 1,734 individuals with moderate/severe pain (39.0%). For the entire population and subjects in the premorbid-stage subgroup, knee injury history, diabetes mellitus, depression, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and valgus malaligned knees were associated with more severe pain. Older age and stronger quadriceps muscles were associated with milder pain. As the disease progressed, the number of significant risk factors decreased. Only age and quadriceps muscle force remained significant in end-stage disease. CONCLUSION: Multiple factors are associated with pain in patients with knee OA. As the disease progresses, the number of significant risk factors gradually reduces. These findings suggest that strategies for managing pain related to knee OA should vary depending on radiographic grades.

Neuroimaging mechanisms of high-frequency repetitive transcranial magnetic stimulation for treatment of amnestic mild cognitive impairment: a double-blind randomized sham-controlled trial.

Individuals with amnestic mild cognitive impairment (aMCI) have a high risk of developing Alzheimer's disease. Although repetitive transcranial magnetic stimulation (rTMS) is considered a potentially effective treatment for cognitive impairment in patients with aMCI, the neuroimaging mechanisms are poorly understood. Therefore, we performed a double-blind randomized sham-controlled trial in which rTMS was applied to the left dorsolateral prefrontal cortex of aMCI patients recruited from a community near the Third Hospital Affiliated to Sun Yat-sen University, China. Twenty-four patients with aMCI were randomly assigned to receive true rTMS (treatment group, n = 12, 6 men and 6 women; age 65.08 ± 4.89 years) or sham stimulation (sham group, n = 12, 5 men and 7 women; age 64.67 ± 4.77 years). rTMS parameters included a stimulation frequency of 10 Hz, stimulation duration of 2 seconds, stimulation interval of 8 seconds, 20 repetitions at 80% of the motor threshold, and 400 pulses per session. rTMS/sham stimulation was performed five times per week over a period of 4 consecutive weeks. Our results showed that compared with baseline, Montreal Cognitive Assessment scores were significantly increased and the value of the amplitude of low-frequency fluctuation (ALFF) was significantly increased at the end of treatment and 1 month after treatment. Compared with the sham group, the ALFF values in the right inferior frontal gyrus, triangular part of the inferior frontal gyrus, right precuneus, left angular gyrus, and right supramarginal gyrus were significantly increased, and the ALFF values in the right superior frontal gyrus were significantly decreased in the treatment group. These findings suggest that high-frequency rTMS can effectively improve cognitive function in aMCI patients and alter spontaneous brain activity in cognitive-related brain areas. This study was approved by the Ethics Committee of Shenzhen Baoan Hospital of Southern Medical University, China (approval No. BYL20190901) on September 3, 2019, and registered in the Chinese Clinical Trials Registry (registration No. ChiCTR1900028180) on December 14, 2019.

Electroacupuncture Preconditioning Improves Myocardial Infarction Injury via Enhancing AMPK-Dependent Autophagy in Rats.

BACKGROUND: Electroacupuncture (EA) pretreatment plays a protective role in myocardial infarction injury. However, the mechanism of electroacupuncture remains unknown. The aim of this study was to confirm the protective effects of electroacupuncture (EA) on myocardial infarction injury and the possible mechanism. METHODS: Sprague-Dawley (SD) rats, used to serve as acute myocardial infarction (AMI) model, were divided into sham group, model (M) group, M+EA group, AMPK inhibitor Compound C (M+EA+CC), and AMPK inhibitor solvent control (M+EA+DMSO) group, respectively. Rats in EA group were pretreated with EA and those in M+EA+CC group with intravenous AMPK inhibitor Compound C. The myocardial morphological changes and infarct size were observed through HE staining and TTC staining, and the concentrations of CK-MB and LDH were detected using ELISA kits. Transmission electron microscopy was employed to observe the autophagosome formation, and the AMPK-dependent autophagy-related protein expression was detected by immunohistochemistry and western blot. RESULTS: EA could alleviate myocardial infarction injury and decrease the concentrations of CK-MB and LDH. Transmission electron microscopy showed that EA could also regulate the AMPK-dependent autophagosome formation and the AMPK-dependent autophagy-related protein expression. AMPK inhibitor Compound C could impair the effect of EA through regulating the concentrations of CK-MB and LDH, autophagosome formation, and autophagy-related protein expression. CONCLUSION: These results indicated that electroacupuncture could improve myocardial infarction injury and induce autophagy, and AMPK-dependent autophagy might be involved in this process.

[Protective effect of bone marrow mesenchymal stem cell-derived microvesicles on glutamate injured PC12 cells].

This study was aimed to investigate the protective effect of bone mesenchymal stem cell-derived microvesicles (BMMSC-MV) on glutamate injured PC12 cells so as to elucidate the mechanism of the neural damage repair. BMMSC were isolated and purified with density-gradient centrifugation method, BMMSC-MV were harvested from the supernatants of BMMSC by hypothermal ultracentrifugation method. The surface markers of BMMSC reacted against different antibodies were detected by flow cytometry. The morphology features of MV were observed under an electron microscope. Experiment was divided into three groups, one was a control group, and the other two were glutamate-injured group and co-culture group of BMMSC-MV and glutamate-damaged cells respectively. MTT test was used to evaluate the proliferative status of PC12 cells and the AnnexinV-FITC detecting kit and Hoechst33342 were used to detect the apoptosis of PC12 cells in different groups. The results showed that BMMSC isolated from rat bone marrow were highly positive for CD29, CD44 and negative for CD31, CD34 and CD45. The morphology of MV was round and the vesicles were homogenous in size. BMMSC-MV exhibited a protective effect on the excitotoxicity-injured PC12 cells, displaying increase of cell viability, decrease of Annexin-V/PI staining positive and nuclear condensed cells. It is concluded that BMMSC-MV can protect PC12 cells from glutamate-induced apoptosis, suggesting that BMMSC-MV may be a potential candidate for treatment of neurological diseases.This study provides the preliminary experimental and theoretical evidence for use of BMMSC-MV in treatment of neural excited damage.