Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis.

Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction.

Membrane-delimited signaling and cytosolic action of MG53 preserve hepatocyte integrity during drug-induced liver injury.

BACKGROUND & AIMS: Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. METHODS: Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. RESULTS: Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. CONCLUSIONS: Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. LAY SUMMARY: Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.

The Prognostic Significance of FKBP1A and Its Related Immune Infiltration in Liver Hepatocellular Carcinoma.

Liver hepatocellular carcinoma (LIHC) remains a global health challenge with poor prognosis and high mortality. FKBP1A was first discovered as a receptor for the immunosuppressant drug FK506 in immune cells and is critical for various tumors and cancers. However, the relationships between FKBP1A expression, cellular distribution, tumor immunity, and prognosis in LIHC remain unclear. Here, we investigated the expression level of FKBP1A and its prognostic value in LIHC via multiple datasets including ONCOMINE, TIMER, GEPIA, UALCAN, HCCDB, Kaplan-Meier plotter, LinkedOmics, and STRING. Human liver tissue microarray was employed to analyze the characteristics of FKBP1A protein including the expression level and pathological alteration in cellular distribution. FKBP1A expression was significantly higher in LIHC and correlated with tumor stage, grade and metastasis. The expression level of the FKBP1A protein was also increased in LIHC patients along with its accumulation in endoplasmic reticulum (ER). High FKBP1A expression was correlated with a poor survival rate in LIHC patients. The analysis of gene co-expression and the regulatory pathway network suggested that FKBP1A is mainly involved in protein synthesis, metabolism and the immune-related pathway. FKBP1A expression had a significantly positive association with the infiltration of hematopoietic immune cells including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Moreover, M2 macrophage infiltration was especially associated with a poor survival prognosis in LIHC. Furthermore, FKBP1A expression was significantly positively correlated with the expression of markers of M2 macrophages and immune checkpoint proteins such as PD-L1, CTLA-4, LAG3 and HAVCR2. Our study demonstrated that FKBP1A could be a potential prognostic target involved in tumor immune cell infiltration in LIHC.

In-vitro characterization and evaluation of mesoporous titanium dioxide composite hydroxyapatite and its effectiveness in occluding dentine tubules.

BACKGROUND: To synthesize mesoporous titanium dioxide composite hydroxyapatite (TiO2-HAP) and to evaluate its effectiveness in sealing of occluding dentine tubules. METHODS: TiO2-HAP was synthesized by chemical precipitation method and characterized using infrared absorption spectrometer, X-ray diffraction, scanning electron microscope, and specific surface area detector. Forty completely extracted molars were prepared and randomly assigned into Control group, Gluma group, HAP group and TiO2-HAP group according to different treatments. The characteristics of HAP and TiO2-HAP and the sealing effectiveness of dentine tubules in these four groups, including infrared spectrum, surface contact angle, pore size distribution, and re-mineralized enamel surface profiles, were analyzed by suitable characterized techniques. The cytotoxicity of the synthesized TiO2-HAP was tested and compared using 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) colorimetry. RESULTS: Our results showed TiO2-HAP group had significantly lower contact angle, higher specific surface area, and wider range of pore size distribution than other groups. The majority of dentinal tubules in the TiO2-HAP group were blocked by white matter in a uniformed manner, and the crystals arranged in order grew along the axial direction. In addition, no significant difference in optical density (OD) value was found between control group and TiO2-HAP group (P > 0.05), and cell growth was good in TiO2-HAP group, indicating no cytotoxicity of TiO2-HAP. CONCLUSIONS: The MTT assay identified that TiO2-HAP had little effect on the L929 cell line. We showed TiO2-HAP might be used as a remineralization agent in enamel caries-like lesions.

Comparative analysis of FKBP family protein: evaluation, structure, and function in mammals and Drosophila melanogaster.

BACKGROUND: FK506-binding proteins (FKBPs) have become the subject of considerable interest in several fields, leading to the identification of several cellular and molecular pathways in which FKBPs impact prenatal development and pathogenesis of many human diseases. MAIN BODY: This analysis revealed differences between how mammalian and Drosophila FKBPs mechanisms function in relation to the immunosuppressant drugs, FK506 and rapamycin. Differences that could be used to design insect-specific pesticides. (1) Molecular phylogenetic analysis of FKBP family proteins revealed that the eight known Drosophila FKBPs share homology with the human FKBP12. This indicates a close evolutionary relationship, and possible origination from a common ancestor. (2) The known FKBPs contain FK domains, that is, a prolyl cis/trans isomerase (PPIase) domain that mediates immune suppression through inhibition of calcineurin. The dFKBP59, CG4735/Shutdown, CG1847, and CG5482 have a Tetratricopeptide receptor domain at the C-terminus, which regulates transcription and protein transportation. (3) FKBP51 and FKBP52 (dFKBP59), along with Cyclophilin 40 and protein phosphatase 5, function as Hsp90 immunophilin co-chaperones within steroid receptor-Hsp90 heterocomplexes. These immunophilins are potential drug targets in pathways associated with normal physiology and may be used to treat a variety of steroid-based diseases by targeting exocytic/endocytic cycling and vesicular trafficking. (4) By associating with presinilin, a critical component of the Notch signaling pathway, FKBP14 is a downstream effector of Notch activation at the membrane. Meanwhile, Shutdown associates with transposons in the PIWI-interacting RNA pathway, playing a crucial role in both germ cells and ovarian somas. Mutations in or silencing of dFKBPs lead to early embryonic lethality in Drosophila. Therefore, further understanding the mechanisms of FK506 and rapamycin binding to immunophilin FKBPs in endocrine, cardiovascular, and neurological function in both mammals and Drosophila would provide prospects in generating unique, insect specific therapeutics targeting the above cellular signaling pathways. CONCLUSION: This review will evaluate the functional roles of FKBP family proteins, and systematically summarize the similarities and differences between FKBP proteins in Drosophila and Mammals. Specific therapeutics targeting cellular signaling pathways will also be discussed.

Identification of Huanglongbing-infected navel oranges based on laser-induced breakdown spectroscopy combined with different chemometric methods.

In order to realize rapid identification of Gannan navel oranges infected by Huanglongbing (HLB), a full optical diagnostic method of laser-induced breakdown spectroscopy (LIBS) was proposed. All navel oranges were collected from Ganzhou, Jiangxi, China, and samples contain healthy and HLB-infected navel oranges. The LIBS spectra of the plasma plume were collected directly from the epidermis of these navel oranges. The navel orange LIBS spectra in the wavelength range of 200-1050 nm were pretreated with smoothing and multiple scatter correction; on the basis of 10×10-fold cross validation, a random forest (RF) model based on continuous wavelet transform (CWT) and principal component analysis (PCA) were analyzed to identify the navel orange of HLB. The results showed that the PCA-RF and CWT-RF models coupled with suitable methods in preprocessing data can identify HLB-infected navel oranges. The average accuracy obtained from the CWT-RF model was 96.86% in the training set and 97.45% in the test set; the average accuracy by the PCA-RF model was 97.64% in the training set and 97.89% in the test set. The overall results demonstrate that LIBS combined with CWT-RF or PCA-RF, as a valuable analytical tool, could be used for HLB-infected navel orange identification.

[Study on the Enhancement Intensity of Cd in Rice with Microwave-Assisted Laser-Induced Breakdown Spectroscopy].

As food safety problem has become the focus of attention all over the world, green detection methods of the contaminants in food is in accordance with the sustainable development of environment. Heavy metal pollutant Cd element in rice was used as the object of study in this work, laser induced breakdown spectroscopy (LIBS) and microwave assisted laser induced breakdown spectroscopy (MA-LIBS) were utilized to detect the blank and laboratory polluted rice samples respectively. The characteristic line of Cd Ⅰ 228.802 nm was employed as analytical line to discuss the enhancement effect of plasmas emission intensity for the analytical line of target element. Meanwhile, the actual concentration of Cd in rice was measured by anodic stripping voltammetry. The result displayed that LIBS can just detect the plasmas signals of the sample which contained 13.69 µg·g-1 cadmium for the laboratory polluted rice samples which concentration range from 2.16 to 13.69 µg·g-1, however, in the same experimental conditions, MA-LIBS can detect the plasmas signals of Cd in all of the contaminated rice samples successfully, and compared with LIBS, the plasmas emission intensity of Cd element was enhanced from 9 to 27 times. The results showed that the plasmas emission intensity of Cd element in rice can be enhanced effectively by MA-LIBS, and the detection sensitivity can be effectively improved.

[Determination of Cu in Shell of Preserved Egg by LIBS Coupled with PLS].

In this work, the content of copper in the shell of preserved eggs were determined directly by Laser induced breakdown spectroscopy (LIBS), and the characteristics lines of Cu was obtained. The samples of eggshell were pretreated by acid wet digestion, and the real content of Cu was obtained by atomic absorption spectrophotometer (AAS). Due to the test precision and accuracy of LIBS was influenced by a serious of factors, for example, the complex matrix effect of sample, the enviro nment noise, the system noise of the instrument, the stability of laser energy and so on. And the conventional unvariate linear calibration curve between LIBS intensity and content of element of sample, such as by use of Schiebe G-Lomakin equation, can not meet the requirement of quantitative analysis. In account of that, a kind of multivariate calibration method is needed. In this work, the data of LIBS spectra were processed by partial least squares (PLS), the precision and accuracy of PLS model were compared by different smoothing treatment and five pretreatment methods. The result showed that the correlation coefficient and the accuracy of the PLS model were improved, and the root mean square error and the average relative error were reduced effectively by 11 point smoothing with Multiplicative scatter correction (MSC) pretreatment. The results of the study show that, heavy metal Cu in preserved egg shells can be direct detected accurately by laser induced breakdown spectroscopy, and the next step batch tests will been conducted to find out the relationship of heavy metal Cu content in the preserved egg between the eggshell, egg white and egg yolk. And the goal of the contents of heavy metals in the egg white, egg yolk can be knew through determinate the eggshell by the LIBS can be achieved, to provide new method for rapid non-destructive testing technology for quality and satety of agricultural products.

FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice.

RATIONALE: FK506 binding protein (FKBP)12 is a known cis-trans peptidyl prolyl isomerase and highly expressed in the heart. Its role in regulating postnatal cardiac function remains largely unknown. METHODS AND RESULTS: We generated FKBP12 overexpressing transgenic (αMyHC-FKBP12) mice and cardiomyocyte-restricted FKBP12 conditional knockout (FKBP12(f/f)/αMyHC-Cre) mice and analyzed their cardiac electrophysiology in vivo and in vitro. A high incidence (38%) of sudden death was found in αMyHC-FKBP12 mice. Surface and ambulatory ECGs documented cardiac conduction defects, which were further confirmed by electric measurements and optical mapping in Langendorff-perfused hearts. αMyHC-FKBP12 hearts had slower action potential upstrokes and longer action potential durations. Whole-cell patch-clamp analyses demonstrated an ≈ 80% reduction in peak density of the tetrodotoxin-resistant, voltage-gated sodium current I(Na) in αMyHC-FKBP12 ventricular cardiomyocytes, a slower recovery of I(Na) from inactivation, shifts of steady-state activation and inactivation curves of I(Na) to more depolarized potentials, and augmentation of late I(Na), suggesting that the arrhythmogenic phenotype of αMyHC-FKBP12 mice is attributable to abnormal I(Na). Ventricular cardiomyocytes isolated from FKBP12(f/f)/αMyHC-Cre hearts showed faster action potential upstrokes and a more than 2-fold increase in peak I(Na) density. Dialysis of exogenous recombinant FKBP12 protein into FKBP12-deficient cardiomyocytes promptly recapitulated alterations in I(Na) seen in αMyHC-FKBP12 myocytes. CONCLUSIONS: FKBP12 is a critical regulator of I(Na) and is important for cardiac arrhythmogenic physiology. FKPB12-mediated dysregulation of I(Na) may underlie clinical arrhythmias associated with FK506 administration.

[Analysis of Cr in soil by LIBS based on conical spatial confinement of plasma].

The present study is to improve the sensitivity of detection and reduce the limit of detection in detecting heavy metal of soil by laser induced breakdown spectroscopy (LIBS). The Cr element of national standard soil was regarded as the research object. In the experiment, a conical cavity with small diameter end of 20 mm and large diameter end of 45 mm respectively was installed below the focusing lens near the experiment sample to mainly confine the signal transmitted by plasma and to some extent to confine the plasma itself in the LIBS setup. In detecting Cr I 425.44 nm, the beast delay time gained from experiment is 1.3 micros, and the relative standard deviation is below 10%. Compared with the setup of non-spatial confinement, the spectral intensity of Cr in the soil sample was enhanced more than 7%. Calibration curve was established in the Cr concentration range from 60 to 400 microg x g(-1). Under the condition of spatial confinement, the liner regression coefficient and the limit of detection were 0.997 71 and 18.85 microg x g(-1) respectively, however, the regression coefficient and the limit of detection were 0.991 22 and 36.99 microg x g(-1) without spatial confinement. So, this shows that conical spatial confinement can/improve the sensitivity of detection and enhance the spectral intensity. And it is a good auxiliary function in detecting Cr in the soil by laser induced breakdown spectroscopy.

microRNA-142-3p regulates osteogenic differentiation of human periodontal ligament stem cells via mediating SGK1.

OBJECTIVE: Human periodontal ligament stem cells (hPDLSCs) refer to one kind of somatic stem cells that are capable of differentiating into multiple cell kinds and undergoing robust clonal self-renewal. This work was unearthed to elucidate the possible molecular mechanism of miR-142-3p in mediating osteogenic differentiation of hPDLSCs by targeting SGK1. METHODS: The hPDLSCs were isolated, cultured, and identified. hPDLSCs were identified by immunofluorescence staining and multiple differentiation ability detection. Cell proliferation ability was assessed by CCK-8 assay. hPDLSCs were induced using osteogenic differentiation medium. ALP activity was detected by alkaline phosphatase (ALP) staining  and ALP activity assay, and mineralized nodule formation was determined by alizarin red staining. The expression levels of osteogenic differentiation marker proteins ALP, RUNX2, and OCN were measured by RT-qPCR. miR-142-3p candidate targets were obtained through bioinformatics analysis. The relationship between miR-142-3p and SKG1 was verified. RESULTS: miR-142-3p in hPDLSCs after osteogenic induction was down-regulated. Elevated miR-142-3p restricted hPDLSCs proliferation, and diminished ALP activity and mineralized nodule formation, as well as the expression of ALP, RUNX2, and OCN, while miR-142-3p inhibition led to inverse results. miR-142-3p inhibited SKG1 expression. SKG1 overexpression promoted hPDLSC proliferation and osteogenic differentiation, and reversed the inhibitory function of miR-142-3p on hPDLSCs. CONCLUSION: This study highlights that miR-142-3p represses osteogenic differentiation of hPDLSCs by reducing SGK1 expression.

Texture-Induced Corrosion Resistance of Dissimilar AA7204/AA6082 Friction Stir Welded Joints.

The quasi in situ EBSD test was applied to study the effect of grain orientation on corrosion behaviors of the thermomechanically affected zone I (TMAZ I) of dissimilar AA6082/AA7204 friction stir welding (FSW) joints in this work. The results show that the structure with grain orientation close to the brass texture ({110}<112>) has excellent corrosion resistance, which contributes to the better corrosion performance of the TMAZ I of the 7204-AS joint than the 7204-RS joint. Furthermore, the brass texture around by S texture ({213}<364>) in the TMAZ I of the 7204-AS joint is slightly corroded, and the orientation of the remaining structure is closer to the ({110}<112>) than before, which indicates that the corrosion, like deformation, is carried out alongside the {110} plane for the structure with grain orientation near {110}<112>. Those findings could provide new insight into the designed FSW joints and improve the corrosion resistance of the wrought aluminum alloy.

Circulating macrophages as the mechanistic link between mosaic loss of Y-chromosome and cardiac disease.

BACKGROUND: Genetics evidences have long linked mosaic loss of Y-chromosome (mLOY) in peripheral leukocytes with a wide range of male age-associated diseases. However, a lack of cellular and molecular mechanistic explanations for this link has limited further investigation into the relationship between mLOY and male age-related disease. Excitingly, Sano et al. have provided the first piece of evidence directly linking mLOY to cardiac fibrosis through mLOY enriched profibrotic transforming growth factor ß1 (TGF-ß1) regulons in hematopoietic macrophages along with suppressed interleukin-1ß (IL-1ß) proinflammatory regulons. The results of this novel finding can be extrapolated to other disease related to mLOY, such as cancer, cardiac disease, and age-related macular degeneration. RESULTS: Sano et al. used a CRISPR-Cas9 gRNAs gene editing induced Y-chromosome ablation mouse model to assess results of a UK biobank prospective analysis implicating the Y-chromosome in male age-related disease. Using this in vivo model, Sano et al. showed that hematopoietic mLOY accelerated cardiac fibrosis and heart failure in male mice through profibrotic pathways. This process was linked to monocyte-macrophage differentiation during hematopoietic development. Mice confirmed to have mLOY in leukocytes, by loss of Y-chromosome genes Kdm5d, Uty, Eif2s3y, and Ddx3y, at similar percentages to the human population were shown to have accelerated rates of interstitial and perivascular fibrosis and abnormal echocardiograms. These mice also recovered poorly from the transverse aortic constriction (TAC) model of heart failure and developed left ventricular dysfunction at higher rates. This was attributed to aberrant proliferation of cardiac MEF-SK4 + fibroblasts promoted by mLOY macrophages enriched in profibrotic regulons and lacking in proinflammatory regulons. These pro-fibrotic macrophages localized to heart and eventually resulted in cardiac fibrosis via enhanced TGF-ß1 and suppressed IL-1ß signaling. Furthermore, treatment of mLOY mice with TGFß1 neutralizing antibody was able to improve their cardiac function. This study by Sano et al. was able to provide a causative link between the known association between mLOY and male cardiac disease morbidity and mortality for the first time, and thereby provide a new target for improving human health. CONCLUSIONS: Using a CRISPR-Cas9 induced Y-chromosome ablation mouse model, Sano et al. has proven mosaic loss of Y-chromosome in peripheral myeloid cells to have a causative effect on male mobility and mortality due to male age-related cardiac disease. They traced the mechanism of this effect to hyper-expression of the profibrotic TGF-ß1 and reduced pro-inflammatory IL-1ß signaling, attenuation of which could provide another potential strategy in improving outcomes against age-related diseases in men.

Clinical observation of autologous platelet rich fibrin assisted revascularization of mature permanent teeth.

OBJECTIVE: To investigate the clinical observation of autologous platelet-rich fibrin (PRF) assisting the revascularization of mature permanent teeth. METHODS: Twenty patients with mature permanent teeth were divided into experimental group and control group. The control group was treated with classic revascularization, and the experimental group was treated with PRF-assisted mature permanent tooth revascularization. RESULTS: After treatment, the total effective rate of the experimental group (100.00%) was higher than that of the control group (50.00%); the thickness of the root canal wall of the experimental group was higher than that of the control group, and the crown root length was lower than that of the control group; The bite degree, chewing function, color, overall aesthetic score, and satisfaction rate of the patients were higher, and the difference was statistically significant (P < 0.05). CONCLUSION: Autologous PRF assists in revascularization of mature permanent teeth, which can achieve ideal results, and promote pulp regeneration.

Mosaic loss of chromosome Y in peripheral blood cells is associated with age-related macular degeneration in men.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 55 years old in the industrialized world. In the past 20 years, approximately 288 million patents have been affected by this disease. Despite this high prevalence, the molecular mechanism for AMD remains unclear, and there remains no effective treatment for this disease. The mosaic loss of Y chromosome (mLOY) has been identified as a common phenomenon in multiple age-related disease (i.e., oncogenesis and cardiovascular disease) has recently been identified by genome-wide analysis to be linked to AMD as well. As the Y chromosome mainly possesses three genomic functions, sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling, here we characterize the Y chromosome euchromatic genes and non-chromosome AMD genes in relevance to cellular proliferation and apoptotic signaling of leukocytes. RESULTS: Using STRING, a publically available database of all protein-protein interaction, Grassmann et al. found the genes on the Y chromosome is mainly believed to take part in three major cellular genomic functions- sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling. Based on data from the Ensembl Genome database, we focus on our discussion on coding genes found in the euchromatins but not the PAR1 and PAR2 regions of the Y chromosomes. All 14 known euchromatic genes on the Y chromosome short arm and all 31 known euchromatic genes on the Y chromosome long arm (Yq) are directly or indirectly involved in the cell cycle (meiosis and mitosis) and proliferation. We sorted non-Y chromosome AMD associated genes into these three categories to identify signaling pathways that may compound with cellular dysregulation due to mLOY. Of the genes associated with AMD, complement pathway genes such as C2, C9 and CFH/ARMD4 are associated with proliferation, receptor-mediated endocytosis genes such as APOE, DAB2 and others associated with apoptotic signaling. Because nucleated cells found in peripheral circulation are mainly composed of leukocytes with reduced expression of CD99, a protein essential for leukocytes adhesion, translocation, and function, mLOY in these cells likely affect retinal degeneration through altered immunological surveillance. In fact, there is precedence that circulating macrophage can stabilize and modify the cardiac rhythm and contractility post ischemic damage. Therefore, the most likely mechanism through which peripheral mLOY affects AMD development in men is through the role affected leukocytes play in retinal proliferation and apoptosis. CONCLUSIONS: mLOY in peripheral blood is newly discovered in AMD by Grassmann et al. as it is a common phenomenon in oncogenesis and cardiac dysfunction. Here the recent data conclude the possible mechanism for the newly identified link between mLOY and AMD, and provide support that mLOY in circulating macrophage-monocyte of affected male patients promotes AMD by targeting the retina and causing macular degeneration.

Overexpression of long noncoding RNA MCM3AP-AS1 promotes osteogenic differentiation of dental pulp stem cells via miR-143-3p/IGFBP5 axis.

MCM3AP-AS1 regulates the cartilage repair in osteoarthritis, but how it regulates osteogenic differentiation of dental pulp stem cells (DPSCs) remains to be determined. DPSCs were isolated and induced for osteogenic differentiation. MCM3AP-AS1 expression was increased along with the osteogenic differentiation of DPSCs, whose expression was positive correlated with those of OCN, alkaline phosphatase (ALP) and RUNX2. On contrary, miR-143-3p expression was decreased along with the osteogenic differentiation and was negatively correlated with those of OCN, ALP and RUNX2. Dual-luciferase reporter gene assay showed that miR-143-3p can be negatively regulated by MCM3AP-AS1 and can regulate IGFBP5. MCM3AP-AS1 overexpression increased the expression levels of osteogenesis-specific genes, ALP activity and mineralized nodules during DPSC osteogenic differentiation, while IGFBP5 knockdown or miR-143-3p overexpression counteracted the effect of MCM3AP-AS1 overexpression in DPSCs. Therefore, this study demonstrated the role of MCM3AP-AS1/miR-143-3p/IGFBP5 axis in regulating DPSC osteogenic differentiation.

Sustained delivery of rhMG53 promotes diabetic wound healing and hair follicle development.

MG53 is an essential component of the cell membrane repair machinery, participating in the healing of dermal wounds. Here we develop a novel delivery system using recombinant human MG53 (rhMG53) protein and a reactive oxygen species (ROS)-scavenging gel to treat diabetic wounds. Mice with ablation of MG53 display defective hair follicle structure, and topical application of rhMG53 can promote hair growth in the mg53 -/- mice. Cell lineage tracing studies reveal a physiological function of MG53 in modulating the proliferation of hair follicle stem cells (HFSCs). We find that rhMG53 protects HFSCs from oxidative stress-induced apoptosis and stimulates differentiation of HSFCs into keratinocytes. The cytoprotective function of MG53 is mediated by STATs and MAPK signaling in HFSCs. The thermosensitive ROS-scavenging gel encapsulated with rhMG53 allows for sustained release of rhMG53 and promotes healing of chronic cutaneous wounds and hair follicle development in the db/db mice. These findings support the potential therapeutic value of using rhMG53 in combination with ROS-scavenging gel to treat diabetic wounds.

MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine.

Under natural conditions, injured cells can be repaired rapidly through inherent biological processes. However, in the case of diabetes, cardiovascular disease, muscular dystrophy, and other degenerative conditions, the natural repair process is impaired. Repair of injury to the cell membrane is an important aspect of physiology. Inadequate membrane repair function is implicated in the pathophysiology of many human disorders. Recent studies show that Mitsugumin 53 (MG53), a TRIM family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. Clarifying the role of MG53 and its molecular mechanism are important for the application of MG53 in regenerative medicine. In this review, we analyze current research dissecting MG53's function in cell membrane repair and tissue regeneration, and highlight the development of recombinant human MG53 protein as a potential therapeutic agent to repair multiple-organ injuries.

Multiple functions of autophagy in vascular calcification.

BACKGROUND: Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. METHODS: In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. RESULTS: Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, ß-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/ß-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA­PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34-beclin-1-related bone mineralization via vascular calcification. CONCLUSION: The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

Influence of Minor Zn Addition on Precipitation Behavior and Intergranular Corrosion Properties of Al-Mg-Si Alloy.

The effect of 0.2 wt.% Zn addition on microstructure, age hardening and intergranular corrosion (IGC) properties of Al-Mg-Si alloy were investigated by scanning electron microscope, transmission electron microscope, hardness testing, and electrochemistry testing. The results showed that the addition of Zn can accelerate the transformation of GP zones into ß″, and make the intragranular precipitates become smaller and with higher density. This is beneficial to the precipitation strengthening of the alloy, leading to obtaining higher hardness and enhancing the age hardening response. The peak hardness of the alloy with the addition of Zn is 125.8 HV which means increasing the hardness by 12.7 HV, compared with the alloy without Zn. However, the addition of Zn makes the precipitate-free zone (PFZ) of the alloy wider, and coarsens the grain boundary precipitates slightly, which result in the reduction of IGC resistance of Al-Mg-Si alloy. The maximum corrosion depth of the Zn-containing alloy is 121.3 µm in the peak age condition, which is 35.7 µm deeper than the alloy without Zn. The result of the potentiodynamic polarization curves also demonstrated the increase of IGC sensitivity. The corrosion current density of the alloy with added Zn is 0.595 µA/cm2 in the peak age condition, while that for the alloy without Zn is 0.199 µA/cm2.