Hemorrhagic Fever with Renal Syndrome Complicated by Acute Pancreatitis, High Intraocular Pressure, and Pulmonary Involvement: a Case Report.

Hemorrhagic fever with renal syndrome (HFRS), a naturally occurring epidemic disease, is primarily caused by hantaviruses. It frequently involves the lungs and is characterized by symptoms such as fever, hemorrhage, and renal failure. However, the occurrence of acute pancreatitis (AP) in HFRS patients can be neglected, and high intraocular pressure (IOP) is exceedingly uncommon. In this report, we discuss the case of a 30-year-old male who presented with fever, nausea, vomiting, and abdominal pain. Physical examination revealed extremity petechiae rashes and elevated IOP. Laboratory tests indicated coagulopathy and renal failure. A computed tomography scan confirmed AP. Further testing revealed a positive anti-hantavirus IgM antibody. The patient received supportive care, fluid hydration, hemofiltration, mannitol, brinzolamide, and brimonidine to reduce IOP. Three days post-admission, the patient developed shortness of breath and chest pain. Subsequent chest computed tomography revealed pulmonary edema and bilateral pleural effusion. Treatment included oxygen supply, respiratory support, and thoracentesis, with continued hemofiltration. The patient recovered, regaining normal pulmonary and renal functions and normalized IOP. This case underscores the importance of comprehensive evaluations and vigilant monitoring in HFRS patients, particularly measuring IOP in those with visual complaints, to save lives and reduce morbidity.

Dynamic Weighting Translation Transfer Learning for Imbalanced Medical Image Classification.

Medical image diagnosis using deep learning has shown significant promise in clinical medicine. However, it often encounters two major difficulties in real-world applications: (1) domain shift, which invalidates the trained model on new datasets, and (2) class imbalance problems leading to model biases towards majority classes. To address these challenges, this paper proposes a transfer learning solution, named Dynamic Weighting Translation Transfer Learning (DTTL), for imbalanced medical image classification. The approach is grounded in information and entropy theory and comprises three modules: Cross-domain Discriminability Adaptation (CDA), Dynamic Domain Translation (DDT), and Balanced Target Learning (BTL). CDA connects discriminative feature learning between source and target domains using a synthetic discriminability loss and a domain-invariant feature learning loss. The DDT unit develops a dynamic translation process for imbalanced classes between two domains, utilizing a confidence-based selection approach to select the most useful synthesized images to create a pseudo-labeled balanced target domain. Finally, the BTL unit performs supervised learning on the reassembled target set to obtain the final diagnostic model. This paper delves into maximizing the entropy of class distributions, while simultaneously minimizing the cross-entropy between the source and target domains to reduce domain discrepancies. By incorporating entropy concepts into our framework, our method not only significantly enhances medical image classification in practical settings but also innovates the application of entropy and information theory within deep learning and medical image processing realms. Extensive experiments demonstrate that DTTL achieves the best performance compared to existing state-of-the-art methods for imbalanced medical image classification tasks.

Gate-Controlled Neuromorphic Functional Transition in an Electrochemical Graphene Transistor.

Neuromorphic devices have attracted significant attention as potential building blocks for the next generation of computing technologies owing to their ability to emulate the functionalities of biological nervous systems. The essential components in artificial neural networks such as synapses and neurons are predominantly implemented by dedicated devices with specific functionalities. In this work, we present a gate-controlled transition of neuromorphic functions between artificial neurons and synapses in monolayer graphene transistors that can be employed as memtransistors or synaptic transistors as required. By harnessing the reliability of reversible electrochemical reactions between carbon atoms and hydrogen ions, we can effectively manipulate the electric conductivity of graphene transistors, resulting in a high on/off resistance ratio, a well-defined set/reset voltage, and a prolonged retention time. Overall, the on-demand switching of neuromorphic functions in a single graphene transistor provides a promising opportunity for developing adaptive neural networks for the upcoming era of artificial intelligence and machine learning.

Dynamic Graph Clustering Learning for Unsupervised Diabetic Retinopathy Classification.

Diabetic retinopathy (DR) is a common complication of diabetes, which can lead to vision loss. Early diagnosis is crucial to prevent the progression of DR. In recent years, deep learning approaches have shown promising results in the development of an intelligent and efficient system for DR classification. However, one major drawback is the need for expert-annotated datasets, which are both time-consuming and costly. To address these challenges, this paper proposes a novel dynamic graph clustering learning (DGCL) method for unsupervised classification of DR, which innovatively deploys the Euclidean and topological features from fundus images for dynamic clustering. Firstly, a multi-structural feature fusion (MFF) module extracts features from the structure of the fundus image and captures topological relationships among multiple samples, generating a fused representation. Secondly, another consistency smoothing clustering (CSC) module combines network updates and deep clustering to ensure stability and smooth performance improvement during model convergence, optimizing the clustering process by iteratively updating the network and refining the clustering results. Lastly, dynamic memory storage is utilized to track and store important information from previous iterations, enhancing the training stability and convergence. During validation, the experimental results with public datasets demonstrated the superiority of our proposed DGCL network.

A Multi-task Deep Feature Selection Method for Brain Imaging Genetics.

Using brain imaging quantitative traits (QTs) for identifying genetic risk factors is an important research topic in brain imaging genetics. Many efforts have been made for this task via building linear models between imaging QTs and genetic factors such as single nucleotide polymorphisms (SNPs). To the best of our knowledge, linear models could not fully uncover the complicated relationship due to the loci's elusive and diverse influences on imaging QTs. In this paper, we propose a novel multi-task deep feature selection (MTDFS) method for brain imaging genetics. MTDFS first builds a multi-task deep neural network to model the complicated associations between imaging QTs and SNPs. And then designs a multi-task one-to-one layer and imposes a combined penalty to identify SNPs that make significant contributions. MTDFS can not only extract the nonlinear relationship but also arms the deep neural network with feature selection. We compared MTDFS to multi-task linear regression (MTLR) and single-task DFS (DFS) methods on the real neuroimaging genetic data. The experimental results showed that MTDFS performed better than MTLR and DFS on the QT-SNP relationship identification and feature selection. Thus, MTDFS is powerful for identifying risk loci and could be a great supplement to brain imaging genetics.

Tafel-Kinetics-Controlled High-Speed Switching in a Electrochemical Graphene Field-Effect Transistor.

Graphene field-effect transistors (FETs) have attracted tremendous attention owing to the single-atomic-layer thickness and high electron mobility for potential applications in next-generation electronics. With regards to switching methodology, the electric-field-induced metal-insulator transition offers a new strategy to produce a large on/off current ratio through reversible electrochemical hydrogenation of the graphene channels. Therefore, the performance of such electrochemical graphene FETs greatly relies on the kinetics of hydrogenation reaction. Here, we show that the switching time can be systemically controlled by the applied gate voltages and geometries of graphene channels. The turn-on and turn-off time display an exponential dependence on the gate voltages, manifesting the dominated Tafel-form kinetics of hydrogenation reaction in a two-dimensional limit. Moreover, the turn-off time is inversely proportional to the channel width but independent of the length, while the turn-on time relies on both the width and length, as well as the off-state gate voltage and duration. Our work improves the response time to the magnitude of tens of microseconds and advances the application of graphene-based electronic devices.

The Giant Spin-to-Charge Conversion of the Layered Rashba Material BiTeI.

Rashba spin-orbit coupling (SOC) could facilitate an efficient interconversion between spin and charge currents. Among various systems, BiTeI holds one of the largest Rashba-type spin splittings. Unlike other Rashba systems (e.g., Bi/Ag and Bi2Se3), an experimental investigation of the spin-to-charge interconversion in BiTeI remains to be explored. Through performing an angle-resolved photoemission spectroscopy (ARPES) measurement, such a large Rashba-type spin splitting with a Rashba parameter αR = 3.68 eV Å is directly identified. By studying the spin pumping effect in the BiTeI/NiFe bilayer, we reveal a very large inverse Rashba-Edelstein length λIREE ≈ 1.92 nm of BiTeI at room temperature. Furthermore, the λIREE monotonously increases to 5.00 nm at 60 K, indicating an enhanced Rashba SOC at low temperature. These results suggest that BiTeI films with the giant Rashba SOC are promising for achieving efficient spin-to-charge interconversion, which could be implemented for building low-power-consumption spin-orbitronic devices.

Young bone marrow transplantation prevents aging-related muscle atrophy in a senescence-accelerated mouse prone 10 model.

BACKGROUND: Young bone marrow transplantation (YBMT) has been shown to stimulate vascular regeneration in pathological conditions, including ageing. Here, we investigated the benefits and mechanisms of the preventive effects of YBMT on loss of muscle mass and function in a senescence-associated mouse prone 10 (SAMP10) model, with a special focus on the role of growth differentiation factor 11 (GDF-11). METHODS: Nine-week-old male SAMP10 mice were randomly assigned to a non-YBMT group (n = 6) and a YBMT group (n = 7) that received the bone marrow of 8-week-old C57BL/6 mice. RESULTS: Compared to the non-YBMT mice, the YBMT mice showed the following significant increases (all P < 0.05 in 6-7 mice): endurance capacity (>61.3%); grip strength (>37.9%), percentage of slow myosin heavy chain fibres (>14.9-15.9%). The YBMT also increased the amounts of proteins or mRNAs for insulin receptor substrate 1, p-Akt, p-extracellular signal-regulated protein kinase1/2, p-mammalian target of rapamycin, Bcl-2, peroxisom proliferator-activated receptor-γ coactivator (PGC-1α), plus cytochrome c oxidase IV and the numbers of proliferating cells (n = 5-7, P < 0.05) and CD34+/integrin-α7+ muscle stem cells (n = 5-6, P < 0.05). The YMBT significantly decreased the levels of gp91phox, caspase-9 proteins and apoptotic cells (n = 5-7, P < 0.05) in both muscles; these beneficial changes were diminished by the blocking of GDF-11 (n = 5-6, P < 0.05). An administration of mouse recombinant GDF-11 improved the YBMT-mediated muscle benefits (n = 5-6, P < 0.05). Cell therapy with young bone marrow from green fluorescent protein (GFP) transgenic mice exhibited GFP+ myofibres in aged muscle tissues. CONCLUSIONS: These findings suggest that YBMT can prevent muscle wasting and dysfunction by mitigating apoptosis and proliferation via a modulation of GDF-11 signalling and mitochondrial dysfunction in SAMP10 mice.

Inhalable particle-bound marine biotoxins in a coastal atmosphere: Concentration levels, influencing factors and health risks.

Characterizing marine biotoxins (MBs) composition in coastal aerosol particles has become essential to tracking sources of atmospheric contaminants and assessing human inhalable exposure risks to air particles. Here, coastal aerosol particles were collected over an almost 3-year period for the analysis of eight representative MBs, including brevetoxin (BTX), okadaic acid (OA), pectenotoxin-2 (PTX-2), domoic acid (DA), tetrodotoxin (TTX), saxitoxin (STX), ciguatoxin (CTX) and ω-Conotoxin. Our data showed that the levels of inhalable airborne marine biotoxins (AMBs) varied greatly among the subcategories and over time. Both in daytime and nighttime, a predominance of coarse-mode AMB particles was found for all the target AMBs. Based on the experimental data, we speculate that an ambient AMB might have multiple sources/production pathways, which include air-sea aerosol production and direct generation and release from toxigenic microalgae/bacteria suspended in surface seawater or air, and different sources may make different contribution. Regardless of the subcategory, the highest deposition efficiency of an individual AMB was found in the head airway region, followed by the alveolar and tracheobronchial regions. This study provides new information about inhalable MBs in the coastal atmosphere. The coexistence of various particle-bound MBs raises concerns about potential health risks from exposure to coastal air particles.

Systematic Review of Efficacy of Interventions for Social Isolation of Older Adults.

Background: The social isolation of older people is a growing public health concern. The proportion of older people in society has increased in recent decades, and it is estimated that ~40% of the population will be aged 50 or above within the next few decades. This systematic review aims to summarize and renew knowledge of the effectiveness of existing interventions for alleviating social isolation of older adults. Methods: Relevant electronic databases, including Cochrane Library, CINAHL, SCOPUS, and Web of Science, were searched by a systematic evaluation method. Eligible randomized controlled trial (RCT) studies were published between 1978 and 2021 in English or Chinese. The primary and secondary outcomes were social isolation and loneliness. The quality of the included RCTs was scored by the Cochrane risk-of-bias tool to assess their quality. Two independent reviewers extracted data, using a standardized form. Narrative synthesis and vote-counting methods were used to summarize and interpret study data. Results: Twenty-four RCTs were finally included in this review. There was evidence of substantial heterogeneity in the interventions delivered. The overall quality of included studies indicated a low-to-medium risk of bias. Eighteen of 24 RCTs showed at least one dimension effect on reducing social isolation. The interventions with accurate targeting of clients in social and public places had more obvious effect. The interventions in which older people are active participants also appeared more likely to be effective. In addition, group intervention activities and individual intervention interviews were effective in improving structural social support; mixed intervention, and group intervention on training support significantly improved functional social support. Conclusions: This study suggests that group and mixed intervention targeting of older adults could be helpful for alleviating social isolation problems. The use of modern technology for remote services could also present good results. More well-conducted RCTs of the effectiveness of social interventions for alleviating social isolation are needed to improve the evidence base. Especially as the debating results of remote interventions, further research in this field should be conducted.

Release of inhalable particles and viable microbes to the air during packaging peeling: Emission profiles and mechanisms.

Packaging is necessary for preserving and delivering products and has significant impacts on human health and the environment. Particle matter (PM) may be released from packages and transferred to the air during a typical peeling process, but little is known about this package-to-air migration route of particles. Here, we investigated the emission profiles of total and biological particles, and the horizontal and vertical dispersion abilities and community structure of viable microbes released from packaging to the air by peeling. The results revealed that a lot of inhalable particles and viable microbes were released from package to the air in different migration directions, and this migration can be regulated by several factors including package material, effective peeling area, peeling speed and angles, as well as the characteristics of the migrant itself. Dispersal of package-borne viable microbes provides direct evidence that viable microbes, including pathogens, can survive the aerosolization caused by peeling and be transferred to air over different distances while remaining alive. Based on the experimental data and visual proof in movies, we speculate that nonbiological particles are package fibers fractured and released to air by the external peeling force exerted on the package and that microbe dispersal is attributed to surface-borne microbe suspension by vibration caused by the peeling force. This investigation provides new information that aerosolized particles can deliver package-borne substances and viable microbes from packaging to the ambient environment, motivating further studies to characterize the health effects of such aerosolized particles and the geographic migration of microbes via packaging.

Increased Circulating Cathepsin L in Patients with Coronary Artery Disease.

Cathepsin L (CatL) is a potent collagenase involved in atherosclerotic vascular remodeling and dysfunction in animals and humans. This study investigated the hypothesis that plasma CatL is associated with the prevalence of coronary artery disease (CAD). Between February May 2011 and January 2013, 206 consecutive subjects were enrolled from among patients who underwent coronary angiography and percutaneous coronary intervention treatment. Age-matched subjects (n = 215) served as controls. Plasma CatL and high-sensitive C-reactive protein (hs-CRP) and high-density lipoprotein cholesterol were measured. The patients with CAD had significantly higher plasma CatL levels compared to the controls (1.4 ± 0.4 versus 0.4 ± 0.2 ng/mL, P < 0.001), and the patients with acute coronary syndrome had significantly higher plasma CatL levels compared to those with stable angina pectoris (1.7 ± 0.7 versus 0.8 ± 0.4 ng/mL, P < 0.01). Linear regression analysis showed that overall, the plasma CatL levels were inversely correlated with the high-density lipoprotein levels (r = -0.32, P < 0.01) and positively with hs-CRP levels (r = 0.35, P < 0.01). Multiple logistic regression analyses shows that cathepsin L levels were independent predictors of CAD (add ratio, 1.8; 95% CI, 1.2 to 2.1; P < 0.01). These data demonstrated that increased levels of plasma CatL are closely associated with the presence of CAD and that circulating CatL serves as a useful biomarker for CAD.

Deficiency of cysteinyl cathepsin K suppresses the development of experimental intimal hyperplasia in response to chronic stress.

BACKGROUND: Chronic psychological stress (CPS) is linked to cardiovascular disease initiation and progression. Given that cysteinyl cathepsin K (CatK) participates in vascular remodeling and atherosclerotic plaque growth in several animal models, we investigated the role of CatK in the development of experimental neointimal hyperplasia in response to chronic stress. METHODS AND RESULTS: At first, male wild-type (CatK) mice that underwent carotid ligation injury were subjected to chronic immobilization stress. On postoperative and stressed day 14, the results demonstrated that stress accelerated injury-induced neointima hyperplasia. On day 4, stressed mice showed following: increased levels of monocyte chemoattractant protein-1, gp91phox, toll-like receptor-2 (TLR2), TLR4, and CatK mRNAs or/and proteins, oxidative stress production, aorta-derived smooth muscle cell (SMC) migration, and macrophage infiltration as well as targeted intracellular proliferating-related molecules. Stressed mice showed increased matrix metalloproteinase-2 (MMP-2) and MMP-9 mRNA expressions and activities and elastin disruption in the injured carotid arteries. Second, CatK and CatK deficiency (CatK) mice received ligation injury and stress to explore the role of CatK. The stress-induced harmful changes were prevented by CatK. Finally, CatK mice that had undergone ligation surgery were randomly assigned to one of two groups and administered vehicle or CatK inhibitor for 14 days. Pharmacological CatK intervention produced a vascular benefit. CONCLUSION: These data indicate that CatK deletion protects against the development of experimental neointimal hyperplasia via the attenuation of inflammatory overaction, oxidative stress production, and VSMC proliferation, suggesting that CatK is a novel therapeutic target for the management of CPS-related restenosis after intravascular intervention therapies.

Cathepsin S-Mediated Negative Regulation of Wnt5a/SC35 Activation Contributes to Ischemia-Induced Neovascularization in Aged Mice.

BACKGROUND: Given that cathepsin S (CatS) gained attention due to its enzymatic and non-enzymatic functions in signaling, the role of CatS in ischemia-induced angiogenesis of aged mice was explored.Methods and Results:To study the role of CatS in the decline in aging-related vascular regeneration capacity, a hindlimb ischemia model was applied to aged wild-type (CatS+/+) and CatS-deficient (CatS-/-) mice. CatS-/-mice exhibited impaired blood flow recovery and capillary formation and increased levels of p-insulin receptor substrate-1, Wnt5a, and SC35 proteins and decreased levels of phospho-endothelial nitric oxide synthase (p-eNOS), p-mTOR, p-Akt, p-ERK1/2, p-glycogen synthase kinase-3α/ß, and galatin-3 proteins, as well as decreased macrophage infiltration and matrix metalloproteinase-2/-9 activities in the ischemic muscles. In vitro, CatS knockdown altered the levels of these targeted essential molecules for angiogenesis. Together, the results suggested that CatS-/-leads to defective endothelial cell functions and that CatS-/-is associated with decreased circulating endothelial progenitor cell (EPC)-like CD31+/c-Kit+cells. This notion was reinforced by the study finding that pharmacological CatS inhibition led to a declined angiogenic capacity accompanied by increased Wnt5a and SC35 levels and decreased eNOS/Akt-ERK1/2 signaling in response to ischemia. CONCLUSIONS: These findings demonstrated that the impairment of ischemia-induced neovascularization in aged CatS-/-mice is due, at least in part, to the attenuation of endothelial cell/EPC functions and/or mobilization associated with Wnt5a/SC35 activation in advanced age.

Cathepsin S Deficiency Mitigated Chronic Stress-Related Neointimal Hyperplasia in Mice.

Background Exposure to chronic psychosocial stress is a risk factor for atherosclerosis-based cardiovascular disease. We previously demonstrated the increased expressions of cathepsin S (CatS) in atherosclerotic lesions. Whether CatS participates directly in stress-related neointimal hyperplasia has been unknown. Methods and Results Male wild-type and CatS-deficient mice that underwent carotid ligation injury were subjected to chronic immobilization stress for morphological and biochemical studies at specific times. On day 14 after stress/surgery, stress enhanced the neointima formation. At the early time points, the stressed mice had increased plaque elastin disruption, cell proliferation, macrophage accumulation, mRNA and/or protein levels of vascular cell adhesion molecule-1, angiotensin II type 1 receptor, monocyte chemoattractant protein-1, gp91phox, stromal cell-derived factor-1, C-X-C chemokine receptor-4, toll-like receptor-2, toll-like receptor-4, SC 35, galectin-3, and CatS as well as targeted intracellular proliferating-related molecules (mammalian target of rapamycin, phosphorylated protein kinase B, and p-glycogen synthase kinase-3α/ß). Stress also increased the plaque matrix metalloproteinase-9 and matrix metalloproteinase-2 mRNA expressions and activities and aorta-derived smooth muscle cell migration and proliferation. The genetic or pharmacological inhibition of CatS by its specific inhibitor (Z- FL -COCHO) ameliorated the stressed arterial targeted molecular and morphological changes and stressed aorta-derived smooth muscle cell migration. Both the genetic and pharmacological interventions had no effect on increased blood pressure in stressed mice. Conclusions These results demonstrate an essential role of CatS in chronic stress-related neointimal hyperplasia in response to injury, possibly via the reduction of toll-like receptor-2/toll-like receptor-4-mediated inflammation, immune action, and smooth muscle cell proliferation, suggesting that CatS will be a novel therapeutic target for stress-related atherosclerosis-based cardiovascular disease.

Adiponectin/AdiopR1 signal inactivation contributes to impaired angiogenesis in mice of advanced age.

BACKGROUND: The mechanism by which angiogenesis declines with aging remains largely unknown. Given that the plasma levels of adiponectin (APN) are decreased in the presence of ischemic cardiovascular disease, we explore the possible mechanisms by which APN/adiponectin receptor1 (AdipoR1) axis inactivation contributes to the decline in vascular regeneration capacity in elderly animals. METHODS AND RESULTS: To study aging-related changes in the APN/AdipoR1 axis and its impact on ischemia-induced angiogenesis, a hindlimb ischemia model was applied to young and aged mice. Aging impaired ischemia-induced blood flow recovery. An ELISA showed that the aged mice had decreased plasma APN levels. Immunostaining showed lesser capillary formation in the aged mice. The aged ischemic muscles had decreased levels of AdipoR1, peroxisome proliferator activated receptor-γ (PPAR-γ), PPAR-γ co-activator 1α (PGC-1α), phospho-AMP-activated protein kinase α (p-AMPK-α), and B cell lymphoma-2 (Bcl-2) and increased levels of cleaved caspase-8 (C-caspase-8) and gp91phox/p22phox genes or/and proteins, nicotinamide adenine dinucleotide phosphate oxidase activity, superoxide production, and matrix metalloproteinase-2/-9 activity as well as increased numbers of infiltrated macrophages and leucocytes. In in vitro experiments, aged endothelial cells had negative changes in the levels of PPAR-γ, PGC-1α, p-AMPK-α, Bcl-2, and C-caspase-8 proteins in response to oxidative stress. Genetic interventions targeted toward APN and AdipoR1 negatively affected the targeted angiogenic protein levels in aged muscles and angiogenic actions and/or aged endothelial events. CONCLUSION: These findings indicate that aging can reduce angiogenesis in response to hypoxia via an impaired APN-AdipoR1-dependent mechanism that may be mediated by PPAR-γ/PGC-1α signaling inactivation in advanced age.

Dose rectification of an imbalance between DPP4 and GLP-1 ameliorates chronic stress-related vascular aging and atherosclerosis?

Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Dipeptidyl peptidase-4 (DPP-4) exerts many physiological and pharmacological functions by regulating its extremely abundant substrates [eg., glucagon-like peptide-1 (GLP-1), stromal cell-derived factor-1α/C-X-C chemokine receptor type-4, etc.]. Over the past decade, emerging data has revealed unexpected roles for DPP-4 and GLP-1 in intracellular signaling, oxidative stress production, lipid metabolism, cell apoptosis, immune activation, insulin resistance, and inflammation. This mini review focuses on recent findings in this field, highlighting an imbalance between DPP4 and GLP-1 as a potential therapeutic target in the management of vascular aging and atherosclerosis in animals under experimental stress conditions.

Cathepsin K activity controls cardiotoxin-induced skeletal muscle repair in mice.

BACKGROUND: Cathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non-enzymatic functions in signalling. Here, we examined whether CatK-deficiency (CatK-/- ) would mitigate injury-related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis. METHODS: Cardiotoxin (CTX, 20 µM/200 µL) was injected into the left gastrocnemius muscle of male wild-type (CatK+/+ ) and CatK-/- mice, and the mice were processed for morphological and biochemical studies. RESULTS: On post-injection Day 14, CatK deletion ameliorated muscle interstitial fibrosis and remodelling and performance. At an early time point (Day 3), CatK-/- reduced the lesion macrophage and leucocyte contents and cell apoptosis, the mRNA levels of monocyte chemoattractant protein-1, toll-like receptor-2 and toll-like receptor-4, and the gelatinolytic activity related to matrix metalloproteinase-2/-9. CatK deletion also restored the protein levels of caspase-3 and cleaved caspase-8 and the ratio of the BAX to the Bcl-2. Moreover, CatK deficiency protected muscle fibre laminin and desmin disorder in response to CTX injury. These beneficial muscle effects were mimicked by CatK-specific inhibitor treatment. In vitro experiments demonstrated that pharmacological CatK inhibition reduced the apoptosis of C2C12 mouse myoblasts and the levels of BAX and caspase-3 proteins induced by CTX. CONCLUSIONS: These results demonstrate that CatK plays an essential role in skeletal muscle loss and fibrosis in response to CTX injury, possibly via a reduction of inflammation and cell apoptosis, suggesting a novel therapeutic strategy for the control of skeletal muscle diseases by regulating CatK activity.

Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia-Induced Neovascularization: The Role of Dipeptidyl Peptidase-4/Glucagon-Like Peptide-1-Adiponectin Axis.

BACKGROUND: Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4/GLP-1 axis in vascular senescence and ischemia-induced neovascularization in mice under chronic stress, with a special focus on adiponectin -mediated peroxisome proliferator activated receptor-γ/its co-activator 1α (PGC-1α) activation. METHODS AND RESULTS: Seven-week-old mice subjected to restraint stress for 4 weeks underwent ischemic surgery and were kept under immobilization stress conditions. Mice that underwent ischemic surgery alone served as controls. We demonstrated that stress impaired the recovery of the ischemic/normal blood-flow ratio throughout the follow-up period and capillary formation. On postoperative day 4, stressed mice showed the following: increased levels of plasma and ischemic muscle DPP4 and decreased levels of GLP-1 and adiponectin in plasma and phospho-AMP-activated protein kinase α (p-AMPKα), vascular endothelial growth factor, peroxisome proliferator activated receptor-γ, PGC-1α, and Sirt1 proteins and insulin receptor 1 and glucose transporter 4 genes in the ischemic tissues, vessels, and/or adipose tissues and numbers of circulating endothelial CD31+/c-Kit+ progenitor cells. Chronic stress accelerated aortic senescence and impaired aortic endothelial sprouting. DPP4 inhibition and GLP-1 receptor activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion. CONCLUSIONS: These results indicate that the DPP4/GLP-1-adiponectin axis is a novel therapeutic target for the treatment of vascular aging and cardiovascular disease under chronic stress conditions.