This study introduces a new scale-dependent viscosity model, in which transesterification reaction of polycarbonate/poly(ethylene terephthalate) (PC/PET) blends with various phase morphologies and ...micro-scale effects have been taken into account. It is found that a
Power-law
model can be used to quantitatively describe the relationship between the degree of transesterification and shear rate employed during compounding of PC and PET. A micro-scale viscosity model, which incorporates the micro-scale effects, has been developed by characterizing the flow using a double-barrel capillary rheometer with different microscale channels. For both neat PC and PC/PET blends, under the conditions of the constant shear rate and melt temperature, the shear viscosity dropped with decreasing capillary diameter because of the wall-slip effect. The proposed viscosity model based on the Cross equation can describe the variation of shear viscosity for PC/PET blends under both macro- and micro-scale conditions. Less than 7% average error is obtained between the model predictions and rheological experimental data. Filling simulation and micro-injection molding (µIM) short-shot experiments were conducted to validate the accuracy of the proposed viscosity model. For all the
L
9
(3
4
) design of experiment (DOE) molding trials, the average relative error under the micro-scale condition was 4.5±1.1%, which is much smaller than that of the average relative error under the macro-scale condition at 11.4±2.7%.
Metformin is an oral biguanide commonly used for treating type II diabetes and has recently been reported to possess antiproliferative properties that can be exploited for the prevention and ...treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Our study shows a marked loss of AMP‐activated protein kinase (AMPK) phosphorylation and nuclear human Forkhead box O1 (FOXO1) protein in estrogen‐dependent endometrial cancer (EC) tumors compared to normal control endometrium. Metformin treatment suppressed EC cell growth in a time‐dependent manner in vitro; this effect was cancelled by cotreatment with an AMPK inhibitor, compound C. Metformin decreased FOXO1 phosphorylation and increased FOXO1 nuclear localization in Ishikawa and HEC‐1B cells, with non‐significant increase in FOXO1 mRNA expression. Moreover, compound C blocked the metformin‐induced changes of FOXO1 and its phosphorylation protein, suggesting that metformin upregulated FOXO1 activity by AMPK activation. Similar results were obtained after treatment with insulin. In addition, transfection with siRNA for FOXO1 cancelled metformin‐inhibited cell growth, indicating that FOXO1 mediated metformin to inhibit EC cell proliferation. A xenograft mouse model further revealed that metformin suppressed HEC‐1B tumor growth, accompanied by downregulated ki‐67 and upregulated AMPK phosphorylation and nuclear FOXO1 protein. Taken together, these data provide a novel mechanism of antineoplastic effect for metformin through the regulation of FOXO1, and suggest that the AMPK–FOXO1 pathway may be a therapeutic target to the development of new antineoplastic drugs.
Metformin may exert its anti‐proliferative effect on EC cells by activating AMPK and thus decreasing phosphorylation of FOXO1 protein, thereby triggering the relocalization of FOXO1 protein from the cytoplasm to the nucleus and resulting in increased FOXO1 activity. This study provide a novel mechanism of anti‐neoplastic effect for metformin through the regulation of FOXO1, and suggest that AMPK‐FOXO1 pathway may be a therapeutic target to the development of new anti‐neoplastic drugs.
The prevalence of diabetes mellitus has exhibited a notable surge in recent years, thereby augmenting the susceptibility to fractures and impeding the process of fracture healing. The primary ...objective of this investigation is to employ synchrotron radiation phase-contrast imaging computed tomography (SR-PCI-CT) to examine the morphological and structural attributes of different types of callus in a murine model of diabetic partial fractures. Additionally, a deep learning image segmentation model was utilized to facilitate both qualitative and quantitative analysis of callus during various time intervals. A total of forty male Kunming mice, aged five weeks, were randomly allocated into two groups, each consisting of twenty mice, namely, simple fracture group (SF) and diabetic fracture group (DF). Mice in DF group were intraperitoneally injected 60 mg/kg 1 % streptozotocin(STZ) solution for 5 consecutive days, and the standard for modeling was that the fasting blood glucose level was ≥11.1 mmol /l one week after the last injection of STZ. The right tibias of all mice were observed to have oblique fractures that did not traverse the entire bone. At three, seven, ten and fourteen days after the fracture occurred, the fractured tibias were extracted for SR-PCI-CT imaging and histological analysis. Furthermore, a deep learning image segmentation model was devised to automatically detect, categorize and quantitatively examine different types of callus. Image J software was utilized to measure the grayscale values of different types of callus and perform quantitative analysis. The findings demonstrated that:1)SR-PCI-CT imaging effectively depicted the morphological attributes of different types of callus of fracture healing. The grayscale values of different types of callus were significantly different(P < 0.01).2)In comparison to the SF group, the DF group exhibited a significant reduction in the total amount of callus during the same period (P < 0.01). Additionally, the peak of cartilage callus in the hypertrophic phase was delayed.3)Histology provides the basis for training algorithms for deep learning image segmentation models. The deep-learning image segmentation models achieved accuracies of 0.69, 0.81 and 0.733 for reserve/proliferative cartilage, hypertrophic cartilage and mineralized cartilage, respectively, in the test set. The corresponding Dice values were 0.72, 0.83 and 0.76, respectively.
In summary, SR-PCI-CT images are close to the histological level, and a variety of cartilage can be identified on synchrotron radiation CT images compared with histological examination, while artificial intelligence image segmentation model can realize automatic analysis and data generation through deep learning, and further determine the objectivity and accuracy of SR-PCI-CT in identifying various cartilage tissues. Therefore, this imaging technique combined with deep learning image segmentation model can effectively evaluate the effect of diabetes on the morphological and structural changes of callus during fracture healing in mice.
•Delayed fracture healing in diabetic mice•SR-PCI-CT showed the morphology of fracture callus in mice.•Artificial intelligence models segment different types of cartilage callus
Androgenetic alopecia (AGA) is a common hair loss disorder resulting in seriously abnormal social interaction and psychological disorders. Transplantation with autologous dermal papilla cells ...represents a prospective therapy. However, the ability of dermal papilla cells to induce hair follicle development is lost upon cell culturing. Long non-coding RNAs (lncRNAs) are an important class of genes involved in various biological functions, are aberrantly expressed in disease and may play roles in the regulation of Wnt signaling, a critical pathway in maintaining the hair follicle-inducing capability of dermal papilla cells. Examination of dermal papilla cells by lncRNA microarray revealed that H19 was highly expressed in early passage dermal papilla cells compared with late-passage dermal papilla cells. In this study, we constructed H19-overexpressing dermal papilla cells to examine the role of H19 on hair follicle inductivity. Dermal papilla cells infected with lentivirus encoding H19 maintained their cell shape, and continued to display both multiple-layer aggregation and hair follicle-inducing ability upon prolonged culture. H19 exerted these effects through inducing miR-29a to activate Wnt signaling by directly downregulating the expression of Wnt suppressors, including DKK1, Kremen2, and sFRP2, thereby forming a novel regulatory feedback loop between H19 and miR-29a to maintain hair follicle- inducing potential. These results suggest that lncRNA H19 maintains the hair follicle-inducing ability of dermal papilla cells through activation of the Wnt pathway and could be a target for treatment of androgenetic alopecia.
Highlights • In this work, we mainly study the change of PI3K-Akt-mTOR signaling pathway in T lymphocytes and Treg cells from patients with active tuberculosis. • The results demonstrate that the ...PI3K-Akt-mTOR signaling pathway in T lymphocytes and CD4+ CD25+ FoxP3+ Treg cells is inhibited by M. tuberculosis infection. • The PI3K-Akt-mTOR signaling pathway in T lymphocytes and CD4+ CD25+ FoxP3+ Treg cells was inhibited, which could explain why M.tuberculosis can induce FoxP3+ Treg cell to expand.
Background/Aims: Hyperuricemia is part of the metabolic-syndrome cluster of abdominal obesity, impaired glucose tolerance, insulin resistance, dyslipidemia, and hypertension. Monocytes/macrophages ...are critical in the development of metabolic syndrome, including gout, obesity and atherosclerosis. However, how high uric acid (HUA) exposure affects monocyte/macrophage function remains unclear. In this study, we investigated the molecular mechanism of HUA exposure in monocytes/macrophages and its impact on oxidized low-density lipoprotein (oxLDL)-induced foam-cell formation in a human monocytic cell line, THP-1. Methods: We primed THP-1 cells with phorbol-12-myristate-13-acetate (PMA) for differentiation, then exposed cells to HUA and detected the production of reactive oxygen species (ROS) and analyzed the level of phospho-AMPKα. THP-1 cells were pre-incubated with Compound C, an AMPK inhibitor, or N-acetyl-L-cysteine (NAC), a ROS scavenger, or HUA before PMA, to assess CD68 expression and phospho-AMPKα level. PMA-primed THP-1 cells were pre-treated with oxLDL before Compound C and HUA treatment. Western blot analysis was used to examine the levels of phospho-AMPKα, CD68, ABCG1, ABCA1, cyclooxygenase-2 (COX-2) and NF-κB (p65). Flow cytometry was used to assess ROS production and CD68 expression in live cells. Oil-red O staining was used to observe oxLDL uptake in cells. Results: HUA treatment increased ROS production in PMA-primed THP-1 cells; NAC blocked HUA-induced oxidative stress. HUA treatment time-dependently increased phospho-AMPKα level in PMA-primed THP-1 cells. The HUA-induced oxidative stress increased phospho-AMPKα levels, which was blocked by NAC. HUA treatment impaired CD68 expression during cell differentiation by activating the AMPK pathway, which was reversed by Compound C treatment. Finally, HUA treatment inhibited oxLDL uptake in the formation of foam cells in THP-1 cells, which was blocked by Compound C treatment. HUA treatment significantly increased the expression of ABCG1 and reversed the oxLDL-reduced ABCG1 expression but did not affect the expression of ABCA1, NF-κB (p65) or COX-2. Conclusions: HUA exposure activated the ROS-AMPK pathway, impaired CD68 expression, and inhibited oxLDL-induced foam-cell formation in a human monocytic cell line, THP-1.
Metformin is used as a first-line therapy for type 2 diabetes, with reports of its usefulness for the prevention and control of several types of cancers. This study investigated the effects of ...metformin on hepatocellular carcinoma (HCC). The human HCC cell lines HepG2 and PLC/PRF/5 were cultured and treated with metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of adenosine monophosphate (AMP)-activated protein kinase. Changes in cell viability and cell cycle distribution were evaluated by MTT and flow cytometry, respectively. Apoptosis was assessed by fluorescent-dye staining. An HCC model was established in 6- to 8-week-old BALB/c-nu mice by subcutaneous injection of PLC/PRF/5 cells. After 1 week, mice were treated intragastrically with metformin or vehicle. Tumor xenograft tissues were examined using immunohistochemistry for evaluation of the the expression of cyclin D1, p21CIP and p27KIP. HCC cells and tissues from the in vitro and in vivo experiments, respectively, were subjected to protein extraction and western blotting. We found that metformin treatment reduced HCC cell viability in a dose-dependent manner similar to AICAR treatment. In addition, metformin treatment induced HCC cell cycle arrest at G1/G0 phase and apoptosis. Intragastric treatment of the mouse PLC/PRF/5 cell xenograft model with metformin showed that metformin not only blocked tumor progression, but also reduced tumor morbidity. Treatment with metformin upregulated the expression of p21CIP and p27KIP, but downregulated cyclin D1 levels, both in vitro and in vivo. Metformin treatment also upregulated the expression of phosphorylated AMPK protein in xenograft tissues. These findings indicate that metformin warrants further evaluation as a novel therapeutic and preventive strategy against HCC.
Psychosocial stress is increasing, causing a growing number of people to suffer from hair loss. Stress-related corticotropin-releasing hormone (CRH) is associated with hair loss, but the mechanism by ...which hair follicles respond to stress and CRH remain poorly understood. The aim of the study is to elucidate the association between CRH and stress-related hair regenerative disorders, and reveal the potential pathological mechanisms. A chronic unpredictable stress mouse model and a chronic social defeat stress mouse model were used to examine the role of CRH and stress-related hair regrowth. Chronic unpredictable stress and chronic social defeat stress increased the expression of CRH and CRH receptors (CRHRs), and contributed to the onset of hair-cycle abnormalities. Psychoemotional stress and stress-related CRH blocked hair follicle regrowth, which could be restored by astressin, a CRHR antagonist. Long-term exposure to either chronic unpredictable stress or CRH induced a decrease in autophagy, which could be partially rescued by astressin. Activating CRHR, by stress or CRH administration, decreased autophagy via the mTOR-ULK1 signaling pathway to mediate hair regenerative disorders, which could be partially reversed through enhancing autophagy by administration of brefeldin A. These findings indicate that CRH-mediated autophagy inhibition play an important role in stress-induced hair regenerative disorders. CRH regulates the local hypothalamic-pituitary-adrenal axis of hair follicles, but also plays an independent pathogenic role in stress-related hair regenerative disorders through CRH-mediated autophagy inhibition. This work contributes to the present understanding of hair loss and suggests that enhancing autophagy may have a therapeutic effect on stress-induced hair loss.
•Psychological stress blocks hair regeneration through CRH-mediated autophagy inhibition.
Alopecia is a prevalent problem of cutaneous appendages and lacks effective therapy. Recently, researchers have been focusing on mesenchymal components of the hair follicle, i.e. dermal papilla ...cells, and we previously identified biglycan secreted by dermal papilla cells as the key factor responsible for hair follicle‐inducing ability. In this research, we hypothesized biglycan played an important role in hair follicle cycle and regeneration through regulating the Wnt signalling pathway. To characterize the hair follicle cycle and the expression pattern of biglycan, we observed hair follicle morphology in C57BL/6 mice on Days 0, 3, 5, 12 and 18 post‐depilation and found that biglycan is highly expressed at both mRNA and protein levels throughout anagen in HFs. To explore the role of biglycan during the phase transit process and regeneration, local injections were administered in C57BL/6 and nude mice. Results showed that local injection of biglycan in anagen HFs delayed catagen progression and involve activating the Wnt/β‐catenin signalling pathway. Furthermore, local injection of biglycan induced HF regeneration and up‐regulated expression of key Wnt factors in nude mice. In addition, cell analyses exhibited biglycan knockdown inactivated the Wnt signalling pathway in early‐passage dermal papilla cell, whereas biglycan overexpression or incubation activated the Wnt signalling pathway in late‐passage dermal papilla cells. These results indicate that biglycan plays a critical role in regulating HF cycle transit and regeneration in a paracrine and autocrine fashion by activating the Wnt/β‐catenin signalling pathway and could be a potential treatment target for hair loss diseases.
•High uric acid levels induce oxidative stress in pancreatic β cells.•High uric acid levels act on β cells through oxidative damage and growth inhibition.•The effects are mediated by the ROS-AMPK-ERK ...signaling pathway.•Uric acid enters pancreatic β cells by an organic anion transporter.
Hyperuricaemia is a disorder of purine metabolism, and is strongly associated with insulin resistance and abnormal glucose metabolism. As the producer of insulin, pancreatic β cells might be affected by elevated serum uric acid levels and contribute to the disregulated glucose metabolism. In this study, we investigated the effect of high uric acid on rat pancreatic β cell function. Under high uric acid condition, proliferation of pancreatic β cells was inhibited, production of reactive oxygen species increased, and glucose stimulated insulin secretion was also compromised. Further examination on signal transduction pathways revealed that uric acid-induced ROS is involved in the activation of adenosine monophosphate-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK). Pharmacological inhibition of ERK activation rescued β cells from growth inhibition. More importantly, activation of ERK induced by uric acid is significantly diminished by AMPK inhibitor, indicating ERK as a downstream target of AMPK in response to high uric acid condition. We also investigated the transportation channel for uric acid into pancreatic β cells. While major urate transporter URAT1 is not expressed in β cells, organic anion transporter (OAT) inhibitor successfully blocked the activation of ERK by uric acid. Our data indicate that high uric acid levels induce oxidative damage and inhibit growth of rat pancreatic β cells by activating the AMPK and ERK signal pathways. Hyperuricemia may contribute to abnormal glucose metabolism by causing oxidative damage and function inhibition of pancreatic β cells.
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