Primate Model Carrying LMNA Mutation Develops Dilated Cardiomyopathy.

To solve the clinical transformation dilemma of lamin A/C (LMNA)-mutated dilated cardiomyopathy (LMD), we developed an LMNA-mutated primate model based on the similarity between the phenotype of primates and humans. We screened out patients with LMD and compared the clinical data of LMD with TTN-mutated and mutation-free dilated cardiomyopathy to obtain the unique phenotype. After establishment of the LMNA c.357-2A>G primate model, primates were continuously observed for 48 months, and echocardiographic, electrophysiological, histologic, and transcriptional data were recorded. The LMD primate model was found to highly simulate the phenotype of clinical LMD. In addition, the LMD primate model shared a similar natural history with humans.

C9orf72 poly(PR) aggregation in nucleus induces ALS/FTD-related neurodegeneration in cynomolgus monkeys.

Poly(PR) is a dipeptide repeat protein comprising proline and arginine residues. It is one of the translational product of expanded G4C2 repeats in the C9orf72 gene, and its accumulation is contributing to the neuropathogenesis of C9orf72-associated amyotrophic lateral sclerosis and/or frontotemporal dementia (C9-ALS/FTD). In this study, we demonstrate that poly(PR) protein alone is sufficient to induce neurodegeneration related to ALS/FTD in cynomolgus monkeys. By delivering poly(PR) via AAV, we observed that the PR proteins were located within the nucleus of infected cells. The expression of (PR)50 protein, consisting of 50 PR repeats, led to increased loss of cortical neurons, cytoplasmic lipofuscin, and gliosis in the brain, as well as demyelination and loss of ChAT positive neurons in the spinal cord of monkeys. While, these pathologies were not observed in monkeys expressing (PR)5, a protein comprising only 5 PR repeats. Furthermore, the (PR)50-expressing monkeys exhibited progressive motor deficits, cognitive impairment, muscle atrophy, and abnormal electromyography (EMG) potentials, which closely resemble clinical symptoms seen in C9-ALS/FTD patients. By longitudinally tracking these monkeys, we found that changes in cystatin C and chitinase-1 (CHIT1) levels in the cerebrospinal fluid (CSF) corresponded to the phenotypic progression of (PR)50-induced disease. Proteomic analysis revealed that the major clusters of dysregulated proteins were nuclear-localized, and downregulation of the MECP2 protein was implicated in the toxic process of poly(PR). This research indicates that poly(PR) expression alone induces neurodegeneration and core phenotypes associated with C9-ALS/FTD in monkeys, which may provide insights into the mechanisms of disease pathogenesis.

Chronic vagus nerve stimulation (VNS) altered IL-6, IL-1ß, CXCL-1 and IL-13 levels in the hippocampus of rats with LiCl-pilocarpine-induced epilepsy.

An increasing number of observations have indicated that the activation of inflammatory processes is involved in the pathogenesis of epilepsy. As an effective adjunctive therapy for medically intractable seizures, vagus nerve stimulation (VNS) is thought to interact with the inflammatory process to play an antiepileptic role. In this study, we examined the levels of multiple cytokine in focal brain tissue and peripheral blood to determine whether the antiepileptic effect of chronic VNS is related to the expression of cytokines. We observed that the frequency and duration of seizures significantly decreased in epileptic rats after two weeks of chronic VNS treatment. Pathological staining showed that the number of neural cells in the hippocampus was higher in the Epi + VNS group than in the Epi group, indicating that chronic VNS had a significant neuroprotective effect on epileptic rats. After comparing the expression of 9 cytokines, we found that the levels of the proinflammatory cytokines IL-6, IL-1ß and CXCL-1 in the hippocampus were significantly increased in the Epi group, while these cytokines were significantly decreased in the Epi + VNS group. Moreover, the level of the anti-inflammatory cytokine IL-13 was found to be reduced in Epi rats, while its levels were increased after VNS treatment. However, these changes in cytokine expression were not found in the hypothalamus or peripheral blood. These results suggest that the antiepileptic mechanism of VNS may work by inhibiting the activation of inflammatory processes in the epileptogenic focus.

Motion Analysis for Jumping Discus Throwing Correction.

The purpose of this study was to explore the kinematical characteristics of jumping discus throwing. Eight male right-handed discus throwers who used to practice the jumping throwing technique were recruited as participants. Two high-speed digital cameras with 120 Hz sampling rate were synchronized to capture the movement. The captured images were processed using a motion analysis suite, and the markers attached to joints on images were digitized manually. Based on the results, throwers should keep smaller the shoulder-hip twisting and the right anterior superior iliac spine (abbreviated: ASIS) in front of the right acromion (for right-handed throwers) from the instant the right foot lands to the instant the left foot lands, before the instant of the right foot lands; keep the discus at a depressed position; and reduce the time before discus release, particularly the time of the non-support phase and the second single-support phase. Additionally, release velocity must be improved because throwing distance is directly proportional to squared release velocity. In conclusion, the current study demonstrated comprehensive kinematical analyses, which can be used to instruct the jumping discus throwing technique with duration and angle characteristics of throwing movement for athletes by coaches with videos.

The Protective Effect of Anthocyanins Extracted from Aronia Melanocarpa Berry in Renal Ischemia-Reperfusion Injury in Mice.

BACKGROUND: Our previous research showed the antioxidant activity of anthocyanins extracted from Aronia melanocarpa of black chokeberry in vitro. Ischemia acute kidney injury is a significant risk in developing progressive and deterioration of renal function leading to clinic chronic kidney disease. There were many attempts to protect the kidney against this progression of renal damage. Current study was designed to examine the effect of pretreatment with three anthocyanins named cyanidin-3-arabinoside, cyanidin-3-glucodise, and cyaniding-3-galactoside against acute ischemia-reperfusion injury in mouse kidney. METHODS: Acute renal injury model was initiated by 30 min clamping bilateral renal pedicle and followed by 24-hour reperfusion in C57Bl/6J mice. Four groups of mice were orally pretreated in 50 mg/g/12 h for two weeks with cyanidin-3-arabinoside, cyanidin-3-glucodise, and cyaniding-3-galactoside and anthocyanins (three-cyanidin mixture), respectively, sham-control group and the renal injury-untreated groups only with saline. RESULTS: The model resulted in renal dysfunction with high serum creatinine, blood urea nitrogen, and changes in proinflammatory cytokines (TNF-ɑ, IL-1ß, IL-6, and MCP-1), renal oxidative stress (SOD, GSH, and CAT), lipid peroxidation (TBARS and MDA), and apoptosis (caspase-9). Pretreatment of two weeks resulted in different extent amelioration of renal dysfunction and tubular damage and suppression of proinflammatory cytokines, oxidative stress, lipid peroxidation, and apoptosis, thus suggesting that cyanidins are potentially effective in acute renal ischemia by the decrease of inflammation, oxidative stress, and lipid peroxidation, as well as apoptosis. CONCLUSION: the current study provided the first attempt to investigate the role of anthocyanins purified from Aronia melanocarpa berry in amelioration of acute renal failure via antioxidant and cytoprotective effects.

Iron and Alzheimer's Disease: From Pathogenesis to Therapeutic Implications.

As people age, iron deposits in different areas of the brain may impair normal cognitive function and behavior. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, and ultimately leads to cell death. There is an imbalance in iron homeostasis in Alzheimer's disease (AD). Excessive iron contributes to the deposition of ß-amyloid and the formation of neurofibrillary tangles, which in turn, promotes the development of AD. Therefore, iron-targeted therapeutic strategies have become a new direction. Iron chelators, such as desferoxamine, deferiprone, deferasirox, and clioquinol, have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Given the limitations and side effects of the long-term application of traditional iron chelators, alpha-lipoic acid and lactoferrin, as self-synthesized naturally small molecules, have shown very intriguing biological activities in blocking Aß-aggregation, tauopathy and neuronal damage. Despite a lack of evidence for any clinical benefits, the conjecture that therapeutic chelation, with a special focus on iron ions, is a valuable approach for treating AD remains widespread.

The Effect of TNF Inhibitors on Cardiovascular Events in Psoriasis and Psoriatic Arthritis: an Updated Meta-Analysis.

TNF inhibitors have been used in psoriasis (Pso) and psoriatic arthritis (PsA), which were associated with increased risk of cardiac and cerebrovascular events. However, whether TNF inhibitors reduce cardiovascular event is still unclear. Therefore, we aimed to evaluate the effect of TNF inhibitors on adverse cardiovascular events (CVEs) in Pso with or without PsA. We undertook a meta-analysis of clinical trials identified in systematic searches of MEDLINE, EMBASE, Wanfang database, Cochrane Database, and Google scholar through December 31, 2015. Five studies (49,795 patients) were included. Overall, compared with topical/photo treatment, TNF inhibitors were associated with a significant lower risk of CVE (RR, 0.58; 95 % CI, 0.43 to 0.77; P < 0.001; I (2) = 66.2 %). Additionally, compared with methotrexate (MTX) treatment, risk of CVE was also markedly decreased in the TNF inhibitor group (RR, 0.67; 95 % CI, 0.52 to 0.88; P = 0.003; I (2) = 9.3 %). Meanwhile, TNF inhibitors were linked to reduced incidence of myocardial infarction compared with topical/photo or MTX treatment (RR, 0.73; 95 % CI, 0.59 to 0.90; P = 0.003; I (2) = 56.2 % and RR, 0.65; 95 % CI, 0.48 to 0.89; P = 0.007; I (2) = 0.0 %, respectively). Furthermore, there was a trend of decreased rate of mortality in the TNF inhibitor group compared with other therapy (RR, 0.90; 95 % CI, 0.54 to 1.50; P = 0.68; I (2) = 70.9 %). TNF inhibitors appear to have net clinical benefits with regard to adverse cardiovascular events in Pso and/or PsA. Rigorous randomized controlled trials will need to evaluate whether TNF inhibitors truly result in reduction of cardiovascular diseases.

[Effect of curcumin on IL-17-induced nitric oxide production and expression of iNOS in human keratinocytes].

AIM: To investigate the effect of curcumin on IL-17-induced NO production, mRNA and protein expression of iNOS in human keratinocyte cell lines(HaCaT cells). METHODS: HaCaT cells were stimulated with IL-17 and incubated with three doses of curcumin for 24h in vitro. After collections of supernatant, total RNA and protein, NO levels in supernatant were detected and fluorescence quantitative PCR and Western blot were performed to determine the effect of curcumin on NO levels and iNOS. RESULTS: IL-17 increased NO levels, and expression of iNOS in HaCaT cells(P<0.01). Curcumin decreased IL-17 induced NO production and the iNOS expression at mRNA (P<0.01) and protein (P<0.01) levels significantly. CONCLUSION: Curcumin down-regulates IL-17-induced NO secretions and iNOS expression in HaCaT cells, thus provides a theoretical basis for the treatment of inflammatory diseases of skin related to keratinocytes.