The prevalence and incidence of Parkinson's disease (PD), an age-related neurodegenerative disease, are higher among elderly people. Independent of etiology, dysfunction and loss of dopaminergic ...neurons are common pathophysiological changes in PD patients with impaired motor and non-motor function. Currently, preventive or therapeutic treatment for combating PD is limited. The ghrelin axis and ghrelin receptor have been implicated in the preservation of dopaminergic neurons and have potential implications in PD treatment. Teaghrelin, a compound originating from Chin-Shin Oolong tea, exhibits ghrelin agonist activity. In this study, the neuroprotective potential of teaghrelin against PD was explored in a cell model in which human neuroblastoma SH-SY5Y cells were treated with the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP
). Upon MPP
exposure, SH-SY5Y cells exhibited decreased mitochondrial complex I activity and apoptotic cell death. Teaghrelin activated AMP-activated protein kinase (AMPK)/sirtuin 1(SIRT1)/peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways to antagonize MPP
-induced cell death. Herein, we propose that teaghrelin is a potential candidate for the therapeutic treatment of PD.
Anesthetics, particularly volatile anesthetics, have been shown to impair glucose metabolism and cause hyperglycemia, closely linking them with mortality and morbidity as related to surgery. Beyond ...being an anesthetic used for general anesthesia and sedation, intravenous hypnotic propofol displays an effect on glucose metabolism. To extend the scope of propofol studies, its effects on glucose metabolism were evaluated in male Sprague-Dawley rats of various ages. Unlike chloral hydrate and isoflurane, propofol had little effect on basal glucose levels in rats at 2 months of age, although it did reduce chloral hydrate- and isoflurane-induced hyperglycemia. Propofol reduced postload glucose levels after either intraperitoneal or oral administration of glucose in both 7- and 12-month-old rats, but not those at 2 months of age. These improved effects regarding propofol on glucose metabolism were accompanied by an increase in insulin, fibroblast growth factor-21 (FGF-21), and glucagon-like peptide-1 (GLP-1) secretion. Additionally, an increase in hepatic FGF-21 expression, GLP-1 signaling, and FGF-21 signaling, along with a decrease in endoplasmic reticulum (ER) stress, were noted in propofol-treated rats at 7 months of age. Current findings imply that propofol may turn into insulin-sensitizing molecules during situations of existing insulin resistance, which involve FGF-21, GLP-1, and ER stress.
This paper presents the motion control and stability analysis of a two-wheeled vehicle (TWV). The TWV is driven using two independent wheel motors, upon which a vehicle body is mounted. A ...mathematical model of the TWV is obtained using dynamic analysis. The TWV is inherently unstable and its motion is controlled through the actions of the wheel motors. Vehicle action depends on both the desired wheel response and the tilt angle. A self-tuning proportional-integral-derivative (PID) control strategy, based on a deduced model, is proposed for implementing a motion control system that stabilizes the TWV and follows the desired motion commands. The controller parameters are tuned automatically, on-line, to overcome the disturbances and parameter variations. Experimental results are presented to demonstrate the reliability and effectiveness of the proposed control scheme.
Abstract
BACKGROUND
Magnesium supplementation has potential for use in nerve regeneration. The expression of some magnesium transporter genes is reflective of the intracellular magnesium levels.
...OBJECTIVE
To assess the expression of various magnesium transporter genes as they relate to neurological alterations in a sciatic nerve injury model.
METHODS
Sciatic nerve injury was induced in rats, which were then fed either basal or high magnesium diets. Magnesium concentrations and 5 magnesium transporter genes (SLC41A1, MAGT1, CNNM2, TRPM6, and TRPM7) were measured in the tissue samples.
RESULTS
The high magnesium diet attenuated cytoskeletal loss in a dose-dependent manner in isolated nerve explants. The high magnesium diet augmented nerve regeneration and led to the restoration of nerve structure, increased S-100, and neurofilaments. This increased regeneration was consistent with the improvement of neurobehavioral and electrophysiological assessment. The denervated muscle morphology was restored with the high magnesium diet, and that was also highly correlated with the increased expression of desmin and acetylcholine receptors in denervated muscle. The plasma magnesium levels were significantly elevated after the animals consumed a high magnesium diet and were reciprocally related to the down-regulation of CNNM2, MagT1, and SCL41A1 in the blood monocytes, nerves, and muscle tissues of the nerve crush injury model.
CONCLUSION
The increased plasma magnesium levels after consuming a high magnesium diet were highly correlated with the down-regulation of magnesium transporter genes in monocytes, nerves, and muscle tissues after sciatic nerve crush injury. The study findings suggest that there are beneficial effects of administering magnesium after a nerve injury.
Dysregulational EGFR, KRAS, and mTOR pathways cause metabolic reprogramming, leading to progression of gastric cancer. Afatinib (Afa) is a broad-spectrum tyrosine kinase inhibitor that reduces cancer ...growth by blocking the EGFR family. MicroRNA 125 (miR-125) reportedly diminishes EGFRs, glycolysis, and anti-apoptosis. Here, a one-shot formulation of miR-125 and Afa was presented for the first time. The formulation comprised solid lipid nanoparticles modified with mitochondrial targeting peptide and EGFR-directed ligand to suppress pan-ErbB-facilitated epithelial–mesenchymal transition and mTOR-mediated metabolism discoordination of glycolysis–glutaminolysis–lipids. Results showed that this cotreatment modulated numerous critical proteins, such as EGFR/HER2/HER3, Kras/ERK/Vimentin, and mTOR/HIF1-α/HK2/LDHA pathways of gastric adenocarcinoma AGS cells. The combinatorial therapy suppressed glutaminolysis, glycolysis, mitochondrial oxidative phosphorylation, and fatty acid synthesis. The cotreatment also notably decreased the levels of lactate, acetyl-CoA, and ATP. The active involvement of mitophagy supported the direction of promoting the apoptosis of AGS cells, which subsequently caused the breakdown of tumor-cell homeostasis and death. In vivo findings in AGS-bearing mice confirmed the superiority of the anti-tumor efficacy and safety of this combination nanomedicine over other formulations. This one-shot formulation disturbed the metabolic reprogramming; alleviated the “Warburg effect” of tumors; interrupted the supply of fatty acid, cholesterol, and triglyceride; and exacerbated the energy depletion in the tumor microenvironment, thereby inhibiting tumor proliferation and aggressiveness. Collectively, the results showed that the two-in-one nanoparticle formulation of miR-125 and Afa was a breakthrough in simplifying drug preparation and administration, as well as effectively inhibiting tumor progression through the versatile targeting of pan-ErbB- and mTOR-mediated mitochondrial dysfunction and dysregulated metabolism.
Hyperglycemia and inflammation, with their augmented interplay, are involved in cases of stroke with poor outcomes. Interrupting this vicious cycle thus has the potential to prevent stroke disease ...progression. Tumor necrosis factor-α (TNF-α) is an emerging molecule, which has inflammatory and metabolic roles. Studies have shown that TNF-α receptor inhibitor R-7050 possesses neuroprotective, antihyperglycemic, and anti-inflammatory effects. Using a rat model of permanent cerebral ischemia, pretreatment with R-7050 offered protection against poststroke neurological deficits, brain infarction, edema, oxidative stress, and caspase 3 activation. In the injured cortical tissues, R-7050 reversed the activation of TNF receptor-I (TNFRI), NF-κB, and interleukin-6 (IL-6), as well as the reduction of zonula occludens-1 (ZO-1). In the in vitro study on bEnd.3 endothelial cells, R-7050 reduced the decline of ZO-1 levels after TNF-α-exposure. R-7050 also reduced the metabolic alterations occurring after ischemic stroke, such as hyperglycemia and increased plasma corticosterone, free fatty acids, C reactive protein, and fibroblast growth factor-15 concentrations. In the gastrocnemius muscles of rats with stroke, R-7050 improved activated TNFRI/NF-κB, oxidative stress, and IL-6 pathways, as well as impaired insulin signaling. Overall, our findings highlight a feasible way to combat stroke disease based on an anti-TNF therapy that involves anti-inflammatory and metabolic mechanisms.
Cell transplantation using bone marrow stromal cells (BMSCs) to alleviate neurological deficits has recently become the focus of research in regenerative medicine. Evidence suggests that secretion of ...various growth-promoting substances likely plays an important role in functional recovery against neurological diseases. In an attempt to identify a possible mechanism underlying the regenerative potential of BMSCs, this study investigated the production and possible contribution of neurotrophic factors by transected sciatic nerve defect in a rat model with a 15 mm gap. Cultured BMSCs became morphologically homogeneous with fibroblast-like shape after
ex vivo expansion. We provided several pieces of evidence for the beneficial effects of implanted fibroblast-like BMSCs on sciatic nerve regeneration. When compared to silicone tube control animals, this treatment led to (i) improved walking behavior as measured by footprint analysis, (ii) reduced loss of gastrocnemius muscle weight and EMG magnitude, and (iii) greater number of regenerating axons within the tube. Cultured fibroblast-like BMSCs constitutively expressed trophic factors and supporting substances, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), collagen, fibronectin, and laminin. The progression of the regenerative process after BMSC implantation was accompanied by elevated expression of neurotrophic factors at both early and later phases. These results taken together, in addition to documented Schwann cell-like differentiation, provide evidence indicating the strong association of neurotrophic factor production and the regenerative potential of implanted BMSCs.
The global prevalence of diabetes mellitus (DM) has reached 20%. Air pollutants with a particle size of less than 2.5 μm (PM2.5) are a globally recognized risk factor for diabetes and glaucoma. We ...examined whether the risk of glaucoma would decrease or increase when patients with DM were exposed to different PM2.5 concentrations. Data were obtained from the National Health Insurance Research Database (NHIRD) of Taiwan and the Air Quality Monitoring Network between 2008 and 2013. This nested case–control study involved 197 DM patients with glaucoma and 788 DM patients without glaucoma. Cases and controls were matched (1:4) by gender, age (±5 years), and index date (±6 months), and their data were entered in a logistic regression model adjusted for gender, age, urbanization level, income level, and comorbidities. The odds ratio (OR) of glaucoma at PM2.5 exposure concentration in the fourth quartile (Q4) compared with in the first quartile (Q1) was 1.7 (95% CI: 1.084–2.764). For glaucoma risk, the OR was 1.013 (95% CI: 1.006–1.020) at a PM2.5 exposure concentration in Q1, 1.004 (95% CI: 1.001–1.007) in the third quartile (Q3), and 1.003 (95% CI: 1.001–1.004) in Q4. In the subgroup analysis of patients living in non-emerging towns and non-agricultural towns, the OR for glaucoma in Q4 compared with in Q1 was 2.1 (95% CI: 1.229–3.406) and 1.8 (95% CI: 1.091–2.803), respectively (p trend = 0.001 and 0.011). For patients without migraine, the OR for glaucoma was 1.7 (95% CI: 1.074–2.782; p = 0.006). These results demonstrate that, for patients with DM, PM2.5 increased the risk of glaucoma and PM2.5 was an independent risk factor for glaucoma in patients with DM.
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•NPC cell motility and proliferation were correlated with fibronectin expression.•Fibronectin activated integrin α5/Src signaling and Rac1/Cdc42.•Hypoxia, TGF-β1, and HIF-1α ...positively controlled fibronectin expression.
Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-associated carcinoma. Fibronectin is regarded as a prognosticator in NPC and its involvement in cell motility has been reported in EBV infection and viral latent membrane protein 1 (LMP1) overexpression NPC cell lines. However, its malignant potential in NPC cell lines without harbouring the EBV genome has not been investigated. We investigatd and compared among four NPC cell lines, and the results revealed a positive association between fibronectin levels and NPC cell motility as well as proliferation. Studies of antibody neutralization, exogenous addition, overexpression, and RNA interference confirmed a migration role of fibronectin in NPC cells involving integrin α5, Src, Rac1, and Cdc42, implying a mesenchymal-like cell movement. Furthermore, hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β1 (TGF-β1) were identified as alternative activators of fibronectin expression and NPC cell migration. Besides cell migration, studies of RNA interference also showed a stimulatory effect of fibronectin in NPC cell proliferation. Mechanistic studies further revealed a subsequent reduction of HIF-1α, TGF-β1, cyclin D1, β-catenin, vimentin, and Slug together with decreased Src and Akt phosphorylation after fibronectin knockdown. Parallel studies in a xenograft tumor mice model further showed that tumor growth correlated well with elevation of circulating fibronectin and activation of the identified intracellular signaling molecules. The results of our study highlight a role of fibronectin in NPC cell motility and proliferation in concerted action with HIF-1α and TGF-β1 possibly through linking molecules Src and Akt. Fibronectin overexpression and autoantibody are known to have potential prognostic value in patients with NPC. Our findings shed light on the biochemical and molecular mechanisms underlying the pathogenic role of fibronectin in this disease.
Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause ...adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.
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