Loss of Ninjurin1 alleviates acetaminophen-induced liver injury via enhancing AMPKα-NRF2 pathway.

Acetaminophen (APAP), a widely used pain and fever reliever, is a major contributor to drug-induced liver injury, as its toxic metabolites such as NAPQI induce oxidative stress and hepatic necrosis. While N-acetylcysteine serves as the primary treatment for APAP-induced liver injury (AILI), its efficacy is confined to a narrow window of 8-24 h post-APAP overdose. Beyond this window, liver transplantation emerges as the final recourse, prompting ongoing research to pinpoint novel therapeutic targets aimed at enhancing AILI treatment outcomes. Nerve injury-induced protein 1 (Ninjurin1; Ninj1), initially recognized as an adhesion molecule, has been implicated in liver damage stemming from factors like TNFα and ischemia-reperfusion. Nonetheless, its role in oxidative stress-related liver diseases, including AILI, remains unexplored. In this study, we observed up-regulation of Ninj1 expression in the livers of both human DILI patients and the AILI mouse model. Through the utilization of Ninj1 null mice, hepatocyte-specific Ninj1 KO mice, and myeloid-specific Ninj1 KO mice, we unveiled that the loss of Ninj1 in hepatocytes, rather than myeloid cells, exerts alleviative effects on AILI irrespective of sex dependency. Further in vitro experiments demonstrated that Ninj1 deficiency shields hepatocytes from APAP-induced oxidative stress, mitochondrial dysfunctions, and cell death by bolstering NRF2 stability via activation of AMPKα. In summary, our findings imply that Ninj1 likely plays a role in AILI, and its deficiency confers protection against APAP-induced hepatotoxicity through the AMPKα-NRF2 pathway.

Deep learning-based automatic segmentation of the mandibular canal on panoramic radiographs: A multi-device study.

Purpose: The objective of this study was to propose a deep-learning model for the detection of the mandibular canal on dental panoramic radiographs. Materials and Methods: A total of 2,100 panoramic radiographs (PANs) were collected from 3 different machines: RAYSCAN Alpha (n=700, PAN A), OP-100 (n=700, PAN B), and CS8100 (n=700, PAN C). Initially, an oral and maxillofacial radiologist coarsely annotated the mandibular canals. For deep learning analysis, convolutional neural networks (CNNs) utilizing U-Net architecture were employed for automated canal segmentation. Seven independent networks were trained using training sets representing all possible combinations of the 3 groups. These networks were then assessed using a hold-out test dataset. Results: Among the 7 networks evaluated, the network trained with all 3 available groups achieved an average precision of 90.6%, a recall of 87.4%, and a Dice similarity coefficient (DSC) of 88.9%. The 3 networks trained using each of the 3 possible 2-group combinations also demonstrated reliable performance for mandibular canal segmentation, as follows: 1) PAN A and B exhibited a mean DSC of 87.9%, 2) PAN A and C displayed a mean DSC of 87.8%, and 3) PAN B and C demonstrated a mean DSC of 88.4%. Conclusion: This multi-device study indicated that the examined CNN-based deep learning approach can achieve excellent canal segmentation performance, with a DSC exceeding 88%. Furthermore, the study highlighted the importance of considering the characteristics of panoramic radiographs when developing a robust deep-learning network, rather than depending solely on the size of the dataset.

Automatic and robust estimation of sex and chronological age from panoramic radiographs using a multi-task deep learning network: a study on a South Korean population.

Sex and chronological age estimation are crucial in forensic investigations and research on individual identification. Although manual methods for sex and age estimation have been proposed, these processes are labor-intensive, time-consuming, and error-prone. The purpose of this study was to estimate sex and chronological age from panoramic radiographs automatically and robustly using a multi-task deep learning network (ForensicNet). ForensicNet consists of a backbone and both sex and age attention branches to learn anatomical context features of sex and chronological age from panoramic radiographs and enables the multi-task estimation of sex and chronological age in an end-to-end manner. To mitigate bias in the data distribution, our dataset was built using 13,200 images with 100 images for each sex and age range of 15-80 years. The ForensicNet with EfficientNet-B3 exhibited superior estimation performance with mean absolute errors of 2.93 ± 2.61 years and a coefficient of determination of 0.957 for chronological age, and achieved accuracy, specificity, and sensitivity values of 0.992, 0.993, and 0.990, respectively, for sex prediction. The network demonstrated that the proposed sex and age attention branches with a convolutional block attention module significantly improved the estimation performance for both sex and chronological age from panoramic radiographs of elderly patients. Consequently, we expect that ForensicNet will contribute to the automatic and accurate estimation of both sex and chronological age from panoramic radiographs.

Evaluation of ATNPD Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease.

BACKGROUND AND OBJECTIVES: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-ß-amyloid 1-42 (Aß42), phosphorylated tau 181 (p-tau181), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aß42. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD ß-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATNPD) using CSF Aß42 (A), p-tau181 (T), and serum NfL (N) and tested ATNPD prediction of longitudinal cognitive decline in PD. METHODS: Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATNPD status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected). RESULTS: Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: p = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ2: p = 1). Patients with PD had overall lower CSF p-tau181 (ß = -0.16, 95% CI -0.23 to -0.092, p = 2.2e-05) and t-tau than controls (ß = -0.13, 95% CI -0.19 to -0.065, p = 4e-04), but not Aß42 (p = 0.061) or NfL (p = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (ß = 0.035, 95% CI 0.022 to 0.048, p = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aß42 (p = 0.18), p-tau181 (p = 1), or t-tau (p = 0.96). Using ATNPD, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (ß = -73, 95% CI -110 to -37, p = 0.00077) than all other ATNPD statuses including A+ alone (A+T-N-; n = 75; 21%). DISCUSSION: In patients with early PD, CSF p-tau181 and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATNPD (incorporating CSF Aß42, CSF p-tau181, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.

Effects of physical activity participation on cognitive impairment in older adults population with disabilities.

Background: Existing research on the association between cognitive function and physical activity in the older adults population with disabilities is limited. Additionally, there is a need to explore avenues for enhancing the longevity and quality of life among these individuals. Objective: This study aimed to investigate the independent and joint associations between cognitive function and levels of physical activity in the older adults population with disabilities. Methods: A total of 315 older adults adults (men = 182, women = 133), identified with disabilities based on medical evaluation, were recruited from the first survey of the Korean Longitudinal Study of Aging (KLoSA). Participants underwent assessments for cognitive function, physical activity (PA), activities of daily living (ADLs), instrumental activities of daily living (IADLs), and grip strength. Results: ADLs (p < 0.001) and IADLs (p < 0.001) scores were significantly higher in the male normal cognitive group compared to both the male and female cognitive impairment groups. In an unadjusted model, disabled older adults individuals who did not meet the recommended PA guidelines showed an increased odds ratio for cognitive dysfunction (OR = 2.29, 95% CI = 1.32-3.97). Those participating in PA at least 1 day per week also demonstrated an elevated odds ratio (OR = 1.22, 95% CI = 1.08-1.38) for cognitive dysfunction compared to those who engaged in regular PA. A negative correlation was observed between K-MMSE scores and grip strength (r = 0.448, p < 0.001). Conclusion: This study provides robust evidence that disabled older adults individuals who do not meet the recommended guidelines for PA or who do not participate in PA at least once a week have an increased likelihood of cognitive impairment compared to those who are regularly active.

Automatic detection of posterior superior alveolar artery in dental cone-beam CT images using a deeply supervised multi-scale 3D network.

OBJECTIVES: This study aimed to develop a robust and accurate deep learning network for detecting the posterior superior alveolar artery (PSAA) in dental cone-beam CT (CBCT) images, focusing on the precise localization of the centre pixel as a critical centreline pixel. METHODS: PSAA locations were manually labelled on dental CBCT data from 150 subjects. The left maxillary sinus images were horizontally flipped. In total, 300 datasets were created. Six different deep learning networks were trained, including 3D U-Net, deeply supervised 3D U-Net (3D U-Net DS), multi-scale deeply supervised 3D U-Net (3D U-Net MSDS), 3D Attention U-Net, 3D V-Net, and 3D Dense U-Net. The performance evaluation involved predicting the centre pixel of the PSAA. This was assessed using mean absolute error (MAE), mean radial error (MRE), and successful detection rate (SDR). RESULTS: The 3D U-Net MSDS achieved the best prediction performance among the tested networks, with an MAE measurement of 0.696 ± 1.552 mm and MRE of 1.101 ± 2.270 mm. In comparison, the 3D U-Net showed the lowest performance. The 3D U-Net MSDS demonstrated a SDR of 95% within a 2 mm MAE. This was a significantly higher result than other networks that achieved a detection rate of over 80%. CONCLUSIONS: This study presents a robust deep learning network for accurate PSAA detection in dental CBCT images, emphasizing precise centre pixel localization. The method achieves high accuracy in locating small vessels, such as the PSAA, and has the potential to enhance detection accuracy and efficiency, thus impacting oral and maxillofacial surgery planning and decision-making.

Automatic detection and classification of nasopalatine duct cyst and periapical cyst on panoramic radiographs using deep convolutional neural networks.

OBJECTIVE: The aim of this study is to evaluate a deep convolutional neural network (DCNN) method for the detection and classification of nasopalatine duct cysts (NPDC) and periapical cysts (PAC) on panoramic radiographs. STUDY DESIGN: A total of 1,209 panoramic radiographs with 606 NPDC and 603 PAC were labeled with a bounding box and divided into training, validation, and test sets with an 8:1:1 ratio. The networks used were EfficientDet-D3, Faster R-CNN, YOLO v5, RetinaNet, and SSD. Mean average precision (mAP) was used to assess performance. Sixty images with no lesion in the anterior maxilla were added to the previous test set and were tested on 2 dentists with no training in radiology (GP) and on EfficientDet-D3. The performances were comparatively examined. RESULTS: The mAP for each DCNN was EfficientDet-D3 93.8%, Faster R-CNN 90.8%, YOLO v5 89.5%, RetinaNet 79.4%, and SSD 60.9%. The classification performance of EfficientDet-D3 was higher than that of the GPs' with accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 94.4%, 94.4%, 97.2%, 94.6%, and 97.2%, respectively. CONCLUSIONS: The proposed method achieved high performance for the detection and classification of NPDC and PAC compared with the GPs and presented promising prospects for clinical application.

Okadaic Acid Is at Least as Toxic as Dinophysistoxin-1 after Repeated Administration to Mice by Gavage.

Okadaic acid (OA) and its analogues cause diarrhetic shellfish poisoning (DSP) in humans, and risk assessments of these toxins require toxicity equivalency factors (TEFs), which represent the relative toxicities of analogues. However, no human death by DSP toxin has been reported, and its current TEF value is based on acute lethality. To properly reflect the symptoms of DSP, such as diarrhea without death, the chronic toxicity of DSP toxins at sublethal doses should be considered. In this study, we obtained acute oral LD50 values for OA and dinophysistoxin-1 (DTX-1) (1069 and 897 µg/kg, respectively) to set sublethal doses. Mice were treated with sublethal doses of OA and DTX-1 for 7 days. The mice lost body weight, and the disease activity index and intestinal crypt depths increased. Furthermore, these changes were more severe in OA-treated mice than in the DTX-1-treated mice. Strikingly, ascites was observed, and its severity was greater in mice treated with OA. Our findings suggest that OA is at least as toxic as DTX-1 after repeated oral administration at a low dose. This is the first study to compare repeated oral dosing of DSP toxins. Further sub-chronic and chronic studies are warranted to determine appropriate TEF values for DSP toxins.

Head and neck manifestations of fibrodysplasia ossificans progressiva: Clinical and imaging findings in 2 cases.

Fibrodysplasia ossificans progressiva is a rare hereditary disorder characterized by progressive heterotopic ossification in muscle and connective tissue, with few reported cases affecting the head and neck region. Although plain radiographic findings and computed tomography features have been well documented, limited reports exist on magnetic resonance findings. This report presents 2 cases of fibrodysplasia ossificans progressiva, one with limited mouth opening due to heterotopic ossification of the lateral pterygoid muscle and the other with restricted neck movement due to heterotopic ossification of the platysma muscle. Clinical findings of restricted mouth opening or limited neck movement, along with radiological findings of associated heterotopic ossification, should prompt consideration of fibrodysplasia ossificans progressiva in the differential diagnosis. Dentists should be particularly vigilant with patients diagnosed with fibrodysplasia ossificans progressiva to avoid exposure to diagnostic biopsy and invasive dental procedures.

Extracellular Prdx1 mediates bacterial infection and inflammatory bone diseases.

AIM: We aimed to determine the role of extracellular peroxiredoxin 1 (Prdx1) in the pathogenesis of bacterial infections and inflammatory bone disease. MATERIALS AND METHODS: We first investigated the role of Prdx1 using knockout mice. Next, we determined the role of extracellular Prdx1 in bacterial infections by using a neutralizing antibody against Prdx1. We finally investigated whether blockade of extracellular Prdx1 affected high- or low-grade inflammatory bone diseases using calvarial osteolysis, collagen-induced arthritis (CIA), and microgravity-induced bone loss in mouse models. KEY FINDINGS: The lack of Prdx1 increased susceptibility to infections by Listeria monocytogenes or Escherichia coli. Prdx1 is released into the serum upon E. coli infection, and blockade of extracellular Prdx1 confers significant protection against bacterial infections. Our data suggested that circulating Prdx1 is increased by the development of osteolytic disease, and that blockade of extracellular Prdx1 exerts therapeutic effects against high- and low-grade inflammatory bone loss. In addition, the release of Prdx1 under inflammatory osteolytic conditions partly depends on non-canonical TIR-domain-containing adapter-inducing interferon-ß (TRIF)-caspase-11-gasdemin D (GSDMD) inflammasome pathways. SIGNIFICANCE: Extracellular Prdx1 is involved in the development of bacterial infections and inflammatory bone disease. Thus, extracellular Prdx1 may represent a novel therapeutic target for bacterial infections or inflammatory osteolytic diseases.

Alzheimer Disease Biomarkers: Moving from CSF to Plasma for Reliable Detection of Amyloid and tau Pathology.

BACKGROUND: Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway. CONTENT: Here we describe the clinical significance of CSF and plasma AD biomarkers to detect disease pathology throughout the Alzheimer continuum and correlate with imaging biomarkers. Use of the AT(N) classification by CSF and imaging biomarkers provides a more objective biologically based diagnosis of AD than clinical diagnosis alone. Significant progress in measuring CSF AD biomarkers using extensively validated highly automated assay systems has facilitated their transition from research use only to approved in vitro diagnostics tests for clinical use. We summarize development of plasma AD biomarkers as screening tools for enrollment and monitoring participants in therapeutic trials and ultimately in clinical care. Finally, we discuss the challenges for AD biomarkers use in clinical trials and precision medicine, emphasizing the possible ethnocultural differences in the levels of AD biomarkers. SUMMARY: CSF AD biomarker measurements using fully automated analytical platforms is possible. Building on this experience, validated blood-based biomarker tests are being implemented on highly automated immunoassay and mass spectrometry platforms. The progress made developing analytically and clinically validated plasma AD biomarkers within the AT(N) classification scheme can accelerate use of AD biomarkers in therapeutic trials and routine clinical practice.

Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials.

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aß production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood-brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.

Heme-binding protein 1 delivered via pericyte-derived extracellular vesicles improves neurovascular regeneration in a mouse model of cavernous nerve injury.

As a peripheral nerve injury disease, cavernous nerve injury (CNI) caused by prostate cancer surgery and other pelvic surgery causes organic damage to cavernous blood vessels and nerves, thereby significantly attenuating the response to phosphodiesterase-5 inhibitors. Here, we investigated the role of heme-binding protein 1 (Hebp1) in erectile function using a mouse model of bilateral CNI, which is known to promote angiogenesis and improve erection in diabetic mice. We found a potent neurovascular regenerative effect of Hebp1 in CNI mice, demonstrating that exogenously delivered Hebp1 improved erectile function by promoting the survival of cavernous endothelial-mural cells and neurons. We further found that endogenous Hebp1 delivered by mouse cavernous pericyte (MCP)-derived extracellular vesicles promoted neurovascular regeneration in CNI mice. Moreover, Hebp1 achieved these effects by reducing vascular permeability through regulation of claudin family proteins. Our findings provide new insights into Hebp1 as a neurovascular regeneration factor and demonstrate its potential therapeutic application to various peripheral nerve injuries.

Development of KEAP1-targeting PROTAC and its antioxidant properties: In vitro and in vivo.

Oxidative stress due to abnormal accumulation of reactive oxygen species (ROS) is an initiator of a large number of human diseases, and thus, the elimination and prevention of excessive ROS are important aspects of preventing the development of such diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is an essential transcription factor that defends against oxidative stress, and its function is negatively controlled by Kelch-like ECH-associated protein 1 (KEAP1). Therefore, activating NRF2 by inhibiting KEAP1 is viewed as a strategy for combating oxidative stress-related diseases. Here, we generated a cereblon (CRBN)-based proteolysis-targeting chimera (PROTAC), which we named SD2267, that induces the proteasomal degradation of KEAP1 and leads to NRF2 activation. As was intended, SD2267 bound to KEAP1, recruited CRBN, and induced the degradation of KEAP1. Furthermore, the KEAP1 degradation efficacy of SD2267 was diminished by MG132 (a proteasomal degradation inhibitor) but not by chloroquine (an autophagy inhibitor), which suggested that KEAP1 degradation by SD2267 was proteasomal degradation-dependent and autophagy-independent. Following KEAP1 degradation, SD2267 induced the nuclear translocation of NRF2, which led to the expression of NRF2 target genes and attenuated ROS accumulation induced by acetaminophen (APAP) in hepatocytes. Based on in vivo pharmacokinetic study, SD2267 was injected intraperitoneally at 1 or 3 mg/kg in APAP-induced liver injury mouse model. We observed that SD2267 degraded hepatic KEAP1 and attenuated APAP-induced liver damage. Summarizing, we described the synthesis of a KEAP1-targeting PROTAC (SD2267) and its efficacy and mode of action in vitro and in vivo. The results obtained suggest that SD2267 could be used to treat hepatic diseases related to oxidative stress.

A case report of an unusual temporomandibular joint mass: Nodular fasciitis.

Nodular fasciitis (NF) is a benign myofibroblastic proliferation that grows very rapidly, mimicking a sarcoma on imaging. It is treated by local excision, and recurrence has been reported in only a few cases, even when excised incompletely. The most prevalent diagnoses of temporomandibular joint (TMJ) masses include synovial chondromatosis, pigmented villonodular synovitis, and sarcomas. Cases of NF in the TMJ are extremely rare, and only 3 cases have been reported to date. Due to its destructive features and rarity, NF has often been misdiagnosed as a more aggressive lesion, which could expose patients to unnecessary and invasive treatment approaches beyond repair. This report presents a case of NF in the TMJ, focusing on various imaging features, along with a literature review aiming to determine the hallmark features of NF in the TMJ and highlight the diagnostic challenges.

Melatonin and Exercise Counteract Sarcopenic Obesity through Preservation of Satellite Cell Function.

Sarcopenic obesity (SO) is characterized by atrophic skeletal muscle impairment (sarcopenia) and obesity, which is associated with adverse outcomes of morbidity and mortality in elderly people. We investigated the effects of melatonin and exercise training on SO in 32-week-old senescence-accelerated mouse-prone-8 (SAMP8) mice fed a normal diet or a high-fat diet for 16 weeks. Melatonin, exercise, or melatonin and exercise for 8 weeks displayed reductions in the SO-induced impairment of skeletal muscle function and atrophy. Specifically, a decrease in mitochondrial calcium retention capacity in skeletal muscles observed in the HFD-con group was attenuated in melatonin and/or exercise intervention groups. More importantly, HFD-con mice displayed a lower number of Pax7+ satellite cells (SCs) and higher expression of p16ink than P8ND mice, which were attenuated by melatonin and/or exercise interventions. The cellular senescence in SC-derived primary myoblasts from HFD-con mice was significantly attenuated in myoblasts from the melatonin and/or exercise groups, which was reproduced in a senescence model of H2O2-treated C2C12 myoblasts. Our results suggest that melatonin and exercise training attenuate SO-induced skeletal muscle dysfunction, at least in part, through preserving the SC pool by inhibiting cellular senescence and attenuating mitochondrial dysfunction.

Novel NF-κB reporter mouse for the non-invasive monitoring of inflammatory diseases.

Bioluminescence imaging is useful for non-invasively monitoring inflammatory reactions associated with disease progression, and since NF-κB is a pivotal transcription factor that alters expressions of inflammatory genes, we generated novel NF-κB luciferase reporter (NF-κB-Luc) mice to understand the dynamics of inflammatory responses in whole body, and also in various type of cells by crossing NF-κB-Luc mice with cell-type specific Cre expressing mice (NF-κB-Luc:[Cre]). Bioluminescence intensity was significantly increased in NF-κB-Luc (NKL) mice exposed to inflammatory stimuli (PMA or LPS). Crossing NF-κB-Luc mice with Alb-cre mice or Lyz-cre mice generated NF-κB-Luc:Alb (NKLA) and NF-κB-Luc:Lyz2 (NKLL) mice, respectively. NKLA and NKLL mice showed enhanced bioluminescence in liver and macrophages, respectively. To confirm that our reporter mice could be utilized for the non-invasive monitoring of inflammation in preclinical models, we conducted a DSS-induced colitis model and a CDAHFD-induced NASH model in our reporter mice. In both models, our reporter mice reflected the development of these diseases over time. In conclusion, we believe that our novel reporter mouse can be utilized as a non-invasive monitoring platform for inflammatory diseases.

Argonaute 2 Restores Erectile Function by Enhancing Angiogenesis and Reducing Reactive Oxygen Species Production in Streptozotocin (STZ)-Induced Type-1 Diabetic Mice.

Severe vascular and nerve damage from diabetes is a leading cause of erectile dysfunction (ED) and poor response to oral phosphodiesterase 5 inhibitors. Argonaute 2 (Ago2), a catalytic engine in mammalian RNA interference, is involved in neurovascular regeneration under inflammatory conditions. In the present study, we report that Ago2 administration can effectively improve penile erection by enhancing cavernous endothelial cell angiogenesis and survival under diabetic conditions. We found that although Ago2 is highly expressed around blood vessels and nerves, it is significantly reduced in the penis tissue of diabetic mice. Exogenous administration of the Ago2 protein restored erectile function in diabetic mice by reducing reactive oxygen species production-signaling pathways (inducing eNOS Ser1177/NF-κB Ser536 signaling) and improving cavernous endothelial angiogenesis, migration, and cell survival. Our study provides new evidence that Ago2 mediation may be a promising therapeutic strategy and a new approach for diabetic ED treatment.

Contribution of High-Intensity Interval Exercise in the Fasted State to Fat Browning: Potential Roles of Lactate and ß-Hydroxybutyrate.

PURPOSE: Fat browning contributes to energy consumption and may have metabolic benefits against obesity; however, the potential roles of lactate and ß-hydroxybutyrate (ß-HB) in fat browning remain unclear. We investigated the roles of a single bout of aerobic exercise that increases lactate and ß-HB levels in the fasted state on the regulation of fat browning in rats and humans. METHODS: Male Sprague-Dawley rats were exposed to 24-h fasting and/or a single bout moderate-intensity aerobic exercise (40 min): sedentary (CON), exercise (ND-EX), fasting (FAST), and exercise + fasting (F-EX). Adult men ( n = 13) were randomly assigned into control with food intake (CON), exercise with intensity at onset of blood lactate accumulation in the fasted state (F-OBLA), and high-intensity interval exercise in the fasted state (F-HIIE) until each participant expended 350 kcal of energy. For evaluating the effects of exercise intensity in rats, we conducted another set of animal experiment, including groups of sedentary fed control, fasting control, and exercise with moderate-intensity or HIIE for 40 min after a 24-h fasting. RESULTS: Regardless of fasting, single bout of exercise increases the concentration of lactate and ß-HB in rats, but the exercise in the fasted state increases the ß-HB level more significantly in rats and humans. F-EX-activated fat browning (AMPK-SirT1-PGC1α pathway and PRDM16) and thermogenic factor (UCP1) in white fat of rats. In rats and humans, exercise in the fasted state increased the blood levels of fat browning-related adipomyokines. In particular, compared with F-OBLA, F-HIIE more efficiently increases free fatty acid as well as blood levels of fat browning adipomyokines in humans, which was correlated with blood levels of lactate and ß-HB. In rats that performed exercise with different intensity, the higher plasma lactate and ß-HB levels, and higher expression of p-AMPK, UCP1, and PRDM16 in white adipose tissue of HIIE group than those of moderate-intensity group, were observed. CONCLUSIONS: A single bout of aerobic exercise in the fasted state significantly induced fat browning-related pathways, free fatty acid, and adipomyokines, particularly F-HIIE in human. Although further evidence for supporting our results is required in humans, aerobic exercise in the fasted state with high intensity that increase lactate and ß-HB may be a modality of fat browning.

Circulating micro-RNAs Differentially Expressed in Korean Alzheimer's Patients With Brain Aß Accumulation Activate Amyloidogenesis.

BACKGROUND: Roles for extracellular vesicles (EVs) enriched with micro-RNAs (miRNAs) have been proposed in Alzheimer's disease (AD) pathogenesis, leading to the discovery of blood miRNAs as AD biomarkers. However, the diagnostic utility of specific miRNAs is not consistent. This study aimed to discover blood miRNAs that are differentially expressed in Korean AD patients, evaluate their clinical performance, and investigate their role in amyloidogenesis. METHODS: We discovered miRNAs differentially expressed in AD (N = 8) from cognitively normal participants (CN, N = 7) or Parkinson's disease (PD) patients (N = 8). We evaluated the clinical performance of these miRNAs in plasma of subgroup (N = 99) and in plasma EVs isolated from the total cohort (N = 251). The effects of miRNAs on amyloidogenesis and on the regulation of their target genes were investigated in vitro. RESULTS: Among 17 upregulated and one downregulated miRNAs in AD (>twofold), miR-122-5p, miR-210-3p, and miR-590-5p were differentially expressed compared with CN or PD. However, the diagnostic performance of the selected plasma or EV miRNAs in total participants were limited (area under the curve < 0.8). Nevertheless, levels of 3 miRNAs in plasma or plasma EVs of participants who were amyloid positron emission tomography (Aß-PET) positive were significantly higher than those from the Aß-PET negative participants (p < .05). The selected miRNAs induced Aß production (p < .05) through activation of ß-cleavage of amyloid precursor protein (CTF-ß; p < .01), and downregulated their target genes (ADAM metallopeptidase domain 10, Brain-derived neurotrophic factor, and Jagged canonical notch ligand 1; p < .05), which was further supported by pathway enrichment analysis of target genes of the miRNAs. CONCLUSION: In conclusion, despite of the limited diagnostic utility of selected miRNAs as plasma or plasma EV biomarkers, the discovered miRNAs may play a role in amyloidogenesis during AD onset and progression.