ABSTRACT
Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking1,2. The molecular mechanism that underlies this temporal pattern is unclear. Here we show that the nuclear receptors REV-ERB-α and REV-ERB-ß (referred to here as 'REV-ERB') in the GABAergic (γ-aminobutyric acid-producing) neurons in the suprachiasmatic nucleus (SCN) (SCNGABA neurons) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviours during regular light-dark cycles. REV-ERB regulates the rhythmic expression of genes that are involved in neurotransmission in the SCN, and modulates the oscillatory firing activity of SCNGABA neurons. Chemogenetic stimulation of SCNGABA neurons at waking leads to glucose intolerance, whereas restoration of the temporal pattern of either SCNGABA neuron firing or REV-ERB expression rescues the time-dependent glucose metabolic phenotype caused by REV-ERB depletion. In individuals with diabetes, an increased level of blood glucose after waking is a defining feature of the 'extended dawn phenomenon'3,4. Patients with type 2 diabetes with the extended dawn phenomenon exhibit a differential temporal pattern of expression of REV-ERB genes compared to patients with type 2 diabetes who do not have the extended dawn phenomenon. These findings provide mechanistic insights into how the central circadian clock regulates the diurnal rhythm of hepatic insulin sensitivity, with implications for our understanding of the extended dawn phenomenon in type 2 diabetes.
Subject(s)
Circadian Rhythm , GABAergic Neurons/physiology , Insulin Resistance , Liver/physiology , Nuclear Receptor Subfamily 1, Group D, Member 1/physiology , Animals , Blood Glucose , Circadian Clocks , Diabetes Mellitus, Type 2 , Female , Glucose/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Photoperiod , Suprachiasmatic Nucleus/cytology , Synaptic TransmissionABSTRACT
Islet fibrosis is associated with the disruption of islet structure and contributes to ß-cell dysfunction, playing an essential role in the pathogenesis of type 2 diabetes. Physical exercise has been shown to attenuate fibrosis in various organs; however, the effect of exercise on islet fibrosis has not been defined. Male Sprague-Dawley rats were divided into four groups: normal diet sedentary [N-Sed], normal diet + exercise [N-Ex], high-fat diet sedentary [H-Sed], and high-fat diet + exercise [H-Ex]. After 60 weeks of exercise, 4452 islets from Masson-stained slides were analyzed. Exercise led to a 68% and 45% reduction in islet fibrosis in the normal and high-fat diet groups and was correlated with a lower serum blood glucose. Fibrotic islets were characterized by irregular shapes and substantial loss of ß-cell mass, which were significantly reduced in the exercise groups. Remarkably, the islets from exercised rats at week 60 were morphologically comparable to those of sedentary rats at 26 weeks. In addition, the protein and RNA levels of collagen and fibronectin, and the protein levels of hydroxyproline in the islets were also attenuated by exercise. This was accompanied by a significant reduction in inflammatory markers in the circulation Interleukin-1 beta (IL-1ß)] and pancreas [IL-1ß, Tumor Necrosis Factor-alpha, Transforming Growth Factor-ß, and Phosphorylated Nuclear Factor Kappa-B p65 subunit], lower macrophage infiltration, and stellate cell activation in the islets of exercised rats. In conclusion, we have demonstrated that long-term exercise preserves pancreatic islet structure and ß-cell mass through anti-inflammatory and anti-fibrotic actions, suggesting additional rationales for the success of exercise training in the prevention and treatment of type 2 diabetes that should be further explored.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , Islets of Langerhans , Male , Rats , Animals , Diabetes Mellitus, Type 2/metabolism , Rats, Sprague-Dawley , Pancreas/metabolism , Insulin-Secreting Cells/metabolism , Fibrosis , Inflammation/metabolism , Islets of Langerhans/metabolismABSTRACT
AIM: To examine the associations of tea consumption (both frequency and type) with (1) prediabetes and diabetes and (2) urinary glucose and sodium excretion in Chinese community-dwelling adults. MATERIALS AND METHODS: In 1923 participants (457 with diabetes, 720 with prediabetes, and 746 with normoglycaemia), the frequency (occasional, frequent, daily, or nil) and type (green, black, dark, or other) of tea consumption were assessed using a standardized questionnaire. Morning spot urinary glucose and urine glucose-to-creatinine ratios (UGCRs) were assessed as markers of urinary glucose excretion. Tanaka's equation was used to estimate 24-h urinary sodium excretion. Logistic and multivariate linear regression analyses were performed. RESULTS: Compared with non-tea drinkers, the corresponding multivariable-adjusted odds ratios (ORs) for prediabetes and diabetes were 0.63 (95% confidence interval [CI] 0.48, 0.83) and 0.58 (95% CI 0.41, 0.82) in participants drinking tea daily. However, only drinking dark tea was associated with reduced ORs for prediabetes (0.49, 95% CI 0.36, 0.66) and diabetes (0.41, 95% CI 0.28, 0.62). Dark tea consumption was associated with increased morning spot urinary glucose (0.22 mmol/L, 95% CI 0.11, 0.34 mmol/L), UGCR (0.15 mmol/mmol, 95% CI 0.05, 0.25 mmol/L) and estimated 24-h urinary sodium (7.78 mEq/day, 95% CI 2.27, 13.28 mEq/day). CONCLUSIONS: Regular tea consumption, especially dark tea, is associated with a reduced risk of dysglycaemia and increased urinary glucose and sodium excretion in Chinese community-dwelling adults.
ABSTRACT
Emerging data have revealed that damage to tubular epithelial cell is a driving force in the progression of diabetic kidney disease (DKD). However, the specific mechanisms by which lipotoxicity contributes to the injury of these cells, thereby influencing the development of DKD, are yet to be fully understood. Here, we analyzed the GSE 30529 microarray datasets of human tubulointerstitial tissue samples from the Gene Expression Omnibus database (GEO). Concurrently, we conducted RNA-sequencing on palmitic acid (PA)-treated human renal proximal tubule epithelial cells (HK2 cells). After normalization, the differentially expressed genes (DEGs) were screened by R software and gene ontology (GO) enrichment analysis was conducted, and lysosomal-associated protein transmembrane 5 (LAPTM5) was finally selected. Our findings indicate that the expression of LAPTM5 was obviously increased in DKD patients, and the correlation between LAPTM5, and other clinical parameters of DKD was analyzed using the Spearman correlation analysis. The potential of LAPTM5 as a prognostic biomarker for DKD was further consolidated through receiver operating characteristic (ROC) analysis. To further verify the function of LAPTM5, we established mouse or in vitro systems mimicking DKD. The results showed that a consistent upregulation of LAPTM5, which was also found to be linked with inflammatory mediators within the context of DKD. Additionally, LAPTM5 silencing significantly downregulated mRNA expression of inflammatory factors in PA-treated HK2 cells. These results indicate that LAPTM5 is a potential biomarker and therapeutic treatment target for DKD. This discovery paves the way for future research and development of targeted interventions aimed at mitigating the progression of this prevalent condition.
Subject(s)
Computational Biology , Diabetic Nephropathies , Membrane Proteins , Animals , Humans , Male , Mice , Biomarkers/metabolism , Cell Line , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/genetics , Diabetic Nephropathies/etiology , Diabetic Nephropathies/pathology , Epithelial Cells/metabolism , Epithelial Cells/drug effects , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice, Inbred C57BL , Palmitic Acid/metabolism , Up-RegulationABSTRACT
Previous studies have demonstrated that excess aldosterone impairs glucose metabolism. However, the underlying mechanism is still misty. Aldosterone has been proved a risk factor of fibrosis and inflammation. And the histology of islets from patients with type 2 diabetes (T2D) also displays inflammation and fibrosis. But it is unclear whether aldosterone has direct impact on islet inflammation and fibrosis in T2D. Islet endothelium plays a significant role in the maintenance of islet beta cell function and has a close relationship with islet fibrosis and inflammation. Therefore, we focused on the effect of aldosterone on the islet endothelium. In this study, we utilized a diabetic db/db mouse model and examined serum aldosterone levels, islet macrophages infiltration, and islet fibrosis. After we confirmed that there was an increased expression of intercellular cell adhesion molecule-1 (ICAM-1) and endothelin-1 (ET-1) in islet of diabetic mice compared with wild type mice. We next determined that aldosterone increased expression of ICAM-1 and ET-1 in both mRNA and protein levels in islet endothelium in vitro. And then we tested the expression of mineralocorticoid receptor (MR) in islet endothelium in vitro and in vivo. Our results showed that aldosterone can up-regulate the expression levels of ICAM-1 and ET-1 through MR. These findings suggest excess aldosterone might participate in islet inflammation and fibrosis in T2D.
Subject(s)
Aldosterone/immunology , Diabetes Mellitus, Type 2/pathology , Endothelin-1/immunology , Intercellular Adhesion Molecule-1/immunology , Islets of Langerhans/pathology , Aldosterone/analysis , Animals , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/immunology , Disease Progression , Endothelin-1/analysis , Endothelin-1/genetics , Endothelium/immunology , Endothelium/pathology , Fibrosis , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Intercellular Adhesion Molecule-1/analysis , Intercellular Adhesion Molecule-1/genetics , Islets of Langerhans/immunology , Mice , Up-RegulationABSTRACT
Material made of artificial molecules fabricated from cage-shaped granules of conductor (CGC) is introduced and its electrical and magnetic characteristics are presented. Its refractive index, calculated using complex relative permittivity and complex relative permeability, is 1.504 at 35 GHz. A two-element lens, consisting of a pair of spherical plano-convex lenses, was designed and fabricated by embedding CGC in poly(methyl methacrylate). The active millimeter-wave imaging system was constructed with the two-element lens by having the curved surfaces face each other. Millimeter-wave (MMW) images of a right trapezoid and twin bars were obtained. The image quality was acceptable, proving that the CGC material has the ability to refract MMWs in MMW imaging and that the ability contrasts with that of some traditional high polymer material.
ABSTRACT
A slab focusing lens in this work has been designed, which consists of electromagnetic-induction materials (cage-shaped granules of conductor materials) and polymethyl methacrylate (PMMA) materials. A compound lens with a thickness of 32 mm is composed of two slab focusing lenses, and has a refractive index of 1.41 at 35 GHz. Millimeter-wave (MMW) images of metallic objects have been obtained with the compound lens. The image quality has been compared by means of the compound lens and the polyethylene lens. The experimental results show good feasibility of the compound lens in MMW imaging.
ABSTRACT
Aiming at exploring clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor, this study divided 60 patients with gastrointestinal tumor into control and observation groups, each containing 30 patients. The observation group was treated with oxaliplatin combined with flurouracil, while the control was treated with FOLFOX4, i.e., intravenously dropping 85mg/m(2)Oxaliplatin (L-OHP), 200mg/m(2) calcium folinate (CF) and intravenously injecting 400mg/m(2) 5-fluorouracil (5-Fu), and 600mg/m(2) 5-Fu; then continuously performing intravenous drop infusion for 22h, every two weeks for a cycle. Hypodermic injection of granulocyte colony-stimulating factor (G-CSF) was conducted immediately when leukocytes occurred the III, IV degree of inhibition. The observation results of curative effect and negative reaction indicated higher effective rate with 83.33% in the observation and 50.00% in the control. Besides, in the observation, negative reactions possessed 10.00% that was much lower than 33.33% in the control. Thereby, the conclusion reached that the treatment of gastrointestinal tumor with oxaliplatin combined with flurouracil was worth promoting.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , China , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Gastrointestinal Neoplasms/pathology , Humans , Infusions, Intravenous , Leucovorin/administration & dosage , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Time Factors , Treatment OutcomeABSTRACT
Interfacial Lewis acid-base pairs are commonly found in ZrO2-supported metal catalysts due to the facile generation of oxygen vacancies of ZrO2. These pairs have been reported to play a crucial role in olefin hydroesterification, especially in the absence of acid promoters and ligands. In this study, a series of ZrO2-supported Ru catalysts with ruthenium(iii) chloride and ruthenium(iii) acetylacetonate as precursors were prepared for the styrene hydroesterification. The catalysts were thoroughly characterized by TPR, TEM, EPR, XPS, and FTIR. The Ru precursors significantly influenced the size and electronic properties of Ru clusters, albeit having minimal impact on oxygen vacancies. Mechanistic studies of styrene hydroesterification over ZrO2-supported Ru catalysts revealed that the carbon monoxide insertion followed the hydrogen transfer step to activated styrene. Higher activity is exhibited over ZrO2-supported Ru catalysts prepared with ruthenium(iii) chloride as a precursor, attributed to the lower adsorption strength of CO over Ru clusters, as evidenced by FTIR and DFT calculations.
ABSTRACT
BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.
Subject(s)
Adenocarcinoma , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Docetaxel , Esophageal Neoplasms , Esophagogastric Junction , Fluorouracil , Leucovorin , Neoadjuvant Therapy , Stomach Neoplasms , Humans , Female , Male , Middle Aged , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Esophagogastric Junction/pathology , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adult , Leucovorin/administration & dosage , Leucovorin/adverse effects , Leucovorin/therapeutic use , Fluorouracil/administration & dosage , Docetaxel/administration & dosage , Docetaxel/adverse effects , Docetaxel/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Oxaliplatin/administration & dosage , Oxaliplatin/adverse effects , Oxaliplatin/therapeutic use , Receptor, ErbB-2/metabolismABSTRACT
BACKGROUND: The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. METHODS: A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. RESULTS: This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. CONCLUSION: The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.
Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Neoadjuvant Therapy , Stomach Neoplasms , Adult , Aged , Female , Humans , Male , Middle Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fluorouracil/therapeutic use , Leucovorin/therapeutic use , Multiomics , Neoadjuvant Therapy/methods , Organoplatinum Compounds/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Treatment OutcomeABSTRACT
BACKGROUND AIMS: Defocused low-energy shock wave (DLSW) therapy has shown effectiveness in regenerative medicine. The mechanism of action was mainly focused on the pathophysiological improvement at the wound tissues. In this study, the activation of stem cells treated by DLSW was first examined as an important pathway during the healing process. METHODS: Cultured rat bone marrow-derived mesenchymal stromal cells (BMSC) were treated by DLSW before each passage. The untreated BMSC served as a control. The secretions of vascular endothelial growth factor (VEGF) and CXC ligand 5 (CXCL5) were tested by means of enzyme-linked immunoassay. Flow cytometry was performed to analyze the BMSC (passage 4) surface antigen expressions (CD166, CD44 and CD34). The expressions of proliferating cell nuclear antigen and Ki67 were analyzed by means of Western blot. The healing abilities of conditioned media of shocked and unshocked BMSC were examined by Matrigel-based capillary-like tube formation assay and rat major pelvic ganglia culture test. RESULTS: The shocked BMSC secreted more VEGF and CXCL5 than did those of unshocked BMSC. The expressions of CD166, CD44 and CD34 showed no significant differences (P > 0.05) between the shocked and unshocked BMSC. The shocked BMSC demonstrated higher expressions of proliferating cell nuclear antigen (P < 0.01) and Ki67 (P < 0.01) than did those of unshocked BMSC. The shocked BMSC conditioned medium showed higher ability to enhance the growth of major pelvic ganglia neurites (P < 0.05) and Matrigel-based endothelial tube-like formation (P < 0.05). CONCLUSIONS: DLSW did not interfere with the expressions of cell surface markers. DLSW enhanced the secretion and proliferation of BMSC and promoted angiogenesis and nerve regeneration in vitro.
Subject(s)
Electroconvulsive Therapy , Neovascularization, Physiologic/radiation effects , Nerve Regeneration/radiation effects , Wound Healing , Animals , Bone Marrow Cells/radiation effects , Chemokine CXCL5/metabolism , Flow Cytometry , Ganglia/growth & development , Mesenchymal Stem Cells/radiation effects , Nerve Regeneration/physiology , Pelvis/growth & development , Rats , Regenerative Medicine , Stem Cells/radiation effects , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Carbenium ions in zeolites: Two important carbenium ions have been observed for the first time under working conditions of the methanol-to-olefins (MTO) reaction over chabazite zeolites using (13) Câ NMR spectroscopy. Their crucial roles in the MTO reaction cycles have been demonstrated by combining experiments and theoretical calculations.
ABSTRACT
As an admixture of cement-based materials, the reaction of fly ash (FA) usually takes place in the late age of curing, so FA will affect the self-healing ability of long-age cement-based materials. The self-healing potential and the characteristics of self-healing products of cementitious materials before and after crack healing were analyzed by microscopic tests, and the mechanism of the effect of fly ash on the self-healing performance of cementitious materials was revealed. The results showed that the increase in fly ash content promoted the improvement of the self-repair performance of cracked specimens at 28 d, especially when the fly ash dosage was 40%, the crack opened after 30 d of healing in water was completely closed, the UPV value after recovery was close to 3000 m/s, the self-repair efficiency of maximum amplitude and main frequency amplitude was up to more than 60%, and the recovery rate of compressive strength was increased to more than 30%. However, the increase in fly ash content was not conducive to the self-repair of cracked samples at 210 d, and with the increase in fly ash content, the crack closure effect weakened, the UPV value after recovery decreased, the crack repair rate based on ultrasonic transmission decreased to about 20%, and the compressive strength recovery rate increased slightly. In addition, calcium carbonate precipitation was the main repair product of crack filling and healing, including calcite and spherulite. With the increase in fly ash content, the content of element C in the self-repair products of 28-day-old specimens gradually increased, and the size of calcium carbonate crystals gradually decreased, but the filling was denser, whereas the calcium carbonate crystals in the self-repair products of 210 d specimens gradually became fine and loose.
ABSTRACT
This study investigated the effect of the interaction between ultrafine slag powder (USL) and limestone (LS) on the rheology behavior, microstructure, and fractal features of UHPC. The results indicated that B2 with mass ratio of 2:1 between the USL and LS obtained the highest compressive strength and the lowest yield stress. The combination of the USL and LS facilitated the cement hydration, ettringite, and monocarboaluminate (Mc) formation, as well as the increase in the polymerization of the C-S-H. The synergistic action between the USL and LS refined the pore structure due to the formation of the Mc, compensating for the consumption of the CH by the pozzolanic reaction, which provided a denser microstructure in the UHPC. The fractal dimension (Ds) of the UHPC was strongly related to the concrete pore structures and the compressive strength, which demonstrated that a new metric called the Ds value may be used to assess the synergistic effect of the UHPC.
ABSTRACT
Pancreatic stellate cells (PSCs) are suggested to play an important role in the development of pancreas and islet fibrosis. However, the precise contributions and solid in vivo evidence of PSCs to the fibrogenesis remain to be elucidated. Here, we developed a novel fate-tracing strategy for PSCs by vitamin A administration in Lrat-cre; Rosa26-tdTomato transgenic mouse. The results showed that stellate cells give rise to 65.7% of myofibroblasts in cerulein-induced pancreatic exocrine fibrosis. In addition, stellate cells in islets increase and contribute partly to myofibroblasts pool in streptozocin-induced acute or chronic islet injury and fibrosis. Furthermore, we substantiated the functional contribution of PSCs to fibrogenesis of pancreatic exocrine and islet in PSCs ablated mice. We also found stellate cells' genetic ablation can improve pancreatic exocrine but not islet fibrosis. Together, our data indicates that stellate cells are vital/partial contributors to myofibroblasts in pancreatic exocrine/islet fibrosis.
ABSTRACT
Owing to its unique physical and chemical properties, graphene oxide (GO) has a wide range of applications in biomedical field. However, with the gradual improvement of biosafety investigations on nanomaterials, growing literatures have pointed out that GO could lead to oxidative stress, aggravation of inflammatory responses, and even irreversible lesions in human multi-tissues, while its damage to small intestinal remained unclear. In this study, we conducted an in-depth study on the toxicological effect of GO on intestinal tissues, and further clarified its toxic effect and molecular mechanism on inducing intestinal cell death. Firstly, we characterized the shape size, potential value, Fourier Transform infrared spectroscopy (FT-IR) characterization and pro-oxidant properties of GO nanosheets. The cytotoxicity of different concentrations of GO to Caco-2 and IEC-6 cell lines was thereafter observed, which was specifically manifested as invoking NADPH Oxidase 1 (NOX1) proteins, accompanied generation of reactive oxygen species (ROS). Since that, more p53 flowed into mitochondria to combine with cyclophilin D (CYPD), thus induced mitochondrial permeability transition pore (mPTP) opening. Through ROS-CyPD-mPTP signaling pathway, GO exerted imbalance of mitochondrial homeostasis, while released cytochrome c (CytC) would ultimate caspase-dependent cell apoptosis. In vivo experiment also confirmed that the microstructure of small intestine was damaged, and the apoptosis rate and oxidative markers were significantly increased in GO-treated Sprague- Dawley (SD) rats (40 mg/kg once every other day from day 1 to day 9 by oral gavage). Based on these findings, we conclude that the adverse effects of oral exposure of GO on the biological system mainly concentrate in the digestive tract, and clarify the key role of ROS-mitochondrial homeostasis-apoptosis axis in GO-derived intestinal toxicity. Considering all these results and the fact that GO exhibited intestinal toxicity, we believe that this research providing a safety reference for its biomedical applications.
Subject(s)
Mitochondrial Permeability Transition Pore , Tumor Suppressor Protein p53 , Animals , Apoptosis , Caco-2 Cells , Graphite , Humans , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins , Rats , Reactive Oxygen Species/metabolism , Spectroscopy, Fourier Transform Infrared , Tumor Suppressor Protein p53/metabolismABSTRACT
Alkali-activated materials, a new kind of low-carbon cement, have received extensive attention. While in order to obtain excellent functions, the modification of alkali-activated materials by nano-materials has become one of the important research directions of alkali-activated materials. Therein, the hydration property, mechanical properties, and action mechanism of the alkali-activated slag with and without graphene oxide (GO) were analyzed and evaluated. Results showed the compressive strength of mortar decreased at 3 days and 28 days by adding GO. While the flexural strength of mortar cured for different ages increased with increasing GO content, and the flexural strength increasing rate reached up to 15.94% at 28 days, thus, the toughening effect of GO was significant. GO accelerated the hydration process of alkali-activated slag because the functional groups offered nucleation sites to induce the generation of more hydration products. Furthermore, the addition of GO increased the number of harmless pores and reduced the pore size, but also introduced a large number of harmful pores, resulting in the reduction of compressive strength.
ABSTRACT
With the construction of projects under severe environments, new and higher requirements are put forward for the properties of concrete, especially the autogenous self-sealing property, which is greatly affected by the curing environment and the state of the water. Herein, six types of curing conditions, including in air with a relative humidity of 30%, 60%, and 95%; flowing water; wet-dry cycles; and static water, are designed to investigate the autogenous self-sealing of mortar under different curing conditions. The results showed that the self-sealing ratios are higher than 60% and the cracks are closed for the mortar undergoing the wet-dry cycles and the static water. However, the self-sealing ratios of mortar are lower than 10% and the cracks are almost unchanged when the mortar is cured in the air with a relative humidity (RH) of 30% and 60%. The static liquid water is more conducive to the continued hydration of cement and the formation of CaCO3 than the flowing water. The research provides guidance for the design of concrete and the improvement of autogenous self-sealing when the concrete serves in different environments.