Analyzing the causal relationship between lipid-lowering drug target genes and epilepsy: a Mendelian randomization study.

Background: Previous research has yielded conflicting results on the link between epilepsy risk and lipid-lowering medications. The aim of this study is to determine whether the risk of epilepsy outcomes is causally related to lipid-lowering medications predicted by genetics. Methods: We used genetic instruments as proxies to the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein cholesterol (LDL cholesterol) from a genome-wide association study. These variants served as controlling factors. Through drug target Mendelian randomization, we systematically assessed the impact of lipid-lowering medications, including HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann-Pick C1-like 1 (NPC1L1) inhibitors, on epilepsy. Results: The analysis demonstrated that a higher expression of HMGCR was associated with an elevated risk of various types of epilepsy, including all types (OR = 1.17, 95% CI:1.03 to 1.32, p = 0.01), focal epilepsy (OR = 1.24, 95% CI:1.08 to 1.43, p = 0.003), and focal epilepsy documented with lesions other than hippocampal sclerosis (OR = 1.05, 95% CI: 1.01 to 1.10, p = 0.02). The risk of juvenile absence epilepsy (JAE) was also associated with higher expression of PCSK9 (OR = 1.06, 95% CI: 1.02 to 1.09, p = 0.002). For other relationships, there was no reliable supporting data available. Conclusion: The drug target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.

Antioxidant Carboxymethyl Chitosan Carbon Dots with Calcium Doping Achieve Ultra-Low Calcium Concentration for Iron-Induced Osteoporosis Treatment by Effectively Enhancing Calcium Bioavailability in Zebrafish.

Iron overloads osteoporosis mainly occurs to postmenopausal women and people requiring repeated blood transfusions. Iron overload increases the activity of osteoclasts and decreases the activity of osteoblasts, leading to the occurrence of osteoporosis. Conventional treatment options include calcium supplements and iron chelators. However, simple calcium supplementation is not effective, and it does not have a good therapeutic effect. Oxidative stress is one of the triggers for osteoporosis. Therefore, the study focuses on the antioxidant aspect of osteoporosis treatment. The present work revealed that antioxidant carboxymethyl chitosan-based carbon dots (AOCDs) can effectively treat iron overload osteoporosis. More interestingly, the functional modification of AOCDs by doping calcium gluconate (AOCDs:Ca) is superior to the use of any single component. AOCDs:Ca have the dual function of antioxidant and calcium supplement. AOCDs:Ca effectively improve the bioavailability of calcium and achieve ultra-low concentration calcium supplement for the treatment of iron-induced osteoporosis in zebrafish.

Lead Exposure Causes Spinal Curvature during Embryonic Development in Zebrafish.

Lead (Pb) is an important raw material for modern industrial production, they enter the aquatic environment in several ways and cause serious harm to aquatic ecosystems. Lead ions (Pb2+) are highly toxic and can accumulate continuously in organisms. In addition to causing biological deaths, it can also cause neurological damage in vertebrates. Our experiment found that Pb2+ caused decreased survival, delayed hatching, decreased frequency of voluntary movements at 24 hpf, increased heart rate at 48 hpf and increased malformation rate in zebrafish embryos. Among them, the morphology of spinal malformations varied, with 0.4 mg/L Pb2+ causing a dorsal bending of the spine of 72 hpf zebrafish and a ventral bending in 120 hpf zebrafish. It was detected that spinal malformations were mainly caused by Pb2+-induced endoplasmic reticulum stress and apoptosis. The genetic changes in somatic segment development which disrupted developmental polarity as well as osteogenesis, resulting in uneven myotomal development. In contrast, calcium ions can rescue the series of responses induced by lead exposure and reduce the occurrence of spinal curvature. This article proposes new findings of lead pollution toxicity in zebrafish.

H2O2/DEM-Promoted Maft Promoter Demethylation Drives Nrf2/ARE Activation in Zebrafish.

The Nrf2/ARE signaling pathway is a cell survival response pathway in response to environmental stresses. The Nrf2/ARE signaling pathway can be activated by stimulating cysteine residues at different positions in the Keap1. However, the epigenetic mechanisms of the Nrf2/ARE pathway under different stimuli are still poorly understood. In this study, we found that both hydrogen peroxide (H2O2) and Diethyl Maleate (DEM) activated the Nrf2/ARE signaling pathway at 120 hpf in zebrafish. H2O2 regulated the demethylation of the maft promoter by inhibiting the expression of methyltransferase. This promotes the mRNA expression of the Nrf2 binding factor maft, thereby promoting the downstream antioxidant genes. The methylation of the Nrf2/ARE signaling pathway was not significantly regulated by DEM. However, under oxidative stress, the methyltransferase inhibitors (decitabine and azacitidine) demethylated the promoter region of maft. It activated the expression of the maft, further improving the Nrf2/ARE signal pathway. At last, antioxidant target genes were activated. It was shown that H2O2 and DEM cooperated with methyltransferase inhibitors, providing an important reference for the treatment of oxidative stress-related diseases and breaking new ground for the study of the mechanism of methyltransferase inhibitors in the process of tumor chemotherapy.

Malting barley carbon dots-mediated oxidative stress promotes insulin resistance in mice via NF-κB pathway and MAPK cascade.

BACKGROUND: Food-borne carbon dots (CDs) are widely generated during food processing and are inevitably ingested by humans causing toxicity. However, the toxic effects of food-borne CDs on the blood glucose metabolism are unknown. RESULTS: In this study, we brewed beer via a representative strategy and extracted the melting-barley CDs (MBCDs) to explore the toxic effects on blood glucose in mice. We found the accumulation of fluorescent labeled MBCDs in various organs and oral administration of MBCDs can cause visceral toxicity, manifested as liver damage. Mice were orally administered MBCDs (5 and 25 mg/kg) for 16 weeks, and increased levels of fasting blood glucose were observed in both MBCDs-treated groups. Transcriptomic analyses revealed that MBCDs activate oxidative stress, inflammatory responses, the MAPK cascade, and PI3K/Akt signaling in mice livers. Mechanistically, MBCDs exposure-induced reactive oxygen species (ROS) overproduction activates the nuclear factor-κB (NF-κB) signaling pathway and MAPK cascade, thereby promoting phosphorylated insulin receptor substrate (IRS)-1 at Ser307 and inducing insulin resistance (IR). Meanwhile, the IR promoted gluconeogenesis, which enhanced MBCDs-induced hyperglycemia of mice. Importantly, inhibition of the ROS significantly attenuated the MBCDs-induced inflammatory response and MAPK cascade, thereby alleviating IR and hyperglycemia in mice. CONCLUSION: In summary, this study revealed that MBCDs promote ROS overproduction and thus induced IR, resulting in imbalance of glucose homeostasis in mice. More importantly, this study was further assessed to reveal an imperative emphasis on the reevaluation of dietary and environmental CDs exposure, and has important implications for T2DM prevention research.

Double-Sided Nano-ZnO: Superior Antibacterial Properties and Induced Hepatotoxicity in Zebrafish Embryos.

Zinc oxide nanoparticles (Nano-ZnO) have been widely used in the food, cosmetics, and biomedical fields due to their excellent antibacterial and antioxidant properties. However, with the widespread application of Nano-ZnO, Nano-ZnO inevitably enters the environment and living organisms, causing harm to human health and ecosystem safety. Therefore, the biosafety and toxicological issues of Nano-ZnO are gradually being emphasized. Our study found that Nano-ZnO has superior antibacterial properties compared to ofloxacin in the fight against Staphylococcus aureus (S. aureus). Given that ofloxacin can inhibit bacterial-induced inflammation, we constructed a model of bacterial inflammation using S. aureus in zebrafish. We found that Nano-ZnO inhibited the NF-κB-mediated inflammatory signaling pathway. However, in the process, we found that Nano-ZnO caused hepatic steatosis in zebrafish. This suggested that Nano-ZnO had a certain hepatotoxicity, but did not affect liver development. Subsequently, we investigated the mechanism of hepatotoxicity produced by Nano-ZnO. Nano-ZnO triggered oxidative stress in the liver by generating ROS, which then induced endoplasmic reticulum stress to occur. It further activated srebp and its downstream genes fasn and acc1, which promoted the accumulation of fatty acid synthesis and the development of steatosis, leading to the development of nonalcoholic fatty liver disease (NAFLD). To address the hepatotoxicity of Nano-ZnO, we added carbon dots for the treatment of NAFLD. The carbon dots were found to normalize the steatotic liver. This provided a new strategy to address the hepatotoxicity caused by Nano-ZnO. In this work, we systematically analyzed the antibacterial advantages of Nano-ZnO in vivo and in vitro, explored the mechanism of Nano-ZnO hepatotoxicity, and proposed a new method to treat Nano-ZnO hepatotoxicity.

Laser derusting on low carbon steel surface based on coordinated application of machine vision and laser-induced breakdown spectroscopy.

Online monitoring and closed-loop control are essential to accurately remove the rust layer and effectively avoid damage to the substrate. A collaborative utilization of machine vision and laser-induced breakdown spectroscopy (LIBS) to monitor and control the laser derusting process on Q235B steel is reported. The optimum overlap ratio of 50% is obtained by using machine vision. Monitoring derusting with different thicknesses relies on the Pearson correlation coefficient of the LIBS spectrum between the rust layer and substrate. By developing a collaborative monitoring and control system on LabVIEW, the functions of date acquisition, coordinate transformation, and data calculation are realized to automatically control the laser derusting process on rusty steel in a large area. The cooperation of two methods can achieve high-quality laser derusting with a derusting degree of 99.1%, roughness of 1.45 µm, and extremely low oxygen content on the surface, which verifies the accuracy and practicability of the developed monitoring system. Moreover, the potentiodynamic polarization curves demonstrate that the performance of the corrosion resistance of the Q235B steel is effectively improved after laser derusting.

Fluorescent Egg White-Based Carbon Dots as a High-Sensitivity Iron Chelator for the Therapy of Nonalcoholic Fatty Liver Disease by Iron Overload in Zebrafish.

Iron overload is the direct cause of many ferroptosis diseases, and it is essential to maintain iron homeostasis. In this paper, we report the Fe3+ chelation and therapy of the iron overload nonalcoholic fatty liver disease (NAFLD) by the fluorescent egg white-based carbon dots (EWCDs) obtained through the microwave-assisted pyrolysis method. As a high-sensitivity sensor, EWCDs show a high correlation between fluorescence emission and the concentration of Fe3+ (R2 = 0.993) in low concentration ranges of 0-25 µM. In vivo and in vitro, the EWCDs show characteristics of high biocompatibility and specific binding of Fe3+. As a novel type of the nano-iron-chelator, EWCDs can successfully attenuate the production of lethal reactive oxygen species. EWCDs not only alleviate the endoplasmic reticulum stress response but also regulate the NF-κB signaling pathway downstream of the Nrf2 signaling pathway. EWCDs prevent hepatocyte apoptosis, regulate fatty acid metabolism, and alleviate inflammation. Ultimately, they alleviate NAFLD induced by iron overload in zebrafish. This work may provide a new idea and method for the application of carbon dots in the field of disease detection and treatment.

Green Synthesis of Fluorescent Carbon Dots from Gynostemma for Bioimaging and Antioxidant in Zebrafish.

Fluorescent carbon dots (CDs) have been synthesized via the calcination method using natural gynostemma as the precursor, without any toxic ingredients or surface passivation chemicals. CDs have a narrow size distribution, and the mean particle size is about 2.5 nm. CDs exhibit good water dispersibility and can emit intense blue fluorescence under 365 nm UV light in an aqueous solution, which can be stable in different conditions. The biotoxicity of CDs on the embryonic development of zebrafish is evaluated, the hatch rate and survival rate of embryos are around 90%, and the malformation rate is less than 10%. Because of the excellent fluorescence stability and biocompatibility, CDs can be used in zebrafish for bioimaging. In addition, the antioxidative stress property of CDs is investigated both in vitro and in vivo, and the presence of CDs can promote the mRNA expression of related genes to encode more antioxidant proteins in zebrafish. Therefore, fluorescent CDs would be a potential candidate for bioimaging and treating diseases caused by excessive oxidation damage, such as cancer, senility, and other diseases associated with aging.

The Stromal Vascular Fraction Improves Maintenance of the Fat Graft Volume: A Systematic Review.

BACKGROUND AND OBJECTIVES: With the continued application of fat grafting in plastic surgery, many studies have focused on various factors to improve maintenance of the fat graft volume, such as platelet-rich plasma, adipose-derived stromal/stem cells, and the stromal vascular fraction (SVF). In addition, many review articles have investigated the functions of platelet-rich plasma and adipose-derived stromal/stem cells in fat grafting, although the usefulness of the SVF remains unclear. The aim of the present review was to determine whether SVF use could maintain a fat graft. METHODS: A systematic review was conducted of the PubMed, Cochrane Central Register of Controlled Trials, and Embase databases of original articles published up to February 2018. RESULTS: Relevant articles were identified by screening the abstracts. A total of 58 full texts were initially identified. After exclusion, 17 articles, including 6 animal studies and 11 clinical studies, were included for analysis. CONCLUSIONS: Most studies found a significant and measurable long-term effect of SVF-enhanced fat grafting on breast augmentation and defects, wound healing, scaring, and facial aesthetic outcomes. Stromal vascular fraction use did not result in a higher instance of complications and, thus, can be considered a safe option for fat grafting.

Human amnion-derived mesenchymal stem cells promote osteogenic and angiogenic differentiation of human adipose-derived stem cells.

Tissue engineering using suitable mesenchymal stem cells (MSCs) shows great potential to regenerate bone defects. Our previous studies have indicated that human amnion-derived mesenchymal stem cells (HAMSCs) could promote the osteogenic differentiation of human bone marrow mesenchymal stem cells (HBMSCs). Human adipose-derived stem cells (HASCs), obtained from adipose tissue in abundance, are capable of multi-lineage differentiation. In this study, the effects of HAMSCs on osteogenic and angiogenic differentiation of HASCs were systematically investigated. Proliferation levels were measured by flow cytometry. Osteoblastic differentiation and mineralization were investigated using chromogenic alkaline phosphatase activity (ALP) activity substrate assays, Alizarin red S staining, real-time polymerase chain reaction (real-time PCR) analysis of osteogenic marker expression, and Western blotting. We found that HAMSCs increased the proliferation and osteoblastic differentiation of HASCs. Moreover, enzyme-linked immunosorbent assay (ELISA) and human umbilical vein endothelial cells (HUVECs) tube formation suggested HAMSCs enhanced angiogenic potential of HASCs via secretion of increased vascular endothelial growth factor (VEGF). Thus, we conclude that HAMSC might be a valuable therapeutic approach to promote HASCs-involved bone regeneration.

Genetic polymorphisms of CYP3A4 among Chinese patients with steroid-induced osteonecrosis of the femoral head.

BACKGROUND: Steroid therapy has been an important reason of nontraumatic osteonecrosis of the femoral head (ONFH). Steroids are metabolized by hepatic cytochrome P4503A, a low endogenous activity of this enzyme can contribute to the pathogenesis of ONFH. The aim of this study was to investigate the associations of polymorphisms of cytochrome P4503A4 (CYP3A4) gene with steroid-induced ONFH in Chinese patients. METHODS: A total of 150 steroid-induced ONFH patients and 250 healthy controls were enrolled. We evaluated 5 single-nucleotide polymorphisms of the CYP3A4 gene in this case-control study. RESULTS: We identified rs2242480 in the CYP3A4 gene that was potentially associated with an increased risk of steroid-induced ONFH in the allele model (P = 0.023; odds ratio [OR]: 1.47; 95% confidence intervals [CI]: 1.05-2.04) and in the additive model (P = 0.028; OR: 1.44; 95% CI: 1.04-1.99) adjusted age + gender. Furthermore, we also observed a protective effect of haplotype "TG" (P = 0.025; OR: 0.69; 95% CI: 0.49-0.96) and a risk effect of haplotype "CG" (P = 0.006; OR: 1.81; 95% CI: 1.19-2.77) of the CYP3A4 gene adjusted age + gender. CONCLUSION: These findings suggested that polymorphisms of CYP3A4 gene may be associated with susceptibility to steroid-induced ONFH.

Calcium sensing receptor mediated the excessive generation of ß-amyloid peptide induced by hypoxia in vivo and in vitro.

Hypoxia played an important role in the pathogenesis of AD. Hypoxia increased Aß formation, then caused Alzheimer's disease. Calcium sensing receptor (CaSR) was involved in the regulation of cell growth, differentiation, hormonal secretion and other physiological function. Increasing evidence supported CaSR might play a more prominent role in susceptibility to AD, but the role of CaSR in Aß overproduction induced by hypoxia and its mechanisms remain unclear. To investigate whether CaSR mediated the overproduction of Aß induced by hypoxia, immunoblot and immunochemistry were employed to determine the expression of CaSR and BACE1 in hippocampal neurons and tissue and Ca(2+) image system was used to measure [Ca(2+)]i in hippocampal neurons. The content of Aß was detected with ELISA kits. Our research found that hypoxia increased the expression of CaSR in hippocampal neurons and tissue and [Ca(2+)]i in hippocampal neurons. Calhex 231, a selective blocher of CaSR, inhibited the increase in [Ca(2+)]i induced by hypoxia. Hypoxia or GdCl3, an agonist of CaSR, increased the expression of BACE1 in hippocampal neurons and tissue, but Calhex 231 or Xesto C (a selective inhibitor of IP3 receptor) partly prevented hypoxia-induced BACE1 overexpression. Hypoxia or GdCl3 increased the content of Aß42 and Aß40 in hippocampal tissue, however Calhex 231 or Xesto C prevented hypoxia-induced the overproduction of Aß42 and Aß40 partly. Based on the above data, we suggested that hypoxia increased [Ca(2+)]i by elevated CaSR expression to promote BACE1 expression, thereby resulting in the overproduction of Aß42 and Aß40.

Resting heart rate, vagal tone, and reactive and proactive aggression in Chinese children.

Abundant research conducted in Western contexts has shown that biological risk factors such as low resting heart rate (HR) might be related to childhood aggression. However, it was unclear (1) how resting HR, as well as other markers of cardiac functions such as resting vagal tone, may be related to subtypes of aggression such as reactive and proactive aggression, and (2) whether the HR-aggression relation can be replicated in non-Western contexts. Therefore, this study examined the concurrent and prospective relations between resting HR, vagal tone, and Chinese children's reactive and proactive aggression. Participants were 183 children (M age=7.64 years, 91 girls) recruited from an elementary school in Zhenjiang, PRC. Children's resting HR and vagal tone were assessed in the second grade (T1). Teachers rated children's reactive and proactive aggression in the second (T1) and fourth grade (T2). Results showed that lower resting HR at T1 was associated with higher reactive and proactive aggression at T1 and T2, and higher vagal tone was associated with lower HR, which in turn was related to higher reactive and proactive aggression at T1 and T2. Lower vagal tone was directly related to higher reactive but not proactive aggression at T1 and T2, whereas lower HR was related to higher reactive aggression at T2 for children with low or moderate vagal tone but was not for children with high vagal tone. These psychophysiological findings from a non-Western context add additional support for both similarities and differences between reactive and proactive aggression in childhood.

Three types of shyness in Chinese children and the relation to effortful control.

Two studies were conducted to further differentiate 3 forms of shyness previously identified in Chinese children--shyness toward strangers, anxious shyness, and regulated shyness--by examining the relation of the 3 forms of shyness to children's inhibited behavior, physiological reactivity (measured by heart period [HP]), and effortful control. In Study 1 (N = 237; M age = 9.17 years), the authors examined the 3 forms of shyness in relation to children's inhibited behavior and HP assessed in 3 conditions: at baseline, during a stranger encounter, and in a card-sorting task with social evaluative cues. Results of confirmatory factor analyses provided support for a 3-factor model of shyness. Shyness toward strangers was associated with children's inhibition (positively) and HP (negatively) in the stranger encounter and children's HP (negatively) in the card-sorting session, whereas anxious shyness was related to children's inhibition (positively) and HP (negatively) in the card-sorting session. Regulated shyness was not associated with children's inhibition in any session but was negatively related to HP in the stranger encounter session. In Study 2 (N = 208; M age = 6.57 years), the authors examined children's shyness toward strangers and effortful control at age 6 years in relation to anxious and regulated shyness 2 years later. Results showed shyness toward strangers was related to regulated shyness among children with high or moderate effortful control, and shyness toward strangers was related to anxious shyness among children with low or moderate effortful control. Findings support a multidimensional view of shyness in Chinese children.