Curcumin, a polyphenolic compound extracted from
Curcuma longa
, has drawn attention for its effective bioactivities against ischemia-induced injury. This study aimed to evaluate the neuroprotective ...effect of curcumin and investigate the underlying mechanism that mediates autophagy and inflammation in an animal model of middle cerebral artery occlusion (MCAO) in rats. Curcumin was delivered to Sprague Dawley male rats at a dose of 200 mg/kg curcumin by intraperitoneal injection 30 min after ischemia-reperfusion (I/R). LY294002, a specific inhibitor of the PI3K/Akt/mTOR pathway, as well as anisomycin, an activator of TLR4/p38/MAPK, was administered by ventricle injection 30 min before MCAO. The same volume of saline was given as a control. Brain infarction and neurological function were determined 24 h post-MCAO. Immunoblotting and immunofluorescence were used to detect alterations in autophagy-relevant proteins Akt, p-Akt, mTOR, p-mTOR, LC3-II, and LC3-I, and inflammation-related proteins TLR4, p-38, p-p38, and IL-1 in the ipsilateral hemisphere. Cerebral I/R injury resulted in significant alterations of LC3-II/LC3-I, IL-1, TLR4, and p-p38. Curcumin in MCAO rats significantly improved brain damage and neurological function by upregulating p-Akt and p-mTOR and downregulating LC3-II/LC3-I, IL-1, TLR4, p-38, and p-p38. However, these protective effects against ischemia could be suppressed when LY294002 or anisomycin was included. Curcumin exerts neuroprotective effects by attenuating autophagic activities through mediating the PI3K/Akt/mTOR pathway, while also suppressing an inflammatory reaction by regulating the TLR4/p38/MAPK pathway. Furthermore, this study indicates that curcumin could be an effective therapy for patients afflicted with ischemia.
•We fabricate a humidity sensor with laser-scribed graphene electrode and graphite oxide sensing layer.•The fabrication process is done by a low power (5 mW) DVD drive.•The LSG-GO humidity sensor ...operates in the relative humidity (RH) range of 19 %–97.4 %.•The LSG based humidity sensor demonstrates high sensitivity (4770.14 pF/% RH).•Excellent sensing stability for more than 30 days has been demonstrated.
Monitoring the environmental humidity are of great significance to human comfort and product quality in many fields. However, high performance humidity sensors are difficult to be widely used because of their cost and complex preparation process. It is also highly desirable to develop a facile fabrication method that is capable of producing humidity sensors of customized size, shape, and geometry. Here, using a low power DVD drive, we successfully fabricate a highly sensitivity and low-cost humidity sensor, consisting of laser-scribed graphene (LSG) electrode and graphite oxide (GO) sensing layer. The LSG-GO humidity sensor operates in the relative humidity (RH) range of 19 %–97.4 %, demonstrating high sensitivity (4770.14 pF/% RH), quick response/recovery, and excellent sensing stability. In addition, the possible humidity sensing mechanism is discussed with the help of impedance spectroscopy. These results indicate that the LSG/GO sensor, enabled by the facile fabrication process with low power DVD drives, demonstrates promising potential with broad application prospects.
We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China.
We collected data on a total of 25,927 confirmed DILI ...cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method.
Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval CI 50.76–52.03), followed by mixed injury (28.30%; 95% CI 27.73–28.87) and cholestatic injury (20.31%; 95% CI 19.80–20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy’s Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86–26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher.
In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.
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Diabetic retinopathy (DR) is a complication of diabetes mellitus (DM) and is the leading cause of vision loss globally. However, the pathogenic mechanism and clinical therapy still needs further ...improvement. The biologic significance of myocardial infarction associated transcript (MIAT) in DR remains unknown. Here, we aim to explore the mechanism between MIAT and DR, which is essential for RD. Streptozotocin (STZ) was used to induce DM mice and high glucose was used to stimulate cells. ChIP was used to detect the binding activity between nuclear factor κB (NF-κB) and the promoter of the MIAT gene, luciferase activity assay was used to detect the target-specific selectivity between
and MIAT. The expressions of MIAT and p-p65 were increased in STZ-induced DM mice and high glucose stimulated rat retinal Müller cells (rMC-1) cells. ChIP results revealed that high glucose promoted the binding activity between NF-κB and MIAT, while Bay11-7082 acted as an inhibitor for NF-κB that suppressed the binding activity.
controled MIAT to regulate its expression and MIAT overexpression suppressed
, but promoted Sp1. High glucose stimulation increased the cell apoptosis and decreased the cell activity, while MIAT suppression reversed the effect induced by high glucose, however,
knockdown reversed the effects induced by MIAT suppression. Our results provided evidence that the mechanism of cell apoptosis in DR might be associated with the regulation of MIAT, however,
acted as a biomarker that was regulated by MIAT and further regulated cell apoptosis in DR.
Recent studies have provided strong evidence that lncRNAs play a functional regulatory role in diabetic retinopathy (DR). The purpose of this study was to investigate the effect of long non-coding ...RNA (lncRNA) X-inactive specific transcript (XIST) in DR.
A DR mouse model was established by intraperitoneal injection of streptozotocin (STZ), and then the mouse retinal Müller cells (mMCs) were isolated from retina tissues of mice. Human retinal Müller cell line (HMCs) and mMCs and were treated with high glucose (HG) to simulate an in vitro DR model. XIST expression was detected by qRT-PCR. Next, XIST overexpression was performed in mMCs and HMCs to examine its effect on the activation of Müller cells and production of pro-inflammatory cytokines. Subsequently, the interaction between XIST and SIRT1 was verified, and the ubiquitination level of SIRT1 as well as the stability of SIRT1 protein were assessed.
XIST was down-regulated in retinal tissues of DR mice and HG-induced HMCs. Overexpression of XIST inhibited HG-induced activation of mMCs and HMCs, and reduced the production of pro-inflammatory cytokines. XIST promoted SIRT1 expression via interacting with SIRT1 and inhibiting the ubiquitination of SIRT1. Furthermore, SIRT1 silencing partly abrogated the effect of XIST overexpression on the activation of mMCs and HMCs as well as the production of pro-inflammatory cytokines induced by HG.
We concluded that XIST restrained the activation of Müller cells and the production of pro-inflammatory cytokines via stabilizing SIRT1.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cerebral venous sinus thrombosis (CVST) is a rare type of stroke, which is life-threatening in severe cases. However, considerably less attention has been concentrated on the mechanism of neural cell ...damage after CVST. This study aims to investigate the role of endoplasmic reticulum stress, oxidative stress, and pyroptosis in a well-established rodent model of CVST. Rat brains were harvested at 0 h, 6 h, days 1, days 3, days 7, and days 14 post-CVST for measurement of corresponding indexes. Endoplasmic reticulum stress sensors (including protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme-1α (IRE1α)), oxidative stress markers (thioredoxin-interacting protein (TXNIP) and peroxynitrite), NLRP3, caspase p20, IL-1β, and gasdermin D (GSDMD, an indicator of pyroptosis) were separately evaluated by Western-blot and Immunohistochemistry/Immunofluorescence. Co-immunoprecipitation and Fluorescent double-labeling were employed to probe into the relationship between TXNIP/peroxynitrite and NLRP3 inflammasome. In the damaged cortex region, profuse p-PERK, p-IRE1α, TXNIP were produced and predominantly localized in neurons accompanied by a small amount expressed in microglia and astrocytes. The levels of 3-nitrotyrosine (3-NT, as a footprint of peroxynitrite), NLRP3, caspase p20, IL-1β, and GSDMD were distinctly elevated post-CVST and cellular localization of peroxynitrite, NLRP3, caspase p20, and IL-1β was largely observed in neurons and/or microglia. Importantly, sites of enhanced TXNIP and 3-NT immunoreactivity were colocalized with increased NLRP3 staining, indicating the involvement of TXNIP and peroxynitrite in NLRP3 inflammasome activation and subsequent pyroptosis. Besides, co-immunoprecipitation also hinted that there might be an interaction or causality between TXNIP/peroxynitrite and NLRP3 inflammasome. We concluded that endoplasmic reticulum stress and oxidative stress may jointly lead to neuronal NLRP3 inflammasome activation and pyroptosis after CVST.
The schematic diagram demonstrating that endoplasmic reticulum stress and oxidative stress may jointly lead to neuronal NLRP3 inflammasome activation and pyroptosis after CVST. CVST cerebral venous sinus thrombosis, ER stress endoplasmic reticulum stress, IRE1α inositol-requiring enzyme-1α, PERK protein kinase RNA-like ER kinase, TXNIP thioredoxin-interacting protein, NLRP3 nucleotide-binding oligomerization domain-like (NOD-like) receptor family pyrin domain-containing 3, IL-1β interleukin-1β, GSDMD gasdermin D. Display omitted
•Endoplasmic reticulum stress relates to the neuronal injury after CVST.•Oxidative stress involves in the neuronal damage post-CVST.•TXNIP and peroxynitrite may jointly contribute to the activation of NLRP3 inflammasome after CVST.•Pyroptosis may be a novel mechanism mediating the neuronal damage post-CVST.
Synovitis, characterized by inflammation of the synovial membrane, is commonly induced by meniscus tears. However, significant differences in inflammatory responses and the key inflammatory mediators ...of synovium induced by different types of meniscal tears remain unclear.
Magnetic resonance imaging (MRI) was employed to identify the type of meniscus tear, and the quantification of synovial inflammation was assessed through H&E staining assay. Transcription and expression levels of IL-1β and IL-6 were evaluated using bioinformatics, ELISA, RT-qPCR, and IHC of CD68 staining assays. The therapeutic potential of Docosapentaenoic Acid (DPA) was determined through network pharmacology, ELISA, and RT-qPCR assays. The safety of DPA was assessed using colony formation and EdU staining assays.
The results indicate that both IL-1β and IL-6 play pivotal roles in synovitis pathogenesis, with distinct expression levels across various subtypes. Among tested meniscus tears, oblique tear and bucket handle tear induced the most severe inflammation, followed by radial tear and longitudinal tear, while horizontal tear resulted in the least inflammation. Furthermore, in synovial inflammation induced by specific meniscus tears, the anterior medial tissues exhibited significantly higher local inflammation than the anterior lateral and suprapatellar regions, highlighting the clinical relevance and practical guidance of anterior medial tissues' inflammatory levels. Additionally, we identified the essential omega-3 fatty acid DPA as a potential therapeutic agent for synovitis, demonstrating efficacy in blocking the transcription and expression of IL-1β and IL-6 with minimal side effects.
These findings provide valuable insights into the nuanced nature of synovial inflammation induced by various meniscal tear classifications and contribute to the development of new adjunctive therapeutic agents in the management of synovitis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Treatment with pegylated interferon (peg-IFN) alfa-2a (40KD) results in hepatitis B "e" antigen (HBeAg) seroconversion 6 months after treatment in up to 36% of HBeAg-positive chronic ...hepatitis B patients. This study explored the efficacy of a novel combination of peg-IFN alfa-2a and entecavir (ETV), a potent nucleoside analogue. Methods. In total, 218 treatment-naive Chinese HBeAg-positive patients were randomized to peg-IFN alfa-2a (180 μg/week) for 48 weeks, either as monotherapy (n = 72), or with 24 weeks of ETV (0.5 mg/daily) added at week 13 (ETV add-on, n = 73), or pretreatment with a 24-week course of ETV, starting peg-IFN alfa-2a at week 21 (ETV pretreatment, n = 73). The primary endpoint was reduction in quantitative HBeAg from baseline to 24 weeks posttreatment. Results. Significant reductions in HBeAg from baseline were achieved in all treatment groups 24 weeks posttreatment; reductions were comparable across treatment arms (shown as log10 Paul Ehrlich international units PEIU/mL): monotherapy: −1.4 (SD, 1.8); ETV add-on: −1.6 (SD, 1.8); ETV pretreatment: −1.3 (SD, 1.7). Rates of HBeAg seroconversion were similar across treatment groups posttreatment (monotherapy: 22 31%; ETV add-on: 18 25%; ETV pretreatment: 19 26%). Significantly greater reductions of hepatitis B virus DNA were achieved with ETV add-on while on treatment, but were not sustained posttreatment. Safety profiles were comparable between treatment groups; adverse events were experienced by 62 (86%) monotherapy, 65 (89%) ETV add-on, and 58 (81%) ETV pretreatment patients. Conclusions. Neither ETV add-on nor ETV pretreatment demonstrated superiority compared with 48 weeks of peg-IFN alfa-2a monotherapy. The optimal treatment strategy using nucleos(t)ide analogues and peg-IFN alfa-2a remains to be determined.
Due to the increasing development of highway reconstruction and expansion projects in China, many large-span highway tunnels are being constructed near existing highway tunnels. Tunneling underneath ...will inevitably cause variation in the surrounding rock displacement and may even lead to collapse. In this study, based on an analysis of extensive field monitoring data from the Gucheng tunnel, the variation law for the surrounding rock full-displacement and the influence of the tunnel-face spatial effect in a large-span mudstone tunnel are analyzed. The change in the full displacement experienced the following sequence: slow pre-displacement growth → rapid increase → slow increase → gradual stability. The displacement released by the excavation of the tunnel construction accounts for 40~60% of the total displacement, and the closer to the excavation contour, the more obvious the displacement release. The final convergence value of vertical displacement is obtained by hyperbolic function regression prediction analysis. Based on this value, Lee and Hoek equations are used for parameter analysis and field-data fitting. It is concluded that the larger the proportion of the early displacement of the surrounding rock before construction to the total displacement, the smaller the influence of the tunnel-face spatial effect on the surrounding rock. The numerical simulation results are compared with actual monitoring results, and good agreement is observed. The larger the burial depth of the tunnel, the smaller the influence range in the tunnel-face spatial effect, and the more concentrated the displacement release. The variation law and the influential range for the surrounding rock full-displacement described in this paper can provide a reference for predicting and controlling the deformation during the construction of future large-span mudstone tunnels.
Cerebral cavernous malformations (CCMs) are vascular abnormalities associated with deregulated angiogenesis. Their pathogenesis and optimal treatment remain unclear. This study aims to investigate ...the molecular signatures of cuproptosis, a newly identified type of cell death, associated with CCMs development. Bulk RNA sequencing (RNA-seq) from 15 CCM and 6 control samples were performed with consensus clustering and clustered to two subtypes based on expression levels of cuproptosis-related genes (CRGs). Differentially expressed genes and immune infiltration between subtypes were then identified. Machine learning algorithms including the least absolute shrinkage and selection operator and random forest were employed to screen for hub genes for CCMs associated with cuproptosis. Furthermore, Pathway enrichment and correlation analysis were used to explore the functions of hub genes and their association with immune phenotypes in CCMs. An external dataset was then employed for validation. Finally, employing the Cellchat algorithm on a single-cell RNA-seq dataset, we explored potential mechanisms underlying the participation of these hub genes in cell-cell communication in CCMs. Our study revealed two distinct CCM subtypes with differential pattern of CRG expression and immune infiltration. Three hub genes (BTBD10, PFDN4, and CEMIP) were identified and validated, which may significantly associate with CCM pathogenesis. These genes were found to be significantly upregulated in CCM endothelial cells (ECs) and were validated through immunofluorescence and western blot analysis. Single-cell RNA-seq analysis revealed the cellular co-expression patterns of these hub genes, particularly highlighting the high expression of BTBD10 and PFDN4 in ECs. Additionally, a significant co-localization was also observed between BTBD10 and the pivotal cuproptosis gene FDX1 in Mki67+ tip cells, indicating the crucial role of cuproptosis for angiogenesis in CCMs. The study also explored the cell-cell communication between subcluster of ECs expressing these hub genes and immune cells, particularly M2 macrophages, suggesting a role for these interactions in CCM pathogenesis. This study identifies molecular signatures linking cuproptosis to CCMs pathogenesis. Three hub genes--PFDN4, CEMIP, and BTBD10--may influence disease progression by modulating immunity. Further research is needed to understand their precise disease mechanisms and evaluate their potential as biomarkers or therapeutic targets for CCMs.
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