Mesenchymal stem cell-loaded hydrogel to inhibit inflammatory reaction in surgical brain injury via mitochondria transfer.

Neurosurgical procedures are the key therapeutic interventions for the cerebral hemorrhage and brain tumors. However, neurosurgical procedures inevitably cause surgical brain injury (SBI), which will induce hemorrhage and inflammation. Gelatin Sponges are still the primary hemostatic materials used in clinical, but their anti-inflammatory efficacy is poor. Herein, we developed a cross-linked gelatin hydrogel (GelMA) to load mesenchymal stem cells (MSC) and directly implant them to the SBI site. Upon contacting the SBI site, the GelMA showed better clotting performance than Gelatin Sponges. Moreover, the MSC can reduce oxidative stress and enhance mitochondrial fusion via mitochondria transfer, resulting in ameliorating mitochondrial damage and reducing inflammation. Thus, the GelMA containing MSC can effectively reduce brain edema and inflammation and improve neurological function in SBI mouse models. In addition, GelMA exhibits excellent hemocompatibility and low cytotoxicity. It also enhances the proliferation of MSCs and decelerates the rapid depletion of MSCs. Therefore, MSC-loaded GelMA exhibits excellent hemostatic and anti-inflammatory effects, making it a potential new-generation biomaterial for SBI.

Occurrence and Exposure Assessment of Nickel in Zhejiang Province, China.

Nickel (Ni) is a silver-white metal with high antioxidative properties, often existing in a bivalent form in the environment. Despite being the fifth most abundant metal on Earth, anthropogenic activities, including industrial processes, have elevated Ni levels in environmental media. This study investigated Ni contamination in various food groups in Zhejiang Province, China, mainly focusing on Ni levels in beans, vegetables, aquatic foods, meat products, cereal products, and fruits. A total of 2628 samples were collected and analyzed. Beans exhibited the highest Ni content in all samples. The overall detection rate of Ni was 86.5%, with variation among food categories. For plant-origin foods, legumes had the highest Ni concentration while for animal-origin foods, shellfish showed the highest median Ni concentration. The results indicate generally acceptable Ni exposure levels among Zhejiang residents, except for children aged 0-6. Beans were identified as the primary contributor to high Ni exposure risk. The paper suggests monitoring Ni contamination in food, especially for vulnerable populations, and provides insights into exposure risks in different age groups.

Genetically predicted mood swings increased risk of cardiovascular disease: Evidence from a Mendelian randomization analysis.

BACKGROUND: Mood swings is linked to a higher risk of cardiovascular diseases (CVDs). However, the causal relationships between them remain unknown. METHODS: We conducted this Mendelian randomization (MR) analysis to evaluate the causal associations between mood swings (n = 373,733) and 5 CVDs, including CAD, MI, HF, AF, and stroke using summary data of large-scale genome-wide association studies (GWAS). FinnGen datasets validated the results. Various MR approaches, sensitivity analyses, multivariable MR (MVMR), and two-step MR mediation analyses were applied. RESULTS: The MR analysis revealed significant causal effects of mood swings on CAD (OR = 1.45, 95 % CI 1.24-1.71; P = 5.52e-6), MI (OR = 1.60, 95 % CI 1.32-1.95; P = 1.77e-6), HF (OR = 1.42, 95 % CI 1.18-1.71; P = 2.32e-4), and stroke (OR = 1.48, 95 % CI 1.19-1.83; P = 3.46e-4), excluding AF (P = 0.16). In the reverse MR analysis, no causal relationships were observed. The results were reproducible using FinnGen data. In the MVMR analysis, the causal effects of mood swings on CAD, MI, HF and stroke still remain significant after adjusting potential confounding factors including BMI, smoking and T2DM, but not for LDL and hypertension. Further mediation analysis indicated hypertension may mediate the causal pathways from mood swings to CAD (18.11 %, 95 % CI: 8.83 %-27.39 %), MI (16.40 %, 95 % CI: 7.93 %-24.87 %), HF (13.06 %, 95 % CI: 6.25 %-19.86 %), and stroke (18.04 %, 95 % CI: 8.73 %-27.34 %). CONCLUSION: Mood swings has a significant causal impact on the development of CAD, MI, HF, and stroke, partly mediated by hypertension.

Cadmium Exposure in Aquatic Products and Health Risk Classification Assessment in Residents of Zhejiang, China.

Cadmium (Cd) pollution of food safety is a prominent food safety concern worldwide. The concentration of Cd in six aquatic food categories collected from 2018 to 2022 was analyzed using inductively coupled plasma mass spectrometry, and the Cd exposure levels were calculated by combining the Cd concentration and food consumption data of 18913 urban and rural residents in Zhejiang Province in 2015-2016. The mean Cd concentration was 0.699 mg/kg and the mean Cd exposure of aquatic foods was 0.00951 mg/kg BW/month for the general population. Marine crustaceans were the largest Cd contributor, corresponding to 82.7%. The regional distribution results showed that the average Cd exposure levels of 11 cities did not exceed the provisional tolerable monthly intake (PTMI). According to the subgroups, the Cd mean exposure level of 2-3-year-old children was significantly higher than that of the other age groups but did not exceed the PTMI. Health risk classification assessment demonstrated that the final risk score was six, and the health risk level of Cd exposure in aquatic products in the Zhejiang population was medium. These results demonstrated that the risk of Cd exposure in certain food types or age groups should be given more concern.

Integrated analysis based on vesicle trafficking-related genes identifying CNIH4 as a novel therapeutic target for glioma.

BACKGROUND: Vesicle trafficking is a highly important process in numerous human diseases, especially in the central nervous system dysfunctions. However, as a key component of vesicle trafficking-related genes (VRGs), Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) has not been systematically elucidated in glioma so far. METHODS: Differentially expressed VRGs were selected using molecular signatures database (MSigDB), The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) mRNA expression profiles. Further exploration of CNIH4 was determined using LASSO-Cox regression algorithms. Then Kaplan-Meier (K-M) plotter, receiver operating characteristic (ROC) curves, and multivariate Cox regression analyses were utilized to assess the independent significance of CNIH4 in the CGGA validation cohort. Functional exploration was performed with Gene Set Enrichment Analysis (GSEA) and then verified using a series of functional experiments in glioma cells. Finally, the consensus clustering algorithm was applied to identify clusters in glioma samples. After that, differences in prognosis, the tumor immune microenvironment (TIME), and therapy response were evaluated between clusters. RESULTS: CNIH4 was shown to be overexpressed in malignant glioma variants and was frequently observed in GCSs and TMZ-resistant cell lines. Higher CNIH4 levels were significantly related to poor outcomes and positively correlated with adverse clinicopathological characteristics. Survival analyses revealed CNIH4 as an independent risk factor that outperformed traditional measures. Enrichment analysis indicated that overactive CNIH4 significantly gathered in stem cell processes. Furthermore, functional assays of silencing CNIH4 expression suppressed stem cell-like properties in vitro and inhibited tumorigenicity in vivo. Finally, the CNIH4-enriched subgroup negatively modulated immunotherapeutic response and reflected lower chemotherapy sensitivity for glioma patients. CONCLUSION: Our study identified CNIH4 as a potential VRG that regulates tumor stemness, microenvironment immunity, and chemotherapy sensitivity. It may serve as a novel prognostic factor and a promising target against glioma therapy.

Ultrasensitive detection of multiple cancer biomarkers by a triple cascade amplification strategy in combination with single particle inductively coupled plasma mass spectrometry.

A versatile triple cascade amplification strategy was developed for ultrasensitive simultaneous detection of multiple cancer biomarkers using single particle inductively coupled plasma mass spectrometry (spICP-MS). The triple cascade amplification strategy consisted of an enhanced RecJf exonuclease-assisted target recycling amplification module, a hybridization chain reaction amplification module, and a signal amplification module based on DNA-templated multiple metal nanoclusters. In the enhanced RecJf exonuclease-assisted target recycling amplification module, the DNA bases at the 5' ends of aptamers for specific recognition of biomarkers were deliberately replaced by the corresponding RNA bases to enhance amplification efficiency. The signal amplification module based on DNA-templated multiple metal nanoclusters was innovatively used to amplify the signals measured by spICP-MS and at the same time effectively suppress possible background interferences. The proposed spICP-MS platform achieved satisfactory quantitative results for both carcinoembryonic antigen (CEA) and a-fetoprotein (AFP) in human serum samples with accuracy comparable to that of the commercial ELISA kits. Moreover, it has wide dynamic ranges for both CEA (0.01-100 ng/mL) and AFP (0.01-200 ng/mL). The limit of detection for CEA and AFP was 0.6 and 0.5 pg/mL, respectively. Compared with conventional biomarkers detection methods, the proposed spICP-MS platform has the advantages of operational simplicity, ultra-high sensitivity, wide dynamic range, and low background. Therefore, it is reasonable to expect that the proposed spICP-MS platform can be further developed to be a promising alternative tool for biomarker detection in fields of clinical diagnosis and biomedical research.

Double Signal Amplification Strategy for Dual-Analyte Fluorescent Aptasensors for Visualizing Cancer Biomarker Proteins.

The simultaneous analysis of diversified biomarkers with high sensitivity and in a point-of-care (POC) manner is of great significance for facile and early cancer diagnosis. Herein, we develop a target amplification-assisted ratiometric fluorescence assay (TARFA) platform integrating the dual-amplification strategy and colorimetric readout technology for sensitive and specific detection of two malignancy-associated biomarkers. Meanwhile, the NIR-excited alkaline-earth sulfide nanodots (ASNDs) with an ultrasmall (<10 nm) diameter and tunable emission wavelength are employed to replace commonly UV/visible light-excited fluorescent labels to minimize background interference from the sample matrix. Unique advantages of the ASNDs, together with superiority of consecutive signal amplification of enzymatic target recycling (ETR) and hybridization chain reaction (HCR), realize the pg/mL-range detection limit in specifically recognizing the vascular endothelial growth factor (VEGF) and soluble interleukin-6 receptors (sIL-6R). The combination detection of the dual analyte exhibits an improved sensitivity for cancer diagnosis. The addition of the target biomarkers leads to an increasingly ratiometric RGB signal, and quantification based on the ratio-dependent signal is more reliable rather than measuring the absolute RGB signals. Moreover, perceptible color transformation makes the TARFA platform competent for visual analysis of the target analytes as convenient as reading the pH indicator strip, and hue-based image analysis also improves the method with fine precision by quantitatively identifying the visual color. This work provides a new kind of NIR-excited aptasensing platform with a low detection limit, high throughput, and great portability, which also highlights the potential of the ASNDs in biomolecular fluorescent labeling.

Contribution of Oxidative Stress Induced by Sonodynamic Therapy to the Calcium Homeostasis Imbalance Enhances Macrophage Infiltration in Glioma Cells.

BACKGROUND: To better understand the Ca2+ overload mechanism of SDT killing gliomas, we examined the hypothesis that the early application of the mechanosensitive Ca2+ channel Piezo1 antagonist (GsMTx4) could have a better anti-tumor effect. METHODS: The in vitro effect of low-energy SDT combined with GsMTx4 or agonist Yoda 1 on both the ROS-induced distribution of Ca2+ as well as on the opening of Piezo1 and the dissociation and polymerization of the Ca2+ lipid complex were assessed. The same groups were also studied to determine their effects on both tumor-bearing BALB/c-nude and C57BL/6 intracranial tumors, and their effects on the tumor-infiltrating macrophages were studied as well. RESULTS: It was determined that ultrasound-activated Piezo1 contributes to the course of intracellular Ca2+ overload, which mediates macrophages (M1 and M2) infiltrating under the oxidative stress caused by SDT. Moreover, we explored the effects of SDT based on the dissociation of the Ca2+ lipid complex by inhibiting the expression of fatty acid binding protein 4 (FABP4). The Piezo1 channel was blocked early and combined with SDT treatment, recruited macrophages in the orthotopic transplantation glioma model. CONCLUSIONS: SDT regulates intracellular Ca2+ signals by upregulating Piezo1 leading to the inhibition of the energy supply from lipid and recruitment of macrophages. Therefore, intervening with the function of the Ca2+ channel on the glioma cell membrane in advance is likely to be the key factor to obtain a better effect combined with SDT treatment.

Ultrasensitive detection of protein biomarkers by MALDI-TOF mass spectrometry based on ZnFe2O4 nanoparticles and mass tagging signal amplification.

A facile MALDI-TOF mass spectrometric platform for quantitative analysis of protein biomarkers was developed based on magnetic ZnFe2O4 nanoparticles and mass tagging signal amplification. In this platform, magnetic ZnFe2O4 nanoparticles functionalized with an aptamer of the biomarker of interest was used to magnetically separate silica nanoparticles modified with another aptamer of the target biomarker and a barcoding peptide from solution phase in the presence of the biomarker of interest. After the silica nanoparticles were dissolved by KHF2, the released barcoding peptide was detected by MALDI-TOF mass spectrometry with magnetic ZnFe2O4 nanoparticles used as assisting matrix of laser desorption ionization. Since the mass spectral intensity of the barcoding peptide is directly related to the concentration of the target biomarker, the proposed platform can be applied to the quantification of the target biomarker in complex biological samples. The effectiveness of the proposed platform was tested on the detection of carcinoembryonic antigen (CEA) in serum. Experimental results revealed that the proposed platform could achieve quite reliable quantitative results for CEA in human serum samples with accuracy comparable to a commercial CEA ELISA Kit. Its limit of detection and limit of quantification for CEA were estimated to be 0.6 × 10-3 and 1.8 × 10-3 ng/mL, respectively, considerably lower than the corresponding values reported in literature. Due to its features of simplicity in design, extremely low background signal, high sensitivity and selectivity, the proposed method can be further developed to be a competitive alternative for the quantification of CEA and other protein biomarkers as well.

Inhibition of Heat Shock Protein 90 by 17-AAG Reduces Inflammation via P2X7 Receptor/NLRP3 Inflammasome Pathway and Increases Neurogenesis After Subarachnoid Hemorrhage in Mice.

Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease that usually has a poor prognosis. Heat shock proteins (HSPs) have been implicated in the mechanisms of SAH-associated damage, including increased inflammation and reduced neurogenesis. The aim of this study was to investigate the effects of HSP90 inhibition on inflammation and neurogenesis in a mouse model of experimental SAH induced by endovascular surgery. Western blotting showed HSP90 levels to be decreased, while neurogenesis, evaluated by 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry, was decreased in the hippocampuses of SAH mice. SAH also induced pro-inflammatory factors such as interleukin-1ß (IL-1ß), capase-1 and the NLRP3 inflammasome. However, intraperitoneal administration of the specific HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) reduced the levels of HSP90, NLRP3, ASC, caspase-1 and IL-1ß, while increasing the levels of brain-derived neurotrophic factor and doublecortin (DCX), as well as the number of BrdU-positive cells in SAH mice. In addition, 17-AGG improved short- and long-term neurobehavioral outcomes. The neuroprotective and anti-inflammatory effects of 17-AGG were reversed by recombinant HSP90 (rHSP90); this detrimental effect of HSP90 was inhibited by the specific P2X7 receptor (P2X7R) inhibitor A438079, indicating that SAH-induced inflammation and inhibition of neurogenesis were likely mediated by HSP90 and the P2X7R/NLRP3 inflammasome pathway. HSP90 inhibition by 17-AAG may be a promising therapeutic strategy for the treatment of SAH.

Association of tumor necrosis factor-α gene promoter polymorphism at sites -308 and -238 with non-alcoholic fatty liver disease: a meta-analysis.

BACKGROUND AND AIM: Environmental and genetic factors play a role in the pathogenesis and natural history of non-alcoholic fatty liver disease (NAFLD). The objective of this study was to quantitatively evaluate the association between tumor necrosis factor (TNF)-α gene promoter polymorphism at sites -308 and -238 and NAFLD susceptibility. METHODS: We performed an extensive search of relevant studies and made a meta-analysis, including eight studies with 837 NAFLD cases and 990 controls in the association between TNF-α -308 polymorphism and NAFLD; and seven studies with 771 cases and 787 controls in TNF-α -238 polymorphism. RESULTS: The combined results showed that there was a significant difference in TNF-α-238 genotype distribution between NAFLD and control based on all studies (GA/AA vs GG [odds ratio = 2.06, 95% confidence interval = 1.58-2.69, P < 0.000,01]). However, the combined results based on all studies showed there was no evidence of association of TNF-α-308 genotype distribution between NAFLD cases and controls (GA/AA vs GG [odds ratio = 1.08, 95% confidence interval = 0.82-1.42, P = 0.60]). When stratifying for race, the significant results did not change materially compared with whole populations. CONCLUSION: This meta-analysis suggested that TNF-α gene promoter polymorphism at position -238 but not -308 might be a risk factor for NAFLD.