Palmitic acid-activated GPRs/KLF7/CCL2 pathway is involved in the crosstalk between bone marrow adipocytes and prostate cancer.

BACKGROUND: Obesity-induced abnormal bone marrow microenvironment is one of the important risk element for bone metastasis in prostate cancer (PCa). The present study aimed to determine whether obesity-induced elevation in palmitic acid (PA), which is the most abundant of the free fatty acids (FFAs), increased CCL2 via the GPRs/KLF7 pathway in bone marrow adipocytes (BMA) to facilitate PCa growth and metastasis. METHODS: We constructed a bone-tumor bearing mouse model with obesity through high-fat diet, and observed the tumor formation ability of PCa cells. In vitro, observe the effect of PA on the expression level of CCL2 in BMA through GPRs/KLF7 signaling pathway. After co-culture of BMA and PCa cells, CCK8 assay and transwell experiment were used to detect the changes in biological behavior of PCa cells stimulated by BMA. RESULTS: The BMA distribution in the bone marrow cavity of BALB/c nude mice fed with the high-fat diet (HFD) was evidently higher than that in the mice fed with the normal diet (ND). Moreover, HFD-induced obesity promoted KLF7/CCL2 expression in BMA and PCa cell growth in the bone marrow cavity of the mice. In the vitro experiment, a conditioned medium with increased CCL2 obtained from the BMA cultured with PA (CM-BMA-PA) was used for culturing the PCa cell lines, which evidently enhanced the proliferation, invasion, and migration ability. KLF7 significantly increased the CCL2 expression and secretion levels in BMA by targeting the promoter region of the CCL2 gene. In addition, GPR40/120 engaged in the PA-induced high KLF7/CCL2 levels in BMA to facilitate the malignant progression of PC-3 cells. CONCLUSIONS: PA-activated GPRs/KLF7/CCL2 pathway in BMA facilitates prostate cancer growth and metastasis.

Soft Self-Healing Robot Driven by New Micro Two-Way Shape Memory Alloy Spring.

Soft robotic bodies are susceptible to mechanical fatigue, punctures, electrical breakdown, and aging, which can result in the degradation of performance or unexpected failure. To overcome these challenges, a soft self-healing robot is created using a thermoplastic methyl thioglycolate-modified styrene-butadiene-styrene (MG-SBS) elastomer tube fabricated by melt-extrusion, to allow the robot to self-heal autonomously at room temperature. After repeated damage and being separated into several parts, the robot is able to heal its stiffness and elongation to break to enable almost complete recovery of robot performance after being allowed to heal at room temperature for 24 h. The self-healing capability of the robot is examined across the material scale to robot scale by detailed investigations of the healing process, healing efficiency, mechanical characterization of the robot, and assessment of dynamic performance before and after healing. The self-healing robot is driven by a new micro two-way shape-memory alloy (TWSMA) spring actuator which achieved a crawling speed of 21.6 cm/min, equivalent to 1.57 body length per minute. An analytical model of the robot is created to understand the robot dynamics and to act as an efficient tool for self-healing robot design and optimization. This work therefore provides a new methodology to create efficient, robust, and damage-tolerant soft robots.

KLF7 promotes adipocyte inflammation and glucose metabolism disorder by activating the PKCζ/NF-κB pathway.

In the obesity context, inflammatory cytokines secreted by adipocytes lead to insulin resistance and are key to metabolic syndrome development. In our previous study, we found that the transcription factor KLF7 promoted the expression of p-p65 and IL-6 in adipocytes. However, the specific molecular mechanism remained unclear. In the present study, we found that the expression of KLF7, PKCζ, p-IκB, p-p65, and IL-6 in epididymal white adipose tissue (Epi WAT) in mice fed a high-fat diet (HFD) was significantly increased. In contrast, the expression of PKCζ, p-IκB, p-p65, and IL-6 was significantly decreased in Epi WAT of KLF7 fat conditional knockout mice. In 3T3-L1 adipocytes, KLF7 promoted the expression of IL-6 via the PKCζ/NF-κB pathway. In addition, we performed luciferase reporter and chromatin immunoprecipitation assays, which confirmed that KLF7 upregulated the expression of PKCζ transcripts in HEK-293T cells. Collectively, our results show that KLF7 promotes the expression of IL-6 by upregulating PKCζ expression and activating the NF-κB signaling pathway in adipocytes.

Caprylic Acid (FFA C8:0) promotes the progression of prostate cancer by up-regulating G protein-coupled receptor 84/ Krüppel-like factor 7.

BACKGROUND: In previous study, we found that the content of medium-chain fatty acid Caprylic Acid (FFA C8:0) may be an important risk factor of obesity induced prostate cancer (PCa). However, the relationship between FFA C8:0 and PCa has not been reported. In this study, we explored whether the FFA C8:0 can promotes the progression of PCa by up-regulating Krüppel-like factor 7 (KLF7). METHODS: We collected tissues from PCa patients and Benign Prostate Hyperplasia (BPH), constructed a primary-tumor bearing mouse model with obesity through high-fat diet, and observed the tumor formation ability of PCa cells. In vitro, CCK8 assay, plate cloning, Transwell and scratch experiment were used to detect the changes in biological behavior of PCa cells stimulated by FFA C8:0. RESULTS: First, we found that the expression level of KLF7 is higher in PCa tissues of patients, and the expression of KLF7 is positively correlated with tumour-promoting gene IL-6, while it is negative correlated with another tumour-suppressor gene p21. Then, this study found that PCa cells were more likely to form tumors in diet induced obese mice. Compared with the normal diet group (ND), the expression levels of KLF7 in tumor tissues in high-fat diet group (HFD) were higher. Futhermore, we verified that high concentrations of FFA C8:0 can promote the biological behavior of PCa cells by activating KLF7/IL-6/p21 signaling pathway, which is mediated by the GPR84. CONCLUSIONS: Our research may provide a potential target for clinical prevention and treatment of PCa which induced by obesity.

Stress-inducible IL-6 is regulated by KLF7 in brown adipocytes.

Stress-inducible interleukin 6 (IL-6) is generated in brown adipocytes via beta-3 adrenergic receptor (ADRB3) signaling, which is necessary in stress hyperglycemia, the kind of metabolic adaptation enabling "fight or flight" response by means of liver gluconeogenesis. Nevertheless, the mechanism of ADRB3 signaling mediates IL-6 in brown adipocytes remains unclear. As a result, it is critical to understand how brown adipocytes produce IL-6 via ADRB3 signaling. We found that the ADRB3 agonist and cold stimulation promoted the expression of KLF7 and IL-6 in brown adipocytes of mice. In parallel to these results in vivo, treatment with ADRB3 agonist promoted the expression of KLF7 and the release of IL-6 in primary brown adipocytes of mice. Notably, we discovered that KLF7 positively controls the expression of IL-6 and downregulated KLF7 largely blunted ADRB3 agonist induced IL-6 expressions in brown adipocytes. Our findings suggest that KLF7 is required for the generation of IL-6 when ADRB3 signaling is activated in brown adipocytes.

Hepatic Glucose Metabolism Disorder Induced by Adipose Tissue-Derived miR-548ag via DPP4 Upregulation.

The present study aimed to explore the molecular mechanism underlying the regulation of glucose metabolism by miR-548ag. For the first time, we found that miR-548ag expression was elevated in the abdominal adipose tissue and serum of subjects with obesity and type 2 diabetes mellitus (T2DM). The conditional knockout of adipose tissue Dicer notably reduced the expression and content of miR-548ag in mouse adipose tissue, serum, and liver tissue. The combined use of RNAseq, an miRNA target gene prediction software, and the dual luciferase reporter assay confirmed that miR-548ag exerts a targeted regulatory effect on DNMT3B and DPP4. miR-548ag and DPP4 expression was increased in the adipose tissue, serum, and liver tissue of diet-induced obese mice, while DNMT3B expression was decreased. It was subsequently confirmed both in vitro and in vivo that adipose tissue-derived miR-548ag impaired glucose tolerance and insulin sensitivity by inhibiting DNMT3B and upregulating DPP4. Moreover, miR-548ag inhibitors significantly improved the adverse metabolic phenotype in both obese mice and db/db mice. These results revealed that the expression of the adipose tissue-derived miR-548ag increased in obese subjects, and that this could upregulate the expression of DPP4 by targeting DNMT3B, ultimately leading to glucose metabolism disorder. Therefore, miR-548ag could be utilized as a potential target in the treatment of T2DM.

miR-548ag functions as an oncogene by suppressing MOB1B in the development of obesity-related endometrial cancer.

Obesity is a high-risk factor in the development of endometrial cancer (EC). Our previous study observed that miR-548ag was significantly overexpressed in the sera of obese individuals. Here, we report the function of miR-548ag and its mechanism in promoting the obesity-related progression of EC. The content of miR-548ag was increased in the serum of obese EC individuals. Bioinformatics analysis indicated that the survival rate of EC patients with a higher expression of miR-548ag was significantly reduced. The Mps One Binder Kinase Activator 1B (MOB1B, the core member of the Hippo signaling pathway) is a direct target gene of miR-548ag, which is inversely correlated with the expression of miR-548ag. The overexpression of miR-548ag enhances the proliferation, invasion, and migration, and inhibits apoptosis by downregulating the expression of MOB1B, leading to the deactivation of the Hippo pathway in EC cell lines and contributing to tumor progression in vivo. Our study has established that miR-548ag functions as an oncogene by suppressing MOB1B in the development of obesity-related EC.

miR-4431 targets TRIP10/PRKD1 and impairs glucose metabolism.

AIM/INTRODUCTION: Obesity is considered an important risk factor for many metabolic disorders, especially type 2 diabetes mellitus, and microRNAs (miRNAs) play a vital role in the development of type 2 diabetes mellitus. Therefore, we conducted this study to investigate the role of miR-4431 in the obesity-associated pathobiology of type 2 diabetes mellitus. MATERIALS AND METHODS: Subjects were divided into normal control (n = 36), obese (n = 36), and type 2 diabetes mellitus (n = 12) groups, and serum miR-4431 levels were analyzed. Adenovirus-vectored miR-4431 mimic or sponge was intraperitoneally injected into the normal diet group and the high-fat diet group (HFD) mice to investigate glucose tolerance, insulin sensitivity, and lipid levels. The downstream target genes of miR-4431 were predicted using bioinformatics, and they were verified in vitro. RESULTS: Serum miR-4431 levels were significantly high in obese and type 2 diabetes mellitus individuals, and positively correlated with the body mass index and fasting plasma glucose levels. In HFD mice, miR-4431 levels in the serum, white adipose tissue, and liver were significantly increased. Moreover, miR-4431 impaired glucose tolerance, insulin sensitivity, and lipid metabolism in mice. Bioinformatic prediction suggested that TRIP10 and PRKD1 could be the downstream target genes of miR-4431. The HFD mice showed a remarkable reduction in the mRNA levels of TRIP10 and PRKD1 in the liver, which were countered by blocking miR-4431. In HepG2 and L02 cells, miR-4431 could downregulate TRIP10 and PRKD1 while blocking glucose uptake. The luciferase reporter assay showed that miR-4431 could bind TRIP10 and PRKD1 3'-UTR. CONCLUSION: miR-4431 targets TRIP10/PRKD1 and impairs glucose metabolism.

Solvent Sorption-Induced Actuation of Composites Based on a Polymer of Intrinsic Microporosity.

Materials that are capable of actuation in response to a variety of external stimuli are of significant interest for applications in sensors, soft robotics, and biomedical devices. Here, we present a class of actuators using composites based on a polymer of intrinsic microporosity (PIM). By adding an activated carbon (AX21) filler to a PIM, the composite exhibits repeatable actuation upon solvent evaporation and wetting and it is possible to achieve highly controlled three-dimensional actuation. Curled composite actuators are shown to open upon exposure to a solvent and close as a result of solvent evaporation. The degree of curling and actuation is controlled by adjusting the amount of filler and evaporation rate of the solvent casting process, while the actuation speed is controlled by adjusting the type of solvent. The range of forces and actuation speed produced by the composite is demonstrated using acetone, ethanol, and dimethyl sulfoxide as the solvent. The maximum contractile stress produced upon solvent desorption in the pure PIM polymer reached 12 MPa, with an ultimate force over 20 000 times the weight of a sample. This form of the composite actuator is insensitive to humidity and water, which makes it applicable in an aqueous environment, and can survive a wide range of temperatures. These characteristics make it a promising actuator for the diverse range of operating conditions in robotic and medical applications. The mechanism of actuation is discussed, which is based on the asymmetric distribution of the carbon filler particles that leads to a bilayer structure and the individual layers expand and contract differently in response to solvent wetting and evaporation, respectively. Finally, we demonstrate the application of the actuator as a potential drug delivery vehicle, with capacity for encapsulating two kinds of drugs and reduced drug leakage in comparison to existing technologies.

Mn2+/Mn4+ co-doped LaM1-xAl11-yO19 (M = Mg, Zn) luminescent materials: electronic structure, energy transfer and optical thermometric properties.

Dual-emitting manganese ion doped LaM1-xAl11-yO19 (M = Mg, Zn) phosphors were prepared by substituting Zn2+/Mg2+ with Mn2+ and replacing Al3+ with Mn4+. The LaM1-xAl11-yO19:xMn2+,yMn4+ phosphors show a narrow green emission band of the Mn2+ ions at 514 nm and a red emission band of the Mn4+ ions at 677 nm. In addition, the thermal stability of luminescence shows that the response of Mn2+ and Mn4+ to the temperature is obviously different in LaMAl11O19, implying the potential of the prepared phosphors as optical thermometers. The decay lifetime of Mn4+ was changed with temperature due to the different fluorescence intensity ratios of Mn2+ and Mn4+, and a dual-mode optical temperature-sensing mechanism was studied in the temperature range of -50-200 °C. The maximum relative sensitivities (Sr) are calculated as 3.22 and 3.13% K-1, respectively. The unique optical thermometric features demonstrate the application potential of LaMAl11O19:Mn2+,Mn4+ in optical thermometry.

Triboelectric and Piezoelectric Nanogenerators for Future Soft Robots and Machines.

The triboelectric nanogenerator (TENG) and piezoelectric nanogenerator (PENG) are two recently developed technologies for effective harvesting of ambient mechanical energy for the creation of self-powered systems. The advantages of TENGs and PENGs which include large open-circuit output voltage, low cost, ease of fabrication, and high conversion efficiency enable their application as new flexible sensors, wearable devices, soft robotics, and machines. This perspective provides an overview of the current state of the art in triboelectric and piezoelectric devices that are used as self-powered sensors and energy harvesters for soft robots and machines; hybrid approaches that combine the advantages of both mechanisms are also discussed. To improve system performance and efficiency, the potential of providing self-powered soft systems with a degree of multifunctionality is investigated. This includes optical sensing, transparency, self-healing, water resistance, photo-luminescence, or an ability to operate in hostile environments such as low temperature, high humidity, or high strain/stretch. Finally, areas for future research directions are identified.

Carbon fibre based flexible piezoresistive composites to empower inherent sensing capabilities for soft actuators.

New materials and technologies in sensing and actuation have led to the development of soft actuators and robots for biomedical systems, assistive devices, exploration and rescue. The use of integrated actuation-sensing materials in such systems is gaining interest, but there are few examples where the body of the actuator or soft robot acts as the sensing element. The development of smart soft actuators that have inherent sensing capabilities can provide advantages of high sensitivity, ease of manufacture and cost efficiency, without impairing actuator dynamics. To achieve this goal, we have prepared soft actuators using piezoresistive composites based on a silicone matrix impregnated with short conductive carbon fibres. The optimum carbon fibre volume fraction to achieve a frequency independent conductivity and piezoresistive response was determined, with in situ mechanical and electrical testing to quantify the piezoresistive properties. The frequency dependent electrical properties and sensitivity of the composites with deformation was explained on the basis of a microstructural resistor-capacitor network model. The piezoresistive composites were used to successfully manufacture a pneumatic soft finger actuator where the resistance change of the actuator body was able to monitor deformation with applied pressure. The creation of soft actuators with an inherent sensing capability is a promising approach for control and operation of future soft robots.