CircHIPK3 promotes neuroinflammation through regulation of the miR-124-3p/STAT3/NLRP3 signaling pathway in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized as a neurodegenerative disease; however, the mechanisms regarding its pathogenesis have not been fully explored. OBJECTIVES: To explore the role of circular RNA homeodomain interacting protein kinase 3 (circHIPK3) in the progression of PD. MATERIAL AND METHODS: The circHIPK3 and microRNA-124 (miR-124) expression in human serum and cerebral fluid was detected using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 92 PD patients and 95 controls. The circHIPK3 was overexpressed and/or silenced in cells to explore its molecular mechanisms and effects on neuroinflammation. The production of intracellular reactive oxygen species (ROS) was assessed using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Interleukin 6 (IL-6), IL-1ß and tumor necrosis factor alpha (TNF-α) production in BV2 cells after the indicated treatment was measured using enzyme-linked immunosorbent assay (ELISA). The protein expression of microglia markers (cluster of differentiation molecule 11b (CD11b) and ionized calcium-binding adapter molecule 1 (Iba-1)), pyroptosis-related factors, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain (ASC), and caspase-1, signal transducer and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3) were examined using western blot analysis. Furthermore, the interaction between circHIPK3, miR-124 and STAT3 was predicted with bioinformatics and examined using fluorescence in situ hybridization (FISH), luciferase reporter assays, RNA pull-down, and RNA immunoprecipitation (RIP). RESULTS: The expression of circHIPK3 in human serum and cerebral fluids was significantly higher than in controls, whereas miR-124 expression was drastically reduced. In addition, lipopolysaccharide (LPS)-treated BV2 cells exhibited higher expression of circHIPK3 and lower miR-124 expression. The SH-SY5Y cells exhibited a significantly impaired viability and elevated apoptotic rate, along with an upregulation of circHIPK3 and a downregulation of miR-124 expression after being treated with supernatants collected from LPS-treated BV2 cells. The upregulation of circHIPK3 increased IL-6, IL-1ß and TNF-α secretion in BV2 cells. The protein expressions of microglia markers (CD11b and Iba-1), as well as pyroptosis-related factors, NLRP3, caspase-1, and ASC, were also increased following the expression of circHIPK3. All these effects were reversed by the addition of miR-124. CONCLUSIONS: The circHIPK3 enhances neuroinflammation by sponging miR-124 and regulating the miR-124-mediated STAT3/NALP3 pathway in PD.

Anti-NMDAR encephalitis with simultaneous hypertrophic pachymeningitis in a 68-year-old male: a rare case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most frequent types of autoimmune encephalitis. However, the instigating mechanisms are as yet not fully ascertained. Cardinal clinical manifestations of anti-NMDAR encephalitis include acute behavioural change, psychosis, and catatonia. As the level of diagnosis increases, encephalitis becomes more common, but there are never been published in patients with anti-NMDAR encephalitis and simultaneous hypertrophic pachymeningitis. CASE PRESENTATION: A sixty-eight-year-old man who presented with mental, behavioral abnormalities, unstable walking, headaches, and erratic hand movements. The neuropsychiatric symptoms and cerebrospinal fluid examination was consistent with the diagnosis criteria of anti-NMDAR encephalitis. Magnetic resonance imaging of the brain showed a thickening of dura mater localized at the left tentorium cerebelli, left cerebral hemisphere, and cerebral falx; the thickening dura mater was characterized by an intense contrast enhancement after the administration of gadolinium. High doses of intravenous methylprednisolone were administrated during his hospitalization. After 5 days, the patient's condition improved. CONCLUSIONS: We herein describe a rare case of a 68-year-old man with anti-NMDAR encephalitis presenting with concomitant hypertrophic pachymeningitis. We systematically expounded anti-NMDAR encephalitis and hypertrophic pachymeningitis, and made bold conjectures on the etiology and pathogenesis of these two diseases, hoping to stimulate new ideas from clinicians and basic medical researchers.

Serum ferritin is a candidate biomarker of disease aggravation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. The mechanism that defines the loss of neurons in ALS is still not clearly understood, and there is no effective therapy to block its progression. Previous studies indicate that a disorder of iron homeostasis exists in ALS and based on this, the change of serum iron and ferritin and the association between iron metabolism and clinical features in Chinese Han patients with ALS was further investigated in the present study, in order to define its pathogenesis. Two cohorts were established: An ALS group consisting of 24 patients and a control group consisting of 38 healthy volunteers. Venous blood samples were collected for serum iron and ferritin analysis. The results indicated that the levels of serum iron were significantly decreased in patients with ALS (P<0.05), while there was no significant difference in serum ferritin between the ALS and control groups. However, the levels of serum ferritin were increased significantly in ALS patients with bulbar-onset (vs. limb-onset in females), dysphagia (vs. without dysphagia), longer disease duration (>12 months vs. ≤12 months in males) and lower ALS Functional Rating Scale-Revised score (<33 vs. ≥33; P<0.05). These results suggested that there was dysregulation of iron metabolism in Chinese Han patients with ALS and that serum ferritin may be a candidate biomarker of aggravation in these patients.

Association of the p22phox polymorphism C242T with the risk of late-onset Alzheimer's disease in a northern Han Chinese population.

The C242T polymorphism of the CYBA gene that encodes p22phox, a component of nicotinamide adenine dinucleotide phosphate oxidase, has been found to modulate reactive oxygen species (ROS) production. Oxidative stress is thought to play a pivotal role in the pathophysiology of Alzheimer's disease (AD), which is manifested as increased availability of ROS because of an imbalanced redox state. Therefore, the aim of this study was to investigate potential associations of the p22phox C242T polymorphism with the risk of late-onset AD (LOAD) in a northern Han Chinese population. Patients with LOAD (n = 276) and 320 control subjects were recruited for the study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the genotypes. No significant differences were found between LOAD and p22phox C242T polymorphism, but a significant association was obtained in the genotype and allele distributions of p22phox C242T between LOAD patients and controls in apolipoprotein E (ApoE) ϵ4 carriers. These results suggested that p22phox C242T polymorphism has a possible role in changing the genetic susceptibility to LOAD in ApoE ϵ4 carriers of this northern Han Chinese population.

[Analysis of the clinical, electrophysiological and genetic features of a family affected with hereditary neuropathy with liability to pressure palsies].

OBJECTIVE: To delineate the clinical, electrophysiological and genetics features of a family where 4 members were affected with hereditary neuropathy with liability to pressure palsies (HNPP). METHODS: Clinical features of the 4 patients were summarized. Electrophysiological examination and genetic analysis were carried out. RESULTS: All of the patients showed recurrent motor and sensory disturbances after minor traction or constriction. Electrophysiology study revealed that the prolonged latency and reduced conduction velocity of peripheral nerve were general and with multiple sites of affection. The nerve locations liable to entrapment showed conduction block. A deletion mutation of peripheral myelin protein 22 (PMP22) gene was identified by genetic analysis. CONCLUSION: HNPP usually affects areas where nerves are liable to entrapment, and presents with motor and sensory disturbances of the innervated areas. Electrophysiological study reveals general nervous demyelination. Genetic analysis can clarify the diagnosis of HNPP.

Association of insulin receptor H1085H C>T, insulin receptor substrate 1 G972R and insulin receptor substrate 2 1057G/A polymorphisms with refractory temporal lobe epilepsy in Han Chinese.

PURPOSE: Insulin/insulin receptor (INSR) signaling plays diverse roles in the central nervous system, including regulation of blood glucose, synaptic plasticity, dendritic growth, modulation of electrophysiological activity, proliferation of astrocytes and neuronal apoptosis. Interestingly, many of these and/or related processes represent biological mechanisms associated with temporal lobe epilepsy (TLE). Thus, insulin signaling may play a role in the development of TLE and its therapeutic responses. We hypothesized that functional polymorphisms in the insulin pathway genes INSR, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with the therapeutic responses of TLE. Therefore, in this study we analyzed the association of three single nucleotide polymorphisms (SNPs) showing a risk for TLE drug resistance using a hospital-based case-control design. METHOD: Two hundred and one patients with refractory TLE and one hundred and seventy-five drug-responsive TLE patients were recruited for the study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the genotypes of INSR His1085His, IRS1 G972R and IRS2 1057G/A. RESULTS: No significant differences between refractory and drug-responsive TLE patients were observed for the IRS1 G972R and IRS2 1057G/A polymorphisms (P>0.05), but a significant association was found for the INSR His1085His polymorphism for both genotypes (P=0.035) and alleles (P=0.011). IRS2 1057G/A combined with the INSR His 1085 His polymorphism increased the odds ratio of drug resistance in TLE (P=0.011, OR=2.263, 95% CI: 1.208-4.239). CONCLUSION: These results suggest that a genetic variation in the insulin signaling pathway genes may affect the therapeutic response of TLE.

Increased iron level in motor cortex of amyotrophic lateral sclerosis patients: an in vivo MR study.

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative disorders, but no definite mechanism has been defined on the loss of motor neurons in ALS and currently no therapy can block its progression. Many lines of evidence indicate that there is a disorder of iron homeostasis in ALS, and thus we sought to test the iron level in ALS patients by susceptibility weighted imaging (SWI). Sixteen ALS patients and 16 healthy persons underwent brain scans using SWI with a 3T Siemens MR scanner. The red nucleus, substantia nigra, globus pallidus, putamen, the head of caudate nucleus, and motor cortex were measured in the filtered phase images and analysed for their SWI phase values as relative marker for iron content. We found that phase shift values were significantly higher in the motor cortex of ALS patients by SWI, indicating increased iron level in this area. In contrast, we found that there were no differences of phase shift values between ALS patients and healthy controls in the other nuclei including the red nucleus, substantia nigra, globus pallidus, putamen and the head of the caudate nucleus. Furthermore, we found that there were no relationships between SWI signal and some clinical features of ALS. In conclusion, these results demonstrate that iron level increases in the motor cortex of ALS and that SWI is a reliable method to test iron in the brain.

Effect of the human SOD1-G93A gene on the Nrf2/ARE signaling pathway in NSC-34 cells.

Dominant mutations in superoxide dismutase 1 (SOD1) are a frequent cause of the lethal neurodegenerative disease amyotrophic lateral sclerosis (ALS). The nuclear factor erythroid 2­related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is the major cellular defense mechanism against oxidative stress, however, its role in ALS remains to be fully elucidated. Therefore, the present study aimed to investigate whether the human SOD1-G93A gene affected the Nrf2/ARE signaling pathway in an ALS cell model. The soma became round and the number of neurites decreased in the NSC-34 cells transfected with the hSOD1-G93A gene, and the neurites were shorter and oxidative stress was increased compared with the normal NSC-34 cells. Furthermore, the mRNA and protein expression of Nrf2, heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 was significantly decreased in the NSC-34 cells transfected with the human SOD1-G93A gene. The present study indicated that human SOD1-G93A damaged the Nrf2/ARE signaling pathway in the ALS cell model and reduced the ability of cells to protect against oxidative injury.

Diazoxide preconditioning antagonizes cytotoxicity induced by epileptic seizures.

Diazoxide, an activator of mitochondrial ATP-sensitive potassium channels, can protect neurons and astrocytes against oxidative stress and apoptosis. In this study, we established a cellular model of epilepsy by culturing hippocampal neurons in magnesium-free medium, and used this to investigate effects of diazoxide preconditioning on the expression of inwardly rectifying potassium channel (Kir) subunits of the ATP-sensitive potassium. We found that neuronal viability was significantly reduced in the epileptic cells, whereas it was enhanced by diazoxide preconditioning. Double immunofluorescence and western blot showed a significant increase in the expression of Kir6.1 and Kir6.2 in epileptic cells, especially at 72 hours after seizures. Diazoxide pretreatment completely reversed this effect at 24 hours after seizures. In addition, Kir6.1 expression was significantly upregulated compared with Kir6.2 in hippocampal neurons after seizures. These findings indicate that diazoxide pretreatment may counteract epileptiform discharge-induced cytotoxicity by suppressing the expression of Kir subunits.