Resveratrol Promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc Signaling Pathway-Mediated Angiogenesis

Background/Aims: Diabetic non-healing skin ulcers represent a serious challenge in clinical practice, in which the hyperglycemia-induced disturbance of angiogenesis, and endothelial dysfunction play a crucial role. Resveratrol (RES), a silent information regulator 1 (SIRT1) agonist, can improve endothelial function and has strong pro-angiogenic properties, and has thus become a research focus for the treatment of diabetic non-healing skin ulcers; however, the underlying mechanism by which RES regulates these processes remains unclear. Therefore, the present study was intended to determine if RES exerts its observed protective role in diabetic wound healing by alleviating hyperglycemia-induced endothelial dysfunction and the disturbance of angiogenesis.Methods: We investigated the effects of RES on cell migration, cell proliferation, apoptosis, tube formation, and the underlying molecular mechanisms in 33 mM high glucose-stimulated human umbilical vein endothelial cells (HUVECs) by semi-quantitative RT-PCR, western blot analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and immunofluorescence in vitro. We further explored the role of RES on endothelial dysfunction and wound healing disturbance in db/db mice by TUNEL staining, immunofluorescence, and photography in vivo.Results: We observed an obvious inhibition of hyperglycemia-triggered endothelial dysfunction and a disturbance of angiogenesis, followed by the promotion of diabetic wound healing via RES, along with restoration of the activity of the hyperglycemia-impaired SIRT1 signaling pathway. Pretreatment with EX-527, a SIRT1 inhibitor, abolished the RES-mediated endothelial protection and pro-angiogenesis action, and then delayed diabetic wound healing. Furthermore, examination of the overexpression of forkhead box O1 (FOXO1), a transcription factor substrate of SIRT1, in HUVECs and db/db mice revealed that RES activated SIRT1 to restore hyperglycemia-triggered endothelial dysfunction and disturbance of angiogenesis, followed by the promotion of diabetic wound healing in a c-Myc-dependent manner. Pretreatment with 10058-F4, a c-Myc inhibitor, repressed RES-mediated endothelial protection, angiogenesis, and diabetic wound healing.Conclusion: Our findings indicate that the positive role of RES in diabetic wound healing via its SIRT1-dependent endothelial protection and pro-angiogenic effects involves the inhibition of FOXO1 and the de-repression of c-Myc expression

Calcitriol restrains microglial M1 polarization and alleviates dopaminergic degeneration in hemiparkinsonian mice by boosting regulatory T‐cell expansion

Abstract Objective Vitamin D deficiency is a risk factor for Parkinson's disease (PD) and vitamin D supplementation robustly alleviates neurodegeneration in PD models. However, the mechanisms underlying this effect require further clarification. Current evidence suggests that harnessing regulatory T cells (Treg) may mitigate neuronal degeneration. In this study, we investigated the therapeutic effects of vitamin D receptor activation by calcitriol on PD, specifically focusing on its role in Treg. Methods Hemiparkinsonian mice model was established through the injection of 6‐OHDA into the striatum. Mice were pretreated with calcitriol before 6‐OHDA injection. The motor performance, dopaminergic neuronal survival, contents of dopamine, and dopamine metabolites were evaluated. The pro‐inflammatory cytokines levels, T‐cell infiltration, mRNA expression of indicated microglial M1/M2 phenotypic markers, and microglial marker in the midbrain were detected. Populations of Treg in the splenic tissues were assessed using a flow cytometry assay. PC61 monoclonal antibody was applied to deplete Treg in vivo. Results We show that calcitriol supplementation notably improved motor performance and reduced dopaminergic degeneration in the 6‐OHDA‐induced PD model. Mechanistically, calcitriol promoted anti‐inflammatory/neuroprotective Treg and inhibited pro‐inflammatory/neurodestructive effector T‐cell generation in this model. This process significantly inhibited T‐cell infiltration in the midbrain, restrained microglial activation, microglial M1 polarization, and decreased pro‐inflammatory cytokines release. This more favorable inflammatory microenvironment rescued dopaminergic degeneration. To further verify that the anti‐inflammatory effects of calcitriol are associated with Treg expansion, we applied an antibody‐mediated Treg depletion assay. As predicted, the anti‐inflammatory effects of calcitriol in the PD model were diminished following Treg depletion. Conclusion These findings suggest that calcitriol's anti‐inflammatory and neuroprotective effects in PD are associated with its potential to boost Treg expansion

Evaluation of the Expansion and Neuronal Differentiation Potency of Cultured Olfactory Epithelium Progenitor Cells from a Rat Model of Depression

Background: Olfactory impairment has been reported in patients with depression and in rodent models of depression. Olfactory epithelium (OE) is the only peripheral neural tissue connected to the brain that has the potential for self-renewal. We hypothesized the olfactory deficit during depression may be related to the dysfunction of OE progenitor cells. The aim of the present study was therefore to evaluate the expansion and neuronal differentiation potency of cultured OE progenitor cells obtained from a rat model of depression. Methods: Rats were exposed to chronic unpredictable mild stress procedures to establish a depressive-like state. Depressive-like behavior and olfactory sensing function were then evaluated and compared with control rats. Primary OE progenitor cells were cultured in vitro. The proliferation potency and survival of OE progenitor cells were assessed by 5-Ethynyl-2′-deoxyuridine staining and Cell Counting Kit-8 (CCK8), respectively, while cellular apoptosis was measured by flow cytometry. The neuronal differentiation potency of OE progenitor cells was evaluated by measurement of the protein and mRNA level of β-3 tubulin, a marker of neural cells. mRNA expression associated with neural stemness was examined by quantitative reverse transcription polymerase chain reaction (RT-PCR). Results: Depressive-like rats showed decreased olfactory function. OE progenitor cells from depressive-like rats showed reduced cell proliferation/survival and neuronal differentiation potency. Moreover, OE progenitor cells from depressive-like rats showed decreased expression of mRNA related to neural stemness. Conclusions: These results indicate the impaired function of OE progenitor cells may contribute to the olfactory deficit observed during depression. The OE may therefore provide a window for the study of depression

Fabrication and Property Evaluation of the Al2O3-TiO2 Composite Coatings Prepared by Plasma Spray

The Al2O3-13 wt.% TiO2 (AT13) composite coatings were prepared on Q235 steel by plasma spray technique. The spray parameters were designed by the orthogonal experiments, and the properties of the coating were evaluated. Results showed that with respect to the bond strength of the coating, the optimized spraying parameters were the plasma current of 530 A, Ar flow of 41 L/min, H2 flow of 10 L/min, and spray standoff distance of 100 mm. The plasma spray process led to the transition of α-Al2O3 to γ-Al2O3, resulting in the increase in the porosity of AT13 coating prepared at nonoptimized parameters. Meanwhile, the porosity and cracks were also increased due to the decrease in the Ar flow and the increase in spray standoff distance. The low porosity, a few cracks, and the uniformly dispersed TiO2 particles contributed the enhanced properties including mechanical and corrosion behaviors of the AT13 coating prepared at optimized parameters. The bond strength, microhardness, and thermal shock resistance of the AT13 coating could reach 25.01 MPa, 1000.6 HV0.5, and 40 times when the coating was prepared at optimized parameters, respectively. Especially, the static Icorr of the AT13 coating prepared at optimized parameters was two order of magnitude less than that of Q235 steel. In addition, the erosion weight loss of Q235 steel could be decreased about 30 times by the protection of the AT13 coating

Metabotropic Glutamate Receptor 8 Suppresses M1 Polarization in Microglia by Alleviating Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

Background: Microglia-mediated neuroinflammation is a hallmark of neurodegeneration. Metabotropic glutamate receptor 8 (GRM8) has been reported to promote neuronal survival in neurodegenerative diseases, yet the effect of GRM8 on neuroinflammation is still unclear. Calcium overload-induced endoplasmic reticulum (ER)-mitochondrial miscommunication has been reported to trigger neuroinflammation in the brain. The aim of this study was to investigate putative anti-inflammatory effects of GRM8 in microglia, specifically focusing on its role in calcium overload-induced ER stress and mitochondrial dysfunction. Methods: BV2 microglial cells were pretreated with GRM8 agonist prior to lipopolysaccharide administration. Pro-inflammatory cytokine levels and the microglial polarization state in BV2 cells were then quantified. Cellular apoptosis and the viability of neuron-like PC12 cells co-cultured with BV2 cells were examined using flow cytometry and a Cell Counting Kit-8, respectively. The concentration of cAMP, inositol-1,4,5-triphosphate receptor (IP3R)-dependent calcium release, ER Ca2+ concentration, mitochondrial function as reflected by reactive oxygen species levels, ATP production, mitochondrial membrane potential, expression of ER stress-sensing protein, and phosphorylation of the nuclear factor kappa B (NF-κB) p65 subunit were also quantified in BV2 cells. Results: GRM8 activation inhibited pro-inflammatory cytokine release and shifted microglia polarization towards an anti-inflammatory-like phenotype in BV2 cells, as well as promoting neuron-like PC12 cell survival when co-cultured with BV2 cells. Mechanistically, microglial GRM8 activation significantly inhibited cAMP production, thereby desensitizing the IP3R located within the ER. This process markedly limited IP3R-dependent calcium release, thus restoring mitochondrial function while inhibiting ER stress and subsequently deactivating NF-κB signaling. Conclusions: Our results indicate that GRM8 activation can protect against microglia-mediated neuroinflammation by attenuating ER stress and mitochondrial dysfunction, and that IP3R-mediated calcium signaling may play a vital role in this process. GRM8 may thus be a potential target for limiting neuroinflammation

Homoploid F1 hybrids and segmental allotetraploids of rice subspecies are similarly more tolerant to N-deficiency than are parental lines

Whether merger of two divergent genomes by hybridization at the homoploid level or coupled with WGD (allopolyploidy) can bestow plants better tolerance to stress conditions remains understudied. In this study, two diploid rice (Oryza sativa L.) subspecies, japonica, and indica, their reciprocal F1 hybrids and segmental allotetraploids were compared for phenotypic performance and gene expression under normal and nitrogen (N)-deficient conditions. We found that F1 hybrids and tetraploids showed higher tolerance at similar levels than did either parent. In parallel, total expression levels of 18 relevant functional genes were less perturbed by nitrogen deficiency in F1 hybrids and tetraploids than in the parents. This is consistent with stable intrinsic partitioning of allelic/homoeologous expression defined by parental legacy in the homoploid F1 hybrids/tetraploids between the two conditions. Our results suggest that genetic additivity at both the homoploid level or allopolyploidy may lead to similar beneficial phenotypic responses to nitrogen stress compared with their parents. The lack of synergistic responses to nitrogen limitation concomitant with WGD, relative to that exhibited by F1 hybrids, adds new empirical evidence in support of the emerging notion that hybridization by itself may play a significant role in plant adaptive evolution in times of stress.This is a manuscript of an article published as Sun, Yue, Ying Wu, Yangzhi Wang, Shengnan Wang, Xiaofei Wang, Guo Li, Xue Zhang et al. "Homoploid F1 hybrids and segmental allotetraploids of rice subspecies are similarly more tolerant to N-deficiency than are parental lines." Journal of Experimental Botany (2021). doi:10.1093/jxb/erab184. Posted with permission.</p

Homoploid F1 hybrids and segmental allotetraploids of rice subspecies are similarly more tolerant to N-deficiency than are parental lines

Whether merger of two divergent genomes by hybridization at the homoploid level or coupled with WGD (allopolyploidy) can bestow plants better tolerance to stress conditions remains understudied. In this study, two diploid rice (Oryza sativa L.) subspecies, japonica, and indica, their reciprocal F1 hybrids and segmental allotetraploids were compared for phenotypic performance and gene expression under normal and nitrogen (N)-deficient conditions. We found that F1 hybrids and tetraploids showed higher tolerance at similar levels than did either parent. In parallel, total expression levels of 18 relevant functional genes were less perturbed by nitrogen deficiency in F1 hybrids and tetraploids than in the parents. This is consistent with stable intrinsic partitioning of allelic/homoeologous expression defined by parental legacy in the homoploid F1 hybrids/tetraploids between the two conditions. Our results suggest that genetic additivity at both the homoploid level or allopolyploidy may lead to similar beneficial phenotypic responses to nitrogen stress compared with their parents. The lack of synergistic responses to nitrogen limitation concomitant with WGD, relative to that exhibited by F1 hybrids, adds new empirical evidence in support of the emerging notion that hybridization by itself may play a significant role in plant adaptive evolution in times of stress

Technology roadmap for flexible sensors

Humans rely increasingly on sensors to address grand challenges and to improve quality of life in the era of digitalization and big data. For ubiquitous sensing, flexible sensors are developed to overcome the limitations of conventional rigid counterparts. Despite rapid advancement in bench-side research over the last decade, the market adoption of flexible sensors remains limited. To ease and to expedite their deployment, here, we identify bottlenecks hindering the maturation of flexible sensors and propose promising solutions. We first analyze challenges in achieving satisfactory sensing performance for real-world applications and then summarize issues in compatible sensor-biology interfaces, followed by brief discussions on powering and connecting sensor networks. Issues en route to commercialization and for sustainable growth of the sector are also analyzed, highlighting environmental concerns and emphasizing nontechnical issues such as business, regulatory, and ethical considerations. Additionally, we look at future intelligent flexible sensors. In proposing a comprehensive roadmap, we hope to steer research efforts towards common goals and to guide coordinated development strategies from disparate communities. Through such collaborative efforts, scientific breakthroughs can be made sooner and capitalized for the betterment of humanity.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)Submitted/Accepted versionY.L., Z.L., M.Z., and X.C. acknowledge the National Research Foundation, Singapore (NRF) under NRF’s Medium Sized Centre: Singapore Hybrid-Integrated Next-Generation μElectronics (SHINE) Centre funding programme, and AME programming funding scheme of Cyber Physiochemical Interface (CPI) project (no. A18A1b0045). Y.L. acknowledges National Natural Science Foundation of China (62201243). C.J. acknowledges funding support from the National Key R&D Program of China (no. 2019YFA0706100), the National Natural Science Foundation of China (82151305), Lingang Laboratory (LG-QS-202202-09). T.Q.T. and N.E.L. acknowledge support by the Basic Science Research Program (no. 2020R1A2C3013480) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT. A.F. acknowledges the AFOSR (grant FA9550-22-1-0423). Y.L. and Y.Z. would like to acknowledge the NSF (award no. 2134664) and NIH (award no. R01HD108473) for financial support. X.F. acknowledges the support from the National Natural Science Foundation of China (grant no. U20A6001). L.Y. would like to thank the A*STAR Central Research Fund (CRF) and the AME Programmatic A18A1b0045 (Cyber Physiochemical Interfaces) for funding support. C.F.G. acknowledges the National Natural Science Foundation of China (no. T2225017). T.Q.T. acknowledges the Brain Pool Program (No. 2020H1D3A2A02111068) through the National Research Foundation (NRF) funded by the Ministry of Science. Z.L. acknowledges the support from RIE2020 AME Programmatic Grant funded by A*STAR-SERC, Singapore (Grant No. A18A1b0045). X.G. acknowledges funding support through the Shanghai Science and Technology Commission (grant no. 19JC1412400), the National Science Fund for Excellent Young Scholars (grant no. 61922057). C.D. acknowledges National Science Foundation CAREER: Conformable Piezoelectrics for Soft Tissue Imaging (grant no. 2044688) and MIT Media Lab Consortium funding. D.K. and O.G.S. acknowledge Leibniz Association and the German Research Foundation DFG (Gottfried Wilhelm Leibniz Program SCHM 1298/22-1, KA5051/1-1 and KA 5051/3-1), as well as the Leibniz association (Leibniz Transfer Program T62/2019). C.W. acknowledges the National Key Research and Development Program of China (grant no. 2021YFA1202600), National Natural Science Foundation of China (grant no. 62174082). A.V.-Y.T., E.Z., Y.Z., X.Z., and J.P. acknowledge the National Research Foundation, Singapore (NRF) under NRF’s Medium Sized Centre: Singapore Hybrid-Integrated Next-Generation μElectronics (SHINE) Centre funding programme, and AME programming funding scheme of Cyber Physiochemical Interface (CPI) project (no. A18A1b0045). R.Z. acknowledges National Natural Science Foundation of China (grant no. 51735007) and Beijing Natural Science Foundation (grant no. 3191001). N.M. acknowledges the support by JST PRESTO Grant Number JPMJPR20B7 and JST Adaptable and Seamless Technology transfer Program through Target-driven R&D (ASTEP) grant number JPMJTM22BK. C.P. acknowledges the Korean government (Ministry of Science and ICT, MSIT) (2022R1A4A3032923). M.W. acknowledges the National Key R&D Program of China under Grant (2021YFB3601200). X.Z. acknowledges National Natural Science Foundation of China (no. 62074029). S.X. acknowledges the 3M nontenured faculty award. T.-W.L. and D.-G.S. acknowledge the Pioneer Research Center Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (grant no. NRF-2022M3C1A3081211). C.T.L. would like to acknowledge support from the Institute for Health Innovation and Technology (iHealthtech), the MechanoBioEngineering Laboratory at the Department of Biomedical Engineering and the Institute for Functional Intelligent Materials (I-FIM) at the National University of Singapore (NUS). C.T.L. also acknowledges support from the National Research Foundation and A*STAR, under its RIE2020 Industry Alignment Fund − Industry Collaboration Projects (IAF-ICP) (grant no. I2001E0059) − SIA-NUS Digital Aviation Corp Lab and the NUS ARTIC Research (grant no. HFM-RP1). X.Y. acknowledges funding support by City University of Hong Kong (grant no. 9667221). T.X. and X.Z. acknowledge National Natural Science Foundation of China (22234006). B.C.K.T. acknowledges Cyber-Physiochemical Interfaces CPI, A*STAR A18A1b0045. H.G. acknowledges a research start-up grant (002479-00001) from Nanyang Technological University and the Agency for Science, Technology and Research (A*STAR) in Singapore. W.G. acknowledges National Science Foundation grant 2145802. D.J.L. acknowledges support from the US National Science Foundation grant number CBET-2223566. G.Y. acknowledges support from The Welch Foundation award F-1861, and Camille Dreyfus Teacher-Scholar Award. M.D.D. acknowledges funding support from NSF (grant no. EEC1160483). J.-H.A acknowledges the National Research Foundation of Korea (NRF-2015R1A3A2066337). J.C. acknowledges the Henry Samueli School of Engineering & Applied Science and the Department of Bioengineering at the University of California, Los Angeles for startup support and a Brain & Behavior Research Foundation Young Investigator Grant. K.T. acknowledges JST AIP Accelerated Program (no. JPMJCR21U1) and JSPS KAKENHI (grant no. JP22H00594). P.S.W. acknowledges the National Science Foundation (CMMI1636136) for support. A.M.A., M.C.H., and P.S.W. thank the National Institute on Drug Abuse (DA045550) for support. S.M. and X.C. appreciated the support from the Smart Grippers for Soft Robotics (SGSR) Programme under the National Research Foundation, Prime Minister’s Office, Singapore under its Campus of Research Excellence and Technological Enterprise (CREATE) programme