CircOGDH Is a Penumbra Biomarker and Therapeutic Target in Acute Ischemic Stroke.

BACKGROUND: Acute ischemic stroke (AIS) is a leading cause of disability and mortality worldwide. Prediction of penumbra existence after AIS is crucial for making decision on reperfusion therapy. Yet a fast, inexpensive, simple, and noninvasive predictive biomarker for the poststroke penumbra with clinical translational potential is still lacking. We aim to investigate whether the CircOGDH (circular RNA derived from oxoglutarate dehydrogenase) is a potential biomarker for penumbra in patients with AIS and its role in ischemic neuronal damage. METHODS: CircOGDH was screened from penumbra of middle cerebral artery occlusion mice and was assessed in plasma of patients with AIS by quantitative polymerase chain reaction. Magnetic resonance imaging was used to examine the penumbra volumes. CircOGDH interacted with miR-5112 (microRNA-5112) in primary cortical neurons was detected by fluorescence in situ hybridization, RNA immunoprecipitation, and luciferase reporter assay. Adenovirus-mediated CircOGDH knockdown ameliorated neuronal apoptosis induced by COL4A4 (Gallus collagen, type IV, alpha IV) overexpression. Transmission electron microscope, nanoparticle tracking analysis, and Western blot were performed to confirm exosomes. RESULTS: CircOGDH expression was dramatically and selectively upregulated in the penumbra tissue of middle cerebral artery occlusion mice and in the plasma of 45 patients with AIS showing a 54-fold enhancement versus noncerebrovascular disease controls. Partial regression analysis revealed that CircOGDH expression was positively correlated with the size of penumbra in patients with AIS. Sequestering of miR-5112 by CircOGDH enhanced COL4A4 expression to elevate neuron damage. Additionally, knockdown of CircOGDH significantly enhanced neuronal cell viability under ischemic conditions. Furthermore, the expression of CircOGDH in brain tissue was closely related to that in the serum of middle cerebral artery occlusion mice. Finally, we found that CircOGDH was highly expressed in plasma exosomes of patients with AIS compared with those in noncerebrovascular disease individuals. CONCLUSIONS: These results demonstrate that CircOGDH is a potential therapeutic target for regulating ischemia neuronal viability, and is enriched in neuron-derived exosomes in the peripheral blood, exhibiting a predictive biomarker of penumbra in patients with AIS.

Comparison of Outcomes between Stent Retriever Combined with Contact Aspiration and Contact Aspiration Alone in Patients without Hyperdense Artery Sign/Susceptibility Vessel Sign.

PURPOSE: To examine the relationship between hyperdense artery sign (HAS)/susceptibility vessel sign (SVS) and thrombus composition and evaluate the effect of HAS/SVS status on the association between first-line thrombectomy techniques and outcomes in patients with acute anterior circulation large vessel occlusion (LVO). MATERIALS AND METHODS: From January 2018 to June 2021, 103 consecutive patients with acute anterior circulation LVO (75 [63.1%] men; median age, 66 years) who underwent thrombectomy and for whom the removed clot was available for histological analyses were retrospectively reviewed. The presence of HAS and SVS was assessed on unenhanced computed tomography (CT) and susceptibility-weighted imaging, respectively. Association of first-line thrombectomy techniques (stent retriever [SR] combined with contact aspiration [CA] vs CA alone) with outcomes was assessed according to HAS/SVS status. RESULTS: Among the included patients, 55 (53.4%) were HAS/SVS-negative, and 69 (67.0%) underwent first-line SR + CA. Higher relative densities of fibrin/platelets (0.56 vs 0.51; P < .001) and lower relative densities of erythrocytes (0.32 vs 0.42; P < .001) were observed in HAS/SVS-negative patients compared with HAS/SVS-positive patients. First-line SR + CA was associated with reduced odds of distal embolization (adjusted odds ratio, 0.18; 95% CI, 0.04-0.83; P = .027) and a more favorable 90-day functional outcome (adjusted odds ratio, 5.29; 95% CI, 1.06-26.34; P = .042) in HAS/SVS-negative patients and a longer recanalization time (53 vs 25 minutes; P = .025) and higher risk of subarachnoid hemorrhage (24.2% vs 0%; P = .044) in HAS/SVS-positive patients. CONCLUSIONS: Absence of HAS/SVS may indicate a higher density of fibrin/platelets in the thrombus, and first-line SR + CA yielded superior functional outcomes than CA alone in patients with acute LVO without HAS/SVS.

Metal-Organic Frameworks Possessing Suitable Pores for Xe/Kr Separation.

Adsorption separation of the Xe/Kr mixture remains a tough issue since Xe and Kr have an inert nature and similar sizes. Here we present a chlorinated metal-organic framework (MOF) [JXNU-19(Cl)] and its nonchlorinated analogue (JXNU-19) for Xe/Kr separation. The two isostructural MOFs constructed from the heptanuclear cobalt-hydroxyl clusters bridged by organic ligands are three-dimensional structures. Detailed contrast of the Xe/Kr adsorption separation properties of the MOF shows that significantly enhanced Xe uptakes and Xe/Kr adsorption selectivity (17.1) are observed for JXNU-19 as compared to JXNU-19(Cl). The main binding sites for Xe in the MOF revealed by computational simulations are far away from the chlorine sites, suggesting that the introduction of the chlorine groups results in the unfavorable Xe adsorption for JXNU-19(Cl). The optimal pores, high surface area, and multiple strong Xe-framework interactions facilitate the effective Xe/Kr separation for JXNU-19.

Introducing molecular imprinting onto nanozymes: toward selective catalytic analysis.

The discovery of enzyme-like catalytic characteristics in nanomaterials triggers the generation of nanozymes and their multifarious applications. As a class of artificial mimetic enzymes, nanozymes are widely recognized to have better stability and lower cost than natural bio-enzymes, but the lack of catalytic specificity hinders their wider use. To solve the problem, several potential strategies are explored, among which molecular imprinting attracts much attention because of its powerful capacity for creating specific binding cavities as biomimetic receptors. Attractively, introducing molecularly imprinted polymers (MIPs) onto nanozyme surfaces can make an impact on the latter's catalytic activity. As a result, in recent years, MIPs featuring universal fabrication, low cost, and good stability have been intensively integrated with nanozymes for biochemical detection. In this critical review, we first summarize the general fabrication of nanozyme@MIPs, followed by clarifying the potential effects of molecular imprinting on the catalytic performance of nanozymes in terms of selectivity and activity. Typical examples are emphatically discussed to highlight the latest progress of nanozyme@MIPs applied in catalytic analysis. In the end, personal viewpoints on the future directions of nanozyme@MIPs are presented, to provide a reference for studying the interactions between MIPs and nanozymes and attract more efforts to advance this promising area.

Balloon angioplasty as first-choice recanalization strategy for intracranial atherosclerosis-related emergent large vessel occlusion with small clot burden.

PURPOSE: The optimal primary recanalization strategy for intracranial atherosclerosis-related emergent large vessel occlusion (ICAS-ELVO) remains controversial. We aimed to explore the safety and efficacy of balloon angioplasty as the first-choice recanalization strategy for ICAS-ELVO with small clot burden. METHODS: Consecutive ICAS-ELVO patients presenting with microcatheter "first-pass effect" during endovascular treatment (EVT) were retrospectively analyzed. Patients were divided into preferred balloon angioplasty (PBA) and preferred mechanical thrombectomy (PMT) groups based on the first-choice recanalization strategy. The reperfusion and clinical outcomes between the two groups were compared. RESULTS: Seventy-six patients with ICAS-ELVO involving the microcatheter "first-pass effect" during EVT were enrolled. Compared with patients in the PMT group, those in the PBA group were associated with (i) a higher rate of first-pass recanalization (54.0% vs. 28.9%, p = .010) and complete reperfusion (expanded thrombolysis in cerebral ischemia ≥ 2c; 76.0% vs. 53.8%, p = .049), (ii) shorter puncture-to-recanalization time (49.5 min vs. 89.0 min, p < .001), (iii) lower operation costs (¥48,499.5 vs. ¥ 99,086.0, p < .001), and (iv) better 90-day functional outcomes (modified Rankin scale:0-1; 44.0% vs. 19.2%, p = .032). Logistic regression analysis revealed that balloon angioplasty as the first-choice recanalization strategy was an independent predictor of 90-day excellent functional outcomes for ICAS-ELVO patients with microcatheter "first-pass effect" (adjusted odds ratio = 6.01, 95% confidence interval: 1.15-31.51, p = .034). CONCLUSION: Direct balloon angioplasty potentially improves 90-day functional outcomes for ICAS-ELVO patients with small clot burden, and may be a more appropriate first-choice recanalization strategy than mechanical thrombectomy for these patients.

Integrated analysis of differently expressed microRNAs and mRNAs at different postnatal stages reveals intramuscular fat deposition regulation in goats (Capra hircus).

Intramuscular fat refers to the adipose tissue distributed in the muscle. It is an important indicator that affects the quality of goat meat, and can directly affect the tenderness and flavor of goat meat. Our previous study revealed the mRNA that may be crucial for intramuscular fat deposition during goat growth; however, how the microRNAs (miRNAs) are involved in the process is largely unclear. In the present study, a total of 401 known miRNAs and 120 goat novel miRNAs, including 110 differentially expressed (DE) miRNAs, were identified among longissimus dorsi from three growth stages (2, 9, and 24 months) by miRNA sequencing. Combining analysis of the DE mRNAs and DE miRNAs was then performed by miRDB and miRwalk, and miR-145-5p and FOXO1, miR-487b-3p, and PPARG coactivator 1 α (PPARGC1A), miR-345-3p, and solute carrier family 2 member 4 (SLC2A4), etc. were shown to closely associate with lipid metabolism, which was then validated by a correlation analysis. The final DE mRNAs were significantly enriched in fatty acid transmembrane transport, fatty acid homeostasis, apelin signaling pathway, glucagon signaling pathway, insulin signaling pathway, and AMPK signaling pathway by gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Besides, miR-145-5p showed a certain effect on goat intramuscular fat metabolism by acting on the possible target gene Forkhead Box O1 (FOXO1). These data provide some theoretical support for improving the quality of goat meat.

mtDNA amplifies beryllium sulfate-induced inflammatory responses via the cGAS-STING pathway in 16HBE cells.

Beryllium sulfate (BeSO4) can cause inflammation through the mechanism, which has not been elucidated. Mitochondrial DNA (mtDNA) is a key contributor of inflammation. With mitochondrial damage, released mtDNA can bind to specific receptors (e.g., cGAS) and then activate related pathway to promote inflammatory responses. To investigate the mechanism of mtDNA in BeSO4-induced inflammatory response in 16HBE cells, we established the BeSO4-induced 16HBE cell inflammation model and the ethidium bromide (EB)-induced ρ016HBE cell model to detect the mtDNA content, oxidative stress-related markers, mitochondrial membrane potential, the expression of the cGAS-STING pathway, and inflammation-related factors. Our results showed that BeSO4 caused oxidative stress, decline of mitochondrial membrane potential, and the release of mtDNA into the cytoplasm of 16HBE cells. In addition, BeSO4 induced inflammation in 16HBE cells by activating the cGAS-STING pathway. Furthermore, mtDNA deletion inhibited the expression of cGAS-STING pathway, IL-10, TNF-α, and IFN-ß. This study revealed a novel mechanism of BeSO4-induced inflammation in 16HBE cells, which contributes to the understanding of the molecular mechanism of beryllium and its compounds-induced toxicity.

Amorphous Drug-Polymer Salts: Maximizing Proton Transfer to Enhance Stability and Release.

An amorphous drug-polymer salt (ADPS) can be remarkably stable against crystallization at high temperature and humidity (e.g., 40°C/75% RH) and provide fast release. Here, we report that process conditions strongly influence the degree of proton transfer (salt formation) between a drug and a polymer and in turn the product's stability and release. For lumefantrine (LMF) formulated with poly(acrylic acid) (PAA), we first show that the amorphous materials prepared by slurry conversion and antisolvent precipitation produce a single trend in which the degree of drug protonation increases with PAA concentration from 0% for pure LMF to ∼100% above 70 wt % PAA, independent of PAA's molecular weight (1.8, 450, and 4000 kg/mol). This profile describes the equilibrium for salt formation and can be modeled as a chemical equilibrium in which the basic molecules compete for the acidic groups on the polymer chain. Relative to this equilibrium, the literature methods of hot-melt extrusion (HME) and rotary evaporation (RE) reached much lower degrees of salt formation. For example, at 40 wt % drug loading, HME reached 5% salt formation and RE 15%, both well below the equilibrium value of 85%. This is noteworthy given the common use of HME and RE in manufacturing amorphous formulations, indicating a need for careful control of process conditions to ensure the full interaction between the drug and the polymer. This need arises due to the low mobility of macromolecules and the mutual hindrance of adjacent reaction sites. We find that a high degree of salt formation enhances drug stability and release. For example, at 50% drug loading, an HME-like formulation with 19% salt formation crystallized faster and released only 20% of the drug relative to a slurry-prepared formulation with 70% salt formation. Based on this work, we recommend slurry conversion as the method for preparing ADPS for its ability to enhance salt formation and continuously adjust drug loading. While this work focused on salt formation, the impact of process conditions on the molecular-level interactions between a drug and a polymer is likely a general issue for amorphous solid dispersions, with consequences on product stability and drug release.

Cucurbituril-Shaped Cd18(triazolate)12 Unit-Based Metal-Organic Framework Exhibiting an C2H2/CO2 Separation Ability.

Herein, a metal-organic framework (MOF), {[(Me2NH2)4][Cd(H2O)6][Cd18(TrZ)12(TPD)15(DMF)6]}n (denoted as JXNU-18, TrZ = triazolate), constructed from the unique cucurbituril-shaped Cd18(TrZ)12 secondary building units bridged by 2,5-thiophenedicarboxylic (TPD2-) ligands, is presented. The formation of the cucurbituril-shaped Cd18(TrZ)12 unit is unprecedented, demonstrating the geometric compatibility of the organic linkers and the coordination configurations of the cadmium atoms. Each Cd18(TrZ)12 unit is connected to eight neighboring Cd18(TrZ)12 units through 30 TPD2- linkers, affording the three-dimensional structure of JXNU-18. More interesting is that JXNU-18 displays an efficient C2H2/CO2 separation ability, as revealed by the gas adsorption experiments and dynamic gas breakthrough experiments, which afford insights into the potential applications of JXNU-18 in gas separation. The tubular pores composed of two Cd18(TrZ)12 units bridged by six 2,5-thiophenedicarboxylic linkers provide the suitable pore space for C2H2 trapping, as unveiled by computational simulations.

An old thrombus may potentially identify patients at higher risk of poor outcome in anterior circulation stroke undergoing thrombectomy.

PURPOSE: To investigate thrombus age and its association with clinical and procedural parameters in patients with acute ischemic stroke (AIS) due to anterior circulation occlusions. METHODS: The thrombi of 107 consecutive AIS patients with occlusions in anterior circulation large-arteries were collected during mechanical recanalization. By hematoxylin-eosin staining analysis, thrombi were classified as fresh (< 3 days) or old (≥ 3 days) according to the hemosiderin positivity. Old thrombi were further classified as thrombi with focal hemosiderin or diffuse hemosiderin according to their predominant distribution. Neuro-interventional data and clinical outcomes were compared based on thrombus age. RESULTS: We identified fresh thrombi in 29 patients and old thrombi in 78 patients. Compared with patients with fresh thrombi, patients with old thrombi were associated with (i) a longer mechanical recanalization time (p = 0.027), (ii) a higher percentage of fibrin/platelets and leukocytes (all p = 0.02) and a lower percentage of erythrocytes (p = 0.001), and (iii) less favorable clinical outcomes at discharge (p = 0.019) and 90 days later (OR = 2.76, 95% CI = 1.09-6.99, p = 0.032). Furthermore, 18 (16.8%) of all patients had focal hemosiderin in old thrombi, which was independently linked to a poor clinical outcome 90 days later (adjusted OR = 5.37, 95% CI = 1.14-25.28, p = 0.034). CONCLUSION: The presence of old thrombi, particularly those with focal hemosiderin, may aid in identifying patients with acute ischemic anterior circulation stroke who are at a higher risk of poor clinical outcome at 3-month follow-up.

Fatty Acid Desaturation Is Suppressed in Mir-26a/b Knockout Goat Mammary Epithelial Cells by Upregulating INSIG1.

MicroRNA-26 (miR-26a and miR-26b) plays a critical role in lipid metabolism, but its endogenous regulatory mechanism in fatty acid metabolism is not clear in goat mammary epithelial cells (GMECs). GMECs with the simultaneous knockout of miR-26a and miR-26b were obtained using the CRISPR/Cas9 system with four sgRNAs. In knockout GMECs, the contents of triglyceride, cholesterol, lipid droplets, and unsaturated fatty acid (UFA) were significantly reduced, and the expression of genes related to fatty acid metabolism was decreased, but the expression level of miR-26 target insulin-induced gene 1 (INSIG1) was significantly increased. Interestingly, the content of UFA in miR-26a and miR-26b simultaneous knockout GMECs was significantly lower than that in wild-type GMECs and miR-26a- and miR-26b-alone knockout cells. After decreasing INSIG1 expression in knockout cells, the contents of triglycerides, cholesterol, lipid droplets, and UFAs were restored, respectively. Our studies demonstrate that the knockout of miR-26a/b suppressed fatty acid desaturation by upregulating the target INSIG1. This provides reference methods and data for studying the functions of miRNA families and using miRNAs to regulate mammary fatty acid synthesis.

Expression Variation of CPT1A Induces Lipid Reconstruction in Goat Intramuscular Precursor Adipocytes.

Intramuscular fat (IMF) deposition is one of the most important factors affecting meat quality and is closely associated with the expression of carnitine palmitoyl transferase 1A (CPT1A) which facilitates the transfer of long-chain fatty acids (LCFAs) into the mitochondria. However, the role of how CPT1A regulates the IMF formation remains unclear. Herein, we established the temporal expression profile of CPT1A during the differentiation of goat intramuscular precursor adipocytes. Functionally, the knockdown of CPT1A by siRNA treatment significantly increased the mRNA expression of adipogenic genes and promoted lipid deposition in goat intramuscular precursor adipocytes. Meanwhile, a CPT1A deficiency inhibited cell proliferation and promoted cell apoptosis significantly. CPT1A was then supported by the overexpression of CPT1A which significantly suppressed the cellular triglyceride deposition and promoted cell proliferation although the cell apoptosis also was increased. For RNA sequencing, a total of 167 differential expression genes (DEGs), including 125 upregulated DEGs and 42 downregulated DEGs, were observed after the RNA silencing of CPT1A compared to the control, and were predicted to enrich in the focal adhesion pathway, cell cycle, apoptosis and the MAPK signaling pathway by KEGG analysis. Specifically, blocking the MAPK signaling pathway by a specific inhibitor (PD169316) rescued the promotion of cell proliferation in CPT1A overexpression adipocytes. In conclusion, the expression variation of CPT1A may reconstruct the lipid distribution between cellular triglyceride deposition and cell proliferation in goat intramuscular precursor adipocyte. Furthermore, we demonstrate that CPT1A promotes the proliferation of goat adipocytes through the MAPK signaling pathway. This work widened the genetic regulator networks of IMF formation and delivered theoretical support for improving meat quality from the aspect of IMF deposition.

Kinetics of Surface Enrichment of a Polymer in a Glass-Forming Molecular Liquid.

X-ray photoelectron spectroscopy has been used to measure the surface concentration and the surface enrichment kinetics of a polymer in a glass-forming molecular liquid. As a model, the bulk-miscible system of maltitol-polyvinylpyrrolidone (PVP) was studied. The PVP concentration is significantly higher at the liquid/vapor interface than in the bulk by up to a factor of 170, and the effect increases with its molecular weight. At a freshly created liquid/vapor interface, the concentration of PVP gradually increases from the bulk value at a rate controlled by bulk diffusion. The polymer diffusion coefficient obtained from the kinetics of surface enrichment agrees with that calculated from viscosity and the Stokes-Einstein equation. Our finding allows prediction of the rate at which the surface composition equilibrates in an amorphous material after milling, fracture, and a change in ambient temperature.

Surface Enrichment of Surfactants in Amorphous Drugs: An X-ray Photoelectron Spectroscopy Study.

Surfactants are commonly incorporated into amorphous formulations to improve the wetting and dissolution of hydrophobic drugs. Using X-ray photoelectron spectroscopy, we find that a surfactant can significantly enrich at the surface of an amorphous drug, up to 100% coverage, wihout phase separation in the bulk. We compared four different surfactants (Span 80, Span 20, Tween 80, and Tween 20) in the same host acetaminophen and the same surfactant Span 80 in four different hosts (acetaminophen, lumefantrine, posaconazole, and itraconazole). For each system, the bulk concentrations of the surfactants were 0, 1, 2, 5, and 10 wt %, which cover the typical concentrations in amorphous formulations, and component miscibility in the bulk was confirmed by differential scanning calorimetry. For all systems investigated, we observed significant surface enrichment of the surfactants. For acetaminophen containing different surfactants, the strongest surface enrichment occurred for the most lipophilic Span 80 (lowest HLB), with nearly full surface coverage. For the same surfactant Span 80 doped in different drugs, the surface enrichment effect increases with the hydrophilicity of the drug (decreasing log P). These effects arise because low-surface-energy molecules (or molecular fragments) tend to enrich at a liquid/vapor interface. This study highlights the potentially large difference between the surface and bulk compositions of an amorphous formulation. Given their high mobility and low glass transition temperature, the surface enrichment of surfactants in an amorphous drug can impact its stability, wetting, and dissolution.

The correlation between enlarged perivascular spaces and cognitive impairment in Parkinson's disease and vascular parkinsonism.

INTRODUCTION: The widespread use of brain magnetic resonance imaging (MRI) has revealed the correlation between enlarged perivascular spaces (EPVS) and cognitive impairment (CI). However, few studies have examined the correlation between MRI-visible EPVS and CI in patients with Parkinson's disease (PD) and vascular parkinsonism (VaP). This study explored how the number and main location of EPVS in PD and VaP are correlated with the occurrence of CI in these diseases to provide radiology markers and other evidence for early clinical diagnosis in a Chinese cohort. METHODS: Clinical data were prospectively collected from 77 patients: 26 patients clinically diagnosed with PD or probable PD, 19 patients clinically diagnosed with VaP, and 32 control subjects with normal cognitive function and no stroke or parkinsonism. The patients with PD and VaP were divided into a CI group and a no CI (NCI) group according to the Montreal Cognitive Assessment Beijing version (MoCA-BJ). The relevant clinical data were statistically analysed. RESULTS: The centrum semiovale (CSO)-EPVS, lacunes, Fazekas scores, global cortical atrophy scale (GCA) scores, Koedam posterior atrophy visual scale (KS) scores, and medial temporal atrophy (MTA) scores were higher in the PD-CI and VaP-CI groups than in the control group (adjusted P < 0.017). The number of basal ganglia (BG)-EPVS in the VaP group was higher than that in the PD and control groups (adjusted P < 0.017). BG-EPVS, Fazekas scores, GCA scores, KS scores, and MTA scores were higher in the VaP-CI group than in the PD-CI group (adjusted P < 0.017). Multivariate logistic regression analysis showed that the differences in BG-EPVS and Fazekas scores were not significant between PD-CI and VaP-CI patients (P > 0.05). CONCLUSION: VaP-CI results from multiple factors and is significantly associated with BG-EPVS, lacunes, white matter hyperintensities and brain atrophy. BG-EPVS can be used as an imaging marker to distinguish VaP-CI from PD-CI.

Serum-derived exosomes from SD rats induce inflammation in macrophages through the mTOR pathway.

Inhalation of beryllium and its compounds can cause lung injuries, resulting from inflammation and oxidative stress. Multivesicular bodies (MVB), such as exosomes, are membrane vesicles produced by early and late endosomes that mediate intercellular communications. However, the role of exosomes in beryllium toxicity has not been elucidated. This current study aimed to investigate the functional role of exosomes in lung injury resulting from beryllium sulfate (BeSO4 ). Here, Sprague-Dawley (SD) rats were exposed to 4, 8, and 12 mg/kg BeSO4 by nonexposed intratracheal instillation. Murine macrophage (RAW 264.7) cells were pretreated with 50 nmol/L rapamycin (an mTOR signaling pathway inhibitor) for 30 min and then cultured for 24 h with 100 µg/mL exosomes, which had been previously isolated from the serum of 12 mg/kg BeSO4 -treated SD rats. Compared with those of the controls, exposure to BeSO4 in vivo increased LDH activity, elevated levels of inflammatory cytokines (IL-10, TNF-α, and IFN-γ) alongside inflammation-related proteins expression (COX-2 and iNOS), and enhanced secretion of exosomes from the SD rat's serum. Moreover, the BeSO4 -Exos-induced upregulation of LDH activity and inflammatory responses in RAW 264.7 cells can be alleviated following pretreatment with rapamycin. Collectively, these results suggest that serum exosomes play an important role in pulmonary inflammation induced by BeSO4 in RAW 264.7 cells via the mTOR pathway.

Hydrogen sulfide alleviates apoptosis and autophagy induced by beryllium sulfate in 16HBE cells.

Beryllium and its compounds are systemic toxicants that are widely applied in many industries. Hydrogen sulfide has been found to protect cells. The present study aimed to determine the protective mechanisms involved in hydrogen sulfide treatment of 16HBE cells following beryllium sulfate-induced injury. 16HBE cells were treated with beryllium sulfate doses ranging between 0 and 300 µM BeSO4 . Additionally, 16HBE cells were subjected to pretreatment with either a 300 µM dose of sodium hydrosulfide (a hydrogen sulfide donor) or 10 mM DL-propargylglycine (a cystathionine-γ-lyase inhibitor) for 6 hr before then being treated with 150 µM beryllium sulfate for 48 hr. This study illustrates that beryllium sulfate induces a reduction in cell viability, increases lactate dehydrogenase (LDH) release, and increases cellular apoptosis and autophagy in 16HBE cells. Interestingly, pretreating 16HBE cells with sodium hydrosulfide significantly reduced the beryllium sulfate-induced apoptosis and autophagy. Moreover, it increased the mitochondrial membrane potential and alleviated the G2/M-phase cell cycle arrest. However, pretreatment with 10 mM DL-propargylglycine promoted the opposite effects. PI3K/Akt/mTOR and Nrf2/ARE signaling pathways are also activated following pretreatment with sodium hydrosulfide. These results indicate the protection provided by hydrogen sulfide in 16HBE cells against beryllium sulfate-induced injury is associated with the inhibition of apoptosis and autophagy through the activation of the PI3K/Akt/mTOR and Nrf2/ARE signaling pathways. Therefore, hydrogen sulfide has the potential to be a promising candidate in the treatment against beryllium disease.

CRISPR/Cas9-Mediated Knockout of miR-130b Affects Mono- and Polyunsaturated Fatty Acid Content via PPARG-PGC1α Axis in Goat Mammary Epithelial Cells.

MicroRNA (miRNA)-130b, as a regulator of lipid metabolism in adipose and mammary gland tissues, is actively involved in lipogenesis, but its endogenous role in fatty acid synthesis remains unclear. Here, we aimed to explore the function and underlying mechanism of miR-130b in fatty acid synthesis using the CRISPR/Cas9 system in primary goat mammary epithelial cells (GMEC). A single clone with deletion of 43 nucleotides showed a significant decrease in miR-130b-5p and miR-130b-3p abundances and an increase of target genes PGC1α and PPARG. In addition, knockout of miR-130b promoted triacylglycerol (TAG) and cholesterol accumulation, and decreased the proportion of monounsaturated fatty acids (MUFA) C16:1, C18:1 and polyunsaturated fatty acids (PUFA) C18:2, C20:3, C20:4, C20:5, C22:6. Similarly, the abundance of fatty acid synthesis genes ACACA and FASN and transcription regulators SREBP1c and SREBP2 was elevated. Subsequently, interference with PPARG instead of PGC1α in knockout cells restored the effect of miR-130b knockout, suggesting that PPARG is responsible for miR-130b regulating fatty acid synthesis. Moreover, disrupting PPARG inhibits PGC1α transcription and translation. These results reveal that miR-130b directly targets the PPARG-PGC1α axis, to inhibit fatty acid synthesis in GMEC. In conclusion, miR-130b could be a potential molecular regulator for improving the beneficial fatty acids content in goat milk.

Renal Artery Partial Occlusion After Aortic Dissection Is Associated With Impaired Renal Function in the Affected Kidney.

BACKGROUND: The renal artery is often involved in aortic dissection, leading to kidney ischaemia and renal dysfunction. However, some patients with aortic dissection with combined renal artery involvement do not show clinical renal dysfunction. This study aimed to analyse the relationship between renal artery involvement and renal function. METHODS: Data and images were collected from 79 patients (Group A), in Beijing Anzhen hospital between January 2015 and December 2017, who had type A aortic dissection, in order to analyse the relationship between renal artery involvement and serum creatinine. In order to further analyse the relationship between renal artery involvement and single kidney function, data from 27 patients (Group B) with aortic dissection from August 2018 to October 2018 were collected. Renal dynamic imaging was conducted, and clinical and image data were recorded. RESULTS: Results showed that patients with one partially occluded renal artery had higher variance of serum creatinine after surgery compared with patients with one false-lumen renal artery (5.8±22.7 µmol/L vs -18.7±22.7 µmol/L; p=0.003). The glomerular filtration rate of a single kidney that had a partially occluded renal artery was lower than that of a single kidney with a normal renal artery (37.77±9.57 vs 42.73±10.54; p=0.04). CONCLUSIONS: A partially occluded renal artery in aortic dissection was associated with impaired renal function after surgery, even though patients did not present high serum creatinine. More attention should be paid to those experiencing aortic dissection.

Ellagic acid attenuates beryllium sulphate-induced oxidative stress and histopathological alterations of spleen in rats.

CONTEXT: Ellagic acid (EA) is a phenolic constituent in certain fruits and has largely been recognized for its role as an antioxidant compound. OBJECTIVE: To evaluate the effect of EA on beryllium sulphate-induced splenic toxicity in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into four groups. The first group was used as control. Group 2 was exposed to BeSO4 (12 mg/kg, b.w.). Groups 3 and 4 were treated with EA (100 and 300 mg/kg, b.w.) daily for 6 weeks after exposing to BeSO4 (12 mg/kg, b.w.). Various biochemical and molecular biomarkers were assessed in blood and spleen. RESULTS: BeSO4-intoxicated rats showed significant higher WBC (6.74 ± 0.20 × 109/L vs. 11.02 ± 1.31 × 109/L, p < 0.05), Neu (1.14 ± 0.11 × 109/L vs. 2.45 ± 0.42 × 109/L, p < 0.05), Lym (3.80 ± 0.83 × 109/L vs. 9.64 ± 1.99 × 109/L, p < 0.05), and PLT (868.4 ± 43.2 × 109/L vs. 1408 ± 77.57 × 109/L, p < 0.05) than normal control animals. Moreover, an increase in MDA with depletion of GSH and SOD activity (all p < 0.05) occurred in the spleen of rats treated with BeSO4. Furthermore, BeSO4-treated rats displayed significantly higher levels of apoptotic markers (Bax, Caspase-3, PARP) (all p < 0.05). EA administration resulted in a significant reversal of hematological and apoptotic markers in beryllium sulphate-intoxicated rats. DISCUSSION AND CONCLUSIONS: Our results suggest EA treatment exerts a significant protective effect on BeSO4-induced splenic toxicity in rats.