Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells

Hepatitis B virus (HBV) X protein (HBx) is considered to play a role in the development of hepatocellular carcinoma (HCC) during HBV infection. HCC was shown to be more prevalent in men than in women. Estrogen, which exerts its biological function through estrogen receptor (ER), can inhibit HBV replication. ERΔ5, an ERα variant lacking exon 5, was found to be preferentially expressed in patients with HCC compared with patients with normal livers. Here, we report the biological role of ERΔ5 and a novel link between HBx and ERα signaling in hepatoma cells. ERΔ5 interacts with ERα in vitro and in vivo and functions as a dominant negative receptor. Both ERα and ERΔ5 associate with HBx. HBx decreases ERα-dependent transcriptional activity, and HBx and ERΔ5 have additive effect on suppression of ERα transactivation. The HBx deletion mutant that lacks the ERα-binding site abolishes the HBx repression of ERα. HBx, ERα and histone deacetylase 1 (HDAC1) form a ternary complex. Trichostatin A, a specific inhibitor of HDAC enzyme, can restore the transcriptional activity of ERα inhibited by HBx. Our data suggest that HBx and ERΔ5 may play a negative role in ERα signaling and that ERα agonists may be developed for HCC therapy

T cell-derived exosomes in tumor immune modulation and immunotherapy

Exosomes are nanoscale vesicles secreted by most cells and have a phospholipid bilayer structure. Exosomes contain DNA, small RNA, proteins, and other substances that can carry proteins and nucleic acids and participate in communication between cells. T cells are an indispensable part of adaptive immunity, and the functions of T cell-derived exosomes have been widely studied. In the more than three decades since the discovery of exosomes, several studies have revealed that T cell-derived exosomes play a novel role in cell-to-cell signaling, especially in the tumor immune response. In this review, we discuss the function of exosomes derived from different T cell subsets, explore applications in tumor immunotherapy, and consider the associated challenges

A combination of curcumin, vorinostat and silibinin reverses Aβ-induced nerve cell toxicity via activation of AKT-MDM2-p53 pathway

Alzheimer’s disease (AD) is a significant health issue for the elderly and becoming increasingly common as the global population ages. Although many efforts have been made to elucidate its pathology, there is still a lack of effective clinical anti-AD agents. Previous research has shown the neuroprotective properties of a combination of curcumin and vorinostat. In this study, nine other neuroprotective agents were investigated to examine whether a three-drug combination of curcumin, vorinostat, and a new drug is more advantageous than the previous two-drug combination in alleviating amyloid beta (Aβ)-induced nerve cell toxicity. Cell viability assay was performed to screen these agents, and further validation tests, including determination of cellular oxidative stress, apoptosis, and activity of the AKT/MDM2/p53 pathway, were performed. Among the nine candidate compounds, only silibinin at 1 µM reduced Aβ25–35-induced toxicity in PC12 cells. The neuroprotective effects of 1 µM silibinin in combination with 5 µM curcumin and 0.5 µM vorinostat (CVS) was shown in PC12 cells, in which it decreased apoptosis and oxidative stress marker levels that were increased by 20 µM Aβ25–35. Western blotting results showed that CVS pretreatment significantly increased the phosphorylation of AKT, BAD, and MDM2, which resulted in decreased intracellular expression of p53. Further, immunofluorescence results showed reduced p53 levels in the nuclei of PC12 cells following CVS pretreatment, indicating a reduction in the p53-mediated transcriptional activity associated with Aβ25–35 exposure. In conclusion, our findings suggested that pretreatment with CVS protected PC12 cells from Aβ25–35-induced toxicity through modulation of the AKT/MDM2/p53 pathway. Thus, CVS may present a new therapeutic option for treating AD

Young plasma reverses anesthesia and surgery-induced cognitive impairment in aged rats by modulating hippocampal synaptic plasticity

We investigated the protective effect of young plasma on anesthesia- and surgery-induced cognitive impairment and the potential underlying mechanism using bioinformatics, functional enrichment analysis, gene set enrichment analysis, Golgi-Cox staining, dendritic spine analysis, immunofluorescence assay, western blot analysis, and transmission electron microscopy. Furthermore, we performed behavioral assessments using the open field test, the novel object recognition test, and the Morris water maze test. We identified 1969 differentially expressed genes induced by young plasma treatment, including 800 upregulated genes and 1169 downregulated genes, highlighting several enriched biological processes (signal release from synapse, postsynaptic density and neuron to neuron synapse). Anesthesia- and surgery-induced cognitive impairment in aged rats was comparatively less severe following young plasma preinfusion. In addition, the decreased levels of synapse-related and tyrosine kinase B/extracellular signal-regulated protein kinase/cyclic adenosine monophosphate response element-binding protein (TrkB/ERK/CREB) signaling pathway-related proteins, dendritic and spine deficits, and ultrastructural changes were ameliorated in aged mice following young plasma preinfusion. Together, these findings suggest that young plasma reverses anesthesia- and surgery-induced cognitive impairment in aged rats and that the mechanism is associated with the activation of the TrkB/ERK/CREB signaling pathway and improvement in hippocampal synaptic plasticity

IL-17A deficiency alleviates cerebral ischemia-reperfusion injury via activating ERK/MAPK pathway in hippocampal CA1 region

Cognitive impairment is a major complication of cerebral ischemia–reperfusion (CIR) injury and has an important impact on the quality of life of patients. However, the precise mechanisms underlying cognitive impairment after CIR injury remain elusive. In the current study, we investigated the role of interleukin 17 A (IL-17A) on CIR injury-induced cognitive impairment in wild-type and IL-17A knockout mice using RNA sequencing analysis, neurological assessments, Golgi–Cox staining, dendritic spine analysis, immunofluorescence assay, and western blot analysis. RNA sequencing identified 195 CIR-induced differentially expressed genes (83 upregulated and 112 downregulated), highlighting several enriched biological processes (negative regulation of phosphorylation, transcription regulator complex, and receptor ligand activity) and signaling pathways (mitogen-activated protein kinase [MAPK], tumor necrosis factor, and IL-17 signaling pathways). We also injected adeno-associated virus into the bilateral hippocampal CA1 regions of CIR mice to upregulate or downregulate cyclic AMP response element-binding protein. IL-17A knockout activated the extracellular signal-regulated kinase (ERK)/MAPK signaling pathway and further improved synaptic plasticity, structure, and function in CIR mice. Together, our findings suggest that IL-17A deficiency alleviates CIR injury by activating the ERK/MAPK signaling pathway and enhancing hippocampal synaptic plasticity

Confinement amorphous cobalt-nickel oxide polyhedral yolk-shell structures for enhanced oxygen evolution performance

Multi-scale regulation strategies ranging from electronic behavior regulation to crystal structure modulation to micro-nano structure construction can effectively improve the properties of materials, thereby bringing about significant improvements in performance. In this paper, we successfully constructed (Co1-xNix)3O4 with Ni substitution (x) unique polyhedral yolk-shell structure (PYSSs) electrocatalysts with confined amorphous regions, and achieved a significant improvement in the performance of oxygen evolution reaction (OER). The substitution of Ni can regulate the electronic coupling between metal sites, thereby optimizing the electronic configuration, creating abundant vacancy defects and enhancing the Co 3d-O 2p covalency. Meantime, the creation of confined amorphous regions can further increase the number of oxygen vacancies and unsaturated metal sites. Especially, the construction of the unique PYSSs structure can increase the effective specific surface area, hold the reaction intermediates for deeper reaction, accelerate the infiltration and transport of the electrolyte, prevent the adhesion of bubbles and accelerate the gas diffusion

Confinement amorphous cobalt-nickel oxide polyhedral yolk-shell structures for enhanced oxygen evolution performance

Multi-scale regulation strategies ranging from electronic behavior regulation to crystal structure modulation to micro-nano structure construction can effectively improve the properties of materials, thereby bringing about significant improvements in performance. In this paper, we successfully constructed (Co1-xNix)3O4 with Ni substitution (x) unique polyhedral yolk-shell structure (PYSSs) electrocatalysts with confined amorphous regions, and achieved a significant improvement in the performance of oxygen evolution reaction (OER). The substitution of Ni can regulate the electronic coupling between metal sites, thereby optimizing the electronic configuration, creating abundant vacancy defects and enhancing the Co 3d-O 2p covalency. Meantime, the creation of confined amorphous regions can further increase the number of oxygen vacancies and unsaturated metal sites. Especially, the construction of the unique PYSSs structure can increase the effective specific surface area, hold the reaction intermediates for deeper reaction, accelerate the infiltration and transport of the electrolyte, prevent the adhesion of bubbles and accelerate the gas diffusion

Residual dynamics and dietary exposure risk of dimethoate and its metabolite in greenhouse celery

This study aimed to explore the residual dynamics and dietary risk of dimethoate and its metabolite omethoate in celery. Celery was sprayed with 40% dimethoate emulsifiable concentrate (EC) at either a low concentration of 600 g a.i./ha or a high concentration of 900 g a.i./ha. Plants in the seedling, transplanting, or middle growth stages were sprayed once, and the samples were collected 90 days after transplantation. Plants in the harvesting stage were sprayed two or three times. The samples were collected on days 3, 5, 7, 10, 14 and 21 after the last pesticide application. The dimethoate and omethoate compounds were extracted from the celery samples using acetonitrile, and their concentrations were detected using ultra-performance liquid chromatography-tandem mass spectrometry. Also, the dietary risk assessments of dimethoate and omethoate were conducted in various populations and on different foods in China. The metabolism led to the formation of omethoate from dimethoate in the celery. The degradation dynamics of dimethoate and total residues in greenhouse celery followed the first-order kinetic equation. The half-lives of the compounds were 2.42 days and 2.92 days, respectively. The celery which received one application during the harvesting stage had a final residue of dimethoate after 14 days, which was lower than the maximum residue limit (MRL) 0.5 mg kg−1 for Chinese celery. The final deposition of the metabolite omethoate after 28 days was less than the maximum residue limit of 0.02 mg kg−1 for Chinese celery. Furthermore, the risk quotients of dimethoate in celery were less than 1; therefore, the level of chronic risk was acceptable after day 21. Only children aged 2–7 years had an HQ of dimethoate more than 1 (an unacceptable level of acute risk), while the acute dietary risks to other populations were within acceptable levels. It was recommended that any dimethoate applications to celery in greenhouses should happen before the celery reached the harvesting stage, with a safety interval of 28 days

Sarm1/Myd88-5 Regulates Neuronal Intrinsic Immune Response to Traumatic Axonal Injuries

Summary: Traumatic injuries can trigger inflammatory reactions, leading to profound neuropathological consequences. However, the immune capacity of neurons, distinct from that of immune cells or glial cells, in response to traumatic insults remains to be fully characterized. In this study, we demonstrate that neurons can detect, cell autonomously, distant axonal damage, resulting in rapid production of a specific collection of cytokines and chemokines. This neuronal immune response appears spatially and temporally separated from injury-induced axon degeneration. We then identify through the genetic screen that this immune response is regulated by TIR-domain adaptor Sarm1/Myd88-5. We further show that Sarm1 functions through the downstream Jnk-c-Jun signal, and blockage of this Sarm1-Jnk-c-Jun pathway effectively abolishes the recruitment of immune cells to injury-afflicted neural tissues. We therefore uncover the key function of the Sarm1 signaling pathway, independent of its known role in axon degeneration, in the neuronal intrinsic immune response to traumatic axonal injuries. : Wang et al. report that neurons possess an intrinsic immune capacity in response to traumatic axonal injuries, which is spatially and temporally separated from injury-induced axon degeneration. This neuronal immune response is regulated by TIR-domain adaptor protein Sarm1/Myd88-5 and its downstream Jnk-c-Jun signal. Keywords: neuronal intrinsic immune response, traumatic injuries, neuroinflammation, Sarm

Inhibition of MicroRNA-383 Ameliorates Injury After Focal Cerebral Ischemia via Targeting PPARγ

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical role in protecting against distinct brain damages, including ischemia. Our previous data have shown that the protein level of PPARγ is increased in the cortex after middle cerebral artery occlusion (MCAO); PPARγ up-regulation contributes to PPARγ activation and is effective in reducing ischemic damage to brain. However, the regulatory mechanism of PPARγ after focal cerebral ischemia in rats is still unclear. In this study, we evaluated the effect of microRNA on PPARγ in rats subjected to MCAO. Methods: Focal cerebral ischemia was established by surgical middle cerebral artery occlusion; the protein level of PPARγ was detected by Western blotting; the level of microRNA-383 (miR-383) was quantified by real-time PCR; the neurological outcomes were defined by infarct volume and neurological deficits. Luciferase assay was used to identify the luciferase activities of PPARγ and miR-383. Results: We showed here that miR-383 level was down-regulated in the ischemic hemisphere of rats 24h after MCAO. Overexpression of miR-383 by miR-383 agomir increased infarct volume and aggravated neurological damage. Administration of miR-383 antagomir had the opposite effects. Furthermore, we found that PPARγ protein was down-regulated by miR-383 overexpression, and up-regulated by miR-383 inhibition both in rat model of MCAO and in primary culture cells. Finally, we found that miR-383 suppressed the luciferase activity of the vector carrying the 3'UTR of PPARγ, whereas mutation of the binding sites relived the repressive effect of miR-383. Conclusion: Our study demonstrated that miR-383 may play a key role in focal cerebral ischemia by regulating PPARγ expression at the post-transcriptional level, and miR-383 may be a potential therapeutic target for stroke