An Acute Bout of Exercise Suppresses Appetite via Central Lactate Metabolism.

Exercise has been reported to elicit a transient suppression of appetite. Plasma lactate, which is produced by exercising muscle, is believed to have a critical effect on exercise-induced appetite suppression. However, the underlying mechanisms and signaling steps of central lactate metabolism remain unexplored. After central oxamate administration, C57BL/6J male mice performed 10 high-intensity interval running at 90% Vmax for 4 minutes each, which separated by 2 minutes at 12 m/min. Food intake and the expression of hypothalamic appetite-regulating neuropeptides including proopiomelanocortin (POMC) and neuropeptide Y (NPY) were investigated following exercise training. Janus kinase 2 (Jak2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway was also determined by Western blot. In addition, hypoxia-inducible factor-1α (HIF-1α) was investigated to explore the effect of central lactate metabolism following exercise. We found that central oxamate administration reversed exercise-induced suppression of food intake, and as well as changes in the expression of POMC and NPY. Moreover, acute exercise led to an increase in the phosphorylation of Jak2 and STAT3 in the hypothalamus, while central lactate inhibition significantly blunted this effect. In addition, HIF-1α expression increased obviously after exercise, while it was attenuated by central oxamate administration. Collectively, our data reveal that central lactate metabolism mediates exercise-induced suppression of appetite and changes in neuropeptides, possibly through enhanced Jak2-STAT3 signaling.

Effects of Curcumin-mediated photodynamic therapy on autophagy and epithelial-mesenchymal transition of lung cancer cells.

BACKGROUND: This study aimed to investigated whether Curcumin-mediated PDT can suppress EMT in lung cancer cells, and explore the roles of autophagy in the process of regulating EMT. METHODS: Lung cancer cell viability was assessed by CCK-8 assay. The expression of epithelial marker and mesenchymal markers, the conversion of LC3-I to LC3-II and the levels of p62 and beclin1 in A549 and SPCA1 cells were measured by Western blotting assay. The Wound healing and Transwell assays were used to detect the migration and invasion abilities of the A549 and SPCA1 cells. Autophagosome formation was detected via observing the colocalization of Lamp-2 with LC3 in A549 cells, and the autophagy ultrastructure was observed by TEM. RESULTS: Curcumin-PDT inhibited EMT, migration and invasion and induced autophagy in lung cancer cells. Curcumin-PDT induced autophagy was involved in the process of PDT inhibiting EMT, but it presented a promoting effect of EMT in lung cancer cells. Curcumin-PDT combined with CQ further inhibited EMT, invasion and migration of lung cancer cells. CONCLUSIONS: The role of PDT-induced autophagy in the regulation of EMT was determined to be a promoting effect in lung cancer. Therefore, Curcumin-mediated PDT combined with autophagy inhibitor further suppressed EMT of lung cancer cells, and may represent a potential strategy against invasion and migration of lung cancer.

Combined effectiveness of extracorporeal radial shockwave therapy and ultrasound-guided trigger point injection of lidocaine in upper trapezius myofascial pain syndrome.

OBJECTIVE: Myofascial pain syndrome (MPS) is a major musculoskeletal problem and a leading cause of disability worldwide. Extracorporeal shockwave therapy (ESWT) and trigger point injection (TPI) have shown positive results for MPS but no previous study has investigated the combined effects of radial shockwave and trigger point injection of lidocaine for upper trapezius myofascial pain syndrome. METHOD: For this purpose, forty-five participants were randomly divided into shockwave (n = 15), shockwave with ultrasound-guided trigger point injection (combined; n = 15), and control (standard care; n = 15) groups. Participants were assessed at baseline, one week and four weeks by using the visual analog scale, neck disability index, electromyography, infrared thermography, and sonoelastography. RESULTS: Compared with control group, both shockwave and combined groups showed a statistically significant reduction in pain (P<0.01), functional disability (P<0.01), skin temperature (P<0.01), and elastic stiffness, with greater reduction in the combined group (P<0.01) than shockwave group (P<0.05) at four weeks. However, no significant difference was found in electrical activity between the groups (P>0.05). The combined group also showed significant differences in pain (P<0.05) and elastic stiffness (P<0.01) compared with shockwave group at four weeks. CONCLUSION: Our study revealed that extracorporeal radial shockwave therapy combined with trigger point injection of lidocaine was more effective for decreasing pain and elastic stiffness in upper trapezius myofascial pain syndrome at four weeks.

C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation.

OBJECTIVE: C1qTNF-related protein 4 (CTRP4) acts in the hypothalamus to modulate food intake in diet-induced obese mice and has been shown to exert an anti-inflammatory effect on macrophages. Since high-fat diet-induced microglial activation and hypothalamic inflammation impair leptin signaling and increase food intake, we aimed to explore the potential connection between the anorexigenic effect of CTRP4 and the suppression of hypothalamic inflammation in mice with DIO. METHODS: Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and the hypothalamic leptin signaling pathway in diet-induced obese mice. Furthermore, central and plasma proinflammatory cytokines, including TNF-α and IL-6, were measured by Western blotting and ELISA. Changes in the hypothalamic NF-κB signaling cascade and microglial activation were also examined in vivo. In addition, NF-κB signaling and proinflammatory factors were investigated in BV-2 cells after CTRP4 intervention. RESULTS: We found that food intake was decreased, while leptin signaling was significantly improved in mice with DIO after CTRP4 overexpression. Central and peripheral TNF-α and IL-6 levels were reduced by central Ad-CTRP4 administration. Hypothalamic NF-κB signaling and microglial activation were also significantly suppressed in vivo. In addition, NF-κB signaling was inhibited in BV-2 cells following CTRP4 intervention, which was consistent with the decreased production of TNF-α and IL-6. CONCLUSIONS: Our data indicate that CTRP4 reverses leptin resistance by inhibiting NF-κB-dependent microglial activation and hypothalamic inflammation.

C1q/TNF-related Protein 4 Induces Signal Transducer and Activator of Transcription 3 Pathway and Modulates Food Intake.

C1q/TNF-related protein 4 (CTRP4) has been reported to decrease food intake and regulate energy homeostasis. However, its underlying mechanism and signaling pathway remain unknown. Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and signal transducer and activator of transcription 3 (STAT3) signaling pathway in normal chow-fed mice. Expressions of neuropeptides including proopiomelanocortin (POMC) and neuropeptide Y (NPY) were studied in hypothalamus by Western blot and immunochemistry. STAT3 and suppressor of cytokine signaling 3 (SOCS3) were determined by Western blot. STAT3 signaling pathway was also investigated in Neuro 2A (N2a) cells after CTRP4 overexpression intervention. We found that food intake decreased significantly in mice under normal chow condition after CTRP4 overexpression. Both immunohistochemistry and Western blot demonstrated that POMC expression was significantly increased while NPY expression was significantly decreased. The changes of neuropeptides were accompanied by significant increased STAT3 phosphorylation and decreased SOCS3 levels. The same changes of neuropeptides and STAT3 signaling were also found in N2a cells after CTRP4 overexpression intervention. Collectively, our data reveals that CTRP4 induces the activation of STAT3 signaling and decreases food intake.

Chemogenetic activation of glutamatergic neurons in the motor cortex promotes functional recovery after ischemic stroke in rats.

Ischemic stroke is a major cause of disability and mortality worldwide, while no unequivocally efficacious drug is currently available to treat post-stroke functional impairments. Animal and clinical investigations suggest that the motor cortex stimulation constitutes a particularly promising approach for promoting function recovery after stroke. However, the cell types and mechanisms involved in stimulation-induced recovery are not well understood. Here, we used chemogenetic technique to selectively activate glutamatergic neurons in the primary motor cortex and investigated whether activation of glutamatergic neurons in the primary motor cortex can promote functional recovery after ischemic stroke in rats. The results showed that chemogenetic activation of the motor cortex glutamatergic neurons significantly decreased the neurological deficit scores, as well as significantly increased the grip test scores and the hanging time. Moreover, the glutamatergic neuronal activation also significantly decreased the escape latencies, increased the swimming speed, target quadrant time, and numbers of crossing platform position in the Morris water maze test. These results demonstrate that selective activation of the glutamatergic neurons in primary motor cortex is sufficient to promote functional recovery after ischemic stroke, and may be of importance in understanding the neural cellular mechanisms underlying the motor cortex stimulation-induced functional recovery.

Gambogic acid inhibits spinal cord injury and inflammation through suppressing the p38 and Akt signaling pathways.

Gamboge is the dry resin secreted by Garcinia hanburyi Hook.f, with the function of promoting blood circulation, detoxification, hemostasis and killing insects, used for the treatment of cancer, brain edema and other diseases. Gambogic acid is the main effective constituent of Gamboge. The present study investigated the protective effects of gambogic acid on spinal cord injury (SCI) and its anti­inflammatory mechanism in an SCI model in vivo. Basso, Beattie and Bresnahan (BBB) testing was used to detect the protective effects of gambogic acid on nerve function of SCI rats. The water content of the spinal cord was used to analyze the protective effects of gambogic acid on the damage of SCI. Treatment with gambogic acid effectively improved BBB scores and inhibited water content of the spinal cord in SCI rats. Also, gambogic acid significantly reduced inflammatory cytokines levels of [tumor necrosis factor­α, interleukin (IL)­6, IL­12 and IL­1ß] and oxidative stress (malondialdehyde, superoxide dismutase, glutathione and glutathione­peroxidase) factors, and suppressed receptor activator of nuclear factor κB ligand, phosphorylated p38 protein expression and toll­like receptor 4/nuclear factor­κB pathway activation, and increased phosphatidylinositol 3­kinase/protein kinase B (Akt) pathway activation in SCI rats. These results provide evidence that gambogic acid inhibits SCI and inflammation through suppressing the p38 and Akt signaling pathways.

Combined application of dexamethasone and hyperbaric oxygen therapy yields better efficacy for patients with delayed encephalopathy after acute carbon monoxide poisoning.

BACKGROUND: Delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) commonly occurs after recovering from acute CO poisoning. This study was performed to assess the efficacy of the combined application of dexamethasone and hyperbaric oxygen (HBO) therapy in patients with DEACMP. PATIENTS AND METHODS: A total of 120 patients with DEACMP were recruited and randomly assigned into the experimental group (receiving dexamethasone 5 mg/day or 10 mg/day plus HBO therapy) and control group (HBO therapy as monotherapy). Meanwhile, the conventional treatments were provided for all the patients. We used the Mini-Mental State Examination (MMSE) scale to assess the cognitive function, the National Institutes of Health Stroke Scale (NIHSS) to assess the neurological function and the remission rate (RR) to assess the clinical efficacy. Myelin basic protein (MBP) in the cerebrospinal fluid (CSF) was also measured. RESULTS: After 4 weeks of treatment, compared to the control group, the experimental group had a significantly higher remission rate (P=0.032), a significantly higher average MMSE score (P=0.037) and a significantly lower average NIHSS score (P=0.002). Meanwhile, there was a trend toward better improvement with dexamethasone 10 mg/day, and the level of MBP in the CSF of patients was significantly lower in the experimental group than in the control group (P<0.0001). The addition of dexamethasone did not significantly increase the incidence of adverse events. CONCLUSION: These results indicate that the combined application of dexamethasone and HBO therapy could yield better efficacy for patients with DEACMP and should be viewed as a potential new therapy.

Effect of Pulsed Electromagnetic Field on Bone Formation and Lipid Metabolism of Glucocorticoid-Induced Osteoporosis Rats through Canonical Wnt Signaling Pathway.

Pulsed electromagnetic field (PEMF) has been suggested as a promising method alternative to drug-based therapies for treating osteoporosis (OP), but the role of PEMF in GIOP animal models still remains unknown. This study was performed to investigate the effect of PEMF on bone formation and lipid metabolism and further explored the several important components and targets of canonical Wnt signaling pathway in GIOP rats. After 12 weeks of intervention, bone mineral density (BMD) level of the whole body increased significantly, serum lipid levels decreased significantly, and trabeculae were thicker in GIOP rats of PEMF group. PEMF stimulation upregulated the mRNA and protein expression of Wnt10b, LRP5, ß-catenin, OPG, and Runx2 and downregulated Axin2, PPAR-γ, C/EBPα, FABP4, and Dkk-1. The results of this study suggested that PEMF stimulation can prevent bone loss and improve lipid metabolism disorders in GIOP rats. Canonical Wnt signaling pathway plays an important role in bone formation and lipid metabolism during PEMF stimulation.

Exploring a Novel Target Treatment on Breast Cancer: Aloe-emodin Mediated Photodynamic Therapy Induced Cell Apoptosis and Inhibited Cell Metastasis.

Photodynamic therapy (PDT) as a clinical cancer therapy, is a mild therapy, which involves application of photosensitizers (PSs) located in target cells and then irradiated by corresponding wavelength. The activation of PSs generates radical oxygen species (ROS) to exert a selective cytotoxic activity for the target cells. Aloe-emodin (AE) has been found to be an anti-tumor agent in many studies, and has also been demonstrated as a photosensitizer, in the recent years. In order to study the mechanisms of aloe-emodin as a photosensitizer, we investigated the mechanisms of photo-cytotoxicity induced by aloe-emodin in breast cancer MCF-7 cells in the present study. Analysis of cell proliferation evidenced that there was a drastic depression after photodynamic treatment with a series of aloe-emodin concentrations and light doses. We observed changes in apoptosis and demonstrated that the mechanisms of apoptosis were involved in mitochondrial and endoplasmic reticulum death pathways. The capacity of adhesion, migration and invasion of breast cells was measured using WST8 and transwell assay and demonstrated that AE-PDT significantly inhibited adhesion, migration and invasion of MCF-7cells. The expression of MMP2, MMP9, VEGF and Nrf2 demonstrated that the metastasis was related to oxidative stress. Analysis of changes in cytoskeleton components (F-actin) evidenced cytoskeleton disorganization after treatment with AE-PDT. Taken together, the present results indicated that PDT with aloe-emodin effectively suppressed cancer development in MCF-7cells, suggesting the potential of AE as a new photosensitizer in PDT which can provide a new modility for treating cancer.

Electrical stimulation of cerebellar fastigial nucleus promotes the expression of growth arrest and DNA damage inducible gene ß and motor function recovery in cerebral ischemia/reperfusion rats.

This study focused on the effects of electrical stimulation of cerebellar fastigial nucleus on the expression of growth arrest and DNA damage inducible gene ß (Gadd45ß) and on motor function recovery after focal cerebral ischemia/reperfusion (I/R) in rats. Sprague-Dawley (SD) rats were randomly divided into 4 groups: sham I/R (control group), I/R (I/R group), I/R with sham stimulation and I/R with electrical stimulation at 6h, 12h, 24h, 2d and 3d after I/R. Cerebral ischemia and reperfusion was established by nylon monofilament occlusion method. Fastigial nucleus (FN) electrical stimulation was applied at 2h after ischemia for 1h. The changes in the expression of Gadd45ß were analyzed by immunohistochemistry, real-time polymerase chain reaction (PCR) and Western-blot respectively. Another group of rats were divided into the same 4 groups. Montoya staircase test score was used to test the motor function of affected forelimb. The levels of Gadd45ß were significantly elevated after I/R injury. FN electrical stimulation treatment elevated the expression of Gadd45ß further and improved motor function recovery. These results suggest that FN electrical stimulation can promote the expression of Gadd45ß and motor function recovery after focal cerebral ischemia.