Effects of environmentally relevant concentration of short-chain chlorinated paraffins on BV2 microglia activation and lipid metabolism, implicating altered neurogenesis.

Short-chain chlorinated paraffins (SCCPs), a class of persistent organic pollutants, have been found to cause diverse organ and systemic toxicity. However, little is known about their neurotoxic effects. In this study, we exposed BV2, a mouse microglia cell line, to environmentally relevant concentration of SCCPs (1 µg/L, 10 µg/L, 100 µg/L) for 24 h to investigate their impacts on the nervous system. Our observations revealed that SCCPs induced the activation of BV2 microglia, as indicated by altered morphology, stimulated cell proliferation, enhanced phagocytic and migratory capabilities. Analysis at the mRNA level confirmed the activation status, with the downregulation of TMEM119 and Tgfbr1, and upregulation of Iba1 and CD11b. The upregulated expression of genes such as cenpe, mki67, Axl, APOE and LPL also validated alterations in cell functions. Moreover, BV2 microglia presented an M2 alternative phenotype upon SCCPs exposure, substantiated by the reduction of NF-κB, TNF-α, IL-1ß, and the elevation of TGF-ß. Additionally, SCCPs caused lipid metabolic changes in BV2 microglia, characterized by the upregulations of long-chain fatty acids and acylcarnitines, reflecting an enhancement of ß-oxidation. This aligns with our findings of increased ATP production upon SCCPs exposure. Intriguingly, cell activation coincided with elevated levels of omega-3 polyunsaturated fatty acids. Furthermore, activated microglial medium remarkably altered the proliferation and differentiation of mouse neural stem cells. Collectively, exposure to environmentally relevant concentrations of SCCPs resulted in activation and lipid metabolic alterations in BV2 microglia, potentially impacting neurogenesis. These findings provide valuable insights for further research on the neurotoxic effect of SCCPs.

Effect of Ulinastatin Combined with Somatostatin on Inflammatory Markers, Hemodynamics and Immune Cells in the Treatment of Severe Pancreatitis.

Objective: Severe pancreatitis presents a formidable clinical challenge, often associated with high mortality rates and compromised quality of life. This study aimed to assess the efficacy of combining ulinastatin with somatostatin in treating severe pancreatitis, with a focus on improving patient outcomes. Methods: We conducted a study on 98 severe pancreatitis patients at our hospital from January 2022 to March 2023. These patients were randomly divided into two groups: a control group (n=49) treated with somatostatin and an experimental group (n=49) treated with ulinastatin plus somatostatin. The control group received 250 micrograms per hour of somatostatin intravenously for 72 hours. The experimental group received 200 000 units of ulinastatin every 8 hours intravenously, along with the same somatostatin regimen. We compared clinical efficacy, inflammatory markers (TNF-α, CRP, IL-6), hemodynamic parameters (MAP, CVP, HR, SVR), and immune cell function between the groups. Results: Post-treatment, the experimental group showed significant improvements compared to the control group (P < .05) in various parameters. Decreases in AMS, TNF-α, CRP, IL-6, MAP, CVP, and CD8+ T-cells were more pronounced in the experimental group. Notably, AMS levels dropped from 450 U/L to 150 U/L, and TNF-α levels from 55 pg/mL to 20 pg/mL in the experimental group. Conversely, increases in HR, SVR, CD4+ T-cells, CD4+/CD8+ ratio, and NK cell counts were observed. For instance, CD4+ T-cells rose from 300 cells/µL to 500 cells/µL. The experimental group exhibited a higher clinical efficacy rate of 97.96%, compared to 85.71% in the control group. The combined treatment of ulinastatin with somatostatin demonstrated significant effectiveness in improving clinical outcomes compared to the control group. Statistical analysis robustly supported these findings, providing confidence in their reliability. Importantly, the combined therapy showed promise in reducing mortality rates and enhancing the quality of life for patients with severe pancreatitis. Conclusion: The findings of this study hold substantial clinical implications, potentially influencing treatment protocols and patient management strategies for severe pancreatitis. The integration of ulinastatin combined with somatostatin into standard care protocols could significantly improve treatment outcomes and patient prognosis.

Evaluation of bevacizumab biosimilar on wound healing complications in patients with colorectal cancer undergoing endoscopic mucosal resection: A systematic review and meta-analysis in anorectal medicine.

Complications related to wound healing pose substantial obstacle in the management of colorectal cancer (CRC), specifically in the field of anorectal medicine. Biosimilars of bevacizumab have emerged as crucial therapeutic agents in the management of these complications. With the particular emphasis on effects of Bevacizumab Biosimilar Plus on wound healing among patients diagnosed with CRC, this review underscores the potential of this anorectal medication to improve patient outcomes and was aimed to assess the safety and efficacy of Bevacizumab Biosimilar Plus in relation to complications associated with wound healing in patients with CRC. The assessment centers on its therapeutic potential and safety profile within the domain of anorectal medicine. In accordance with the PRISMA guidelines, a comprehensive literature search was performed, resulting in the identification of 19 pertinent studies out of an initial 918. Priority was given to assessing the safety and adverse effects of Bevacizumab Biosimilar Plus in conjunction with its effectiveness in wound healing. The extracted data comprised the following: study design, patient demographics, comprehensive treatment regimens, wound healing-specific outcomes and adverse effects. The evaluation of study quality was conducted utilizing the instruments provided by the Cochrane Collaboration and the Newcastle-Ottawa Scale (NOS). Bevacizumab Biosimilar Plus demonstrates efficacy in the management of wound healing complications among patients with CRC, with a safety and efficacy profile similar to that of the original Bevacizumab, according to the analysis. Notably, several studies reported improved rates of wound healing in relation to the biosimilar. The safety profiles exhibited similarities to the anticipated anti-VEGF agent effects. In wound management, the biosimilar also demonstrated advantages in terms of prolonged efficacy. In addition, analyses of cost-effectiveness suggested that the use of biosimilars could result in cost reductions. Bevacizumab Biosimilar Plus exhibited potential as an anorectal medication for the effective management of wound healing complications in patients with CRC. This has substantial ramifications for improving the quality of patient care, encompassing the affordability and effectiveness of treatments.

Single-cell transcriptomic analysis reveals the adverse effects of cadmium on the trajectory of neuronal maturation.

Cadmium (Cd) is an extensively existing environmental pollutant that has neurotoxic effects. However, the molecular mechanism of Cd on neuronal maturation is unveiled. Single-cell RNA sequencing (scRNA-seq) has been widely used to uncover cellular heterogeneity and is a powerful tool to reconstruct the developmental trajectory of neurons. In this study, neural stem cells (NSCs) from subventricular zone (SVZ) of newborn mice were treated with CdCl2 for 24 h and differentiated for 7 days to obtain neuronal lineage cells. Then scRNA-seq analysis identified five cell stages with different maturity in neuronal lineage cells. Our findings revealed that Cd altered the trajectory of maturation of neuronal lineage cells by decreasing the number of cells in different stages and hindering their maturation. Cd induced differential transcriptome expression in different cell subpopulations in a stage-specific manner. Specifically, Cd induced oxidative damage and changed the proportion of cell cycle phases in the early stage of neuronal development. Furthermore, the autocrine and paracrine signals of Wnt5a were downregulated in the low mature neurons in response to Cd. Importantly, activation of Wnt5a effectively rescued the number of neurons and promoted their maturation. Taken together, the findings of this study provide new and comprehensive insights into the adverse effect of Cd on neuronal maturation.

Integrated metabolomic and transcriptomic analysis reveals perturbed glycerophospholipid metabolism in mouse neural stem cells exposed to cadmium.

Cadmium (Cd) is a ubiquitous heavy metal with neurotoxicity. Our previous study reported that Cd could inhibit the proliferation of mouse neural stem cells (mNSCs). However, the underlying mechanisms are obscure. In recent years, the rapid growth of multi-omics techniques enables us to explore the cellular responses that occurred after toxicant exposure at the molecular level. In this study, we used a combination of metabolomics and transcriptomics approaches to investigate the effects of exposure to Cd on mNSCs. After treatment with Cd, the metabolites and transcripts in mNSCs changed significantly with 110 differentially expressed metabolites and 2135 differentially expressed genes identified, respectively. The altered metabolites were mainly involved in glycerophospholipid metabolism, arginine and proline metabolism, arginine biosynthesis, glyoxylate and dicarboxylate metabolism. Meanwhile, the transcriptomic data demonstrated perturbed membrane function and signal transduction. Furthermore, integrated analysis of metabolomic and transcriptomic data suggested that glycerophospholipid metabolism might be the major metabolic pathway affected by Cd in mNSCs. More interestingly, the supplementation of lysophosphatidylethanolamine (LPE) attenuated Cd-induced mitochondrial impairment and the inhibition of cell proliferation and differentiation in mNSCs, further supporting our analysis. Overall, the study provides new insights into the mechanisms of Cd-induced neurotoxicity.

Minimally Invasive Hypoglossal Nerve Stimulator Enabled by ECG Sensor and WPT to Manage Obstructive Sleep Apnea.

A hypoglossal nerve stimulator (HGNS) is an invasive device that is used to treat obstructive sleep apnea (OSA) through electrical stimulation. The conventional implantable HGNS device consists of a stimuli generator, a breathing sensor, and electrodes connected to the hypoglossal nerve via leads. However, this implant is bulky and causes significant trauma. In this paper, we propose a minimally invasive HGNS based on an electrocardiogram (ECG) sensor and wireless power transfer (WPT), consisting of a wearable breathing monitor and an implantable stimulator. The breathing external monitor utilizes an ECG sensor to identify abnormal breathing patterns associated with OSA with 88.68% accuracy, achieved through the utilization of a convolutional neural network (CNN) algorithm. With a skin thickness of 5 mm and a receiving coil diameter of 9 mm, the power conversion efficiency was measured as 31.8%. The implantable device, on the other hand, is composed of a front-end CMOS power management module (PMM), a binary-phase-shift-keying (BPSK)-based data demodulator, and a bipolar biphasic current stimuli generator. The PMM, with a silicon area of 0.06 mm2 (excluding PADs), demonstrated a power conversion efficiency of 77.5% when operating at a receiving frequency of 2 MHz. Furthermore, it offers three-voltage options (1.2 V, 1.8 V, and 3.1 V). Within the data receiver component, a low-power BPSK demodulator was ingeniously incorporated, consuming only 42 µW when supplied with a voltage of 0.7 V. The performance was achieved through the implementation of the self-biased phase-locked-loop (PLL) technique. The stimuli generator delivers biphasic constant currents, providing a 5 bit programmable range spanning from 0 to 2.4 mA. The functionality of the proposed ECG- and WPT-based HGNS was validated, representing a highly promising solution for the effective management of OSA, all while minimizing the trauma and space requirements.

Anthocyanin improves kidney function in diabetic kidney disease by regulating amino acid metabolism.

BACKGROUND: Diabetic kidney disease (DKD) is among the most important causes for chronic kidney disease. Anthocyanins (ANT) are polyphenolic compounds present in various food and play an important role in ameliorating hyperglycemia and insulin sensitivity. However, the effects of ANT in DKD are still poorly understood. This study aimed to investigate the effect of ANT (cyanidin-3-O-glucoside [C3G]) on the renal function of DKD, and whether the anti-DKD effect of ANT is related to metabolic pathways. METHODS: To explore the role of ANT in DKD, we performed the examination of blood glucose, renal function, and histopathology. As for the mechanism, we designed the label-free quantification proteomics and nontargeted metabolomics analysis for kidney and serum. Subsequently, we revealed the anti-DKD effect of ANT through the bioinformatic analysis. RESULTS: We showed that the fasting blood glucose level (- 6.1 mmol/L, P = 0.037), perimeter of glomerular lesions (- 24.1 µm, P = 0.030), fibrosis score of glomerular (- 8.8%, P = 0.002), and kidney function (Cystatin C: - 701.4 pg/mL, P = 0.043; urine creatinine: - 701.4 mmol/L, P = 0.032) were significantly alleviated in DKD mice after ANT treatment compared to untreated in the 20th week. Further, proteins and metabolites in the kidneys of DKD mice were observed to be dramatically altered due to changes in amino acid metabolism with ANT treatment; mainly, taurine and hypotaurine metabolism pathway was upregulated (P = 0.0001, t value = 5.97). Furthermore, upregulated tryptophan metabolism (P < 0.0001, t value = 5.94) and tyrosine metabolism (P = 0.0037, t value = 2.91) pathways had effects on serum of DKD mice as responsed ANT regulating. CONCLUSIONS: Our results suggested that prevention of the progression of DKD by ANT could be related to the regulation of amino acid metabolism. The use of dietary ANT may be one of the dietary strategies to prevent and treat DKD.

N-acetylcysteine prevents oxidized low-density lipoprotein-induced reduction of MG53 and enhances MG53 protective effect on bone marrow stem cells.

MG53 is an important membrane repair protein and partially protects bone marrow multipotent adult progenitor cells (MAPCs) against oxidized low-density lipoprotein (ox-LDL). The present study was to test the hypothesis that the limited protective effect of MG53 on MAPCs was due to ox-LDL-induced reduction of MG53. MAPCs were cultured with and without ox-LDL (0-20 µg/mL) for up to 48 hours with or without MG53 and antioxidant N-acetylcysteine (NAC). Serum MG53 level was measured in ox-LDL-treated mice with or without NAC treatment. Ox-LDL induced significant membrane damage and substantially impaired MAPC survival with selective inhibition of Akt phosphorylation. NAC treatment effectively prevented ox-LDL-induced reduction of Akt phosphorylation without protecting MAPCs against ox-LDL. While having no effect on Akt phosphorylation, MG53 significantly decreased ox-LDL-induced membrane damage and partially improved the survival, proliferation and apoptosis of MAPCs in vitro. Ox-LDL significantly decreased MG53 level in vitro and serum MG53 level in vivo without changing MG53 clearance. NAC treatment prevented ox-LDL-induced MG53 reduction both in vitro and in vivo. Combined NAC and MG53 treatment significantly improved MAPC survival against ox-LDL. These data suggested that NAC enhanced the protective effect of MG53 on MAPCs against ox-LDL through preventing ox-LDL-induced reduction of MG53.

Catheter ablation for treatment of patients with atrial fibrillation and heart failure: a meta-analysis of randomized controlled trials.

BACKGROUND: There is a little evidence for the effects of catheter ablation (CA) on hard endpoints in patients with atrial fibrillation (AF) and heart failure (HF). METHODS: PubMed, Embase and Cochrane Library were searched for randomized controlled trials (RCTs) enrolling patients with AF and HF who were assigned to CA, rate control or medical rhythm control groups. This meta-analysis was performed by using random-effect models. RESULTS: Seven RCTs enrolling 856 participants were included in this meta-analysis. CA reduced the risks of all-cause mortality (risk ratio [RR] 0.52, 95% CI 0.35 to 0.76), HF readmission (RR 0.58, 95% CI 0.46 to 0.66) and the composite of all-cause mortality and HF readmission (RR 0.55, 95% CI 0.47 to 0.66) when compared with control. But there was no significant difference in cerebrovascular accident (RR 0.56, 95% CI 0.23 to 1.36) between two groups. Compared with control, CA was associated with improvement in left ventricular ejection fraction (mean difference [MD] 7.57, 95% CI 3.72 to 11.41), left ventricular end systolic volume (MD -14.51, 95% CI -26.84 to - 2.07), and left ventricular end diastolic volume (MD -3.78, 95% CI -18.51 to 10.96). Patients undergoing CA exhibited increased peak oxygen consumption (MD 3.16, 95% CI 1.09 to 5.23), longer 6-min walk test distance (MD 26.67, 95% CI 12.07 to 41.27), and reduced Minnesota Living with Heart Failure Questionnaire scores (MD -9.49, 95% CI -14.64 to - 4.34) than those in control group. Compared with control, CA was associated with improved New York Heart Association class (MD -0.74, 95% CI -0.83 to - 0.64) and lower B-type natriuretic peptide levels (MD -105.96, 95% CI -230.56 to 19.64). CONCLUSIONS: CA was associated with improved survival, morphologic changes, functional capacity and quality of life relative to control. CA should be considered in patients with AF and HF.

Apln-CreERT:mT/mG reporter mice as a tool for sprouting angiogenesis study.

BACKGROUND: Angiogenesis is defined as a new blood vessel sprouting from pre-existing vessels, and the sprouting angiogenesis is the start phase of angiogenesis, which is critical for both physiological and pathological processes, such as embryonic development, organ growth, wound healing, tumor growth, diabetic retinopathy and age-related macular degeneration. Better understanding of the mechanisms of sprout angiogenesis will provide a rationale for the treatments of these angiogenesis related diseases. METHODS: mT/mG tool mice are crossed with Apln-CreERT mice to generate Apln-CreERT: mT/mG mice, then we used neonatal retinal angiogenesis model to observe the angiogenic pattern of Apln-CreERT:mT/mG mice compared with Cdh5-CreERT:mT/mG mice. FACS analysis was used to sort eGFP and tdTomato endothelial cells (ECs) for measuring Apelin and Cdh5 expression. Retinal sprouting angiogenesis pattern was also observed at different neonatal time when induced by tamoxifen and at hypoxia condition, as well as in vivo tumor in real-time angiogenesis in a dorsal skinfold window chamber in Apln-CreERT:mT/mG mice. RESULTS: Apln-CreERT:mT/mG mice exhibited eGFP signal only in the sprouting angiogenesis, with less eGFP expression in the retinal "optic nerve" area than in that of Cdh5-CreERT: mT/mG mice, which might be due to relative mature vessels in the "optic nerve" area. The ECs sorted by FACS confirmed that the Apelin expression level was higher in eGFP ECs than tdTomato ECs of "optic nerve" area. Further we found that GFP-labeled sprouting angiogenesis decreased gradually following tamoxifen administration from P5-P7, but increased significantly during hypoxia in Apln-CreERT:mT/mG mice. At last, using Apln-CreERT:mT/mG mice we found tumor sprouting angiogenesis in dorsal skinfold, but not in the normal skinfold tissue. CONCLUSIONS: Apln-CreERT:mT/mG mouse line is a useful tool to differentiate sprouting angiogenesis from whole blood vessels in the investigation of retinal and tumor sprouting angiogenesis in vivo.

[Efficacy of tongfu mixture for treating post-ERCP pancreatitis: a clinical study].

OBJECTIVE: To observe the clinical efficacy of Tongfu Mixture (TM) for post-ERCP pancreatitis (PEP). METHODS: Totally 54 PEP patients were randomly assigned to the control group (treated by routine therapy, 26 cases) and the TM treatment group (treated by TM, 28 cases). Clinical indices including the alleviation time of abdominal pain/distention, gastrointestinal function recovery time, and the post-surgical length of stay were observed. Blood amylase (AMY), C-reactive protein (CRP), plasma endotoxin (PLS), TNF-alpha, and IL-6 were detected before surgery, 12 h, 48 h, and 96 h after surgery. RESULTS: The alleviation time of abdominal pain/distention, the gastrointestinal function recovery time, and the post-surgical length of stay were obviously shorter in the TM treatment group than those in the control group (P < 0.05). The recovery of AMY and CRP were better in the TM treatment group than in the control group at post-operative 48 h and 96 h (P < 0.05). The levels of LPS, TNF-alpha, and IL-6 were lower in the TM group than in the control group at post-operative 96 h (P < 0.05). CONCLUSION: TM showed better clinical efficacy and could significantly decrease the post-surgical length of stay. post-ERCP pancreatitis; integrative medicine; Tongfu Mixture

Enhanced removal of phosphate from aqueous solutions by oxygen vacancy-rich MgO microspheres: Performance and mechanism.

The efficient removal of phosphate from water environments was extremely significant to control eutrophication of water bodies and prevent further deterioration of water quality. In this study, oxygen vacancy-rich magnesium oxide (OV-MgO) microspheres were synthesized by a simple solvothermal method coupling high-temperature calcination. The effects of adsorbent dosage, contact time, initial pH and coexisting components on phosphate adsorption performance were examined. The physicochemical properties of OV-MgO microspheres and the phosphate removal mechanisms were analyzed by various characterization techniques. The maximum adsorption capacity predicted by the Sips isotherm model was 379.7 mg P/g for OV-MgO microspheres. The phosphate adsorption in this study had a fast adsorption kinetics and a high selectivity. OV-MgO microspheres had a good acid resistance for phosphate adsorption, but their adsorption capacity decreased under alkaline conditions. The electrostatic attraction, ligand exchange, surface precipitation, inner-sphere surface complexation and oxygen vacancy capture were mainly responsible for efficient removal of phosphate from aqueous solutions. This study probably promoted the development of oxygen vacancy-rich metal (hydr)oxides with potential application prospects.

Effects of quaternization sites and crossing methods on the slow-release and antibacterial effects of hydroxypropyltrimethyl ammonium chloride chitosan/dialdehyde chitosan-based film.

In this study, the active food packaging film were prepared using hydroxypropyltrimethyl ammonium chloride chitosan with different substitution sites (O-HACC & N-HACC) and dialdehyde chitosan (DCS) grafted with protocatechuic acid (PA). To explore the effect of chitosan quaternization positions and crosslinking approaches on the slow-release and antibacterial properties, the double-crosslinked film were fabricated through the self-coupling reaction of PA and Schiff base reaction between amino groups on HACC and aldehyde groups on DCS. The HACC/DCS-based film exhibited stable porous three-dimensional networks with high nisin loading ratios (>90 %). With the participation of the catechol-catechol structure, the dense double-crosslinked film effectively restricted the diffusion of the water molecules, resulting in excellent slow-release properties fitting with the Korsmeyer-Peppas kinetic model. Especially, O-HACC/PA-g-DCS film, which had more reaction sites for Schiff base crosslinking than N-HACC, exhibited the equilibrium swelling ratio of 800 % at 60 h and could sustainably release nisin via non-Fickian diffusion behavior until 48 h. Moreover, the HACC/DCS-based double-crosslinked film performed good long-time antibacterial activity and preservation effects on salmon. On the 10th day of storage, the TVBN of N-HACC/PA-g-DCS and O-HACC/PA-g-DCS groups were only 28.26 ± 1.93 and 29.06 ± 1.68 mg/100 g and still lower than the thresholds.

Arsenic-enhanced plant growth in As-hyperaccumulator Pteris vittata: Metabolomic investigations and molecular mechanisms.

The first-known As-hyperaccumulator Pteris vittata is efficient in As uptake and translocation, which can be used for phytoremediation of As-contaminated soils. However, the underlying mechanisms of As-enhanced plant growth are unknown. We used untargeted metabolomics to investigate the potential metabolites and associated metabolic pathways regulating As-enhanced plant growth in P. vittata. After 60 days of growth in an MS-agar medium containing 15 mg kg-1 As, P. vittata biomass was 33-34 % greater than the no-As control. Similarly, the As contents in P. vittata roots and fronds were 272 and 1300 mg kg-1, considerably greater than the no-As control. Univariate and multivariate analyses based on electrospray ionization indicate that As exposure changed the expression of 1604 and 1248 metabolites in positive and negative modes. By comparing with the no-As control, As exposure significantly changed the expression of 14 metabolites including abscisic acid, d-glucose, raffinose, stachyose, chitobiose, xylitol, gibberellic acids, castasterone, citric acid, riboflavin-5-phosphate, ubiquinone, ubiquinol, UDP-glucose, and GDP-glucose. These metabolites are involved in phytohormone synthesis, energy metabolism, and sugar metabolism and may all potentially contribute to regulating As-enhanced plant growth in P. vittata. Our data provide clues to understanding the metabolic regulations of As-enhanced plant growth in P. vittata, which helps to enhance its phytoremediation efficiency of As-contaminated soils.

Unraveling paraquat-induced toxicity on mouse neural stem cells: Dose-response metabolomics insights and identification of sensitive biomarkers for risk assessment.

Exposure to pesticide could contribute to neurodevelopmental and neurodegenerative disorders. Notably, research suggests that prenatal or early postnatal exposure to paraquat (PQ), an herbicide, might trigger neurodevelopmental toxicity in neural stem cells (NSCs) via oxidative stress. However, the molecular mechanisms of PQ-induced perturbations in NSCs, particularly at the metabolite level, are not fully understood. Using a dose-response metabolomics approach, we examined metabolic changes in murine NSCs exposed to different PQ doses (0, 10, 20, 40 µM) for 24h. At 20 µM, PQ treatment led to significant metabolic alterations, highlighting unique toxic mechanisms. Metabolic perturbations, mainly affecting amino acid metabolism pathways (e.g., phenylalanine, tyrosine, arginine, tryptophan, and pyrimidine metabolism), were associated with oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. Dose-response models were used to identify potential biomarkers (e.g., Putrescine, L-arginine, ornithine, L-histidine, N-acetyl-L-phenylalanine, thymidine) reflecting early damage from low-dose PQ exposure. These biomarkers could be used as points of departure (PoD) for characterizing PQ exposure hazard in risk assessment. Our study offers insights into mechanisms and risk assessment related to PQ-induced neurotoxicity in NSCs.

Injectable Inflammation-Responsive Hydrogels for Microenvironmental Regulation of Intervertebral Disc Degeneration.

Chronic local inflammation and excessive cell apoptosis in nucleus pulposus (NP) tissue are the main causes of intervertebral disc degeneration (IDD). Stimuli-responsive hydrogels have great potential in the treatment of IDD by facilitating localized and controlled drug delivery. Herein, an injectable drug-loaded dual stimuli-responsive adhesive hydrogel for microenvironmental regulation of IDD, is developed. The gelatin methacryloyl is functionalized with phenylboronic acid groups to enhance drug loading capacity and enable dual stimuli-responsive behavior, while the incorporation of oxidized hyaluronic acid further improves the adhesive properties. The prepared hydrogel exhibits an enhanced drug loading capacity for diol-containing drugs, pH- and reactive oxygen species (ROS)-responsive behaviors, excellent radical scavenging efficiency, potent antibacterial activity, and favorable biocompatibility. Furthermore, the hydrogel shows a beneficial protective efficacy on NP cells within an in vitro oxidative stress microenvironment. The in vivo results demonstrate the hydrogel's excellent therapeutic effect on treating IDD by maintaining water retention, restoring disc height, and promoting NP regeneration, indicating that this hydrogel holds great potential as a promising therapeutic approach for regulating the microenvironment and alleviating the progression of IDD.

Injectable pathological microenvironment-responsive anti-inflammatory hydrogels for ameliorating intervertebral disc degeneration.

Chronic local inflammation and resulting cellular dysfunction of nucleus pulposus (NP) cells are important pathogenic factors of intervertebral disc degeneration (IDD). Injectable pathological microenvironment-responsive hydrogels hold significant potential for treating IDD by adapting to dynamic microenvironment of IDD. Herein, we proposed an injectable gelatin-based hydrogel drug delivery system that could respond to the pathological microenvironment of IDD for controlled release of anti-inflammatory drug to promote degenerative NP repair. The hydrogel system was prepared by conjugating phenylboronic acid-modified gelatin methacryloyl (GP) with the naturally extracted anti-inflammatory drug epigallocatechin-3-gallate (EGCG) through dynamic boronic esters. The hydrogel exhibited excellent degradability, injectability, antioxidant properties, anti-inflammatory effects, and biocompatibility. It also displayed responsive-release of EGCG under high reactive oxygen species (ROS) levels and acidic conditions. The hydrogel demonstrated remarkable cytoprotective effects on NP cells in both hyperactive ROS environments and inflammatory cytokine-overexpressed environments in vitro. In vivo studies revealed that the hydrogel injected in situ could effectively ameliorate the intervertebral disc degeneration by maintaining the disc height and NP tissue structure in a rat IDD model. The hydrogel system exhibited excellent biocompatibility and responsive-release of diol-containing drugs in pathological microenvironments, indicating its potential application as a drug delivery platform.

The Preparation and Properties of Amino-Carboxymethyl Chitosan-Based Antibacterial Hydrogel Loaded with ε-Polylysine.

In this paper, amino-carboxymethyl chitosan (ACC) was prepared through amino carboxymethylation, which introduces -COOH and -NH2 groups to the chitosan (CS) chains. Meanwhile, dialdehyde starch (DAS) was produced by oxidizing corn starch using sodium periodate. To attain the optimal loading and long-time release of ε-polylysine (ε-PL), the ACC/DAS hydrogels were synthesized through the Schiff base reaction between the amino group on ACC and the aldehyde group in DAS. The molecular structure, microcosmic properties, loading capacity, and bacteriostatic properties of the four types of hydrogels containing different mass concentrations of ACC were investigated. The results showed that the dynamic imine bond C=N existed in the ACC/DAS hydrogels, which proved that the hydrogels were formed by the cross-linking of the Schiff base reaction. With the increasing mass concentration of the ACC, the cross-sectional morphology of the hydrogel became smoother, the thermal stability increased, and the swelling behavior was gradually enhanced. The tight network structure improved the ε-PL loading efficiency, with the highest value of 99.2%. Moreover, the loading of ε-PL gave the hydrogel good antibacterial properties. These results indicate that ACC/DAS hydrogel is potential in food preservation.

Vasoactive intestinal peptide exerts therapeutic action by regulating PTEN in a model of Sjögren's disease.

INTRODUCTION: Sjögren's disease (SjD) is a chronic autoimmune disease characterized by the loss of the secretory function of the exocrine glands. At present, drugs that can both correct the immune imbalance and improve exocrine gland function are needed. Meanwhile, vasoactive intestinal peptide (VIP) has been reported as a candidate with anti-inflammatory and immunoregulatory properties for treating autoimmune diseases. METHODS: Nonobese diabetic (NOD) mice and the primary splenic lymphocyte cells (SPLCs) were used to construct the SS model. The therapeutic effects of VIP for SjD by evaluating water consumption, histopathology, T cell subsets, and related cytokines. RT-qPCR and Western blot analysis were used to identify the expression of the PTEN/PI3K/AKT pathway. RESULTS: We found that VIP therapy in NOD mice could increase the expression of PTEN and VIP/VPAC1 receptor, as well as decrease the PI3K/AKT pathway. In vitro, the results showed that the PTEN knockdown decreased the Treg/Th17 ratio and enhanced the phosphorylated PI3K/AKT pathway, which were reversed with VIP treatment. CONCLUSIONS: VIP exerts potential therapeutic action in SjD by upregulating PTEN through the PI3K/AKT pathway and Treg/Th17 cell balance.

The binary combined toxicity of lithium, lead, and manganese on the proliferation of murine neural stem cells using two different models.

As persistent environmental pollutants, more than thirty metals impose a potential global threat to the environment and humans, which has raised scientific concerns. Although the toxic effects of metals had been extensively studied, there is a paucity of information on their mixture toxicity. In this study, we examined the individual and binary combined toxicity of three common metals such as lithium (Li), lead (Pb), and manganese (Mn) on the proliferation of murine neural stem cells (mNSCs), respectively. Li, Pb, and Mn reduced cell proliferation at the concentration of 5.00 mM, 2.50 µM, and 5.00 µM, respectively (all p < 0.050), in a dose-dependent manner of each metal solely on mNSCs with the cytotoxicity rank as Pb > Mn > Li. Furthermore, the interactions of metal mixtures on mNSCs were determined by using response-additivity and dose-additivity models. Pb + Mn mixtures showed a more than additive effect (synergistic) of toxicity in both two methods. In the dose-additivity method, Pb + Li and Li + Mn mixtures exhibited synergistic effects in the compound with a high ratio of Li (25.0% Pb/75.0% Li, 75.0% Li/25.0% Mn), whereas they are antagonistic in the lower or equal ratio of Li (such as 75.0% Pb/25.0% Li, 25.0% Li/75.0% Mn). Besides, the interactions of Li + Mn mixtures showed some discrepancies between different endpoints. In conclusion, our study highlights the complexity of the mixtures' interaction patterns and the possible neuroprotective effect of Li under certain conditions. In the future, more research on different levels of metal mixtures, especially Li metal, is necessary to evaluate their underlying interactions and contribute to establishing risk assessment systems.