Development and Assessment of a Prediction Model for Alzheimer's Disease Diagnosis Based on Thermoregulation-Related Genes.

BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative condition among the elderly population and the most common form of dementia, however, we lack potent interventions to arrest its inherent pathogenic vectors. Robust evidence indicates thermoregulatory perturbations during and before the onset of symptoms. Therefore, temperature-regulated biomarkers may offer clues to therapeutic targets during the presymptomatic stage. OBJECTIVE: The purpose of this study is to develop and assess a thermoregulation-related gene prediction model for Alzheimer's Disease diagnosis. METHOD: This study aims to utilize microarray bioinformatic analysis to identify the potential biomarkers of AD by analyzing four microarray datasets (GSE48350, GSE5281, GSE122063, and GSE181279) of AD patients. Furthermore, thermoregulation-associated hub genes were identified, and the expression patterns in the brain were explored. In addition, we explored the infiltration of immune cells with thermoregulation-related hub genes. Diagnostic marker validation was then performed at the single-cell level. Finally, the prediction of targeted drugs was performed based on the hub genes. RESULTS: Through the analysis of four datasets pertaining to AD, a total of five genes associated with temperature regulation were identified. Notably, CCK, CXCR4, SLC27A4, and SLC17A6 emerged as diagnostic markers indicative of AD-related brain injury. Furthermore, in the examination of peripheral blood samples from AD patients, SLC27A4 and CXCR4 were identified as pivotal diagnostic indicators. Regrettably, animal experimentation was not pursued to validate the data; rather, an assessment of temperature regulation-related genes was conducted. Future investigations will be undertaken to establish the correlation between these genes and AD pathology. CONCLUSION: Overall, CCK, CXCR4, SLC27A4, and SLC17A6 can be considered pivotal biomarkers for diagnosing the pathogenesis and molecular functions of AD.

Neuroprotective effects of galectin­1 on cerebral ischemia/reperfusion injury by regulating oxidative stress.

Oxidative stress contributes to the pathology of cerebral ischemia/reperfusion (I/R) injury. Galectin-1 has shown an anti-oxidative stress effect. The present study investigated whether this anti-oxidative stress effect can account for the neuroprotective actions of galectin-1 induced by cerebral I/R injury. A cerebral I/R injury model was created in C57Bl/6 mice by transient occlusion of the middle cerebral artery, after which the mice were treated with galectin-1 for 3 days. Infarct volumes were measured. A rotarod test and neurological deficit score assessment was performed to evaluate the neurological deficits. Oxidative stress was evaluated by measuring the levels of reactive oxygen species (ROS) and lipid peroxidation malondialdehyde (MDA), while the anti-oxidative stress status was assessed by measuring molecules such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidation enzyme (GSH-Px) in the ischemic cerebral hemisphere of mice. The inflammatory cytokines, including Interleukin 1 (IL-1), IL-6 and tumor necrosis factor alpha (TNF-α) were measured, and the expression of microglia was evaluated by immunohistochemistry in the ischemic cerebral hemisphere of mice. Galectin-1 treatment ameliorated neurological deficits and reduced infarct volumes in the mice model with cerebral I/R injury. Moreover, it was demonstrated that galectin-1 can significantly alleviate cerebral I/R injury in the ischemic cerebral hemisphere by decreasing the production of ROS and MDA, but increasing the production of CAT, SOD and GSH-Px. Galectin-1 treatment decreased microglia expression, and IL-1, IL-6 and TNF-α levels in the ischemic cerebral hemisphere of mice. Galectin-1 could improve the outcome of cerebral I/R injury by alleviating oxidative stress. Moreover, the neuroprotective effect of galectin-1 in cerebral ischemia could be related to its anti-oxidative stress effect.

MiR34 contributes to spinal muscular atrophy and AAV9-mediated delivery of MiR34a ameliorates the motor deficits in SMA mice.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by the selective loss of spinal motor neurons (MNs) and concomitant muscle weakness. Mutation of SMN1 is known to cause SMA, and restoring SMN protein levels via antisense oligonucleotide treatment is effective for ameliorating symptoms. However, this approach is hindered by exorbitant costs, invasive procedures, and poor treatment responses of some patients. Here, we seek to circumvent these hurdles by identifying reliable biomarkers that could predict treatment efficacy. We uncovered that MiR34 exhibits consistent downregulation during SMA progression in both human and rodent contexts. Importantly, Mir34 family-knockout mice display axon swelling and reduced neuromuscular junction (NMJ) endplates, recapitulating SMA pathology. Introducing MiR34a via scAAV9 improved the motor ability of SMNΔ7 mice, possibly by restoring NMJ endplate size. Finally, we observed a consistent decreasing trend in MiR34 family expression in the cerebrospinal fluid (CSF) of type I SMA patients during the loading phase of nusinersen treatment. Baseline CSF MiR34 levels before nusinersen injection proved predictive of patient motor skills 1 year later. Thus, we propose that MiR34 may serve as a biomarker of SMA since it is associated with the pathology and can help evaluate the therapeutic effects of nusinersen.

Development of a cell-free strategy to recover aged skeletal muscle after disuse.

Extended periods of bed rest and limb immobilization are required for healing post-injury or disease, yet disuse can result in significant muscle atrophy and decreased quality of life in older adults. Physical rehabilitation is commonly prescribed to recover these deficits, yet accumulation of reactive oxygen species and sustained rates of protein degradation persist during the rehabilitation period that can significantly delay or prevent recovery. Pericytes, considered the primary mesenchymal and vascular stromal cell in skeletal muscle, secrete beneficial factors that maintain baseline muscle mass, yet minimal information exists regarding the pericyte response to disuse and recovery. In the current study, single-cell RNA sequencing and functional assays were performed to demonstrate that pericytes in mouse skeletal muscle lose the capacity to synthesize antioxidants during disuse and recovery. This information was used to guide the design of a strategy in which healthy donor pericytes were stimulated with hydrogen peroxide (H2 O2 ) to produce small extracellular vesicles (sEVs) that effectively restored myofibre size in adult and aged muscle after disuse. Proteomic assessment detected 11 differentially regulated proteins in primed sEVs that may account for recovery of muscle, including proteins associated with extracellular matrix composition and anti-inflammatory and antioxidant processes. This study demonstrates that healthy H2 O2 -primed pericyte-derived sEVs effectively improve skeletal muscle recovery after immobilization, presenting a novel acellular approach to rebuild muscle mass in older adults after a period of disuse. KEY POINTS: Previous studies suggest that prolonged oxidative stress is a barrier to skeletal muscle recovery after a period of immobilization. In this study we demonstrate that muscle-resident perivascular stromal cells (pericytes) become dysfunctional and lack the capacity to mount an antioxidant defence after disuse in mice. Hydrogen peroxide treatment of healthy pericytes in vitro simulates the release of small extracellular vesicles (sEVs) that effectively recover skeletal muscle fibre size and extracellular matrix remodelling in young adult and aged mice after disuse. Pericyte-derived sEVs present a novel acellular strategy to recover skeletal muscle after disuse.

Cyclic mechanical stretch regulates the AMPK/Egr1 pathway in tenocytes via Ca2+-mediated mechanosensing.

PURPOSE: Mechanical stimuli are essential for the maintenance of tendon tissue homeostasis. The study aims to elucidate the mechanobiological mechanisms underlying the maintenance of tenocyte homeostasis by cyclic mechanical stretch under high-glucose (HG) condition. MATERIALS AND METHODS: Primary tenocytes were isolated from rat Achilles tendon and 2D-cultured under HG condition. The in vitro effects of a single bout, 2-h cyclic biaxial stretch session (1 Hz, 8%) on primary rat tenocytes were explored through Flexcell system. Cell viability, tenogenic gene expression, intracellular calcium concentration, focal adhesion kinase (FAK) expression, and signaling pathway activation were analyzed in tenocytes with or without mechanical stretch. RESULTS: Mechanical stretch increased tenocyte proliferation and upregulated early growth response protein 1 (Egr1) expression. An increase in intracellular calcium was observed after 30 min of stretching. Mechanical stretch phosphorylated FAK, calmodulin-dependent protein kinase kinase 2 (CaMKK2), and 5' adenosine monophosphate-activated protein kinase (AMPK) in a time-dependent manner, and these effects were abrogated after blocking intracellular calcium. Inhibition of FAK, CaMKK2, and AMPK downregulated the expression of Egr1. In addition, mechanical stretch reinforced cytoskeletal organization via calcium (Ca2+)/FAK signaling. CONCLUSIONS: Our study demonstrated that mechanical stretch-induced calcium influx activated CaMKK2/AMPK signaling and FAK-cytoskeleton reorganization, thereby promoting the expression of Egr1, which may help maintain tendon cell characteristics and homeostasis in the context of diabetic tendinopathy.

Optimization of a pericyte therapy to improve muscle recovery after limb immobilization.

Extended bed rest or limb immobilization can significantly reduce skeletal muscle mass and function. Recovery may be incomplete, particularly in older adults. Our laboratory recently reported that vascular mural cell (pericyte) quantity is compromised after immobilization and appropriate replacement immediately before remobilization can effectively recover myofiber size in mice. Identification of a single cell surface marker for isolation of the most therapeutic pericyte would streamline efforts to optimize muscle recovery. The purpose of this study was to compare the capacity for neural/glial antigen 2 (Cspg4/NG2+) and melanoma cell adhesion molecule (Mcam/CD146+) positive pericytes to uniquely recover skeletal muscle post-disuse. A single hindlimb from adult C57BL/6J mice was immobilized in full dorsiflexion via a surgical staple inserted through the center of the foot and body of the gastrocnemius. Fourteen days after immobilization, the staple was removed and pericytes, either NG2+CD45-CD31-[Lin-], CD146+NG2-Lin-, or CD146+Lin- pericytes, were injected into the atrophied tibialis anterior (TA) muscle. TA muscles were excised 14 days after transplantation and remobilization. Pericyte transplantation did not significantly improve muscle mass or myofiber cross-sectional area (CSA) after 14 days of remobilization. However, injection of CD146+ pericytes significantly increased Type IIa quantity, capillarization, and collagen remodeling compared with NG2+ pericytes (P < 0.05). Our results suggest that selection of pericytes based on CD146 rather than NG2 results in the isolation of therapeutic mural cells with high capacity to positively remodel skeletal muscle after a period of immobilization.NEW & NOTEWORTHY In this study, pericytes were isolated from mouse skeletal muscle based on cell surface marker expression of neural/glial antigen 2 (NG2) or melanoma cell adhesion molecule (Mcam/CD146) and then compared for the capacity to recover skeletal muscle after a period of immobilization in recipient mice. We report that CD146+Lin- pericytes exhibit higher capacity than NG2+Lin- pericytes to recover Type IIa fiber quantity, capillary content, and collagen turnover after disuse.

Increases in Integrin-ILK-RICTOR-Akt Proteins, Muscle Mass, and Strength after Eccentric Cycling Training.

PURPOSE: Recently, it has been suggested that a cellular pathway composed of integrin, integrin-linked kinase (ILK), rapamycin-insensitive companion of mTOR (RICTOR), and Akt may facilitate long-term structural and functional adaptations associated with exercise, independent of the mTORC1 pathway. Therefore, we examined changes in integrin-ILK-RICTOR-Akt protein in vastus lateralis (VL) before and after 8 wk of eccentric cycling training (ECC), which was expected to increase muscle function and VL cross-sectional area (CSA). METHODS: Eleven men (23 ± 4 yr) completed 24 sessions of ECC with progressive increases in intensity and duration, resulting in a twofold increase in work from the first three (75.4 ± 14.1 kJ) to the last three sessions (150.7 ± 28.4 kJ). Outcome measures included lower limb lean mass, VL CSA, static strength, and peak and average cycling power output. These measures and VL samples were taken before and 4-5 d after the last training session. RESULTS: Significant (P < 0.05) increases in integrin-ß1 (1.64-fold) and RICTOR (2.99-fold) protein as well as the phosphorylated-to-total ILK ratio (1.70-fold) were found, but integrin-α7 and Akt did not change. Increases in lower limb, thigh, and trunk lean mass (2.8%-5.3%, P < 0.05) and CSA (13.3% ± 9.0%, P < 0.001) were observed. Static strength (18.1% ± 10.8%) and both peak (8.6% ± 10.5%) and average power output (7.4% ± 8.3%) also increased (P < 0.05). However, no significant correlations were found between the magnitude of increases in protein and the magnitude of increases in CSA, static strength, or power output. CONCLUSIONS: In addition to increased muscle mass, strength, and power, we demonstrate that ECC increases integrin-ß1 and RICTOR total protein and p-ILK/t-ILK, which may play a role in protection against muscle damage as well as anabolic signaling to induce muscle adaptations.

Targeting the MicroRNA-490-3p-ATG4B-Autophagy Axis Relieves Myocardial Injury in Ischemia Reperfusion.

We investigated the potential role of miR-490-3p in ischemia reperfusion (IR) injury. We first determined the expression of miR-490-3p and autophagy-related 4B cysteine (ATG4B) in IR. Then, to explore whether miR-490-3p would affect autophagy, apoptosis, and IR injury, we evaluated apoptosis, autophagy, and infarct size via gain- and loss-of-function experiments. Furthermore, we used adenovirus to enhance or inhibit the expression of ATG4B, and then measured autophagy, apoptosis, and IR injury. miR-490-3p was downregulated in the hearts during the process of IR, while ATG4B was upregulated. The inhibition of miR-490-3p or overexpression of ATG4B could promote the expression of LC3II, increase the autolysosomes, inhibit the expression of p62, and reduce infarct size. On all accounts, the inhibition of miR-490-3p could promote autophagy to reduce myocardial IR injury by upregulating ATG4B, a finding that provides new insights for the protective mechanism of autophagy in IR. Graphical Abstract.

Laminin-111 Improves the Anabolic Response to Mechanical Load in Aged Skeletal Muscle.

Anabolic resistance to a mechanical stimulus may contribute to the loss of skeletal muscle mass observed with age. In this study, young and aged mice were injected with saline or human LM-111 (1 mg/kg). One week later, the myotendinous junction of the gastrocnemius muscle was removed via myotenectomy (MTE), thus placing a chronic mechanical stimulus on the remaining plantaris muscle for 2 weeks. LM-111 increased α7B integrin protein expression and clustering of the α7B integrin near DAPI+ nuclei in aged muscle in response to MTE. LM-111 reduced CD11b+ immune cells, enhanced repair, and improved the growth response to loading in aged plantaris muscle. These results suggest that LM-111 may represent a novel therapeutic approach to prevent and/or treat sarcopenia.

Surface Tethering of Inflammation-Modulatory Nanostimulators to Stem Cells for Ischemic Muscle Repair.

Stem cell transplantation has been a promising treatment for peripheral arterial diseases in the past decade. Stem cells act as living bioreactors of paracrine factors that orchestrate tissue regeneration. Prestimulated adipose-derived stem cells (ADSCs) have been proposed as potential candidates but have been met with challenges in activating their secretory activities for clinical use. Here, we propose that tethering the ADSC surface with nanoparticles releasing tumor necrosis factor α (TNFα), named nanostimulator, would stimulate cellular secretory activity in situ. We examined this hypothesis by complexing octadecylamine-grafted hyaluronic acid onto a liposomal carrier of TNFα. Hyaluronic acid increased the liposomal stability and association to CD44 on ADSC surface. ADSCs tethered with these TNFα carriers exhibited up-regulated secretion of proangiogenic vascular endothelial growth factor and immunomodulatory prosteoglandin E2 (PGE2) while decreasing secretion of antiangiogenic pigment epithelium-derived factors. Accordingly, ADSCs tethered with nanostimulators promoted vascularization in a 3D microvascular chip and enhanced recovery of perfusion, walking, and muscle mass in a murine ischemic hindlimb compared to untreated ADSCs. We propose that this surface tethering strategy for in situ stimulation of stem cells would replace the costly and cumbersome preconditioning process and expedite clinical use of stem cells for improved treatments of various injuries and diseases.

Aloperine Activates the PI3K/Akt Pathway and Protects Against Coronary Microembolisation-Induced Myocardial Injury in Rats.

BACKGROUND: Coronary microembolisation (CME)-induced myocardial apoptosis is a key factor in progressive cardiac dysfunction. Aloperine (ALO) plays a protective role in the cardiovascular system, but its role and the mechanism -underlying its protection against CME are unclear. Therefore, we aimed to verify whether ALO has a protective effect against CME-induced myocardial injury, as well as whether this effect has a relationship with regulation of the PI3K/Akt pathway for rats. METHODS: Forty Sprague-Dawley rats were randomised into 4 equal groups: CME, CME + ALO, CME + ALO + LY294002 (LY) and a Sham group. Twelve hours after surgery, the rats' cardiac function, apoptosis index, microinfarct and serum cardiac-troponin I (cTnI) level were measured. Levels of p-Akt, total Akt, Bcl-2, Bax and cleaved caspase-3 were detected. RESULTS: ALO improved cardiac dysfunction induced by CME, while also decreasing serum levels of cTnI and microinfarct areas. In addition, ALO inhibited myocardial apoptosis, which may have been partially as a result of downregulated cleaved caspase-3 and Bax, upregulated Bcl-2 and increased protein levels in phosphorylated Akt. However, these ALO effects were blocked if ALO was administered along with LY. CONCLUSIONS: ALO can inhibit cardiomyocyte apoptosis and consequently attenuate CME-induced myocardial injury. These functions are realised by activating PI3K/Akt signalling pathway.

Resveratrol Attenuates Cardiomyocyte Apoptosis in Rats Induced by Coronary Microembolization Through SIRT1-Mediated Deacetylation of p53.

OBJECTIVE: Coronary microembolization (CME)-induced cardiomyocyte apoptosis is the primary factor in causing cardiac dysfunction. Resveratrol (RES) is known to play a protective role in a variety of cardiovascular diseases, yet it is not known whether RES has a protective role in CME. Therefore, the effect of RES on cardiomyocyte apoptosis and cardiac function damage which are induced by CME in rats was investigated in this study. METHODS: Fifty Sprague-Dawley rats were separated into 5 groups randomly (10 rats were included in each): sham group, CME group, RES+CME group, RES+CME+Sirtuin-1 (SIRT-1) inhibitor EX527 (RES+CME+EX) group, and CME+EX group. Cardiac function, serum c-troponin I (cTnI) level, apoptotic index, and microinfarct were measured by cardiac ultrasound, myocardial enzyme assessment, TdT-mediated dUTP Nick-end labeling and hematoxylin-basic fuchsin-picric acid staining. The levels of p53, p53 acetylation, SIRT-1, Bax, Bcl-2, and cleaved caspase-3 were detected by Western blot. RESULTS: Myocardial dysfunction, enhanced apoptotic index as well as cTnI were caused after the operation of CME. Coronary microembolization induced increased expression of p53 acetylation and cleaved caspase-3, while the SIRT-1 and Bcl-2/Bax ratio was reduced. The CME effect was reversed by RES while EX527 attenuated this protective effect. CONCLUSIONS: Resveratrol can improve cardiac function, in the sense that it attenuates CME-induced cardiomyocyte apoptosis, which is perhaps associated with its inhibition pro-apoptotic pathway of p53 which is transcription-independent.

Nobiletin protects against myocardial injury and myocardial apoptosis following coronary microembolization via activating PI3K/Akt pathway in rats.

It has been found that use of drugs which upregulate the PI3K/Akt pathway can effectively reduce cardiomyocyte apoptosis which has been induced by coronary microembolization (CME). However, whether this functional protein is able to be modified through pretreatment via nobiletin (NOB) in models of CME has not yet been investigated. Therefore, this study set out to explore the cardioprotective effect of NOB on rats with myocardial injuries induced by CME and also explored the potential mechanism which underlies this cardioprotective effect. The study used 40 Sprague-Dawley (SD) rats, which were randomized into four groups: the sham, CME, CME+NOB, and CME+NOB+LY294002 (LY) groups. Twelve hours after surgery, levels of microinfarct, serum c-troponin I (cTnI), cardiac function, apoptotic index, and oxidative stress [superoxide dismutase (SOD) and malondialdehyde (MDA)] were measured for rats in each group. Western blot analysis was performed to detect any protein involved in the PI3K/Akt pathway. Nobiletin improved cardiac dysfunction which had been induced by CME, decreased serum level of cTnI and MDA, and increased serum SOD activities. In addition, nobiletin inhibited myocardial apoptosis, which may be connected to downregulated apoptotic index, upregulated Bcl-2, and cleaved caspase-3 and Bax, while it increased protein levels in phosphorylated Akt. However, when nobiletin was co-administered with LY294002, a PI3K (phosphatidylinositol 3-kinase)/Akt inhibitor, all of the previously mentioned effects were blocked. Nobiletin is able to inhibit cardiomyocyte apoptosis and can consequently attenuate CME-induced myocardial injuries. These functions are realized through the activation of the PI3K/Akt signaling pathway as well as by reducing oxidative stress.

ILK promotes survival and self-renewal of hypoxic MSCs via the activation of lncTCF7-Wnt pathway induced by IL-6/STAT3 signaling.

Mesenchymal stem cells (MSCs) have been applied in treating various diseases including myocardial infarction (MI) and achieved a bit of success; however, the decreased survival rate of MSCs after transplantation greatly limited the efficacy for cell therapy. How to improve the MSC survival rate in stem cell transplantation has undoubtedly become urgent and genetic engineering may be an ideal and feasible way. In this study, we explored the effects on MSCs survival and self-renewal by overexpression of integrin-linked kinase (ILK) in MSCs under hypoxic stimulation and aimed to reveal the molecular mechanisms from the point of paracrine function of MSCs. We first found that overexpression of ILK induced the expression and secretion of IL-6 increased significantly in MSCs under hypoxic stimulation, and the survival and self-renewal of MSCs exposed to hypoxia were enhanced after ILK overexpression. Then the activation of JAK2/STAT3 signaling was detected because of the increased IL-6, and an lncRNA, named lncTCF7, was upregulated remarkably, promoting the activation of Wnt pathway that was required for keeping cell viability and stemness of MSCs. Moreover, we further verified that inhibition of STAT3 signaling by WP1066 and silencing lncTCF7 expression eliminated the protective effects of ILK overexpression on cell survival and self-renewal of MSCs under hypoxic sitmulation. In conclusion, our results uncovered a novel function of ILK to promote MSC survival and self-renewal, suggesting more application potentials of MSC cell therapy on MI.

Hyperglycemia Augments the Adipogenic Transdifferentiation Potential of Tenocytes and Is Alleviated by Cyclic Mechanical Stretch.

Diabetes mellitus is associated with damage to tendons, which may result from cellular dysfunction in response to a hyperglycemic environment. Tenocytes express diminished levels of tendon-associated genes under hyperglycemic conditions. In contrast, mechanical stretch enhances tenogenic differentiation. However, whether hyperglycemia increases the non-tenogenic differentiation potential of tenocytes and whether this can be mitigated by mechanical stretch remains elusive. We explored the in vitro effects of high glucose and mechanical stretch on rat primary tenocytes. Specifically, non-tenogenic gene expression, adipogenic potential, cell migration rate, filamentous actin expression, and the activation of signaling pathways were analyzed in tenocytes treated with high glucose, followed by the presence or absence of mechanical stretch. We analyzed tenocyte phenotype in vivo by immunohistochemistry using an STZ (streptozotocin)-induced long-term diabetic mouse model. High glucose-treated tenocytes expressed higher levels of the adipogenic transcription factors PPARγ and C/EBPs. PPARγ was also highly expressed in diabetic tendons. In addition, increased adipogenic differentiation and decreased cell migration induced by high glucose implicated a fibroblast-to-adipocyte phenotypic change. By applying mechanical stretch to tenocytes in high-glucose conditions, adipogenic differentiation was repressed, while cell motility was enhanced, and fibroblastic morphology and gene expression profiles were strengthened. In part, these effects resulted from a stretch-induced activation of ERK (extracellular signal-regulated kinases) and a concomitant inactivation of Akt. Our results show that mechanical stretch alleviates the augmented adipogenic transdifferentiation potential of high glucose-treated tenocytes and helps maintain their fibroblastic characteristics. The alterations induced by high glucose highlight possible pathological mechanisms for diabetic tendinopathy. Furthermore, the beneficial effects of mechanical stretch on tenocytes suggest that an appropriate physical load possesses therapeutic potential for diabetic tendinopathy.

High glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway.

Diabetes mellitus (DM) is associated with higher risk of tendinopathy, which reduces tolerance to exercise and functional activities and affects lifestyle and glycemic control. Expression of tendon-related genes and matrix metabolism in tenocytes are essential for maintaining physiological functions of tendon. However, the molecular mechanisms involved in diabetic tendinopathy remain unclear. We hypothesized that high glucose (HG) alters the characteristics of tenocyte. Using in vitro 2-week culture of tenocytes, we found that expression of tendon-related genes, including Egr1, Mkx, TGF-ß1, Col1a2, and Bgn, was significantly decreased in HG culture and that higher glucose consumption occurred. Down-regulation of Egr1 by siRNA decreased Scx, Mkx, TGF-ß1, Col1a1, Col1a2, and Bgn expression. Blocking AMPK activation with Compound C reduced the expression of Egr1, Scx, TGF-ß1, Col1a1, Col1a2, and Bgn in the low glucose condition. In addition, histological examination of tendons from diabetic mice displayed larger interfibrillar space and uneven glycoprotein deposition. Thus, we concluded that high glucose alters tendon homeostasis through downregulation of the AMPK/Egr1 pathway and the expression of downstream tendon-related genes in tenocytes. The findings render a molecular basis of the mechanism of diabetic tendinopathy and may help develop preventive and therapeutic strategies for the pathology.

Using four wavelength-multiplexed self-seeding Fabry-Perot lasers for 10 Gbps upstream traffic in TDM-PON.

In this paper, we propose and experimentally investigate a simple self-injection Fabry-Perot laser scheme on each optical network unit (ONU) for 10 Gbps TDM passive optical networks (PONs). Based on the proposed four wavelength-multiplexed 2.5 Gbps lasers, the 10 Gbps uplink traffic can be achieved at a cost-effective way. The network architecture and performance have also been analyzed and discussed.