Protective prototype-Beta and Delta-Omicron chimeric RBD-dimer vaccines against SARS-CoV-2.

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.

Circular RNA vaccines against SARS-CoV-2 and emerging variants.

As the emerging variants of SARS-CoV-2 continue to drive the worldwide pandemic, there is a constant demand for vaccines that offer more effective and broad-spectrum protection. Here, we report a circular RNA (circRNA) vaccine that elicited potent neutralizing antibodies and T cell responses by expressing the trimeric RBD of the spike protein, providing robust protection against SARS-CoV-2 in both mice and rhesus macaques. Notably, the circRNA vaccine enabled higher and more durable antigen production than the 1mΨ-modified mRNA vaccine and elicited a higher proportion of neutralizing antibodies and distinct Th1-skewed immune responses. Importantly, we found that the circRNARBD-Omicron vaccine induced effective neutralizing antibodies against the Omicron but not the Delta variant. In contrast, the circRNARBD-Delta vaccine protected against both Delta and Omicron or functioned as a booster after two doses of either native- or Delta-specific vaccination, making it a favorable choice against the current variants of concern (VOCs) of SARS-CoV-2.

Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion.

Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown. To "benchmark" exhaustion in human Tregs, we used a method known to induce exhaustion in conventional T cells: expression of a tonic-signaling chimeric antigen receptor (TS-CAR). We found that TS-CAR-expressing Tregs rapidly acquired a phenotype that resembled exhaustion and had major changes in their transcriptome, metabolism, and epigenome. Similar to conventional T cells, TS-CAR Tregs upregulated expression of inhibitory receptors and transcription factors such as PD-1, TIM3, TOX and BLIMP1, and displayed a global increase in chromatin accessibility-enriched AP-1 family transcription factor binding sites. However, they also displayed Treg-specific changes such as high expression of 4-1BB, LAP, and GARP. DNA methylation analysis and comparison to a CD8+ T cell-based multipotency index showed that Tregs naturally exist in a relatively differentiated state, with further TS-CAR-induced changes. Functionally, TS-CAR Tregs remained stable and suppressive in vitro but were nonfunctional in vivo, as tested in a model of xenogeneic graft-versus-host disease. These data are the first comprehensive investigation of exhaustion in Tregs and reveal key similarities and differences with exhausted conventional T cells. The finding that human Tregs are susceptible to chronic stimulation-driven dysfunction has important implications for the design of CAR Treg adoptive immunotherapy strategies.

KAT8/SIRT7-mediated Fascin-K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Facilely tuning the intrinsic catalytic sites of the spinel oxide for peroxymonosulfate activation: From fundamental investigation to pilot-scale demonstration.

Heterogeneous peroxymonosulfate (PMS)-based advanced oxidation processes (AOPs) have shown a great potential for pollutant degradation, but their feasibility for large-scale water treatment application has not been demonstrated. Herein, we develop a facile coprecipitation method for the scalable production (∼10 kg) of the Cu-Fe-Mn spinel oxide (CuFeMnO). Such a catalyst has rich oxygen vacancies and symmetry-breaking sites, which endorse it with a superior PMS-catalytic capacity. We find that the working reactive species and their contributions are highly dependent on the properties of target organic pollutants. For the organics with electron-donating group (e.g., -OH), high-valent metal species are mainly responsible for the pollutant degradation, whereas for the organics with electron-withdrawing group (e.g., -COOH and -NO2), hydroxyl radical (•OH) as the secondary oxidant also plays an important role. We demonstrate that the CuFeMnO-PMS system is able to achieve efficient and stable removal of the pollutants in the secondary effluent from a municipal wastewater plant at both bench and pilot scales. Moreover, we explore the application prospect of this PMS-based AOP process for large-scale wastewater treatment. This work describes an opportunity to scalably prepare robust spinel oxide catalysts for water purification and is beneficial to the practical applications of the heterogeneous PMS-AOPs.

Charge Redistribution in Mechanochemical Reactions for Solid Interfaces.

Mechanochemical strategies are widely used in various fields, ranging from friction and wear to mechanosynthesis, yet how the mechanical stress activates the chemical reactions at the electronic level is still open. We used first-principles density functional theory to study the rule of the stress-modified electronic states in transmitting mechanical energy to trigger chemical responses for different mechanochemical systems. The electron density redistribution among initial, transition, and final configurations is defined to correlate the energy evolution during reactions. We found that stress-induced changes in electron density redistribution are linearly related to activation energy and reaction energy, indicating the transition from mechanical work to chemical reactivity. The correlation coefficient is defined as the term "interface reactivity coefficient" to evaluate the susceptibility of chemical reactivity to mechanical action for material interfaces. The study may shed light on the electronic mechanism of the mechanochemical reactions behind the fundamental model as well as the mechanochemical phenomena.

eIF3i promotes colorectal cancer cell survival via augmenting PHGDH translation.

Translational regulation is one of the decisive steps in gene expression, and its dysregulation is closely related to tumorigenesis. Eukaryotic translation initiation factor 3 subunit i (eIF3i) promotes tumor growth by selectively regulating gene translation, but the underlying mechanisms are largely unknown. Here, we show that eIF3i is significantly increased in colorectal cancer (CRC) and reinforces the proliferation of CRC cells. Using ribosome profiling and proteomics analysis, several genes regulated by eIF3i at the translation level were identified, including D-3-phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in the de novo serine synthesis pathway that participates in metabolic reprogramming of tumor cells. PHGDH knockdown significantly represses CRC cell proliferation and partially attenuates the excessive growth induced by eIF3i overexpression. Mechanistically, METTL3-mediated N6-methyladenosine modification on PHGDH mRNA promotes its binding with eIF3i, ultimately leading to a higher translational rate. In addition, knocking down eIF3i and PHGDH impedes tumor growth in vivo. Collectively, this study not only uncovered a novel regulatory mechanism for PHGDH translation but also demonstrated that eIF3i is a critical metabolic regulator in human cancer.

Small RNAs contribute to citrus Huanglongbing tolerance by manipulating methyl salicylate signaling and exogenous methyl salicylate primes citrus groves from emerging infection.

Citrus production is severely threatened by the devastating Huanglongbing (HLB) disease globally. By studying and analyzing the defensive behaviors of an HLB-tolerant citrus cultivar 'Shatangju', we discovered that citrus can sense Candidatus Liberibacter asiaticus (CLas) infection and induce immune responses against HLB, which can be further strengthened by both endogenously produced and exogenously applied methyl salicylate (MeSA). This immune circuit is turned on by an miR2977-SAMT (encoding a citrus Salicylate [SA] O-methyltransferase) cascade, by which CLas infection leads to more in planta MeSA production and aerial emission. We provided both transgenic and multi-year trail evidences that MeSA is an effective community immune signal. Ambient MeSA accumulation and foliage application can effectively induce defense gene expression and significantly boost citrus performance. We also found that miRNAs are battle fields between citrus and CLas, and about 30% of the differential gene expression upon CLas infection are regulated by miRNAs. Furthermore, CLas hijacks host key processes by manipulating key citrus miRNAs, and citrus employs miRNAs that coordinately regulate defense-related genes. Based on our results, we proposed that miRNAs and associated components are key targets for engineering or breeding resistant citrus varieties. We anticipate that MeSA-based management, either induced expression or external application, would be a promising tool for HLB control.

Cyclic guanosine monophosphate-adenosine monophosphate synthetase/stimulator of interferon genes signaling aggravated corneal allograft rejection through neutrophil extracellular traps.

The activation of innate immunity following transplantation has been identified as a crucial factor in allograft inflammation and rejection. However, the role of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling-mediated innate immunity in the pathogenesis of allograft rejection remains unclear. Utilizing a well-established murine model of corneal transplantation, we demonstrated increased expression of cGAS and STING in rejected-corneal allografts compared with syngeneic (Syn) and normal (Nor) corneas, along with significant activation of the cGAS/STING pathway, as evidenced by the enhanced phosphorylation of TANK-binding kinase 1and interferon regulatory factor 3. Pharmacological and genetic inhibition of cGAS/STING signaling markedly delayed corneal transplantation rejection, resulting in prolonged survival time and reduced inflammatory infiltration. Furthermore, we observed an increase in the formation of neutrophil extracellular traps (NETs) in rejected allografts, and the inhibition of NET formation through targeting peptidylarginine deiminase 4 and DNase I treatment significantly alleviated immune rejection and reduced cGAS/STING signaling activity. Conversely, subconjunctival injection of NETs accelerated corneal transplantation rejection and enhanced the activation of the cGAS/STING pathway. Collectively, these findings demonstrate that NETs contribute to the exacerbation of allograft rejection via cGAS/STING signaling, highlighting the targeting of the NETs/cGAS/STING signaling pathway as a potential strategy for prolonging allograft survival.

Application of Aptamer-SERS Nanotags for Unveiling the PD-L1 Immunomarker Progression Correlated to the Cell Metabolic Bioprocess.

In recent years, the expression and progression of programmed cell death ligand 1 (PD-L1) as an immunomarker in the context of a cell metabolic environment has gained significant attention in cancer research. However, intercellular bioprocesses that control the dynamics of PD-L1 have been largely unexplored. This study aimed to explore the cell metabolic states and conditions that govern dynamic variations of PD-L1 within the cell metabolic environment using an aptamer-based surface-enhanced Raman scattering (SERS) approach. The aptamer-SERS technique offers a sensitive, rapid, and powerful analytical tool for targeted and nondestructive detection of an immunomarker with high sensitivity and specificity. By combining aptamer-SERS with cell state profiling, we investigated the modulation in PD-L1 expression under different metabolic states, including glucose deprivation, metabolic coenzyme activity, and altered time/concentration-based cytokine availability. The most intriguing features in our findings include the cell-specific responses, cell differentiation by revealing distinct patterns, and dynamics of PD-L1 in different cell lines. Additionally, the time-dependent variations in PD-L1 expression, coupled with the dose-dependent relationship between glucose concentration and PD-L1 levels, underscore the complex interplay between immune checkpoint regulation and cellular metabolism. Therefore, this work demonstrates the advantages of using highly-sensitive and specific aptamer-SERS nanotags for investigating the immune checkpoint dynamics and related metabolic bioprocess.

Tuning the Surface Stability and Li/Na Storage of MXenes by Controlling the Surface Termination Coverage.

2D transition metal carbides and/or nitrides, MXenes, are a class of widely studied materials with great potential for energy storage applications. The control of surface chemistry is an effective approach for preparing novel MXenes and modifying their electrochemical properties. However, an in-depth and systematic atomic-scale study of the effect of surface termination on MXene stability and electrochemical performance is scarce and thus is highly desired. Here, through high-throughput first-principles calculations, 28 stable chalcogen-functionalized M2 CTz (M = V, Nb, and Ta, T = S, Se, and Te) under different chemical environments are identified. The reduction of termination coverage improves electrical conductivity but weakens in-plane stiffness. Intriguingly, based on charge transfer mechanism, the diffusion barrier of lithium/sodium atoms on the M2 CTz exhibits a volcano-like relationship with termination coverage, and the ion diffusion channel formed in half termination coverage greatly accelerates lithium ion diffusion and returns to or exceeds sodium ion diffusion rate at full termination coverage. V2 CSe2 /Nb2 CSz not only displays the large lithium/sodium capacity (592/409-466 mAhg-1 ) but also exhibits low barrier energy and open-circuit voltage, suggesting a promising candidate anode material for lithium/sodium-ion batteries. These findings provide insights into the design and fabrication of MXenes and tuning the electrochemical performance of MXenes by controlling termination coverage.

Intercalation of Metal into Transition Metal Dichalcogenides in Molten Salts.

Van der Waals (vdW)-layered materials have drawn tremendous interests due to their unique properties. Atom intercalation in the vdW gap of layered materials can tune their electronic structure and generate unexpected properties. Here a chemical-scissor-mediated method that enables metal intercalation into transition metal dichalcogenides (TMDCs) in molten salts is reported. By using this approach, various guest metal atoms (Mn, Fe, Co, Ni, Cu, and Ag) are intercalated into various TMDC hosts (such as TiS2 , NbS2 , TaS2 , TiSe2 , NbSe2 , TaSe2 , and Ti0.5 V0.5 S2 ). The structure of the intercalated compound and intercalation mechanism are investigated. The results indicate that the vdW gap and valence state of TMDCs can be modified through metal intercalation, and the intercalation behavior is dictated by the electron work function. The adjustable charge transfer and intercalation endow a channel for rapid mass transfer to enhance the electrochemical performances. Such a chemical-scissor-mediated intercalation provides an approach to tune the physical and chemical properties of TMDCs, which may open an avenue in functional application ranging from energy conversion to electronics.

Extraordinary Structural Reconstruction of Nanolaminated Ta2FeC MAX Phase for Enhanced Oxygen Evolution Performance.

Renewable energy technologies, such as water splitting, heavily depend on the oxygen evolution reaction (OER). Nanolaminated ternary compounds, referred to as MAX phases, show great promise for creating efficient electrocatalysts for OER. However, their limited intrinsic oxidative resistance hinders the utilization of conductivity in Mn+1Xn layers, leading to reduced activity. In this study, a method is proposed to improve the poor inoxidizability of MAX phases by carefully adjusting the elemental composition between Mn+1Xn layers and single-atom-thick A layers. The resulting Ta2FeC catalyst demonstrates superior performance compared to conventional Fe/C-based catalysts with a remarkable record-low overpotential of 247 mV (@10 mA cm-2) and sustained activity for over 240 h. Notably, during OER processing, the single-atom-thick Fe layer undergoes self-reconstruction and enrichment from the interior of the Ta2FeC MAX phase toward its surface, forming a Ta2FeC@Ta2C@FeOOH heterostructure. Through density functional theory (DFT) calculations, this study has found that the incorporation of Ta2FeC@Ta2C not only enhances the conductivity of FeOOH but also reduces the covalency of Fe─O bonds, thus alleviating the oxidation of Fe3+ and O2-. This implies that the Ta2FeC@Ta2C@FeOOH heterostructure experiences less lattice oxygen loss during the OER process compared to pure FeOOH, leading to significantly improved stability. These results highlight promising avenues for further exploration of MAX phases by strategically engineering M- and A-site engineering through multi-metal substitution, to develop M2AX@M2X@AOOH-based catalysts for oxygen evolution.

Plasma exosomes from patients with active thyroid-associated orbitopathy induce inflammation and fibrosis in orbital fibroblasts.

BACKGROUND: The pathogenesis of thyroid-associated orbitopathy (TAO) remains incompletely understand. The interaction between immunocytes and orbital fibroblasts (OFs) play a critical role in orbital inflammatory and fibrosis. Accumulating reports indicate that a significant portion of plasma exosomes (Pla-Exos) are derived from immune cells; however, their impact upon OFs function is unclear. METHODS: OFs were primary cultured from inactive TAO patients. Exosomes isolated from plasma samples of patients with active TAO and healthy controls (HCs) were utilized for functional and RNA cargo analysis. Functional analysis in thymocyte differentiation antigen-1+ (Thy-1+) OFs measured expression of inflammatory and fibrotic markers (mRNAs and proteins) and cell activity in response to Pla-Exos. RNA cargo analysis was performed by RNA sequencing and RT-qPCR. Thy-1+ OFs were transfected with miR-144-3p mimics/inhibitors to evaluate its regulation of inflammation, fibrosis, and proliferation. RESULTS: Pla-Exos derived from active TAO patients (Pla-ExosTAO-A) induced stronger production of inflammatory cytokines and hyaluronic acid (HA) in Thy-1+ OFs while inhibiting their proliferation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and single sample gene set enrichment analysis (ssGSEA) suggested that the difference in mRNA expression levels between Pla-ExosTAO-A and Pla-ExosHC was closely related to immune cells. Differential expression analysis revealed that 62 upregulated and 45 downregulated miRNAs in Pla-ExosTAO-A, with the elevation of miR-144-3p in both Pla-Exos and PBMCs in active TAO group. KEGG analysis revealed that the target genes of differentially expressed miRNA and miR-144-3p enriched in immune-related signaling pathways. Overexpression of the miR-144-3p mimic significantly upregulated the secretion of inflammatory cytokines and HA in Thy-1+ OFs while inhibiting their proliferation. CONCLUSION: Pla-Exos derived from patients with active TAO were immune-active, which may be a long-term stimulus casual for inflammatory and fibrotic progression of TAO. Our finding suggests that Pla-Exos could be used as biomarkers or treatment targets in TAO patients.

Metabolically healthy obesity, transition from metabolic healthy to unhealthy status, and carotid atherosclerosis.

BACKGROUND: Evidence of the effects of metabolically healthy obesity (MHO) on atherosclerosis is limited; the transition effects of metabolic health and obesity phenotypes have been ignored. We examined the association between metabolic health and the transition to atherosclerosis risk across body mass index (BMI) categories in a community population. METHODS: This cross-sectional study was based on a national representative survey that included 50,885 community participants aged ≥40 years. It was conducted from 01 December 2017 to 31 December 2020, in 13 urban and 13 rural regions across Hunan China. Metabolic health was defined as meeting less than three abnormalities in blood pressure, glucose, high-density lipoprotein cholesterol, triglycerides, or waist circumference. The participants were cross-classified at baseline based on their metabolic health and obesity. In addition, the relationship between atherosclerosis and transitions in metabolic health status based on 4733 participants from baseline to the second survey after 2 years was considered. The relationship between metabolic health status and the risk of transition to Carotid atherosclerosis (CA) was assessed using logistic regression and Cox proportional hazards regression analyses. RESULTS: In this study, the mean age of the participants was 60.7 years (standard deviation [SD], 10.91), 53.0% were female, and 51.2% had CA. As compared with metabolically healthy normal weight (MHN), those with MHO phenotype (odd ratio [OR] 1.10, 95% confidence interval [CI] 1.02-1.21), metabolically unhealthy normal weight (OR 1.27, 95% CI 1.19-1.35), metabolically unhealthy overweight (OR 1.41, 95% CI 1.33-1.48), and metabolically unhealthy obese (OR 1.54, 95% CI 1.44-1.64) had higher risk for CA. However, during the follow-up of 2 years, almost 33% of the participants transitioned to a metabolically unhealthy status. As compared with stable healthy normal weight, transition from metabolically healthy to unhealthy status (hazard ratios [HR] 1.21, 95% [CI] 1.02-1.43) and stable metabolically unhealthy overweight or obesity (MUOO) (HR 1.32, 95% CI 1.17-1.48) were associated with higher risk of CA. CONCLUSIONS: In the community population, obesity remains a risk factor for CA despite metabolic health. However, the risks were highest for metabolically unhealthy status across all BMI categories. A large proportion of metabolically healthy overweight or participants with obesity converts to an unhealthy phenotype over time, which is associated with an increased risk of CA.

Magnetic-Field-Induced Spin Regulation in Electrocatalytic Reactions.

The utilization of a magnetic field to manipulate spin states has emerged as a novel approach to enhance efficiency in electrocatalytic reactions, distinguishing from traditional strategies that focus on tuning activation energy barriers. Currently, this approach is specifically tailored to reactions where spin states change during the catalytic process, such as the oxidation of singlet H2O to triplet O2. In the magnetically enhanced oxygen evolution reaction (OER) procedure, the parallel spin alignment on the ferromagnetic catalyst was induced by the external magnetic field, facilitating the triplet O-O bonding, which is the rate limiting step in OER. This review centers on recent advancements in harnessing external magnetic fields to enhance OER performance, delving into mechanistic approaches for this magnetic promotion. Additionally, we provide a summary of magnetic field application in other electrocatalytic reactions, including oxygen reduction, methanol oxidation, and CO2 reduction.

Human umbilical cord mesenchymal stem cells-derived exosomal circDLGAP4 promotes angiogenesis after cerebral ischemia-reperfusion injury by regulating miR-320/KLF5 axis.

Accumulating evidence suggests that human umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSCs-Exos) are a promising therapeutic strategy for cerebral ischemia-reperfusion injury (CIRI). However, the underlying mechanism remains unclear. hUC-MSCs-Exos were identified by electron microscopy, NTA, and Western blotting. In the hypoxia/reoxygenation (H/R) cell model, human brain microvascular endothelial cells (HBMECs) were cocultured with hUC-MSCs-Exos. Then, cell viability, migration, apoptosis, and tube formation were measured by MTT, flow cytometry, transwell, and tube formation assays. RT-qPCR and Western blotting were used to detect the changes in RNA and protein. RNA pull-down and dual luciferase reporter assays confirmed the relationship between circDLGAP4, miR-320, and KLF5. Ischemia-reperfusion (I/R) rat model was established for in vivo experiments. hUC-MSCs-Exos increased the expression levels of circDLGAP4 and KLF5 but decreased miR-320 in H/R-treated HBMECs by transferring exosomal circDLGAP4. Knockdown of circDLGAP4 in hUC-MSCs-Exos reversed the promoting effects of hUC-MSCs-Exos on cell viability, migration, and tube formation in H/R-treated HBMECs in vitro and also abolished the protective effects of hUC-MSCs-Exos on cerebrovascular injury in I/R rats. Mechanistically, exosomal circDLGAP4 negatively regulated miR-320 in HBMECs, which directly bound to KLF5. In addition, the downregulation of miR-320 could reverse the regulatory effect of exosomal shcircDLGAL5 in H/R-treated HBMECs by upregulating KLF5. hUC-MSCs-Exos-derived circDLGAP4 reduced cerebrovascular injury by regulating miR-320/KLF5 signaling. These results provide a stem cell-based approach to treat CIRI.

Exosomal circBBS2 inhibits ferroptosis by targeting miR-494 to activate SLC7A11 signaling in ischemic stroke.

Umbilical cord-mesenchymal stem cells (UC-MSCs)-derived exosomes have been considered as an effective treatment for ischemic stroke. CircRNA BBS2 (circBBS2) was demonstrated to be down-regulated in patients with ischemic stroke. However, the role of UC-MSCs-derived exosomal circBBS2 in ischemic stroke and potential mechanisms remain unclear. Hypoxia/reperfusion (H/R)-exposed SH-SY5Y cells and middle cerebral artery occlusion (MCAO)-treated rats were served as in vitro and in vivo models of ischemic stroke. Target gene expression was detected by qRT-PCR. Cell viability was assessed by MTT assay. Ferroptosis was determined by iron, MDA, GSH, and lipid ROS levels. Protein levels were measured by Western blotting. The target relationships among circBBS2, miR-494, and SLC7A11 were validated by RNA-pull down, RIP, and dual-luciferase reporter assays. TTC and HE staining were performed to evaluate cerebral infarction volume and neuropathological changes. circBBS2 was lowly expressed and ferroptosis was triggered in MCAO rats and H/R-stimulated SH-SY5Y cells. UC-MSCs-derived exosomes enhanced cell viability and restrained ferroptosis via increasing circBBS2 expression in SH-SY5Y cells. Mechanistically, circBBS2 sponged miR-494 to enhance the SLC7A11 level. Knockdown of miR-494 or SLC7A11 reversed the effects of silencing circBBS2 or miR-494 on ferroptosis of SH-SY5Y cells, respectively. Furthermore, UC-MSCs-derived exosomes attenuated ischemic stroke in rats via delivering circBBS2 to inhibit ferroptosis. UC-MSCs-derived exosomal circBBS2 enhanced SLC7A11 expression via sponging miR-494, therefore repressing ferroptosis and relieving ischemic stroke. Our findings shed light on a novel mechanism for UC-MSCs-derived exosomes in the treatment of ischemic stroke.

Lithium Exposure and Risk of Major Neurocognitive Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Published studies on the association between lithium use and the decreased risk of major neurocognitive disorders (MNCDs) have shown disparities in their conclusions. We aimed to provide updated evidence of this association. METHODS: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Library from inception until August 31, 2023. All the observational studies evaluating the association between lithium use and MNCD risk were eligible for inclusion. Pooled odds ratios (ORs) and 95% prediction intervals were computed using random-effects models. RESULTS: Eight studies with 377,060 subjects were included in the analysis. In the general population on the association between lithium use versus nonuse and dementia, the OR was 0.94 (95% confidence interval [CI] = 0.77-1.24). Further analysis also demonstrated that lithium use was not associated with an increased risk of Alzheimer's disease (OR = 0.69, 95% CI: 0.31-1.65). When the analysis was restricted to individuals with bipolar disorder to reduce the confounding by clinical indication, lithium exposure was also not associated with a decreased risk of MNCD (OR = 0.9, 95% CI = 0.71-1.15). CONCLUSION: The results of this systematic review and meta-analysis do not support a significant association between lithium use and the risk of MNCD.

Auranofin inhibits the occurrence of colorectal cancer by promoting mTOR-dependent autophagy and inhibiting epithelial-mesenchymal transformation.

Colorectal cancer (CRC) is one of the world's most common and deadly cancers. According to GLOBOCAN2020's global incidence rate and mortality estimates, CRC is the third main cause of cancer and the second leading cause of cancer-related deaths worldwide. The US Food and Drug Administration has approved auranofin for the treatment of rheumatoid arthritis. It is a gold-containing chemical that inhibits thioredoxin reductase. Auranofin has a number of biological activities, including anticancer activity, although it has not been researched extensively in CRC, and the mechanism of action on CRC cells is still unknown. The goal of this research was to see how Auranofin affected CRC cells in vivo and in vitro . The two chemical libraries were tested for drugs that make CRC cells more responsive. The CCK-8 technique was used to determine the cell survival rate. The invasion, migration, and proliferation of cells were assessed using a transwell test and a colony cloning experiment. An electron microscope was used to observe autophagosome formation. Western blotting was also used to determine the degree of expression of related proteins in cells. Auranofin's tumor-suppressing properties were further tested in a xenograft tumor model of human SW620 CRC cells. Auranofin dramatically reduced the occurrence of CRC by decreasing the proliferation, migration, and invasion of CRC cells, according to our findings. Through a mTOR-dependent mechanism, auranofin inhibits the epithelial-mesenchymal transition (EMT) and induces autophagy in CRC cells. Finally, in-vivo tests revealed that auranofin suppressed tumor growth in xenograft mice while causing no harm. In summary, auranofin suppresses CRC cell growth, invasion, and migration. Auranofin inhibits the occurrence and progression of CRC by decreasing EMT and inducing autophagy in CRC cells via a mTOR-dependent mechanism. These findings suggest that auranofin could be a potential chemotherapeutic medication for the treatment of human CRC.