α-Synuclein Induces Neuroinflammation Injury through the IL6ST-AS/STAT3/HIF-1α Axis.

The aggregation of α-synuclein (α-syn) promotes neuroinflammation and neuronal apoptosis, which eventually contribute to the pathogenesis of Parkinson's disease (PD). Our microarray analysis and experimental data indicated a significant expression difference of the long noncoding RNA IL6ST-AS and its anti-sense strand, IL6ST, in α-synuclein-induced microglia, compared with unstimulated microglia. IL6ST is a key component of the IL6R/IL6ST complex in the microglial membrane, which recognizes extracellular inflammatory factors, such as IL6. Studies have shown that the binding of IL6 to the IL6R/IL6ST complex could activate the JAK2-STAT3 pathway and promote an excessive immune response in glia cells. Meanwhile, the phosphorylation and activation of STAT3 could increase the transcription of HIF1A, encoding a hypoxia-inducible factor related to cytotoxic damage. Our results indicated that the overexpression of IL6ST-AS induced by exogenous α-synuclein could inhibit the expression of IL6ST and the activation of JAK2-STAT3 pathway in HMC3 cells. In addition, a reduction in STAT3 resulted in the transcription inhibition of HIF1A and the acceleration of oxidative stress injury in SH-SY5Y cells co-cultured with α-synuclein-induced HMC3 cells. Our findings indicate that IL6ST-AS is an important factor that regulates microglia activation and neuronal necrosis in the progression of PD. In the HMC3 and SH-SY5Y cell co-culture system, the overexpression of IL6ST-AS led to microglial dysfunction and neurotoxicology through the IL6ST-AS/STAT3/HIF-1α axis. Our research revealed the relationships among α-synuclein, IL6ST, STAT3, and HIF-1α in the pathological process of PD and provided a new inflammation hypothesis for the pathogenesis of PD.

Diphenyl Diselenide Alleviates Tert-Butyl Hydrogen Peroxide-Induced Oxidative Stress and Lipopolysaccharide-Induced Inflammation in Rat Glomerular Mesangial Cells.

Hyperglycemia, oxidative stress, and inflammation play key roles in the onset and development of diabetic complications such as diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple organic selenium compound with anti-hyperglycemic, anti-inflammatory, and anti-oxidative activities. Nevertheless, in vitro, the role and molecular mechanism of DPDS on DN remains unknown. Therefore, we investigated the effects of DPDS on tert-butyl hydrogen peroxide (t-BHP)-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation in rat glomerular mesangial (HBZY-1) cells and explored the underlying mechanisms. DPDS attenuated t-BHP-induced cytotoxicity, concurrent with decreased intracellular ROS and MDA contents and increased SOD activity and GSH content. Moreover, DPDS augmented the protein and mRNA expression of Nrf2, HO-1, NQO1, and GCLC in t-BHP-stimulated HBZY-1 cells. In addition, DPDS suppressed LPS-induced elevations of intracellular content and mRNA expression of interleukin (IL)-6, IL-1ß and TNF-α. Furthermore, LPS-induced NFκB activation and high phosphorylation of JNK and ERK1/2 were markedly suppressed by DPDS in HBZY-1 cells. In summary, these data demonstrated that DPDS improves t-BHP-induced oxidative stress by activating the Nrf2/Keap1 pathway, and also improves LPS-induced inflammation via inhibition of the NFκB/MAPK pathways in HBZY-1 cells, suggesting that DPDS has the potential to be developed as a candidate for the prevention and treatment of DN.

Hepatic Proteomic Analysis of Selenoprotein T Knockout Mice by TMT: Implications for the Role of Selenoprotein T in Glucose and Lipid Metabolism.

Selenoprotein T (SELENOT, SelT), a thioredoxin-like enzyme, exerts an essential oxidoreductase activity in the endoplasmic reticulum. However, its precise function remains unknown. To gain more understanding of SELENOT function, a conventional global Selenot knockout (KO) mouse model was constructed for the first time using the CRISPR/Cas9 technique. Deletion of SELENOT caused male sterility, reduced size/body weight, lower fed and/or fasting blood glucose levels and lower fasting serum insulin levels, and improved blood lipid profile. Tandem mass tag (TMT) proteomics analysis was conducted to explore the differentially expressed proteins (DEPs) in the liver of male mice, revealing 60 up-regulated and 94 down-regulated DEPs in KO mice. The proteomic results were validated by western blot of three selected DEPs. The elevated expression of Glycogen [starch] synthase, liver (Gys2) is consistent with the hypoglycemic phenotype in KO mice. Furthermore, the bioinformatics analysis showed that Selenot-KO-induced DEPs were mainly related to lipid metabolism, cancer, peroxisome proliferator-activated receptor (PPAR) signaling pathway, complement and coagulation cascades, and protein digestion and absorption. Overall, these findings provide a holistic perspective into SELENOT function and novel insights into the role of SELENOT in glucose and lipid metabolism, and thus, enhance our understanding of SELENOT function.

Selenoprotein F knockout leads to glucose and lipid metabolism disorders in mice.

Selenoprotein F (Selenof), an endoplasmic reticulum (ER)-resident protein, is considered to be involved in glycoprotein folding and quality control in the ER. However, its function has not yet been thoroughly addressed. In this study, proteomics analysis revealed that Selenof deficiency in mice led to the differential expression of hepatic proteins associated with glucose and lipid metabolism. The phenotype analysis revealed that Selenof knockout mice showed glucose intolerance and insulin reduction, even with a normal diet. Additionally, Selenof knockout exacerbated high-fat diet-induced obesity, hyperglycemia, glucose intolerance, and hepatic steatosis. Furthermore, lipoprotein lipase and carboxylesterase 1D, two glycoproteins involved in lipid metabolism, were significantly decreased in the liver of Selenof knockout mice with a normal or high-fat diet. Collectively, these findings suggested that Selenof deficiency might cause the perturbation of glycoprotein quality control and thus contribute to glucose and lipid metabolism disorders, implying a novel biological function of Selenof.

DNA-Conjugated Amphiphilic Aggregation-Induced Emission Probe for Cancer Tissue Imaging and Prognosis Analysis.

Detection of an ultralow concentration of mRNA is important in the prognosis of gene-related diseases. In this study, a DNA-conjugated amphiphilic aggregation-induced emission probe (TPE-R-DNA) was synthesized for cancer tissue imaging and prognosis analysis based on an exonuclease III-aided target recycling technique. TPE-R-DNA comprise two components: a hydrophobic component that serves as the "turn-on" long wavelength fluorescence imaging agent (TPE-R-N3); and a hydrophilic single DNA strand (Alk-DNA) which acts as specific recognition part for target mRNA. In the absence of target mRNA, TPE-R-DNA had almost no fluorescence because of its high water solubility. Conversely, the TPE-R-DNA was digested by exonuclease III (Exo III) in the presence of MnSOD mRNA to release the hydrophobic fluorogens (TPE-R-AT). Subsequently, TPE-R-AT formed aggregates, and therefore, fluorescence signal was distinctly observed. For the first time, the structure of the hydrolysis product (TPE-R-AT), containing two bases A and T, was proved by the mass spectrum (MS) and high-performance liquid chromatography (HPLC). Moreover, the detection limit toward mRNA could be achieved in as low as 0.6 pM. Furthermore, the fluorescent signal can be used to confirm the MnSOD mRNA expression level in cancer tissue. The MnSOD mRNA expression in renal cancer was lower than in renal cancer adjacent tissue. In particular, the expression level was analyzed to predict prognosis of cancer patients. Our results demonstrate that a shorter survival time was evident among patients in lower MnSOD mRNA expression. Thereby, it indicates great potential for the development of an ultrasensitive biosensing platform for the application in disease prognosis.

Rifampicin Prevents SH-SY5Y Cells from Rotenone-Induced Apoptosis via the PI3K/Akt/GSK-3ß/CREB Signaling Pathway.

In addition to its original application for treating tuberculosis, rifampicin has multiple potential neuroprotective effects in chronic neurodegenerative diseases including Parkinson's disease (PD) and Alzheimer's disease. Inflammatory reactions and the PI3K/Akt pathway are strongly implicated in dopaminergic neuronal death in PD. This study aims to investigate whether rifampicin protects rotenone-lesioned SH-SY5Y cells via regulating PI3K/Akt/GSK-3ß/CREB pathway. Rotenone-treated SH-SY5Y cells were used as the cell model to investigate the neuroprotective effects of rifampicin. Cell viability and apoptosis of SH-SY5Y cells were determined by CCK-8 assay and flow cytometry, respectively. The expression of Akt, p-Akt, GSK-3ß, p-GSK-3ß, CREB and p-CREB were measured by Western blot. Our results showed that the cell viability and level of phospho-CREB significantly decreased in SH-SY5Y cells exposed to rotenone when compared to the control group. Both the cell viability and the expression of phospho-CREB in cells pretreated with rifampicin were higher than those of cells exposed to rotenone alone. Moreover, pretreatment of SH-SY5Y cells with rifampicin enhanced phosphorylation of Akt and suppressed activity of GSK-3ß. The addition of LY294002, a PI3K inhibitor, could suppress phosphorylation of Akt and CREB and activate GSK-3ß, resulting in abolishment of neuroprotective effects of rifampicin on cells exposed to rotenone. Rifampicin provides neuroprotection against dopaminergic degeneration, partially via the PI3K/Akt/GSK-3ß/CREB signaling pathway. These findings suggest that rifampicin could be an effective and promising neuroprotective candidate for treating PD.

Selenoprotein Gene Nomenclature.

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.

Selenite and ebselen supplementation attenuates D-galactose-induced oxidative stress and increases expression of SELR and SEP15 in rat lens.

Selenite and ebselen supplementation has been shown to possess anti-cataract potential in some experimental animal models of cataract, however, the underlying mechanisms remain unclear. The present study was designed to evaluate the anti-cataract effects and the underlying mechanisms of selenite and ebselen supplementation on galactose induced cataract in rats, a common animal model of sugar cataract. Transmission electron microscopy images of lens fiber cells (LFC) and lens epithelial cells (LEC) were observed in D-galactose-induced experimental cataractous rats treated with or without selenite and ebselen, also redox homeostasis and expression of proteins such as selenoprotein R (SELR), 15kD selenoprotein (SEP15), superoxide dismutase 1 (SOD1), catalase (CAT), ß-crystallin protein, aldose reductase (AR) and glucose-regulated protein 78 (GRP78) were estimated in the lenses. The results showed that D-galactose injection injured rat lens and resulted in cataract formation; however, selenite and ebselen supplementation markedly alleviated ultrastructural injury of LFC and LEC. Moreover, selenite and ebselen supplementation could mitigate the oxidative damage in rat lens and increase the protein expressions of SELR, SEP15, SOD1, CAT and ß-crystallin, as well as decrease the protein expressions of AR and GRP78. Taken together, these findings for the first time reveal the anti-cataract potential of selenite and ebselen in galactosemic cataract, and provide important new insights into the anti-cataract mechanisms of selenite and ebselen in sugar cataract.

Selenoprotein R Protects Human Lens Epithelial Cells against D-Galactose-Induced Apoptosis by Regulating Oxidative Stress and Endoplasmic Reticulum Stress.

Selenium is an essential micronutrient for humans. Much of selenium's beneficial influence on health is attributed to its presence within 25 selenoproteins. Selenoprotein R (SelR), known as methionine sulfoxide reductase B1 (MsrB1), is a selenium-dependent enzyme that, like other Msrs, is required for lens cell viability. In order to investigate the roles of SelR in protecting human lens epithelial (hLE) cells against damage, the influences of SelR gene knockdown on d-galactose-induced apoptosis in hLE cells were studied. The results showed that both d-galactose and SelR gene knockdown by siRNA independently induced oxidative stress. When SelR-gene-silenced hLE cells were exposed to d-galactose, glucose-regulated protein 78 (GRP78) protein level was further increased, mitochondrial membrane potential was significantly decreased and accompanied by a release of mitochondrial cytochrome c. At the same time, the apoptosis cells percentage and the caspase-3 activity were visibly elevated in hLE cells. These results suggested that SelR might protect hLE cell mitochondria and mitigating apoptosis in hLE cells against oxidative stress and endoplasmic reticulum (ER) stress induced by d-galactose, implying that selenium as a micronutrient may play important roles in hLE cells.

Catalpol ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by suppressing the JNK and NF-κB pathways.

Catalpol, a bioactive component from the root of Rehmannia glutinosa, has been shown to possess hypoglycemic effects in type 2 diabetic animal models, however, the underlying mechanisms remain poorly understood. Here we investigated the effect of catalpol on high-fat diet (HFD)-induced insulin resistance and adipose tissue inflammation in mice. Oral administration of catalpol at 100 mg/kg for 4 weeks had no effect on body weight of HFD-induced obese mice, but it significantly improved fasting glucose and insulin levels, glucose tolerance and insulin tolerance. Moreover, macrophage infiltration into adipose tissue was markedly reduced by catalpol. Intriguingly, catalpol also significantly reduced mRNA expressions of M1 pro-inflammatory cytokines, but increased M2 anti-inflammatory gene expressions in adipose tissue. Concurrently, catalpol significantly suppressed the c-Jun NH2-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) signaling pathways in adipose tissue. Collectively, these results suggest that catalpol may ameliorate HFD-induced insulin resistance in mice by attenuating adipose tissue inflammation and suppressing the JNK and NF-κB pathways, and thus provide important new insights into the underlying mechanisms of the antidiabetic effect of catalpol.

Knockdown of 15-kDa selenoprotein (Sep15) increases hLE cells' susceptibility to tunicamycin-induced apoptosis.

In this work, we investigated the effect of Sep15 gene knockdown on apoptosis in human lens epithelial (hLE) cells, trying to understand the relevance of Sep15 to cataract formation in the Sep15 knockout (KO) mice. The results showed that sole knockdown of Sep15 by RNA interference did not result in apoptosis; however, reduction of Sep15 expression aggravated tunicamycin (Tm)-induced cell apoptosis and caspases activation. Furthermore, Tm-induced mitochondrial dysfunction was also exacerbated under the Sep15 knockdown condition by measurement of mitochondrial membrane potential decrease and human cytochrome c release into cytosol. Interestingly, the knockdown of Sep15 exacerbated Tm-induced oxidative stress while endoplasmic reticulum (ER) stress was not correspondingly elevated. These results suggest that the protective role of Sep15 against Tm-induced apoptosis in hLE cells is operated via inhibiting oxidative stress rather than regulating Tm-induced ER stress, and the protective role becomes dependent on Sep15 only in acute stress condition.

Selenite exacerbates hepatic insulin resistance in mouse model of type 2 diabetes through oxidative stress-mediated JNK pathway.

Recent evidence suggests a potential pro-diabetic effect of selenite treatment in type 2 diabetics; however, the underlying mechanisms remain elusive. Here we investigated the effects and the underlying mechanisms of selenite treatment in a nongenetic mouse model of type 2 diabetes. High-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice were orally gavaged with selenite at 0.5 or 2.0mg/kg body weight/day or vehicle for 4 weeks. High-dose selenite treatment significantly elevated fasting plasma insulin levels and insulin resistance index, in parallel with impaired glucose tolerance, insulin tolerance and pyruvate tolerance. High-dose selenite treatment also attenuated hepatic IRS1/Akt/FoxO1 signaling and pyruvate kinase gene expressions, but elevated the gene expressions of phosphoenolpyruvate carboxyl kinase (PEPCK), glucose 6-phosphatase (G6Pase), peroxisomal proliferator-activated receptor-γ coactivator 1α (PGC-1α) and selenoprotein P (SelP) in the liver. Furthermore, high-dose selenite treatment caused significant increases in MDA contents, protein carbonyl contents, and a decrease in GSH/GSSG ratio in the liver, concurrent with enhanced ASK1/MKK4/JNK signaling. Taken together, these findings suggest that high-dose selenite treatment exacerbates hepatic insulin resistance in mouse model of type 2 diabetes, at least in part through oxidative stress-mediated JNK pathway, providing new mechanistic insights into the pro-diabetic effect of selenite in type 2 diabetes.

Effect of methionine sulfoxide reductase B1 (SelR) gene silencing on peroxynitrite-induced F-actin disruption in human lens epithelial cells.

F-actin plays a crucial role in fundamental cellular processes, and is extremely susceptible to peroxynitrite attack due to the high abundance of tyrosine in the peptide. Methionine sulfoxide reductase (Msr) B1 is a selenium-dependent enzyme (selenoprotein R) that may act as a reactive oxygen species (ROS) scavenger. However, its function in coping with reactive nitrogen species (RNS)-mediated stress and the physiological significance remain unclear. Thus, the present study was conducted to elucidate the role and mechanism of MsrB1 in protecting human lens epithelial (hLE) cells against peroxynitrite-induced F-actin disruption. While exposure to high concentrations of peroxynitrite and gene silencing of MsrB1 by siRNA alone caused disassembly of F-actin via inactivation of extracellular signal-regulated kinase (ERK) in hLE cells, the latter substantially aggravated the disassembly of F-actin triggered by the former. This aggravation concurred with elevated nitration of F-actin and inactivation of ERK compared with that induced by the peroxynitrite treatment alone. In conclusion, MsrB1 protected hLE cells against the peroxynitrite-induced F-actin disruption, and the protection was mediated by inhibiting the resultant nitration of F-actin and inactivation of ERKs.

Selenium suppresses oxidative-stress-enhanced vascular smooth muscle cell calcification by inhibiting the activation of the PI3K/AKT and ERK signaling pathways and endoplasmic reticulum stress.

Vascular calcification is a prominent feature of many diseases, including atherosclerosis, and it has emerged as a powerful predictor of cardiovascular morbidity and mortality. A number of studies have examined the association between selenium and risk of cardiovascular diseases, but little is known about the role of selenium in vascular calcification. To determine the role of selenium in regulating vascular calcification, we assessed the effect of sodium selenite on oxidative-stress-enhanced vascular smooth muscle cell (VSMC) calcification and the underlying mechanism. Oxidative stress induced by xanthine/xanthine oxidase increased apoptosis, as determined by Hoechst 33342 staining and annexin V/propidium iodide staining, and it enhanced osteoblastic differentiation and calcification of VSMCs, on the basis of alkaline phosphatase activity, the expression of Runx2 and type I collagen, and calcium deposition. These effects of oxidative stress were significantly inhibited by selenite. The following processes may explain the inhibitory effects of selenite: (1) selenite significantly suppressed oxidative stress, as evidenced by the decrease of the oxidative status of the cell and lipid peroxidation levels, as well as by the increase of the total protein thiol content and the activity of the antioxidant selenoenzyme glutathione peroxidase; (2) selenite significantly attenuated oxidative-stress-induced activation of the phosphatidylinositol 3-kinase/AKT and extracellular-signal-regulated kinase signaling pathways, resulting in decreased osteoblastic differentiation of VSMCs; (3) selenite significantly inhibited oxidative-stress-activated endoplasmic reticulum stress, thereby leading to decreased apoptosis. Our results suggest a potential role of selenium in the prevention of vascular calcification, which may provide more mechanistic insights into the relationship between selenium and cardiovascular diseases.

[Removal of heavy metals from extract of Angelica sinensis by EDTA-modified chitosan magnetic adsorbent].

The concentrations of heavy metals in the extracting solutions of traditional Chinese medicine are usually very low. Furthermore, a vast number of organic components contained in the extracting solutions would be able to coordinate with heavy metals, which might lead to great difficulty in high efficient removal of them from the extracting solutions. This paper was focused on the removal of heavy metals of low concentrations from the extracting solution of Angelica sinensis by applying an EDTA-modified chitosan magnetic adsorbent (EDTA-modified chitosan/SiO2/Fe3O4, abbreviated as EDCMS). The results showed that EDCMS exhibited high efficiency for the removal of heavy metals, such as Cu, Cd and Pb, e.g. the removal percentage of Cd and Pb reached 90% and 94.7%, respectively. Besides, some amounts of other heavy metals like Zn and Mn were also removed by EDCMS. In addition, the total solid contents, the amount of ferulic acid and the HPLC fingerprints of the extracting solution were not changed significantly during the heavy metal removal process. These results indicate that EDCMS may act as an applicable and efficient candidate for the removal of heavy metals from the extracting solution of A. sinensis.

Central nervous system complications in SARS-CoV-2-infected patients.

OBJECTIVE: To investigate the clinical manifestations, treatment and prognosis of COVID-19-associated central nervous system (CNS) complications. METHODS: In this single-centre observation study, we recruited patients with COVID-19-associated CNS complications at the neurology inpatient department of the Eighth Affiliated Hospital, Sun Yat-Sen University (Futian, Shenzhen) from Dec 2022 to Feb 2023. Patients were analysed for demographics, clinical manifestations, cerebrospinal fluid properties, electroencephalographic features, neuroimaging characteristics, and treatment outcome. All patients were followed-up at 1 and 2 months after discharge until Apr 2023. RESULTS: Of the 12 patients with COVID-19-associated CNS complications, the CNS symptoms occur between 0 days and 4 weeks after SARS-CoV-2 infection. The most common CNS symptoms were memory deficits (4/12, 33%), Unresponsiveness (4/12, 33%), mental and behavioural disorders (4/12, 33%). Seven of 12 cases can be categorized as probable SARS-CoV-2 encephalitis, and 5 cases can be described as brainstem encephalitis, acute disseminated encephalomyelitis, optic neuritis, multiple sclerosis or tremor probably associated with SARS-CoV-2 infection. Six patients received antiviral therapy, and 11 patients received glucocorticoid therapy, of which 3 patients received human immunoglobulin synchronously. Nine patients recovered well, two patients had residual neurological dysfunction, and one patient passed away from complications associated with tumor. CONCLUSION: In this observational study, we found that the inflammatory or immune-related complications were relatively common manifestations of COVID-19-associated CNS complications, including different phenotypes of encephalitis and CNS inflammatory demyelinating diseases. Most patients recovered well, but a few patients had significant neurological dysfunctions remaining.

Involvement of MsrB1 in the regulation of redox balance and inhibition of peroxynitrite-induced apoptosis in human lens epithelial cells.

Methionine sulfoxide reductases (Msrs) in lens cells are important for the maintenance of lens cell viability and resistance to oxidative stress damage. Peroxynitrite (ONOO(-)), as a strong oxidizing and nitrating agent, occurred in diabetic retinopathy patients and diabetic model animal. In an attempt to shed light on the roles of MsrB1, known as selenoprotein R, in protecting human lens epithelial (HLE) cells against peroxynitrite damage, and contribution of loss of its normal activity to cataract, the influences of MsrB1 gene silencing on peroxynitrite-induced apoptosis in HLE cells were studied. The results showed that both exogenous peroxynitrite and MsrB1 gene silencing by short interfering RNA (siRNA) independently resulted in oxidative stress, endoplasmic reticulum (ER) stress, activation of caspase-3 as well as an increase of apoptosis in HLE cells; moreover, when MsrB1-gene-silenced cells were exposed to 300 µM peroxynitrite, these indexes were further aggravated at the same conditions and DNA strand breaks occurred. The results demonstrate that in HLE cells MsrB1 may play important roles in regulating redox balance and mitigating ER stress as induced by oxidative stress under physiological conditions; MsrB1 may also protect HLE cells against peroxynitrite-induced apoptosis by inhibiting the activation of caspase-3 and oxidative damage of DNA under pathological conditions. Our results imply that loss of its normal activity is likely to contribute to cataract.

Exploration of the α-syn/T199678/miR-519-3p/KLF9 pathway in a PD-related α-syn pathology.

BACKGROUND: Kruppel-like factor 9 (KLF9) plays a key role as an inducer of cellular oxidative stress in the modulation of cell death and in oxidant-dependent tissue injury. Our previous study indicated that lncRNA-T199678 (T199678) affected the expression of KLF9 in an α-synuclein (α-syn) induced cellular model. However, the roles of interactions among α-syn, T199678, KLF9 and related microRNAs (miRNAs) in the Parkinson's disease (PD)-related α-syn pathology are unclear and were therefore investigated in this study. METHODS: An α-syn-injected mouse model and an α-syn exposed SY-SH5Y cellular model were used in this study. We confirmed the utility of these established models with morphological and behavioral methods. We checked how expression of T199678 and KLF9 were affected by α-syn and demonstrated their interaction by fluorescence in situ hybridization (FISH) staining and western blots. We analyzed expression in ROS+ cells by immunohistochemistry. Finally, we obtained seven miRNAs through bioinformatic analysis simultaneously affected by T199678 and α-syn and verified these with RT-PCR. RESULTS: We found that expression of KLF9 was regulated by T199678, whereas expression of T199678 was not affected by KLF9 in the α-syn exposed SY-SH5Y cells. These findings suggest that KLF9 is the downstream gene regulated by T199678, whereas miR-519-3p may play a contributing role. We also confirmed that α-syn injection upregulated the expression of ROS, which could be downregulated by upregulation of T199678, indicating an anti-oxidative role of T199678 in the α-syn-related mechanisms. CONCLUSIONS: Our results indicate the existence of a potential α-syn/T199678/miR-519-3p /KLF9 pathway in PD-related α-syn pathology. This pathway might explain oxidative stress processes in α-syn-related mechanisms, which requires further verification.

PCSK9 inhibitors for anti-inflammation in atherosclerosis: protocol for a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: Atherosclerosis is the leading cause of cardiovascular disease (CVD), which is one of the most common causes of morbidity and mortality worldwide. Lipid accumulation and inflammation play a crucial role in the pathogenesis of atherosclerosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an emerging lipid-lowering agent reported as a potential anti-inflammation effect in the prevention of CVD. However, the anti-inflammatory effect is still elusive. Therefore, a systematic review and meta-analysis is needed to analyse the anti-inflammatory effect of PCSK9 inhibitors on atherosclerosis in practice. METHODS AND ANALYSIS: This protocol was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. We will include double-blind, randomised controlled trials that reported changes in the levels of inflammatory markers, with an intervention arm of PCSK9 inhibitors and a treatment duration of more than 2 weeks. The following databases will be mainly searched from 1 January 2003 to the formal search date: PubMed, Embase, Web of Science and the Cochrane Central Register of Controlled Trials. The primary aim is to assess the effect of PCSK9 inhibitors on inflammatory markers, including circulating inflammatory markers such as C-reactive protein, high-sensitivity C-reactive protein, white cell counts, IL-1ß, IL-6 and TNF-α and local inflammatory markers such as the most diseased segment target-to-background ratio of the index vessel in adult patients with atherosclerosis. We will assess the quality of evidence, heterogeneity and report bias following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. ETHICS AND DISSEMINATION: Due to the systematic review being based on published studies, no ethics approval is required. The study results will be presented at international conferences and published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022297710.

Influence of SelS gene silence on beta-Mercaptoethanol-mediated endoplasmic reticulum stress and cell apoptosis in HepG2 cells.

Selenoprotein S (SelS), a transmembrane selenoprotein, may be related to the response of endoplasmic reticulum (ER) stress. In this report, the influence of selenite supplementation and SelS gene silence on beta-mercaptoethanol (beta-ME)-mediated ER stress and cell apoptosis in HepG2 cells were examined. The results showed that SelS protein expression was markedly increased by 10 mM beta-ME and 100 nM sodium selenite in HepG2 cells. GRP78 protein level was significantly increased after treatment with 10 mM beta-ME in HepG2 cells, which suggested that beta-ME was also an ER stress inducer. Meanwhile, beta-ME (10 mM) was found to induce cell apoptosis, which was alleviated obviously when cells were pretreated with 100 nM selenite before exposure to beta-ME. Moreover, the suppression of SelS gene by siRNA could aggravate HepG2 cell apoptosis induced by beta-ME significantly. In conclusion, these results suggested that beta-ME, also an ER stress agent, could induce cell apoptosis, and SelS may play an important role in protecting cells from apoptosis induced by ER stress in HepG2 cells.