Peripheral cutaneous synucleinopathy characteristics in genetic Parkinson's disease.

Background: Cutaneous phosphorylated alpha-synuclein (p-α-syn) deposition is an important biomarker of idiopathic Parkinson's disease (iPD). Recent studies have reported synucleinopathies in patients with common genetic forms of PD. Objective: This study aimed to detect p-α-syn deposition characteristic in rare genetic PD patients with CHCHD2 or RAB39B mutations. Moreover, this study also aimed to describe peripheral alpha-synuclein prion-like activity in genetic PD patients, and acquire whether the cutaneous synucleinopathy characteristics of genetic PD are consistent with central neuropathologies. Methods: We performed four skin biopsy samples from the distal leg (DL) and proximal neck (C7) of 161 participants, including four patients with CHCHD2 mutations, two patients with RAB39B mutations, 16 patients with PRKN mutations, 14 patients with LRRK2 mutations, five patients with GBA mutations, 100 iPD patients, and 20 healthy controls. We detected cutaneous synucleinopathies using immunofluorescence staining and a seeding amplification assay (SAA). A systematic literature review was also conducted, involving 64 skin biopsies and 205 autopsies of genetic PD patients with synucleinopathy. Results: P-α-syn was deposited in the peripheral cutaneous nerves of PD patients with CHCHD2, LRRK2, or GBA mutations but not in those with RAB39B or PRKN mutations. There were no significant differences in the location or rate of α-syn-positive deposits between genetic PD and iPD patients. Peripheral cutaneous synucleinopathy appears to well represent brain synucleinopathy of genetic PD, especially autosomal dominant PD (AD-PD). Cutaneous α-synuclein SAA analysis of iPD and LRRK2 and GBA mutation patients revealed prion-like activity. Conclusion: P-α-syn deposition in peripheral cutaneous nerves, detected using SAA and immunofluorescence staining, may serve as an accurate biomarker for genetic PD and iPD in the future.

Evaluating nomogram models for predicting survival outcomes in gastric gastrointestinal stromal tumors with SEER database analysis.

Gastrointestinal stromal tumors (GISTs) predominantly develop in the stomach. While nomogram offer tremendous therapeutic promise, there is yet no ideal nomogram comparison customized specifically for handling categorical data and model selection related gastric GISTs. (1) We selected 5463 patients with gastric GISTs from the SEER Research Plus database spanning from 2000 to 2020; (2) We proposed an advanced missing data imputation algorithm specifically designed for categorical variables; (3) We constructed five Cox nomogram models, each employing distinct methods for the selection and modeling of categorical variables, including Cox (Two-Stage), Lasso-Cox, Ridge-Cox, Elastic Net-Cox, and Cox With Lasso; (4) We conducted a comprehensive comparison of both overall survival (OS) and cancer-specific survival (CSS) tasks at six different time points; (5) To ensure robustness, we performed 50 randomized splits for each task, maintaining a 7:3 ratio between the training and test cohorts with no discernible statistical differences. Among the five models, the Cox (Two-Stage) nomogram contains the fewest features. Notably, at Near-term, Mid-term, and Long-term intervals, the Cox (Two-Stage) model attains the highest Area Under the Curve (AUC), top-1 ratio, and top-3 ratio in both OS and CSS tasks. For the prediction of survival in patients with gastric GISTs, the Cox (Two-Stage) nomogram stands as a simple, stable, and accurate predictive model with substantial promise for clinical application. To enhance the clinical utility and accessibility of our findings, we have deployed the nomogram model online, allowing healthcare professionals and researchers worldwide to access and utilize this predictive tool.

Assessing the impact of novel risk loci on Alzheimer's and Parkinson's diseases in a Chinese Han cohort.

Background: Overwhelming evidence points to that genetic factors contributing to the development of Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-Wide Association Study (GWAS) has come a long way in the last decade. So far, a large number of GWAS studies have been published on neurological diseases and many other diseases, providing us with a wealth of genetic information and unique biological insights. Methods: Genomic DNA was extracted from both patients' and controls' peripheral blood samples utilizing the Blood Genome Extraction Kit. Single nucleotide polymorphisms (SNPs) were genotyped employing the enhanced multiple ligase detection reaction (iMLDR) technology. Results: A case-control study was conducted, involving 211 AD patients, 508 PD patients (including 117 with dementia), and 412 healthy individuals. Age and sex stratification analysis revealed that rs871269/TNIP1 was associated with LOAD (p = 0.035), and rs5011436/TMEM106B was associated with AD in males (p = 0.044) in the genotype model. In the allele model, rs871269/TNIP1 was found to be associated with PD in the Chinese Han population (p = 0.0035, OR 0.741, 95% CI 0.559-0.983), and rs708382/GRN was identified as a risk factor for Parkinson's disease dementia (PDD) in the Chinese Han population (p = 0.004, odds ratio (OR) 0.354, 95% confidence interval (CI) 0.171-0.733). However, no significant associations with AD or PD were observed for the remaining four loci (rs113020870/AGRN, rs6891966/HAVCR2, rs2452170/NTN5, rs1761461/LILRB2) in terms of allele or genotype frequencies. Conclusion: This study identifies rs871269/TNIP1 as a potential risk factor for both LOAD and PD, rs708382/GRN as a risk factor for PDD, and rs5011436/TMEM106B as associated with AD in males when stratified by age.

Plasma neurofilament light as a promising biomarker in neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder lacking reliable biomarkers. This study investigates plasma protein levels as potential biomarkers of disease severity and progression in NIID. In this study, we enrolled 30 NIID patients and 36 age- and sex-matched controls, following them for 1-2 years. Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and tau were measured using ultrasensitive single molecule array (Simoa) assays. Disease severity was evaluated with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL), and CNS symptom counts, in addition to neuroimaging data. Our study revealed that NIID patients has significantly higher plasma NfL (median, 35.2 vs. 8.61 pg/mL, p < 0.001) and GFAP (102 vs. 79.0 pg/mL, p = 0.010) levels compared to controls, with NfL emerging as a robust diagnostic marker (AUC = 0.956). NfL levels were notably higher in acute-onset NIID (77.5 vs. 28.8 pg/mL, p = 0.001). NfL correlated strongly with disease severity, including MMSE (ρ = - 0.687, p < 0.001), MoCA (ρ = - 0.670, p < 0.001), ADL (ρ = 0.587, p = 0.001), CNS symptoms (ρ = 0.369, p = 0.045), and white matter hyperintensity volume (ρ = 0.620, p = 0.004). Higher baseline NfL (≥ 35.2 pg/mL) associated with increased ADL scores, CNS symptoms, and white matter hyperintensity at follow-up. UCH-L1 and total tau levels showed no significant differences. Our results suggested the potential of NfL as a promising biomarker of disease severity and progression in NIID.

Predictors of Outcome After Traumatic Brain Injury: Experience at a Tertiary Healthcare Facility in Inner Mongolia, China.

BACKGROUND: Traumatic brain injury (TBI) is 1 of the leading causes of death in all age groups globally. Understanding TBI causative factors and early interventions that may result in poor outcomes plays an important role in decreasing the mortality and disability associated with TBI. METHODS: In this retrospective case-control study, we collected electronic case data from patients with TBI who visited our hospital between 2018 and 2022. We collected patient information from accident to discharge, and by using linear regression predicted factors influencing death from TBI. RESULTS: A total of 957 patients with a mean age of 56.4 ± 17.0 years and a Glasgow Coma Scale score of 12 ± 3.7 on admission were included in the study. Of the total, 54 patients died in the hospital. Multifactorial logistic regression showed that the Glasgow Coma Scale scores, degree of injury on admission, surgical treatment, and brainstem hemorrhage all had a significant effect on the survival status of the patients at discharge. CONCLUSIONS: Understanding the causes, patterns, and distribution of people with TBI in this study will benefit our country and others to develop policies, research, health management, and rehabilitation tools at the national level.

EEG Power Spectral Density in NREM Sleep is Associated with the Degree of Hypoxia in Patients with Obstructive Sleep Apnea.

Purpose: Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder. Research conducted on patients with OSA using electroencephalography (EEG) has revealed a noticeable shift in the overnight polysomnography (PSG) power spectrum. To better quantify the effects of OSA on brain function and to identify the most reliable predictors of pathological cortical activation, this study quantified the PSG power and its association with the degree of hypoxia in OSA patients. Patients and Methods: This retrospective study recruited 93 patients with OSA. OSA patients were divided into three groups based on their apnea-hypopnea index (AHI) scores. The clinical characteristics and sleep macrostructure of these patients were examined, followed by an analysis of PSG signals. Power spectral density (PSD) in five frequency bands was analyzed during nonrapid eye movement (NREM) sleep, rapid eye movement (REM) sleep, and wakefulness. Finally, correlation analysis was conducted to assess the relationships among PSD, PSG parameters, and serum levels of S100ß and uric acid. Results: Obstructive sleep apnea occurred during both the NREM and REM sleep phases. Except for a decrease in the duration of N2 sleep and an increase in the microarousal index, there were no significant differences in sleep architecture based on disease severity. Compared to the mild OSA group, the theta and alpha band PSD in the frontal and occipital regions during NREM sleep and wakefulness were significantly decreased in the moderate and severe OSA groups. Correlation analysis revealed that theta PSD in N1 and N3 stages were negatively correlated the AHI, oxygen desaturation index, SaO2<90% and microarousal index. Conclusion: These findings imply that patients with more severe OSA exhibited considerable NREM hypoxia and abnormal brain activity in the frontal and occipital regions. Therefore, sleep EEG oscillation may be a useful neurophysiological indicator for assessing brain function and disease severity in patients with OSA.

Genetic spectrum and clinical features of adult leukoencephalopathies in a Chinese cohort.

OBJECTIVE: Leukoencephalopathies are a group of heterogeneous disorders characterized by the degeneration of white matter, resulting in a variety of progressive neurological symptoms. To date, over 60 genes linked to genetic leukoencephalopathies have been discovered through whole-exome sequencing (WES) and long-read sequencing. Nonetheless, the genetic diversity and clinical variability of these disorders among various racial groups remain largely unknown. Therefore, this study aims to analyze the genetic spectrum and clinical features of Chinese adult leukoencephalopathies and compare the genetic profiles in different populations. METHODS: A total of 129 patients suspected of possible genetic leukoencephalopathy were enrolled and underwent WES and dynamic mutation analysis. Bioinformatics tools were used to predict the pathogenicity of these mutations. Skin biopsies were conducted for further diagnosis. Genetic data sources from different populations were collected from published articles. RESULTS: Genetic diagnosis was established in 48.1% of patients, with WES identifying 57 pathogenic or likely pathogenic variants in 39.5% of cases. NOTCH3 and NOTCH2NLC were the most common mutated genes, accounting for 12.4% and 8.5% of cases, respectively. Dynamic mutation analysis revealed NOTCH2NLC GGC repeat expansions in 8.5% of patients. Different mutations resulted in varying clinical symptoms and imaging findings. Comparisons of genetic profiles between different populations showed distinct mutational spectrums in adult leukoencephalopathies. INTERPRETATION: This study highlights the importance of genetic testing for accurate diagnosis and improved clinical management of these disorders. It also sheds light on the genetic heterogeneity of adult leukoencephalopathies across different races, emphasizing the need for further research on this topic.

A comprehensive study of clinicopathological and genetic features of neuronal intranuclear inclusion disease.

BACKGROUND: The discovery of skin intranuclear inclusions and GGC repeat expansion of NOTCH2NLC has greatly promoted the diagnosis of neuronal intranuclear inclusion disease (NIID). With highly heterogeneous clinical manifestations, NIID patients tend to be underdiagnosed at early stages. METHODS: This study comprehensively studied clinical manifestations, magnetic resonance imaging (MRI), and peripheral nerve conduction in 24 NIID and 166 other neurodegenerative disease (ND) subjects. The nomogram was plotted using the "rms" package, and the t-distributed stochastic neighbor embedding algorithm was performed. Associations between skin intranuclear inclusions and NOTCH2NLC GGC repeats were further analyzed. RESULTS: The clinical, MRI, and peripheral nerve conduction features seriously overlapped in NIID and ND patients; they were assigned variables according to their frequency and specificity in NIID patients. A nomogram that could distinguish NIID from ND was constructed according to the assigned variables and cutoff values of the above features. The occurrence of skin intranuclear inclusions and NOTCH2NLC GGC repeats ≥ 60 showed 100% consistency, and intranuclear inclusion frequency positively correlated with NOTCH2NLC GGC repeats. A hierarchical diagnostic flowchart for definite NIID was further established. CONCLUSION: We provide a novel nomogram with the potential to realize early identification and update the diagnostic flowchart for definitive diagnosis. Moreover, this is the first study to define the association between skin pathology and NOTCH2NLC genetics in NIID.

Neutrophil Percentage-to-Albumin Ratio: A Good Parameter for the Evaluation of the Severity of Anti-NMDAR Encephalitis at Admission and Prediction of Short-Term Prognosis.

Objectives: The purpose of this study was to investigate the association of neutrophil percentage-to-albumin ratio (NPAR) with the severity at admission and discharge (short-term prognosis) in patients with anti-N-methyl-D-aspartic acid receptor (NMDAR) encephalitis. Methods: Multivariable logistic regression models such as NPAR were constructed based on univariable regression results. Receiver operating characteristic (ROC) curves, nomograms, and concordance index (c-index) were used to evaluate the efficacy of the models in assessing disease severity at admission and predicting short-term prognosis, validated by bootstrap, Hosmer-Lemeshow goodness-of-fit test, calibration curves, and decision curve analysis. Results: A total of 181 patients with anti-NMDAR encephalitis diagnosed at the First Affiliated Hospital of Zhengzhou University were included. The results showed that NPAR had good sensitivity and specificity in assessing disease severity at admission and predicting short-term prognosis. The multivariable logistic regression models based on NPAR and other influencing factors had good discrimination, consistency, accuracy, calibration ability, applicability, and validity in assessing the severity at admission and predicting short-term prognosis. Conclusion: NPAR has good clinical value in assessing disease severity at admission and predicting short-term prognosis of patients with anti-NMDAR encephalitis.

Systemic Inflammation Index Values Are Associated With Worsened Disease Severity and Poor Response to Autoimmune Encephalitis Treatment.

Both specific and innate immune responses play important roles in autoimmune encephalitis (AE). We aimed to explore the predictive value of the systemic inflammation index (SII) at admission as a peripheral biomarker of treatment response of AE. A total of 146 patients diagnosed with AE in the First Affiliated Hospital of Zhengzhou University from January 1, 2018 to September 22, 2020 were retrospectively and consecutively analyzed as per the inclusion criteria and divided into two groups according to their response to immunotherapy after 30 days. The predictive value of the SII as a peripheral biomarker for AE treatment response was calculated using the receiver operating characteristic curve analysis, which showed that the best SII cut-off value for predicting poor response to AE treatment was 863.3; the area under the curve was 0.75, with 83.0% sensitivity and 72.0% specificity. The risk factors for poor response to AE treatment were analyzed; univariable analysis showed that the rate of decreased level of consciousness, rate of cognitive or mental behavior abnormality, cerebrospinal fluid pressure, blood neutrophils, platelets, time until treatment initiation, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and SII were significantly higher in patients with poor response to AE immunotherapy after 30 days than in patients with good response. Meanwhile, the blood lymphocyte counts and Glasgow Coma Scale (GCS) scores in patients with poor response were significantly lower than those in patients with good response (all p < 0.05), and multivariable binary logistic regression with backward stepwise method showed that decreased levels of consciousness, time until treatment initiation and SII were associated with poor response to immunotherapy. Moreover, the SII ≤ 863.3 group had lower rates of decreased consciousness levels, admission to the intensive care unit, and mechanical ventilation; lower cerebrospinal fluid pressure, blood neutrophil count, and platelet count; and higher blood lymphocyte count and GCS scores. The SII was associated with worsened disease severity and poor response to treatment after 30 days of the initially diagnosed AE, and patients with an SII > 863.3 were more likely to have poor response to immunotherapy.

Research on the Glial-Lymphatic System and Its Relationship With Alzheimer's Disease.

Metabolic waste clearance is essential to maintain body homeostasis, in which the lymphatic system plays a vital role. Conversely, in recent years, studies have identified the glial-lymphatic system in the brain, which primarily comprises the inflow of fluid along the para-arterial space. Aquaporin-4 mediates the convection of interstitial fluid in the brain and outflow along the paravenous space. ß-Amyloid deposition is a characteristic pathological change in Alzheimer's disease, and some studies have found that the glial-lymphatic system plays an important role in its clearance. Thus, the glial-lymphatic system may influence Alzheimer's disease severity and outcome; therefore, this review summarizes the current and available research on the glial-lymphatic system and Alzheimer's disease.

Peripheral synucleinopathy in Parkinson disease with LRRK2 G2385R variants.

OBJECTIVE: Recent studies demonstrated cutaneous phosphorylated α synuclein (p-syn) deposition in idiopathic and some monogenetic Parkinson disease (PD) patients, suggesting synucleinopathy identical to that in the brain. Although the LRRK2 Gly2385Arg (G2385R) variant is a common PD risk factor in the Chinese population, the pathogenesis of PD with G2385R variant has not been reported. We investigated whether synucleinopathy and small fiber neuropathy (SFN) are associated with the G2385R variant. METHODS: We performed genotyping in 59 PD patients and 30 healthy controls from the skin biopsy database. The scale of SFN was assessed, as well as bright-field immunohistochemistry against antiprotein gene product 9.5 (PGP9.5) and double-labeling immunofluorescence with anti-PGP9.5 and anti-p-syn. RESULTS: (1) p-syn deposited in the skin nerve fibers of G2385R carrier PD patients, which was a different pattern from noncarriers, without no difference observed between proximal and distal regions; (2) decreased distal intraepidermal nerve fiber density was found in both the G2385R carrier and the noncarrier PD group, and was negatively correlated with composite autonomic symptom score-31 item (COMPASS-31) scores; (3) PD patients with the G2385R variant showed a more peculiar clinical profile than noncarriers with a higher nonmotor symptoms scale, COMPASS-31 score, and levodopa equivalent dose, in addition to an increased prevalence of certain autonomic symptoms or rapid eye movement sleep behavior disorders. INTERPRETATION: Synucleinopathy is related to the LRRK2 G2385R genotype and implies a different pathogenesis in G2385R variant carriers and noncarriers. This study also extended the clinical profiles of PD patients with the G2385R variant.

Optimization of the Detection Method for Phosphorylated α-Synuclein in Parkinson Disease by Skin Biopsy.

Background: Recent studies have found deposition of phosphorylated α-synuclein (p-syn) in Parkinson disease (PD) patients' skin, indicating p-syn may be a potential biomarker of PD. However, the sensitivity of the p-syn detection varied largely from 5. 3 to 100%, this influenced the clinical use of this detection method to some extent. Objective: This study aimed to optimize the skin biopsy method for detecting p-syn deposition in patients with PD. Methods: Ninety PD patients and 30 healthy controls underwent skin biopsies at 2-3 of the following sites: the distal leg, thigh, cervical region, or forearm. Skin biopsy samples were cut to 50- and 15-µm thickness sections. Deposition of p-syn were detected by using double immunofluorescence labeling of protein gene production 9.5 (PGP9.5) /p-syn. Statistical data analysis was performed using SPSS 25.0 software. Results: Deposition of p-syn were found in 75/90 PD patients but not in healthy controls (p < 0.001). The positive deposition rate of p-syn in the single cervical site was significantly higher than that in the distal leg, thigh, and forearm site. Two samples from the cervical region had a higher p-syn positive rate compared to single cervical site (90.5 vs. 66.7%, p = 0.037). There was no significant difference between the p-syn positive rate of samples from the distal leg/cervical sites and 2 samples from cervical region (80 vs. 90.5%, p = 0.261). Next, the p-syn positive deposition rate of 2-biopsy samples including distal leg/cervical sites and double samples in the cervical site were comparable to the 3-biopsy samples. The 50-µm section had a significantly higher p-syn positive rate than the 15-µm section (p = 0.049). Conclusions: Two biopsy sites (cervical/distal leg) or 2 samples from the cervical site were considered to be priority biopsy sites for detecting p-syn in PD patients. Thick sections may provide a higher p-syn positive rate than thin sections for skin biopsies. These findings provide an optimized p-syn detection method, indicate the valuable pathology biomarker of PD and will promote the clinical use of skin biopsy in the future.

Injectable pegylated niclosamide (polyethylene glycol-modified niclosamide) for cancer therapy.

Niclosamide is an antihelminthic drug. Recent studies show that niclosamide exerts antitumor activity through inhibiting multiple signals including Wnt/ß-catenin, mTORC1, signal transducer and activator of transcription 3, NF-κB, notch signals; however, the insolubility and poor bioavailability limits its potential clinic use, the aim of the present work is to synthesize an injectable pegylated niclosamide (polyethylene glycol-modified niclosamide) and investigate its antitumor activity in vitro and in vivo. The pegylated niclosamide (mPEG5000-Nic) was synthesized and the chemical structure was identified by Fourier transform infrared spectra and 1 H nuclear magnetic resonance spectra. The antitumor activity was evaluated in CT26 and HCT116 colon cancer cells in vitro and nude mouse xenograft model of CT26 cells in vivo. The water solubility of niclosamide in mPEG5000-Nic was significantly increased. Niclosamide could be released from mPEG5000-Nic nanoparticles in PBS solution. mPEG5000-Nic inhibited the cell viability of CT26 and HCT116 cells in vitro. No animal death was observed in mice with intraperitoneal injection of mPEG5000-Nic (equivalent to 1000 mg/kg niclosamide) within 24 hr, indicating that mPEG5000-Nic was less toxic. In nude mouse, xenograft model of CT26 colon carcinoma, intraperitoneal injection of mPEG5000-Nic (equivalent to niclosamide 50 mg/kg) inhibited tumor growth but had no effect on animal body weight and heart, liver, kidney, and lung weight in vivo. Meanwhile, in the same model, intraperitoneal injection of the positive clinic drug 5-fluorouracil not only inhibited the tumor growth, but also reduced the animal body weight. Our study demonstrates that pegylated niclosamide is novel niclosamide delivery system with clinical perspective for cancer therapy.

Regulation of aquaporin 4 expression by lipoxin A4 in astrocytes stimulated by lipopolysaccharide.

Aquaporin (AQP4) could be associated with inflammation, common in central nervous system diseases. We investigated the effect of lipoxin A4 (LXA4) on the activation of astrocytes, AQP4 expression, and inflammatory response induced by lipopolysaccharide (LPS). Astrocytes were cultured in vitro and changes in transcript and protein levels of AQP4, interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and cyclooxygenase-2 (COX-2), and protein levels of P38 and phospho-P38 were determined. The LPS group showed increased AQP4, IL-1ß, TNF-α, and COX-2 levels, whereas they decreased in the LPS + LXA4 group, suggesting that LXA4 inhibits AQP4 expression. Furthermore, levels of phospho-P38 increased in the LPS group, but decreased in the LPS + LXA4 group. In conclusion, LXA4 alleviated the LPS-induced increase in AQP4 expression and inflammatory cytokine secretion by astrocytes, possibly by inhibiting P38 phosphorylation. For the first time, we found that LXA4 may inhibit the expression of inflammatory factors by regulating the expression of AQP4. AQP4 on astrocytes is likely to be the target of anti-inflammatory effect of LXA4.

Lipoxin A4 Regulates Lipopolysaccharide-Induced BV2 Microglial Activation and Differentiation via the Notch Signaling Pathway.

Inflammatory responses contribute to the pathogenesis of various neurological diseases, and microglia plays an important role in the process. Activated microglia can differentiate into the pro-inflammatory, tissue-damaging M1 phenotype or the anti-inflammatory, tissue-repairing M2 phenotype. Regulating microglia differentiation, hence limiting a harmful response, might help improve the prognosis of inflammation-related nervous system diseases. The present study aimed 1. to observe the anti-inflammatory effect of lipoxin A4 (LXA4) on the inflammatory response associated to lipopolysaccharide (LPS)-induced microglia activation, 2. to clarify that LXA4 modulates the activation and differentiation of microglia induced by LPS stimulation, 3. to determine whether LXA4 regulates the activation and differentiation of microglia through the Notch signaling pathway, 4. to provide a foundation for the use of LXA4 for the treatment of inflammatory related neurological diseases. To construct a model of cellular inflammation, immortalized murine BV2 microglia cells were provided 200 ng/ml LPS. To measure the mRNA and protein levels of inflammatory factors (interleukin [IL]-1ß, IL-10, and tumor necrosis factor [TNF]-α) and M1 and M2 microglia markers (inducible nitric oxide synthase [iNOS], cluster of differentiation [CD]32, arginase [Arg]1, and CD206), we performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), immunofluorescence, or flow cytometry. To determine the mRNA and protein levels of Notch signaling components (Notch1, Hes1, and Hes5), we performed qRT-PCR and western blot. LXA4 inhibits the expression of Notch1 and Hes1 associated with M1 type microglial differentiation and decreases the M1 type microglia marker iNOS and related inflammatory factors IL-1ß and TNF-α. Moreover, LXA4 upregulates the expression of the M2-associated Hes5, as well as the expression of the M2 microglia marker Arg1 and the associated inflammatory factor IL-10. These effects are blocked by the administration of the γ-secretase inhibitor DAPT, a specific blocker of the Notch signaling pathway. LXA4 inhibits the microglia activation induced by LPS and the differentiation into M1 type with pro-inflammatory effect, while promoting the differentiation to M2 type with anti-inflammatory effect. LXA4 downregulates the inflammatory mediators IL-1ß, TNF-α, and iNOS, while upregulating the anti-inflammatory mediator IL-10, which acts through the Notch signaling pathway.

Mitochondrial uncoupler BAM15 inhibits artery constriction and potently activates AMPK in vascular smooth muscle cells.

Our previous studies found that mitochondrial uncouplers CCCP and niclosamide inhibited artery constriction and the mechanism involved AMPK activation in vascular smooth muscle cells. BAM15 is a novel type of mitochondrial uncoupler. The aim of the present study is to identify the vasoactivity of BAM15 and characterize the BAM15-induced AMPK activation in vascular smooth muscle cells (A10 cells). BAM15 relaxed phenylephrine (PE)-induced constricted rat mesenteric arteries with intact and denuded endothelium. Pretreatment with BAM15 inhibited PE-induced constriction of rat mesenteric arteries with intact and denuded endothelium. BAM15, CCCP, and niclosamide had the comparable IC50 value of vasorelaxation in PE-induced constriction of rat mesenteric arteries. BAM15 was less cytotoxic in A10 cells compared with CCCP and niclosamide. BAM15 depolarized mitochondrial membrane potential, induced mitochondrial fission, increased mitochondrial ROS production, and increased mitochondrial oxygen consumption rate in A10 cells. BAM15 potently activated AMPK in A10 cells and the efficacy of BAM15 was stronger than that of CCCP, niclosamide, and AMPK positive activators metformin and AICAR. In conclusion, BAM15 activates AMPK in vascular smooth muscle cells with higher potency than that of CCCP, niclosamide and the known AMPK activators metformin and AICAR. The present work indicates that BAM15 is a potent AMPK activator.

Research Progress in Understanding the Relationship Between Heme Oxygenase-1 and Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a fatal acute cerebrovascular disease, with a high morbidity and mortality. Following ICH, erythrocytes release heme and several of its metabolites, thereby contributing to brain edema and secondary brain damage. Heme oxygenase is the initial and rate-limiting enzyme of heme catabolism, and the expression of heme oxygenase-1 (HO-1) is rapidly induced following acute brain injury. As HO-1 exerts it effects via various metabolites, its role during ICH remains complex. Therefore, in-depth studies regarding the role of HO-1 in secondary brain damage following ICH may provide a theoretical basis for neuroprotective function after ICH. The present review aims to summarize recent key studies regarding the effects of HO-1 following ICH, as well as its influence on ICH prognosis.