RND3 modulates microglial polarization and alleviates neuroinflammation in Parkinson's disease by suppressing NLRP3 inflammasome activation.

Neuroinflammation mediated by microglia plays an important role in the etiology of Parkinson's disease (PD). Rho family GTPase 3 (RND3) exerts anti-inflammatory effects and may act as a potential new inducer of neuroprotective phenotypes in microglia. However, whether RND3 can be used to regulate microglia activation or reduce neuroinflammation in PD remains elusive. The study investigated the microglia modulating effects and potential anti-inflammatory effects of RND3 in vivo and in vitro, using animal models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and cell models of BV-2 cells stimulated by LPS plus IFN-γ with or without RND3-overexpression. The results showed that RND3 was highly expressed in the MPTP-induced PD mouse model and BV-2 cells treated with LPS and IFN-γ. In vivo experiments confirmed that RND3 overexpression could modulate microglia phenotype and ameliorate MPTP-induced neuroinflammation through inhibiting activation of the NLRP3 inflammasome in substantia nigra pars compacta (SNpc). In vitro study showed that RND3 overexpression could attenuate the production of pro-inflammatory factors in BV2 cells stimulated by LPS and IFN-γ. Mechanistically, RND3 reduced the activation of the NLRP3 inflammasome upon LPS and IFN-γ stimulation. Taken together, these findings suggest that RND3 modulates microglial polarization and alleviates neuroinflammation in Parkinson's disease by suppressing NLRP3 inflammasome activation.

Costunolide ameliorates angiotensin II-induced atrial inflammation and fibrosis by regulating mitochondrial function and oxidative stress in mice: A possible therapeutic approach for atrial fibrillation.

Atrial fibrillation (AF) is a cardiac disease characterized by disordered atrial electrical activity. Atrial inflammation and fibrosis are involved in AF progression. Costunolide (COS) is a sesquiterpene lactone containing anti-inflammatory and anti-fibrotic activities. This study aims to explore the underlying mechanisms by which COS protects against AF. Male C57BL/6 mice (8- to 10-week-old) were infused with angiotensin (Ang) II for 3 weeks. Meanwhile, different doses of COS (COS-L: 10 mg/kg, COS-H: 20 mg/kg) were administered to mice by intragastric treatment. The results showed irregular and rapid heart rates in Ang II-treated mice. Moreover, the levels of inflammatory cytokines and fibrotic factors were elevated in mice. COS triggered a reduction of Ang II-induced inflammation and fibrosis, which conferred a protective effect. Mechanistically, mitochondrial dysfunction with mitochondrial respiration inhibition and aberrant ATP levels were observed after Ang II treatment. Moreover, Ang-II-induced excessive reactive oxygen species caused oxidative stress, which was further aggravated by inhibiting Nrf2 nuclear translocation. Importantly, COS diminished these Ang-II-mediated effects in mice. In conclusion, COS attenuated inflammation and fibrosis in Ang-II-treated mice by alleviating mitochondrial dysfunction and oxidative stress. Our findings represent a potential therapeutic option for AF treatment.

RuSe2-CoTe Heterogeneous Surfaces Coated with NC Layer for Excellent HER Performance under Alkaline Condition.

Electrocatalytic hydrogen production has been a promising high-purity hydrogen production technology, attracting a large number of researchers' research interest. Ru has a hydrogen binding capacity similar to Pt, but its price is far lower than Pt, making it a promising alternative to Pt. However, a single Se electronic structure modulation is not sufficient to enable RuSe2 to be used for practical applications on a large scale due to the lack of electrons. Therefore, choosing a suitable way to electronically modulate the Ru atoms in RuSe2 can effectively improve the activity of the catalyst. Cobalt telluride (CoTe) can significantly enhance electrocatalytic performance due to tellurium's low electronegativity and excellent metal properties. In this work, the NC layer possesses excellent electrical conductivity and CoTe acts as an electron donor to optimize the electronic structure locally and trigger electron transfer efficiently. The RuSe2-CoTe/NC electrode requires an overpotential of only 25.4 mV (10 mA cm-2), which is superior to that of RuSe2/NF (65 mV) and CoTe/NC (115 mV). Meanwhile, the Tafel slope of RuSe2-CoTe/NC (67.8 mV dec-1) was better than that of RuSe2/NF (113.6 mV dec-1) and CoTe/NC (209.5 mV dec-1), showing that the build-up of the superior heterojunction makes the RuSe2-CoTe/NC with better hydrogen evolution reaction (HER) reaction kinetics. In addition, after 30 h of long-term stability testing, no significant decrease in catalytic activity was observed, proving the good stability of the RuSe2-CoTe/NC catalyst.

Spindle Nanorods of CeO2 and NiS Heterointerface Coated by the NC Layer: A High-Performance Bifunctional Electrocatalyst for Water Splitting.

Currently, nickel sulfides are widely employed in the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER), thanks to the narrow electronegativity difference of only 0.67 eV between nickel and sulfur. Among them, NiS stands out in terms of the OER performance; however, its HER performance and stability remain somewhat inadequate. The construction of heterogeneous interfaces can efficiently improve the HER performance and regulate the electronic structure of the NiS catalyst. CeO2 has been discovered to possess exceptional electronic modulation capabilities, which may lead to the effective enhancement of both HER and OER of the NiS catalyst. As a result, a nitrogen-doped carbon-coated CeO2-NiS heterogeneous interface catalyst (NC/NiS-CeO2) is designed as a bifunctional electrocatalyst for HER and OER with high performance. The NC/NiS-CeO2 catalyst demonstrates excellent HER (47 mV at 10 mA cm-2) and OER (92 mV at 10 mA cm-2) performances in a 1 M KOH alkaline solution. Characterization analysis reveals that the coupling of the heterostructure interface, which consists of CeO2 and NiS, significantly enhances electron conduction, the synergistic effect, and the electrocatalytic activity of the electrode. This study demonstrates that the HER and OER activity can be effectively improved by constructing a rational heterogeneous interface.

Z-Scheme CdIn2S4/Bi2WO6 Heterojunction for High Piezo-Photo Synergetic Performance.

The piezoelectric effect triggered by mechanical energy could establish an internal electric field to effectively modulate the separation behavior of carriers. Herein, a novel CdIn2S4/Bi2WO6 (CIS/BWO) piezo-photocatalyst for removing diclofenac (DCF) from water was constructed for the first time. Encouragingly, the photocatalytic degradation activity of CIS/BWO was effectively promoted through the piezoelectric effect. Specifically, 10% CIS/BWO exhibited promising DCF degradation performance under co-excitation of light irradiation and ultrasonic vibration, with a degradation efficiency of 99.9% within 40 min, much higher than that of pure photocatalysts (72.3%) and piezocatalysts (60.3%). Meanwhile, an in-depth study of the charge carrier separation mechanism of the CIS/BWO composite under the piezo-photo synergy condition was proposed. Both the built-in electric field induced by the piezoelectric effect in BWO and the Z-scheme transfer path of the CIS/BWO heterojunction are beneficial to interfacial charge transfer. Moreover, the Z-scheme mechanism was further demonstrated by trapping experiments and the electron spin resonance (ESR) technique. Finally, the corresponding intermediates of DCF over CIS/BWO composites and possible degradation pathways were also investigated by DFT calculations and liquid chromatography-mass spectrometry.

Efficient Charge Separation via MoSe2 Nanosheets with Tunable 1T Phase Contents: Piezoreduction of Cr(VI) to Cr(III) and Piezodegradation of RhB.

Piezocatalysis is a promising technology to address environmental pollution by converting mechanical energy into chemical energy. Herein, MoSe2 nanosheets with different 1T phase percentages (ranging from 30 to 80%) were constructed by adjusting hydrothermal temperature. Moreover, the roles of phase engineering in the piezocatalysis were thoroughly investigated by degrading rhodamine B and reducing Cr(VI) in ultrasonic vibration conditions. In particular, MoSe2 prepared at 220 °C (MoSe2-220) exhibits ultrahigh observed constant kobs and degradation rate k, which is superior to most reported catalysts to date. The experimental results indicate that the introduction of the 1T phase increases the active sites of the material, improves the conductivity, and inhibits the recombination of electrons and holes. Moreover, an internal electric field in the 2H phase induced by piezoelectric polarization is facilitated to separate electron-hole pairs, enabling the degradation and reduction to proceed. The capture experiments and EPR tests further confirm that •O2- and •OH are main reactive species, and a rational mechanism is finally put forward. This study offers a clear understanding of phase engineering in piezocatalysis and provides an efficiency strategy to construct highly efficient piezocatalysts.

The Role of Computed Tomography in The Diagnosis of Rare Congenital Heart Disease: Interrupted Aortic Arch.

Interrupted aortic arch (IAA) is a rare congenital anomaly of the aortic arch and an anatomical interruption of the lumen between the ascending and descending aorta. Computed tomography (CT) has become a reliable noninvasive diagnostic method for congenital IAA. The purpose of this study was to investigate the imaging features of IAA and improve the understanding and diagnosis of the disease. The imaging features and postoperative pathological data of 25 patients with IAA confirmed by dual-source computed tomography (DSCT) angiography were analyzed in this retrospective study. Among the 25 patients with IAA, 15 were type A, seven were type B, 0 were types C and D, and two were type E. The diameter of the pulmonary artery trunk in type A was larger than that in type B (P < 0.05). However, there were no significant differences between types A and B along the ascending aorta diameter, descending aorta, ascending aorta/descending aorta ratio, left pulmonary artery main trunk diameter, right pulmonary artery main trunk diameter, left pulmonary artery trunk/pulmonary artery trunk ratio, right pulmonary artery trunk/pulmonary artery trunk ratio, and left pulmonary artery trunk/right pulmonary artery trunk ratio. The imaging findings of IAA have typical and specific signs, and the types of IAA are not comprehensive. One type of patient identification can be added: Patients who are dissected between the left common carotid artery and left subclavian artery opening, and the descending aorta is circulated by the chest collaterals. Patients with a wide pulmonary artery in the IAA are usually type A patients. Patients with IAA after surgical repair require lifetime follow up, mainly to monitor left ventricular outflow tract obstruction and recurrent aortic coarctation. This study was approved by the Ethics Committee of Kunming Yan'an Hospital (Kunming City, Yunnan Province, China), and consent was waived because of the retrospective data collection.

SnoN residue (1-366) attenuates hypertrophic scars through resistance to transforming growth factor-ß1-induced degradation.

Hypertrophic scars (HSs) are characterized by fibroblast hyperproliferation and excessive matrix deposition. During wound healing, transforming growth factor (TGF)-ß1/Smad signaling acts as a key regulator. As a transcriptional corepressor of TGF-ß1/Smads, SnoN is expressed at low levels in many fibrotic diseases due to TGF-ß1/Smad-induced degradation. SnoN residue (1-366; SR) is resistant to TGF-ß1-induced degradation. However, the expression and role of SR in HSs are unknown. Here, we inhibited TGF-ß1/Smad signaling via overexpression of SR to block fibroblast transdifferentiation, proliferation, and collagen deposition during HS formation. Our results showed that SnoN was downregulated in HS fibroblasts (HSFs) owing to TGF-ß1/Smad-induced degradation. Overexpression of SR in normal human dermal fibroblasts (NHDFs) and HSFs successfully blocked phosphorylation of Smad2 and Smad3, thereby inhibiting NHDF transdifferentiation and HSF proliferation and reducing type I collagen (ColI) and type III collagen (ColIII) production and secretion. In addition, we applied overexpressed full-length SnoN (SF) and SR to wound granulation tissue in a rabbit model of HSs. SR reduced wound scarring, improved collagen deposition and arrangement of scar tissue, and decreased mRNA and protein expression of ColI, ColIII, and α-smooth muscle actin (α-SMA) more effectively than SF in vivo. These results suggest that SR could be a promising therapy for the prevention of HS.

SecinH3 Attenuates TDP-43 p.Q331K-Induced Neuronal Toxicity by Suppressing Endoplasmic Reticulum Stress and Enhancing Autophagic Flux.

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, neurodegenerative disease. The transactivating response region DNA binding protein 43 (TDP-43) p.Q331K mutation (TDP-43 Q331K) has previously been identified in ALS as a disease-causing mutation with neurotoxicity. SecinH3, a cytohesin inhibitor, has neuroprotective effects against mutant superoxide dismutase 1 (SOD1) toxicity. However, whether SecinH3 protects against mutant TDP-43 p.Q331K protein toxicity and its potential molecular mechanisms have not yet been investigated. To determine whether TDP-43 Q331K induces neuronal toxicity, SH-SY5Y, a human derived neuronal cell line were selected as an in vitro model of neuronal function. SH-SY5Y cells were transiently transfected with TDP-43 wild-type or TDP-43 Q331K. Remarkably, TDP-43 Q331K induced neuronal damage via endoplasmic reticulum (ER) stress-mediated apoptosis and the impairment of the autophagic flux. SecinH3 was demonstrated to successfully attenuate the TDP-43 Q331K-induced neuronal toxicity by suppressing ER stress-mediated apoptosis and enhancing the autophagic flux. Taken together, our in vitro study provided evidence that SecinH3 exerts neuroprotective effects against TDP-43 Q331K-mediated neuronal toxicity and was able to elucidate its mode of action. SecinH3 could, therefore, be considered a promising candidate as a therapeutic agent of ALS. © 2018 IUBMB Life, 71(1):192-199, 2019.

High thoracic sympathetic block improves coronary microcirculation disturbance in rats with chronic heart failure.

INTRODUCTION: Coronary microcirculation disturbance plays an important role in chronic heart failure (CHF). High thoracic sympathetic block (HTSB) is effective to treat CHF, but its impact on coronary microcirculation is unclear. METHODS: Forty male Wistar rats were subcutaneously injected with isoproterenol (340 mg/kg) for 2 days. Eight weeks later, 24 surviving rats were randomized to the CHF and HTSB groups and 10 rats were used as the control group. 50 µl of saline and ropivacaine (0.2%) were epidurally infused everyday in the CHF and HTSB group respectively. Four weeks later, echocardiography and pathological and ultrastructural examination, capillary histochemical staining and vascular endothelial growth factor (VEGF) immunohistochemical staining in left ventricular (LV) subendocardial myocardium were performed. RESULTS: Compared with the control group, LV dilation and dysfunction, myocardial focal necrosis, capillary spasm appeared in the CHF group. HTSB ameliorated LV dilation and dysfunction, myocardial necrosis and capillary spasm. Rats in the CHF group had less myocardial capillary density and more VEGF expression than in the control group (1591 ±â€¯99 vs. 1972 ±â€¯118/mm2, 0.62 ±â€¯0.13 vs. 0.33 ±â€¯0.10 optic density, all p < 0.05). Myocardial capillary density (1782 ±â€¯96/mm2) was more and VEGF expression (0.47 ±â€¯0.12 optic density) was less in the HTSB group than in the CHF group (all p < 0.05). CONCLUSION: HTSB improves coronary microcirculation disturbance in CHF, which may contribute to reversing myocardial remodeling and dysfunction. HTSB stimulates myocardial capillary growth independent of VEGF.

The Neurovascular Protective Effect of S14G-Humanin in a Murine MCAO Model and Brain Endothelial Cells.

Endothelial dysfunction is fundamental to ischemic stroke and brain injury. The humanin analogue S14G-humanin (HNG) has been shown to be a cytoprotective derivative. In this study, we investigated the neuroprotective effects of HNG in vivo and in vitro. In a murine middle cerebral artery occlusion (MCAO) stroke model, HNG ameliorates cerebral infarction and suppresses the production of TNF-α, IL-1ß, IL-6 and MCP-1 cytokines. HNG inhibits the expression of vascular adhesion molecules such as VCAM-1 and ICAM-1 in the cortex tissue. In mouse brain endothelial cells bEnd.3, HNG protects cell survival under oxygen deprivation (OGD) conditions. HNG suppresses ROS production as well as that of the same panel of cytokines and vascular adhesion molecules induced by OGD. HNG also reduces the numbers of THP-1 cells attached to bEnd.3 by OGD. Mechanistically, we show that HNG exerts its effect via inhibition of the NF- κB pathway factor IKKα, activation of IκBα and accumulation of p65 in the nucleus. Our data conclude that S14G-humanin serves as a neuroprotective factor, especially in brain vascular disorders. © 2018 IUBMB Life, 70(7):691-699, 2018.

Dachengqi Decoction Attenuates Intestinal Vascular Endothelial Injury in Severe Acute Pancreatitis in Vitro and in Vivo.

BACKGROUND/AIMS: Dachengqi decoction (DCQD) is a well-known traditional Chinese herbal drug with strong anti-inflammatory effects. Angiopoietin-1 (Ang-1) plays a vital role in maintaining the stability and integrity of the vascular wall and prevents vascular leakage due to inflammatory mediators. Our previous work found that DCQD protects against pancreatic injury in rats with severe acute pancreatitis (SAP). This study aims to investigate the effects of DCQD on intestinal endothelial damage in both damaged human umbilical vein endothelial cells (HUVECs) and SAP rats. METHODS: HUVECs were randomly divided into four groups: control group, TNF-α group, TNF-α plus Ang-1 group (Ang-1 group), and TNF-α plus DCQD group (DCQD group). Cells were incubated for 6 h, 12 h, and 24 h, before collection. The treatment concentration of DCQD was decided based on a Cell Counting Kit-8 (CCK-8) assay. The monolayer permeability of the HUVECs was assessed by measuring the transendothelial electrical resistance (TEER). Apoptosis was analyzed by flow cytometry. mRNA and protein expression of aquaporin 1 (AQP-1), matrix metalloproteinase 9 (MMP9), and junctional adhesion molecule-C (JAM-C) was evaluated by RT-PCR, immunocytofluorescence, and western blot. Forty male Sprague-Dawley rats were randomized into a control group, SAP group, SAP plus Ang-1 group (Ang-1 group), and SAP plus DCQD group (DCQD group). SAP was induced by intraperitoneal injection of cerulein and lipopolysaccharide (LPS), while the control group received 0.9% saline solution. Evans blue was injected through the penile vein and the rats were then sacrificed 12 h after modeling. Levels of serum amylase, TNF-α, IL-1ß, IL-2, and IL-6 were determined by using ELISA. Intestinal tissue was analysed by histology, and capillary permeability in the tissues was evaluated by Evans blue extravasation assay. Protein and mRNA expression of AQP-1, MMP9, and JAM-C were assessed by immunohistofluorescence, western blot, and RT-PCR. RESULTS: DCQD reduced the permeability of HUVEC induced by TNF-α in vitro. Furthermore, DCQD altered the mRNA and protein levels of JAM-C, MMP9, and AQP-1 in HUVECs after TNF-α induction. SAP intestinal injury induced by cerulein combined with lipopolysaccharides was concomitant with increased expression of JAM-C and MMP9, and reduced expression of AQP-1 in intestinal tissue. Pretreatment with DCQD attenuated SAP intestinal injury and lowered the levels of serum amylase, TNF-α, IL-1ß, IL-2, and IL-6 effectively. Our study demonstrated that DCQD decreased the expression of JAM-C and MMP9 and increased the expression of AQP-1 both in vitro and in vivo. CONCLUSION: DCQD can reduce capillary endothelial damage in acute pancreatitis-associated intestinal injury and the mechanism may be associated with the regulation of endothelial barrier function-associated proteins AQP-1, MMP9, and JAM-C.

Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma.

The long noncoding RNA Malat1 has been reported to be an oncogene that promotes tumor progress and correlates with prognosis in glioma. Growing evidence shows that autophagy plays a very important role in tumorigenesis and tumor cell survival, but whether Malat1 regulates autophagy in glioma is still unclear. In this study, we found that Malat1 expression and autophagy activity were significantly increased in glioma tissues compared with adjacent normal tissues. Additionally, Malat1 level was positively correlated with the expression of LC3-II (autophagy marker) mRNA in vivo. In vitro assays revealed that Malat1 significantly promoted autophagy activation and cell proliferation in glioma cells. More importantly, inhibition of autophagy by 3-MA relieved Malat1-induced cell proliferation. These data demonstrated that Malat1 activates autophagy and increases cell proliferation in glioma. We further investigated the molecular mechanisms whereby Malat1 functioned on glioma cell autophagy and proliferation. We found that Malat1 served as an endogenous sponge to reduce miR-101 expression by directly binding to miR-101. Moreover, Malat1 abolished the suppression effects of miR-101 on glioma cell autophagy and proliferation, which involved in upregulating the expression of miR-101 targets STMN1, RAB5A and ATG4D. Overall, our study elucidated a novel Malat1-miR-101-STMN1/RAB5A/ATG4D regulatory network that Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma cells.

Effect of High Thoracic Sympathetic Nerve Block on Serum Collagen Biomarkers in Patients with Chronic Heart Failure.

OBJECTIVES: The impact of high thoracic sympathetic block (HTSB) on myocardial fibrosis in chronic heart failure (HF) is unclear. Myocardial collagen synthesis can be assessed by measuring circulating biomarkers. We observed the effect of HTSB on serum collagen biomarkers in HF. METHODS: Forty-four patients were randomized to a control and a HTSB group. They received routine medications. Repeated epidural injections were given to the HTSB group for 4 weeks. Echocardiography and measurements of serum carboxy-terminal propeptide of procollagen type I (PICP) and amino-terminal propeptide of procollagen type III (PIIINP) were performed at baseline and 4 weeks later. RESULTS: There were significant reductions in left atrial diameter, left ventricular (LV) diameter and volume, LV weight index (LVWI) and serum PICP and PIIINP levels in the HTSB group (p < 0.05). The changes in LV end-systolic volume and ejection fraction (LVEF) were greater in the HTSB group than in the control group (p < 0.05). In the HTSB group, the decreases in PICP and PIIINP were correlated with the decrease in LVWI (PICP: r = 0.695, p = 0.000; PIIINP: r = 0.642, p = 0.001), and the decrease in PICP was negatively associated with the rise in LVEF (r = -0.813, p = 0.000). CONCLUSION: HTSB reduces myocardial fibrosis in HF, which may accompany the improvement of LV hypertrophy and dysfunction.

Inorganic Arsenic Induces NRF2-Regulated Antioxidant Defenses in Both Cerebral Cortex and Hippocampus in Vivo.

Inorganic arsenic is reported to induce the reactive oxygen species-mediated oxidative stress, which is supposed to be one of the main mechanisms of arsenic-related neurological diseases. Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of antioxidant defense systems, up-regulates the expression of target genes to fight against oxidative damages caused by harmful substances, including metals. In the present study, mice were used as a model to investigate the oxidative stress levels and the expressions of NRF2-regulated antioxidant substances in both cerebral cortex and hippocampus with 5, 10 and 20 mg/kg NaAsO2 exposure intra-gastrically. Our results showed that acute NaAsO2 treatment resulted in decreased total anti-oxidative capacity (T-AOC) and increased maleic dialdehyde production in the nervous system. We also detected rapidly elevation of NRF2 protein levels by enhancement of Nrf2 transcription, especially at 20 mg/kg NaAsO2 exposure group. In the meantime, mRNA and protein levels of Nrf2 encoding antioxidant enzymes heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) were consistently elevated time- and dose-dependently both in the cerebral cortex and hippocampus. Taken together, the presence study demonstrated the activation of NRF2 pathway, an early antioxidant defensive response, in both cerebral cortex and hippocampus upon inorganic arsenic (iAs) exposure in vivo. A better knowledge on the roles of NRF2 pathway in maintaining cellular redox homeostasis would be helpful for the strategies on improvement of neurotoxicity related to this metalloid.

Dachengqi Decoction Attenuates Inflammatory Response via Inhibiting HMGB1 Mediated NF-κB and P38 MAPK Signaling Pathways in Severe Acute Pancreatitis.

BACKGROUND/AIMS: Severe acute pancreatitis (SAP) is a sudden inflammation of the pancreas. The traditional Chinese medicine formula Dachengqi decoction (DCQD) is proven to be beneficial in the comprehensive treatment for pancreatitis patients in clinical practice. However, the molecular mechanism of DCQD on SAP remains unclear. High mobility group box 1(HMGB1) that functions as a damage-associated molecular pattern molecule (DAMP) has attracted much interest. METHODS: In this study, we used lipopolysaccharide (LPS) and cerulein to induce severe acute pancreatitis in C57BL/6 mice with subsequent administration with low, medium and high dose (2.3 g/kg, 7 g/kg and 21 g/kg, respectively) of DCQD. RESULTS: DCQD treatment improved the pathological score and decreased serum amylase and lipase in a dose-dependent manner. In addition, it suppressed the immune cell-induced secretion of HMGB1 and its translocation from the nucleus to the cytoplasm, thus repressing the expression of IL-6 and TNF-α. Further, pretreatment with DCQD decreased responses of TLRs, and suppressed the activation of NF-κB and p38 MAPK pathway. CONCLUSION: Decreasing the secretion of HMGB1 could reduce pro-inflammatory cytokines, which may help cutting down the risks of development from localized pathological changes to a systemic inflammatory response syndrome and even lead to multiple organ failure.

Early B Cell Factor 3 (EBF3) attenuates Parkinson's disease through directly regulating contactin-associated protein-like 4 (CNTNAP4) transcription: An experimental study.

Parkinson's disease (PD) is a gradually debilitating neurodegenerative syndrome. Here, we analyzed GSE7621 chip data obtained from the Gene Expression Omnibus (GEO) database to explore the pathogenesis of PD. Early B Cell Factor 3 (EBF3), a member of the highly evolutionarily conserved EBF-transcription factor family, is involved in neuronal development. EBF3 expression is low in the substantia nigra of patients with PD. However, whether EBF3 is implicated in dopaminergic neuron death during PD has not yet been investigated. Therefore, we aimed to reveal the potential anti-apoptotic effect and molecular mechanism of EBF3 in PD. We established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model in vivo and a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model in vitro. EBF3 was downregulated in the substantia nigra of PD mice and SH-SY5Y cells treated with MPP+, and the m6A methylation modification level was low. Fat mass and obesity-associated protein (FTO) siRNA upregulated m6A methylation modification of EBF3 and extended the EBF3 mRNA half-life. Functionally, as demonstrated by the results of the open-field test, pole test and gait analysis, EBF3 overexpression ameliorated MPTP-induced behavioral disorder. Further, EBF3 overexpression suppressed neuronal apoptosis in vivo, as evidenced by decreased TUNEL+ cells, and the increased activation of caspase-3 and caspase-9. Similar results were obtained in vitro, as reflected by increased cell viability, decreased LDH activity and restored mitochondrial function, collectively protecting SH-SY5Y cells from MPP+-induced apoptosis. Mechanistically, the results of luciferase reporter, ch-IP and DNA pull-down assays confirmed that, as a transcription factor, EBF3 bound to the promoter of CNTNAP4 (a protein associated with neuronal differentiation) and directly regulated CNTNAP4 transcription. Strikingly, CNTNAP4 knockdown markedly abolished the effect of EBF3 on cell apoptosis, thus aggravating PD. In conclusion, the low level of m6A methylation modification may contribute to the low expression of EBF3 during PD. Additionally, EBF3 attenuates PD by activating CNTNAP4 transcription, suggesting that EBF3 may be a novel therapeutic target in PD.

Genetic analysis of 37 cases with primary periodic paralysis in Chinese patients.

BACKGROUND: Primary periodic paralysis (PPP) is an inherited disorders of ion channel dysfunction characterized by recurrent episodes of flaccid muscle weakness, which can classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. However, PPP is charactered by remarkable clinical and genetic heterogeneity, and the diagnosis of suspected patients is based on the characteristic clinical presentation then confirmed by genetic testing. At present, there are only limited cohort studies on PPP in the Chinese population. RESULTS: We included 37 patients with a clinical diagnosis of PPP. Eleven (29.7%) patients were tested using a specific gene panel and 26 (70.3%) by the whole-exome sequencing (WES). Twenty-two cases had a genetic variant identified, representing a diagnostic rate of 59.5% (22/37). All the identified mutations were either in the SCN4A or the CACNA1S gene. The overall detection rate was comparable between the panel (54.5%: 6/11) and WES (61.5%: 16/26). The remaining patients unresolved through panel sequencing were further analyzed by WES, without the detection of any mutation. The novel atypical splicing variant c.2020-5G > A affects the normal splicing of the SCN4A mRNA, which was confirmed by minigene splicing assay. Among 21 patients with HypoPP, 15 patients were classified as HypoPP-2 with SCN4A variants, and 6 HypoPP-1 patients had CACNA1S variants. CONCLUSIONS: Our results suggest that SCN4A alleles are the main cause in our cohort, with the remainder caused by CACNA1S alleles, which are the predominant cause in Europe and the United States. Additionally, this study identified 3 novel SCN4A and 2 novel CACNA1S variants, broadening the mutation spectrum of genes associated with PPP.

Static and dynamic interactions within the triple-network model in stroke patients with multidomain cognitive impairments.

BACKGROUND: Internal capsule strokes often result in multidomain cognitive impairments across memory, attention, and executive function, typically due to disruptions in brain network connectivity. Our study examines these impairments by analyzing interactions within the triple-network model, focusing on both static and dynamic aspects. METHODS: We collected resting-state fMRI data from 62 left (CI_L) and 56 right (CI_R) internal capsule stroke patients, along with 57 healthy controls (HC). Using independent component analysis to extract the default mode (DMN), executive control (ECN), and salience networks (SAN), we conducted static and dynamic functional network connectivity analyses (DFNC) to identify differences between stroke patients and controls. For DFNC, we used k-means clustering to focus on temporal properties and multilayer network analysis to examine integration and modularity Q, where integration represents dynamic interactions between networks, and modularity Q measures how well the network is divided into distinct modules. We then calculated the correlations between SFNC/DFNC properties with significant inter-group differences and cognitive scales. RESULTS: Compared to HC, both CI_L and CI_R patients showed increased static FCs between SAN and DMN and decreased dynamic interactions between ECN and other networks. CI_R patients also had heightened static FCs between SAN and ECN and maintained a state with strongly positive FNCs across all networks in the triple-network model. Additionally, CI_R patients displayed decreased modularity Q. CONCLUSION: These findings highlight that stroke can result in the disruption of static and dynamic interactions in the triple network model, aiding our understanding of the neuropathological basis for multidomain cognitive deficits after internal capsule stroke.

Assessment of endogenous antioxidative compounds and antioxidant activities of lager beers.

BACKGROUND: Flavour stability is increasingly becoming the limiting factor in the shelf life of beer. Increasing the antioxidant activity of beer itself could suppress the rate of oxidative reaction and improve the flavour stability of beer. This report describes the levels of phenolic compounds, melanoidins and sulfur dioxide, and antioxidant activities of 40 lager beers. The relationships between antioxidative compounds and antioxidant activity were elucidated by multivariate analysis techniques. RESULTS: The results showed that the total phenolic content and the melanoidins content correlated well (P < 0.05) with antioxidant activity, while there was no significant correlation (P > 0.05) between total sulfur dioxide content and antioxidant activity. Satisfactory discrimination among beer samples with significantly different antioxidant activity was achieved by principal component analysis. Results from stepwise linear regression further demonstrated that different antioxidative components responsible for antioxidant activity were dependent on the assay used. The phenolic compound group is by far the most antioxidative compounds in beer and total phenolic content, melanoidins and sulfur dioxide together made a 22-68% contribution to the antioxidant activities of beers. CONCLUSION: Therefore, it might be an efficient means for brewers to increase total phenolic content during brewing for improvement in flavour stability of the final beer.