Models for Meibomian gland dysfunction: In vivo and in vitro.

Meibomian gland dysfunction (MGD) is a chronic abnormality of the Meibomian glands (MGs) that is recognized as the leading cause of evaporative dry eye worldwide. Despite its prevalence, however, the pathophysiology of MGD remains elusive, and effective disease management continues to be a challenge. In the past 50 years, different models have been developed to illustrate the pathophysiological nature of MGD and the underlying disease mechanisms. An understanding of these models is crucial if researchers are to select an appropriate model to address specific questions related to MGD and to develop new treatments. Here, we summarize the various models of MGD, discuss their applications and limitations, and provide perspectives for future studies in the field.

Disappearing Negative Valence: A Content Analysis of HPV Vaccine Newspaper Coverage in China (2000-2018).

News coverage of the human papillomavirus (HPV) vaccine grew rapidly in China in 2016 when the vaccine was approved. Drawing upon framing theory, the present study analyzed the content of 491 Chinese newspaper reports on the HPV vaccine published between June 2000 and December 2018 to investigate what and how information and valence about the vaccine was relayed to the public. The results indicated that, while the Chinese media failed to provide comprehensive and accurate information about HPV and the HPV vaccine, they showed a positive evaluation of the HPV vaccine demand and market. In addition, there was a decline in negative coverage after the vaccine was approved. This study extended the literature on HPV vaccine coverage by combining issue-specific framing and valence framing, considering the Chinese-specific vaccine market for presentation and the value of such products, which is rare in previous studies. Practical implications of the findings for health promotion were also discussed.

Chronic Sleep Deprivation Impairs Visual Functions via Oxidative Damage in Mice.

Sleep deprivation (SD) is a global public health burden, and has a detrimental role in the nervous system. Retina is an important part of the central nervous system; however, whether SD affects retinal structures and functions remains largely unknown. Herein, chronic SD mouse model indicated that loss of sleep for 4 months could result in reductions in the visual functions, but without obvious morphologic changes of the retina. Ultrastructural analysis by transmission electron microscope revealed the deterioration of mitochondria, which was accompanied with the decrease of multiple mitochondrial proteins in the retina. Mechanistically, oxidative stress was provoked by chronic SD, which could be ameliorated after rest, and thus restore retinal homeostasis. Moreover, the supplementation of two antioxidants, α-lipoic acid and N-acetyl-l-cysteine, could reduce retinal reactive oxygen species, repair damaged mitochondria, and, as a result, improve the retinal functions. Overall, this work demonstrated the essential roles of sleep in maintaining the integrity and health of the retina. More importantly, it points towards supplementation of antioxidants as an effective intervention strategy for people experiencing sleep shortages.

Accurate detection and grading of pterygium through smartphone by a fusion training model.

BACKGROUND/AIMS: To improve the accuracy of pterygium screening and detection through smartphones, we established a fusion training model by blending a large number of slit-lamp image data with a small proportion of smartphone data. METHOD: Two datasets were used, a slit-lamp image dataset containing 20 987 images and a smartphone-based image dataset containing 1094 images. The RFRC (Faster RCNN based on ResNet101) model for the detection model. The SRU-Net (U-Net based on SE-ResNeXt50) for the segmentation models. The open-cv algorithm measured the width, length and area of pterygium in the cornea. RESULTS: The detection model (trained by slit-lamp images) obtained the mean accuracy of 95.24%. The fusion segmentation model (trained by smartphone and slit-lamp images) achieved a microaverage F1 score of 0.8981, sensitivity of 0.8709, specificity of 0.9668 and area under the curve (AUC) of 0.9295. Compared with the same group of patients' smartphone and slit-lamp images, the fusion model performance in smartphone-based images (F1 score of 0.9313, sensitivity of 0.9360, specificity of 0.9613, AUC of 0.9426, accuracy of 92.38%) is close to the model (trained by slit-lamp images) in slit-lamp images (F1 score of 0.9448, sensitivity of 0.9165, specificity of 0.9689, AUC of 0.9569 and accuracy of 94.29%). CONCLUSION: Our fusion model method got high pterygium detection and grading accuracy in insufficient smartphone data, and its performance is comparable to experienced ophthalmologists and works well in different smartphone brands.

MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice.

Mammalian Müller glia (MG) possess limited regenerative capacities. However, the intrinsic capacity of mammalian MG to transdifferentiate to generate mature neurons without transgenic manipulations remains speculative. Here we show that MAP4K4, MAP4K6 and MAP4K7, which are conserved Misshapen subfamily of ste20 kinases homologs, repress YAP activity in mammalian MG and therefore restrict their ability to be reprogrammed. However, by treating with a small molecule inhibitor of MAP4K4/6/7, mouse MG regain their ability to proliferate and enter into a retinal progenitor cell (RPC)-like state after NMDA-induced retinal damage; such plasticity was lost in YAP knockout MG. Moreover, spontaneous trans-differentiation of MG into retinal neurons expressing both amacrine and retinal ganglion cell (RGC) markers occurs after inhibitor withdrawal. Taken together, these findings suggest that MAP4Ks block the reprogramming capacity of MG in a YAP-dependent manner in adult mammals, which provides a novel avenue for the pharmaceutical induction of retinal regeneration in vivo.

Transitory alkali exposure on meibomian gland orifices induces meibomian gland dysfunction.

PURPOSE: To determine pathological changes of meibomian glands (MGs) after transient exposure of the rat eyelid margin to alkali solution. METHODS: Filter paper infiltrated with 1 N sodium hydroxide solution was applied to the eyelid margin of Sprague-Dawley rats for 30 s under general anesthesia, without touching the conjunctiva, after which the ocular surface and eyelid margin were examined by slit-lamp microscopy. In vivo confocal microscopy and stereomicroscopy were subsequently applied to observe MG morphology on day 5, day 10 and day 30 post alkali injury. Eyelid cross-sections were processed for H&E staining, Oil red O staining and immunofluorescent staining. RESULTS: After alkali injury, there was marked plugging of MG orifices, telangiectasia and hypertrophy of the eyelid margin, while corneal epithelium was intact at post-injury days 5 and 10. However, 30 days after alkali injury, mild corneal epithelial damage was observed. Degeneration of MG acini was observed at days 5 and became aggravated at days 10 and 30, along with MG duct dilation and acini loss. Oil red O staining showed lipid accumulation in the dilated duct. Inflammatory cell infiltration and the presence of apoptotic cells was seen in the MG loci 5 days post injury, but diminished at days 10 and 30. Cytokeratin 10 expression was increased in dilated duct, while cytokeratin 14, PPAR-γ, Ki67 and LRIG1 expression were decreased in the acini of injured loci. CONCLUSIONS: Transitory alkali exposure of the rat eyelid margin obstructs the MG orifice and induces pathological changes of MG dysfunction.

Optimal vaccination strategies for COVID-19 in population migration between two regions scenario.

Population movements had a significant impact on the spread of COVID-19, and vaccination is considered the most effective means for humans to face viral infections. This study identifies the optimal control strategy for COVID-19 prevention and control, and explores the impact of short-term and long-term migration on the optimal proportion of vaccine allocation between two regions. We proposed to establish the SIR (Susceptible-Infectious-Recovered) model and determine the stability by calculating the disease free equilibrium and Jacobi matrix of the model. We then established the vaccine optimization model, solved the optimal vaccine distribution strategy by gradient descent method and explored the impact of short-term and long-term migration on the optimal vaccine allocation ratio. The stability analysis revealed that the virus could not be eliminated only by reducing the migration rates and infection rates. we introduced the vaccine methods and obtained the optimal vaccine allocation ratio in Shenzhen and Hong Kong as p1:p2=0.000341: 0.001739, and the daily vaccination rate we need to impose in each region as p1:p2=0.00068:0.001901. The presence or absence of short-term migration had no greater impact on the distribution of the vaccine, whereas Rv with long-term migration had a greater effect than no migration. We found that migration rates could not eliminate the outbreak in both regions and that adopting an effective vaccine distribution strategy could be more effective in eliminating the outbreak. And for different allocation scenarios with limited vaccine supply, we obtained the optimal allocation most favorable to control the epidemic.

Hyperglycemia Induces Meibomian Gland Dysfunction.

Purpose: Patients diagnosed with diabetes are inclined to have abnormalities on stability of tear film and disorder of meibomian gland (MG). This study aims to explore the pathological change of MG induced by diabetes in a rat model. Methods: Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin (STZ) to establish a diabetic animal model. Lipid accumulation in MG was detected by Oil Red O staining and LipidTox staining. Cell proliferation status was determined by Ki67 and P63 immunostaining, whereas cell apoptosis was confirmed by TUNEL assay. Gene expression of inflammatory cytokines and adhesion molecules IL-1α, IL-1ß, ELAM1, ICAM1, and VCAM1 were detected by RT-PCR. Activation of ERK, NF-κB, and AMPK signaling pathways was determined by Western Blot analysis. Oxidative stress-related factors NOX4, 4HNE, Nrf2, HO-1, and SOD2 were detected by immunostaining or Western Blot analysis. Tom20 and Tim23 immunostaining and transmission electron microscopy were performed to evaluate the mitochondria functional and structure change. Results: Four months after STZ injection, there was acini dropout in MG of diabetic rats. Evident infiltration of inflammatory cells, increased expression of inflammatory factors, and adhesion molecules, as well as activated ERK and NF-κB signaling pathways were identified. Oxidative stress of MG was evident in 4-month diabetic rats. Phospho-AMPK was downregulated in MG of 2-month diabetic rats and more prominent in 4-month rats. After metformin treatment, phospho-AMPK was upregulated and the morphology of MG was well maintained. Moreover, inflammation and oxidative stress of MG were alleviated after metformin intervention. Conclusions: Long-term diabetes may lead to Meibomian gland dysfunction (MGD). AMPK may be a therapeutic target of MGD induced by diabetes.

Structure and immunological activity of an arabinan-rich acidic polysaccharide from Atractylodes lancea (Thunb.) DC.

An arabinan-rich acidic polysaccharide, named ALP4-2 ([α]20 D = +197.8 (c 1.0 mg/mL, H2O); and Mw = 5.59 × 103 g/mol), was obtained from Atractylodes lancea (Thunb.) DC. ALP4-2 is mainly comprised of Ara along with a small amount of GalA, Gal, Rha, Glc and Xyl. The structure was decorated by glycosidic linkages of α-Araf-(1→, →3)-α-Araf-(1→, →5)-α-Araf-(1→, →3,5)-α-Araf-(1→, →2,4)-α-Rhap-(1→, α-GalAp-(1→, →4)-α-GalAp-6-OMe-(1→, →4)-α-GalAp-6-OMe and ß-Galp-(1→ with a ratio of 6:1:7:5:5:1:7:1:4. The structure, configuration and microstructure of ALP4-2 was proposed by comprehensive considerations of results from SEC-MALLS-RID, SEC-HRMS, GC-MS, and 1D/2D NMR spectroscopy. Except for a high methyl ester in full pectin regions, an abundant arabinan moiety is observed in ALP4-2 with highly complex and branched characteristics. The immunoactivity displayed that ALP4-2 can significantly promote phagocytosis of macrophage without cytotoxicity, and stimulate nitric oxide and cytokines (TNF-α, IL-6 and IL-10) release on RAW 264.7.

Long-Term Sleep Deprivation-Induced Myocardial Remodeling and Mitochondrial Dysfunction in Mice Were Attenuated by Lipoic Acid and N-Acetylcysteine.

The impact of long-term sleep deprivation on the heart and its underlying mechanisms are poorly understood. The present study aimed to investigate the impact of chronic sleep deprivation (CSD) on the heart and mitochondrial function and explore an effective drug for treating CSD-induced heart dysfunction. We used a modified method to induce CSD in mice; lipoic acid (LA) and N-acetylcysteine (NAC) were used to treat CSD mice. Echocardiography, hematoxylin-eosin (H&E) staining, Sirius red staining, and immunohistochemistry were used to determine heart function and cardiac fibrosis. The serum levels of brain natriuretic peptide (BNP), superoxide Dismutase (SOD), micro malondialdehyde (MDA), and glutathione (GSH) were measured to determine cardiovascular and oxidative stress-related damage. Transmission electron microscopy was used to investigate mitochondrial damage. RNA-seq and Western blotting were used to explore related pathways. We found that the left ventricular ejection fraction (LVEF) and fraction shortening (LVFS) values were significantly decreased and myocardial hypertrophy was induced, accompanied by damaged mitochondria, elevated reactive oxygen species (ROS), and reduced SOD levels. RNA-sequence analysis of the heart tissue showed that various differentially expressed genes in the metabolic pathway were enriched. Sirtuin 1 (Sirt1) and Glutathione S-transferase A3 (Gsta3) may be responsible for CSD-induced heart and mitochondrial dysfunction. Pharmacological inhibition of ROS by treating CSD mice with LA and NAC effectively reduced heart damage and mitochondrial dysfunction by regulating Sirt1 and Gsta3 expression. Our data contribute to understanding the pathways of CSD-induced heart dysfunction, and pharmacological targeting to ROS may represent a strategy to prevent CSD-induced heart damage.

Inhibition of ceramide de novo synthesis ameliorates meibomian gland dysfunction induced by SCD1 deficiency.

High expression of stearoyl-CoA desaturase-1 (SCD1) in meibomian glands produces monounsaturated fatty acids that allow the biosynthesis of glycerolipids and other wax-esters but only the low production of sphingolipids. Here, we found that SCD1 deficiency in mice induces the spill of free fatty acids into a parallel pathway for ceramide biosynthesis, resulting in severe meibomian gland dysfunction associated with meibum accumulation in duct lumen and orifices and subsequent atrophy and loss of acinar cells. Genetic and pharmacological inhibition of SCD1 in mice resulted in meibomian gland pathological phenotypes, including local lipid microenvironment alterations, reduced normal cellular differentiation, increased keratinization, inflammatory cell infiltration, cell apoptosis, and mitochondrial dysfunction. However, inhibition of serine palmitoyltransferase, the initial enzyme in ceramide biosynthesis, improved meibomian gland metabolism and morphology in SCD1-deficient mice, resulting in normal cell differentiation and reduced inflammation infiltration, cell apoptosis, and keratinization. These results indicate that elevated levels of endogenous ceramides are a sign of MGD and suggest that inhibition of ceramide de novo biosynthesis could be a new clinical approach to treating MGD.

High-Fat Diet Induces Inflammation of Meibomian Gland.

Purpose: To determine if a high-fat diet (HFD) induces meibomian gland (MG) inflammation in mice. Methods: Male C57BL/6J mice were fed a standard diet (SD), HFD, or HFD supplemented with the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist rosiglitazone for various durations. Body weight, blood lipid levels, and eyelid changes were monitored at regular intervals. MG sections were subjected to hematoxylin and eosin staining, LipidTox staining, TUNEL assay, and immunostaining. Quantitative RT-PCR and western blot analyses were performed to detect relative gene expression and signaling pathway activation in MGs. Results: MG acinus accumulated more lipids in the mice fed the HFD. Periglandular CD45-positive and F4/80-positive cell infiltration were more evident in the HFD mice, and they were accompanied by upregulation of inflammation-related cytokines. PPAR-γ downregulation accompanied activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways in the HFD mice. There was increased acini cell apoptosis and mitochondria damage in mice fed the HFD. MG inflammation was ameliorated following a shift to the standard diet and rosiglitazone treatment in the mice fed the HFD. Conclusions: HFD-induced declines in PPAR-γ expression and MAPK and NF-κB signaling pathway activation resulted in MG inflammation and dysfunction in mice.

Ultrafiltration isolation, structures and anti-tumor potentials of two arabinose- and galactose-rich pectins from leaves of Aralia elata.

Two novel arabinose- and galactose-rich pectic polysaccharides, AELP-B5 (Mw, 4.25 × 104 g/mol) and B6 (Mw, 1.56 × 104 g/mol), were rapidly obtained from the leaves of Aralia elata (Miq.) Seem. with anion resin and sequenced ultrafiltration membrane columns. The structural backbone and branched chains of AELP-B5 and B6 were preliminarily elucidated by mild acid hydrolysis with HILIC-ESI--MS/MS. The planar structures and spatial configurations were further identified using UPLC-QDa and GC-MS for compositions, Smith degradation and methylation analysis, FT-IR, NMR (1H/13C, DEPT, HSQC, HMBC, COSY, NOESY and TOCSY) and SEC-MALLS-RID. (1) AELP-B5 possessed →4GalA1→ as smooth regions (HG) and a repeating disaccharide moiety of →4GalA1→2Rha1→ as hairy regions (RG-I) with a 1:5 molar ratio, whereas AELP-B6 had a distinguishing 1:1 molar ratio between the HG and RG-I; (2) complex side chains were constituted of T-α-Araf, 1,3-α-Araf, 1,5-α-Araf, T-ß-Galp, 1,3-ß-Galp, 1,4-ß-Galp, 1,6-ß-Galp, 1,3,4-ß-Galp and 1,3,4,6-ß-Galp connected at C-4 of the rhamnosyl units in RG-I of AELP-B5 and B6; and (3) both possessed highly branched and compact coil conformations. The CCK-8 assay illustrated that AELP-B6 possessed higher cytotoxicity against HepG2 and HT-29 than that of AELP-B5. Surface plasmon resonance showed the binding affinity of AELP-B6 to galectin-3 (6.488 × 10-5 M) was about 10 times stronger than that of AELP-B5 (4.588 × 10-4 M). The above findings provide a molecular structure and bioactivity basis for future potential applications of AELP in the food and medical industries.

What affected Chinese parents' decisions about tuberculosis (TB) treatment: Implications based on a cross-sectional survey.

OBJECTIVE: Although progress has been made in tuberculosis (TB) treatment, China still remains one of the high-burden TB countries. One important reason that has not received sufficient scholarly attention is that Chinese individuals tend to underestimate the threat of TB. This contributed to the high rate of delay in seeking TB treatment and noncompliance with doctors' regimen. Hence, this research examined how TB knowledge affected Chinese parents' risk perceptions and their efficacy appraisal in TB treatment, and how their risk perception and efficacy appraisal affected their intentions to seek timely TB treatment for their children and adhere to doctors' regimen. METHODS: We conducted an online cross-sectional survey with 1129 parents of children attending kindergarten, primary school, and middle school in Shajing, a region with high TB incidence in China. Perceived severity of TB threat to self and to others, perceived susceptibility, response efficacy, and self-efficacy were measured, in addition to TB knowledge and intentions to seek timely TB treatment and adhere to doctors' regimens. RESULTS: Ordinal least squares regression demonstrated that TB knowledge was positively associated with perceived severity of TB threat to self, perceived severity of TB threat to others, perceived susceptibility, response efficacy, and self-efficacy, but it did not affect their medical decisions. In addition, binary logistic regression revealed that response efficacy and self-efficacy predicted both intentions positively, and perceived severity of TB threat to self only enhanced Chinese individuals' intention to follow doctors' regimens. CONCLUSION: Health education aimed at knowledge improvement may be effective in changing one's perceptions of the given health threat but may not be effective to change their behavior. Thus, practitioners need to focus on changing Chinese parents' perceptions of TB rather than simply improving their knowledge. Specifically, it is necessary to lower their efficacy in self-management and enhance their perceived infectiousness of TB.

TLR2/4 promotes PGE2 production to increase tissue damage in Escherichia coli-infected bovine endometrial explants via MyD88/p38 MAPK pathway.

Prostaglandin E2 (PGE2), a lipid mediator, is released by several cell types including endometrial cells and plays a central role in bacterial infection of the endometrium during inflammation. PGE2 production accumulated in Escherichia coli (E. coli) -infected bovine endometrial tissue, which increased E. coli-infected endometrial tissue damage. However, the mechanisms of PGE2 accumulation in the E. coli-infected endometrium during inflammation-associated endometrial tissue damage remain unclear. This study was conducted to investigate the role of Toll-like receptors (TLRs) 2 and 4 in increased PGE2 production in E. coli-infected endometrial tissue. E. coli and TLR2/4 agonists significantly induced cyclooxygenase-2 and microsomal prostaglandin E synthase-1 expression and PGE2 synthesis detected by RT-PCR, Western blot, and ELISA in the endometrial tissue. The expression and synthesis were dramatically decreased by TLR4, myeloid differentiation factor88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) inhibitors in E. coli-infected endometrial tissue. These inhibitors also significantly decreased proinflammatory factor (interleukin-6 and tumor necrosis factor-α) and damage-associated molecular pattern (high mobility group box-1 and hyaluronan-binding protein-1) release and tissue damage measured by double-label immunofluorescence in E. coli-infected endometrial explants. Our work provides in vitro evidence that TLR2/4-MyD88/p38 MAPK promotes PGE2 synthesis and E. coli-infected endometrial tissue damage, which may be useful for improving PGE2-based therapies for endometritis.

Hyperlipidemia induces meibomian gland dysfunction.

PURPOSE: To investigate the pathological changes of the meibomian gland (MG) and ocular surface in Apolipoprotein E knockout (ApoE-/-) mice and to investigate the association of meibomian gland dysfunction (MGD) with hyperlipidemia. METHODS: Total plasma cholesterol was measured in different ages of ApoE-/- and wild type (WT) mice, whilst the ocular surfaces were observed by slit-lamp biomicroscopy. MG sections were subjected to H&E staining, Oil Red O staining, TUNEL assay and immunostaining. Quantitate RT-PCR and Western blot analyses were performed to detect the relative gene expression in MGs. The 5-month-old ApoE-/- mice were administered with rosiglitazone or GW9662 + rosiglitazone via oral gavage for 2 months to determine their effect on MG pathological change. RESULTS: We found eyelid abnormality, MG dropout, abnormal MG acinar morphology, dilated MG duct and plugging of the MG orifice in ApoE-/- mice. MG acini in ApoE-/- mice showed exaggerated lipid accumulation. Abnormal keratinization increased in MG duct, accompanied with decreased proliferation and increased apoptosis in ApoE-/- mice. Inflammatory cells infiltrated into the surrounding microenvironment of MG acini, and the NF-κB signaling pathway was activated in MG acinar cells. Oxidative stress was evident in MG acinar cells of ApoE-/- mice. Further investigation showed downregulation of PPAR-γ in MG acinar cells of ApoE-/- mice. PPAR-γ agonist rosiglitazone treatment reduced the morbidity of eyelid, as well as corneal pathological changes and MG inflammation in ApoE-/- mice. CONCLUSION: MGD and hyperlipidemia are closely associated in ApoE-/- mice, which represent a new model to study the pathophysiology of MGD related to dyslipidemia.

Sleep deprivation disrupts the lacrimal system and induces dry eye disease.

Sleep deficiency is a common public health problem associated with many diseases, such as obesity and cardiovascular disease. In this study, we established a sleep deprivation (SD) mouse model using a 'stick over water' method and observed the effect of sleep deficiency on ocular surface health. We found that SD decreased aqueous tear secretion; increased corneal epithelial cell defects, corneal sensitivity, and apoptosis; and induced squamous metaplasia of the corneal epithelium. These pathological changes mimic the typical features of dry eye. However, there was no obvious corneal inflammation and conjunctival goblet cell change after SD for 10 days. Meanwhile, lacrimal gland hypertrophy along with abnormal lipid metabolites, secretory proteins and free amino-acid profiles became apparent as the SD duration increased. Furthermore, the ocular surface changes induced by SD for 10 days were largely reversed after 14 days of rest. We conclude that SD compromises lacrimal system function and induces dry eye. These findings will benefit the clinical diagnosis and treatment of sleep-disorder-related ocular surface diseases.

Ectodysplasin A protein promotes corneal epithelial cell proliferation.

The EDA gene encodes ectodysplasin A (Eda), which if mutated causes X-linked hypohidrotic ectodermal dysplasia (XLHED) disease in humans. Ocular surface changes occur in XLHED patients whereas its underlying mechanism remains elusive. In this study, we found Eda was highly expressed in meibomian glands, and it was detected in human tears but not serum. Corneal epithelial integrity was defective and the thickness was reduced in the early postnatal stage of Eda mutant Tabby mice. Corneal epithelial cell proliferation decreased and the epithelial wound healing was delayed in Tabby mice, whereas it was restored by exogenous Eda. Eda exposure promoted mouse corneal epithelial wound healing during organ culture, whereas scratch wound assay showed that it did not affect human corneal epithelial cell line migration. Epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and phosphorylated ERK1/2 (p-ERK) were down-regulated in Tabby mice corneal epithelium. Eda treatment up-regulated the expression of Ki67, EGFR, p-EGFR, and p-ERK in human corneal epithelial cells in a dose-dependent manner. In conclusion, Eda protein can be secreted from meibomian glands and promotes corneal epithelial cell proliferation through regulation of the EGFR signaling pathway. Eda release into the tears plays an essential role in the maintenance of corneal epithelial homeostasis.

Male Men1 heterozygous mice exhibit fasting hyperglycemia in the early stage of MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited syndrome characterized by multiple tumors in the parathyroid glands, endocrine pancreas and anterior pituitary. Recent clinical studies have revealed a strong association between MEN1 syndrome and the risk of developing diabetes mellitus; however, the underlying mechanisms remain unknown. In this study, heterozygous Men1 knockout (Men1(+/-)) mice were used as MEN1 models to investigate MEN1-associated glucose metabolic phenotypes and mechanisms. Heterozygous deficiency of Men1 in 12-month-old male mice induced fasting hyperglycemia, along with increased serum insulin levels. However, male Men1(+/-) mice did not show insulin resistance, as evidenced by Akt activation in hepatic tissues and an insulin tolerance test. Increased glucose levels following pyruvate challenge and expression of key gluconeogenic genes suggested increased hepatic glucose output in the male Men1(+/-) mice. This effect could be partly due to higher basal serum glucagon levels, which resulted from pancreatic islet cell proliferation induced by heterozygous loss of Men1 Taken together, our results indicate that fasted male Men1(+/-) mice, in the early stage of development of MEN1, display glucose metabolic disorders. These disorders are caused not by direct induction of insulin resistance, but via increased glucagon secretion and the consequent stimulation of hepatic glucose production.

A novel protective mechanism for mitochondrial aldehyde dehydrogenase (ALDH2) in type i diabetes-induced cardiac dysfunction: role of AMPK-regulated autophagy.

Mitochondrial aldehyde dehydrogenase (ALDH2) is known to offer myocardial protection against stress conditions including ischemia-reperfusion injury, alcoholism and diabetes mellitus although the precise mechanism is unclear. This study was designed to evaluate the effect of ALDH2 on diabetes-induced myocardial injury with a focus on autophagy. Wild-type FVB and ALDH2 transgenic mice were challenged with streptozotozin (STZ, 200mg/kg, i.p.) for 3months to induce experimental diabetic cardiomyopathy. Diabetes triggered cardiac remodeling and contractile dysfunction as evidenced by cardiac hypertrophy, decreased cell shortening and prolonged relengthening duration, the effects of which were mitigated by ALDH2. Lectin staining displayed that diabetes promoted cardiac hypertrophy, the effect of which was alleviated by ALDH2. Western blot analysis revealed dampened autophagy protein markers including LC3B ratio and Atg7 along with upregulated p62 following experimental diabetes, the effect of which was reconciled by ALDH2. Phosphorylation level of AMPK was decreased and its downstream signaling molecule FOXO3a was upregulated in both diabetic cardiac tissue and in H9C2 cells with high glucose exposure. All these effect were partly abolished by ALDH2 overexpression and ALDH2 agonist Alda1. High glucose challenge dampened autophagy in H9C2 cells as evidenced by enhanced p62 levels and decreased levels of Atg7 and LC3B, the effect of which was alleviated by the ALDH2 activator Alda-1. High glucose-induced cell death and apoptosis were reversed by Alda-1. The autophagy inhibitor 3-MA and the AMPK inhibitor compound C mitigated Alda-1-offered beneficial effect whereas the autophagy inducer rapamycin mimicked or exacerbated high glucose-induced cell injury. Moreover, compound C nullified Alda-1-induced protection against STZ-induced changes in autophagy and function. Our results suggested that ALDH2 protects against diabetes-induced myocardial dysfunction possibly through an AMPK -dependent regulation of autophagy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.