ABSTRACT
Postoperative Delirium (POD) can cause poor patient outcomes in older adults who undergo surgery. In this study, we tested plasma extracellular vesicle (EV) miRNAs obtained before the delirium event to find predictive POD biomarkers after spine surgery. We recruited patients who are over 70 years old and have undergone spine surgery. Finally, POD patients (n=31) were included, with no-POD patients matched in age, sex, medical history, and type of surgery (n=31). Peripheral blood was collected from patients in the operating room after the operation was completed. EVs were isolated from plasma, and the 798 miRNA expression level from EVs was measured using a NanoString platform. Sixty-two patients were included in the study; all were Korean, 67.7% were females, and the median age was 75 years. Preoperative medical history was not statistically different between no-POD and POD patients except for hypertension and the American Society of Anesthesiologists (ASA) physical status. From the miRNA profiling, we identified 142 significantly differentially expressed miRNAs in POD patients compared to no-POD patients, which are associated with psychological/neurological disorders. The top 10 differentially expressed miRNAs including miR-548ar-5p and miR-627-5p were all upregulated in POD patients and the results were validated using qRT-PCR from the independent sets of samples (n=96). We demonstrated the potential of plasma EV-miRNAs as predictive biomarkers to identify the risk group of POD after spine surgery. It also provides opportunities for future studies investigating the role of EV-miRNAs in delirium pathology.
ABSTRACT
Although zinc's involvement in bone calcification is well-established, its role in vascular calcification, characterized by abnormal calcium and phosphorus deposition in soft tissues and a key aspect of various vascular diseases, including atherosclerosis, remains unclear. This review focuses on zinc's action in vascular smooth muscle cell (VSMC) calcification, including the vascular calcification mechanism. Accumulated research has indicated that zinc deficiency induces calcification in VSMCs and the aorta, primarily through apoptosis accompanied by a downregulation of smooth muscle cell markers. Moreover, zinc deficiency-induced vascular calcification operates independently of the action of alkaline phosphatase (ALP) activity, typically associated with osteogenic processes, but is partly regulated via inorganic phosphate transporter-1 (Pit-1). To date, research has shown that zinc regulates vascular calcification through a mechanism distinct from that of osteogenic calcification, providing insight into its dual effects on physiological and pathological calcification and thereby explaining the "zinc paradox," wherein zinc simultaneously increases osteoblastic calcification and decreases VSMC calcification.
ABSTRACT
Obesity is a major public health issue due to its association with type 2 diabetes, hypertension, and other cardiovascular risks. The BBSome, a complex of eight conserved Bardet-Biedl syndrome (BBS) proteins, has emerged as a key regulator of energy and glucose homeostasis as well as cardiovascular function. However, the importance of adipocyte BBSome in controlling these physiological processes is not clear. Here, we show that adipocyte-specific constitutive disruption of the BBSome through selective deletion of the Bbs1 gene adiponectin (AdipoCre/Bbs1fl/fl mice) does not affect body weight under normal chow or high-fat and high-sucrose diet (HFHSD). However, constitutive BBSome deficiency caused impairment in glucose tolerance and insulin sensitivity. Similar phenotypes were observed after inducible adipocyte-specific disruption of the BBSome (AdipoCreERT2/Bbs1fl/fl mice). Interestingly, a significant increase in renal sympathetic nerve activity, measured using multifiber recording in the conscious state, was observed in AdipoCre/Bbs1fl/fl mice on both chow and HFHSD. A significant increase in tail-cuff arterial pressure was also observed in chow-fed AdipoCre/Bbs1fl/fl mice, but this was not reproduced when arterial pressure was measured by radiotelemetry. Moreover, AdipoCre/Bbs1fl/fl mice had no significant alterations in vascular reactivity. On the other hand, AdipoCre/Bbs1fl/fl mice displayed impaired baroreceptor reflex sensitivity when fed HFHSD, but not on normal chow. Taken together, these data highlight the relevance of the adipocyte BBSome for the regulation of glucose homeostasis and sympathetic traffic. The BBSome also contributes to baroreflex sensitivity under HFHSD, but not normal chow.NEW & NOTEWORTHY The current study show how genetic manipulation of fat cells impacts various functions of the body including sensitivity to the hormone insulin.
Subject(s)
Adipocytes , Adiponectin , Animals , Adipocytes/metabolism , Adiponectin/metabolism , Adiponectin/genetics , Mice , Insulin Resistance , Male , Obesity/physiopathology , Obesity/metabolism , Obesity/genetics , Mice, Knockout , Sympathetic Nervous System/physiopathology , Diet, High-Fat , Mice, Inbred C57BL , Disease Models, Animal , Autonomic Nervous System Diseases/physiopathology , Autonomic Nervous System Diseases/genetics , Autonomic Nervous System Diseases/metabolism , Bardet-Biedl Syndrome/genetics , Bardet-Biedl Syndrome/physiopathology , Bardet-Biedl Syndrome/metabolism , Microtubule-Associated ProteinsABSTRACT
BACKGROUND: Abnormal amyloid ß (Aß) deposits in the brain are a hallmark of Alzheimer's disease (AD). Insufficient sleep duration and poor sleep quality are risk factors for developing AD. Sleep may play a role in Aß regulation, but the magnitude of the relationship between sleep and Aß deposition remains unclear. This systematic review examines the relationship between sleep (i.e., duration and efficiency) with Aß deposition in later-life adults. METHODS: A search of PubMed, CINAHL, Embase, and PsycINFO generated 5,005 published articles. Fifteen studies met the inclusion criteria for qualitative syntheses; thirteen studies for quantitative syntheses related to sleep duration and Aß; and nine studies for quantitative syntheses related to sleep efficiency and Aß. RESULTS: Mean ages of the samples ranged from 63 to 76 years. Studies measured Aß using cerebrospinal fluid, serum, and positron emission tomography scans with two tracers: Carbone 11-labeled Pittsburgh compound B or fluorine 18-labeled. Sleep duration was measured subjectively using interviews or questionnaires, or objectively using polysomnography or actigraphy. Study analyses accounted for demographic and lifestyle factors. Based on 13 eligible articles, our synthesis demonstrated that the average association between sleep duration and Aß was not statistically significant (Fisher's Z = -0.055, 95% CI = -0.117 ~ 0.008). We found that longer self-report sleep duration is associated with lower Aß (Fisher's Z = -0.062, 95% CI = -0.119 ~ -0.005), whereas the objectively measured sleep duration was not associated with Aß (Fisher's Z = 0.002, 95% CI = -0.108 ~ 0.113). Based on 9 eligible articles for sleep efficiency, our synthesis also demonstrated that the average association between sleep efficiency and Aß was not statistically significant (Fisher's Z = 0.048, 95% CI = -0.066 ~ 0.161). CONCLUSION: The findings from this review suggest that shorter self-reported sleep duration is associated with higher Aß levels. Given the heterogeneous nature of the sleep measures and outcomes, it is still difficult to determine the exact relationship between sleep and Aß. Future studies with larger sample sizes should focus on comprehensive sleep characteristics and use longitudinal designs to better understand the relationship between sleep and AD.
Subject(s)
Amyloid beta-Peptides , Sleep , Humans , Amyloid beta-Peptides/metabolism , Sleep/physiology , Aged , Sleep Quality , Time Factors , Cognition/physiology , Alzheimer Disease/metabolism , Alzheimer Disease/diagnosis , Middle Aged , Sleep DurationABSTRACT
Obesity is associated with an increased incidence of asthma. However, the mechanisms underlying this association are not fully understood. In this study, we investigated the role of thioredoxin-interacting protein (TXNIP) in obesity-induced asthma. Asthma was induced by intranasal injection of a protease from Aspergillus oryzae in normal diet (ND)- or high fat diet (HFD)-fed mice to investigate the symptoms. We measured TXNIP expression in the lungs of patients with asthma and in ND or HFD asthmatic mice. To explore the role of TXNIP in asthma pathogenesis, we induced asthma in the same manner in alveolar type 2 cell-specific TXNIP deficient (TXNIPCre) mice. In addition, the expression levels of pro-inflammatory cytokines were compared based on TXNIP gene expression in A549 cells stimulated with recombinant human tumor necrosis factor alpha. Compared to ND-fed mice, HFD-fed mice had elevated levels of free fatty acids and adipokines, resulting in high reactive oxygen species levels and more severe asthma symptoms. TXNIP expression was increased in both, asthmatic patients and HFD asthmatic mice. However, in experiments using TXNIPCre mice, despite being TXNIP deficient, TXNIPCre mice exhibited exacerbated asthma symptoms. Consistent with this, in vitro studies showed highest expression levels of pro-inflammatory cytokines in TXNIP-silenced cells. Overall, our findings suggest that increased TXNIP levels in obesity-induced asthma is compensatory to protect against inflammatory responses.
Subject(s)
Asthma , Carrier Proteins , Diet, High-Fat , Obesity , Thioredoxins , Animals , Asthma/metabolism , Asthma/etiology , Asthma/pathology , Asthma/genetics , Mice , Humans , Obesity/metabolism , Obesity/genetics , Obesity/etiology , Carrier Proteins/metabolism , Carrier Proteins/genetics , Diet, High-Fat/adverse effects , Thioredoxins/metabolism , Thioredoxins/genetics , Alveolar Epithelial Cells/metabolism , Reactive Oxygen Species/metabolism , Cytokines/metabolism , Disease Models, Animal , Male , A549 Cells , Mice, KnockoutABSTRACT
Progesterone (P4) is a crucial reproductive hormone that acts as a precursor for all other endogenous steroids. P4 modulates transcriptional activity during reproduction by binding to progesterone receptors (PR). However, the physiological role of P4 in the liver is understudied. P4-mediated lipid metabolism in the liver was investigated in this study, as P4 facilitates insulin resistance and influences energy metabolism. While exogenous lipids are mainly obtained from food, the liver synthesizes endogenous triglycerides and cholesterol from a carbohydrate diet. Hepatic de novo lipogenesis (DNL) is primarily determined by acetyl-CoA and its biosynthetic pathways, which involve fatty acid and cholesterol synthesis. While P4 increased the hepatic levels of sterol regulatory element-binding protein 1â¯C (SREBP-1â¯C), peroxisome proliferator-activated receptor-gamma (PPARγ), acetyl-CoA carboxylase (ACC), and CD36, co-treatment with the P4 receptor antagonist RU486 blocked these proteins and P4-mediated lipogenesis. RNA sequencing was used to assess the role of P4 in lipogenic events, such as fatty liver and fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism. P4 induced hepatic DNL and lipid anabolism were confirmed in the liver of ovarian resection mice fed a high-fat diet or in pregnant mice. P4 increased lipogenesis directly in mice exposed to P4 and indirectly in fetuses exposed to maternal P4. The lipid balance between lipogenesis and lipolysis determines fat build-up and is linked to lipid metabolism dysfunction, which involves the breakdown and storage of fats for energy and the synthesis of structural and functional lipids. Therefore, P4 may impact the lipid metabolism and reproductive development during gestation.
Subject(s)
Lipogenesis , Progesterone , Female , Pregnancy , Animals , Mice , Progesterone/pharmacology , Liver , Cholesterol , Fatty Acids , LipidsABSTRACT
Tomato chlorosis virus (ToCV) is an emerging pathogen that cause severe yellow leaf disorder syndrome in tomato plants. In this study, we aimed to generate a recombinant ToCV tagged with green fluorescent protein (GFP) to enable real-time monitoring of viral infection in living plants. Transformation of the full-length cDNA construct of ToCV RNA1 into Escherichia coli resulted in instability issues, which were successfully overcome by inserting a plant intron into RNA1. Subsequently, a GFP tag was engineered into a cDNA construct of ToCV RNA2. The resulting recombinant ToCV-GFP could systemically infect Nicotiana benthamiana plants, and GFP expression was observed along the major veins. Utilizing ToCV-GFP, we also showed that ToCV engages in antagonistic relationships with two different tomato-infecting viruses in mixed infections in N. benthamiana. This study demonstrates the potential of ToCV-GFP as a valuable tool for the visual tracking of infection and movement of criniviruses in living plants.
Subject(s)
Crinivirus , Solanum lycopersicum , Animals , Crinivirus/genetics , DNA, Complementary/genetics , Plant Diseases , Insect Vectors , Plants , Solanum lycopersicum/geneticsABSTRACT
Inorganic phosphate (Pi) is a critical determinant of calcification, and its concentration is regulated by alkaline phosphatase (ALP) and Pit1. ALP is a key regulator of osteogenic calcification and acts by modulating local inorganic phosphate (Pi) concentrations through hydrolyzing pyrophosphate in the extracellular matrix (ECM). Pit1, a sodium-dependent phosphate transporter, regulates calcification via facilitating phosphate uptake within the cells. To investigate whether zinc differentially regulates osteoblastic and vascular calcifications, we examined ALP activity and Pit1 in osteoblastic and vascular smooth muscle cells (VSMCs). Our findings demonstrate that calcification in osteoblastic MC3T3-E1 cells is decreased via diminished ALP action under zinc deficiency. In contrast, zinc-deficiency-induced calcification in VSMCs is independent of ALP action, as demonstrated by very weak ALP activity and expression in calcified VSMCs. In zinc-deficient A7r5 VSMC, P accumulation increased with increasing Na phosphate concentration (3-7 mM) but not with ß-GP treatment, which requires ALP activity to generate Pi. Ca deposition also increased with Na phosphate in a dose-dependent manner; in contrast, ß-GP did not affect Ca deposition. In osteoblastic cells, Pit1 expression was not affected by zinc treatments. In contrast, Pit1 expression is highly upregulated in A7r5 VSMC under zinc deficiency. Using phosphonoformic acid, a competitive inhibitor of Pit1, we showed that calcification is inhibited in both A7r5 and MC3T3-E1 cells, indicating a requirement for Pit1 in both calcifications. Moreover, the downregulation of VSMC markers under zinc deficiency was restored by blocking Pit1. Taken together, our results imply that zinc-deficiency-induced calcification in VSMC is independent of ALP action in contrast to osteoblastic calcification. Moreover, Pit1 expression in VSMCs is a target for zinc deficiency and may mediate the inhibition of VSMC marker expression under zinc deficiency.
Subject(s)
Malnutrition , Vascular Calcification , Humans , Up-Regulation , Muscle, Smooth, Vascular , Alkaline Phosphatase , Zinc/pharmacologyABSTRACT
Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor ß-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.
Subject(s)
Liver Diseases, Alcoholic , Nitric Oxide , Animals , Humans , Mice , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cytokines/metabolism , Endothelial Cells/metabolism , Inflammation/metabolism , Liver/metabolism , Liver Cirrhosis/metabolism , Liver Diseases, Alcoholic/genetics , Liver Diseases, Alcoholic/metabolism , Nitric Oxide/metabolismABSTRACT
BACKGROUND: Middle-aged adults have the highest obesity rates, leading to significant health complications in later years. Obesity triggers the release of altered molecules, including extracellular vesicles (EVs) from excess adipose tissue (AT), contributing to various health complications. In this study, we assessed the effects of age and a high-fat diet on AT-derived EV miRNA profiles to understand their potential roles in aging and obesity. METHOD: C57BL/6 male mice were subjected to a normal chow diet (NCD) or a high-fat diet (HFD) for either 10-12 weeks (young mice, n = 10) or 50-61 weeks (middle-aged mice, n = 12). After evaluating metabolic characteristics, peri-gonadal white AT was isolated and cultured to obtain EVs. AT-derived EV miRNAs were profiled using a NanoString miRNA panel (n = 599). RESULTS: Middle-aged mice exhibited obesity regardless of diet. Young mice fed an HFD showed similar metabolic traits to middle-aged mice. In the NCD group, 131 differentially expressed miRNAs (DE-miRNAs) emerged in middle-aged mice compared to young mice, including miR-21, miR-148a, and miR-29a, associated with cancer, neuro/psychological disorders, and reproductive diseases. In the HFD group, 55 DE-miRNAs were revealed in middle-aged mice compared to young mice. These miRNAs were associated with significantly suppressed IGF1R activity. CONCLUSION: This study demonstrates the potential significant impact of miRNAs of AT EVs on aging- and obesity-related diseases.
ABSTRACT
Inflammatory bowel disease (IBD) affects millions of people worldwide and is considered a significant risk factor for colorectal cancer. Recent in vivo and in vitro studies reported that ellagic acid (EA) exhibits important antioxidant and anti-inflammatory properties. In this study, we investigated the preventive effects of EA against dextran sulfate sodium (DSS)-induced acute colitis, liver, and brain injury in mice through the gut-liver-brain axis. Acute colitis, liver, and brain injury were induced by treatment with 5% (w/v) DSS in the drinking water for 7 days. Freshly prepared EA (60 mg/kg/day) was orally administered, while control (CON) group mice were treated similarly by daily oral administrations with a vehicle (water). All the mice were euthanized 24 h after the final treatment with EA. The blood, liver, colon, and brain samples were collected for further histological and biochemical analyses. Co-treatment with a physiologically relevant dose (60 mg/kg/day) of EA for 7 days significantly reduced the DSS-induced gut barrier dysfunction; endotoxemia; and inflammatory gut, liver, and brain injury in mice by modulating gut microbiota composition and inhibiting the elevated oxidative and nitrative stress marker proteins. Our results further demonstrated that the preventive effect of EA on the DSS-induced IBD mouse model was mediated by blocking the NF-κB and mitogen-activated protein kinase (MAPK) pathway. Therefore, EA co-treatment significantly attenuated the pro-inflammatory and oxidative stress markers by suppressing the activation of NF-κB/MAPK pathways in gut, liver, and brain injury. These results suggest that EA, effective in attenuating IBD in a mouse model, deserves further consideration as a potential therapeutic for the treatment of inflammatory diseases.
ABSTRACT
Alcoholic liver disease (ALD) is damage to the liver and mainly caused by binge alcohol. ALD have decreased junctional protein expression and modulated intestinal permeability. We investigated whether plant-releasing exosome-like nanovesicles can prevent liver damage and leaky gut from binge alcohol. In this study, we characterized the exosome-like nanovesicles from pomegranate juice and confirmed the round shape of a lipid bilayer. After 14 days of pomegranate-derived exosome-like nanovesicle (PNVs) pretreatment, binge alcohol (6 g/kg/dose) was administered to mice three times orally every 12 h. Exposure to binge alcohol increased levels of oxidative and nitric oxide stress marker proteins such as CYP2E1, 3-Nitrotyrosine, and inducible nitric oxide synthase in both liver and gut damage. Also, binge alcohol significantly elevated the plasma endotoxemia, inflammatory fatty liver, and leaky gut. However, PNVs reduced the oxidative stress and apoptosis marker proteins and prevented the leaky gut and endotoxemia. Markedly, PNV treatment significantly prevented a decrease in the amount of intestinal junctional proteins and an increase in leaky gut in mice exposed to alcohol. These results showed that PNVs can prevent leaky gut and liver damage caused by binge alcohol and suggest that it may be useful hepatoprotective or intestinal protective agents for the first time.
ABSTRACT
Osteoblasts and osteoclasts play crucial roles in bone formation and bone resorption. We found that plum-derived exosome-like nanovesicles (PENVs) suppressed osteoclast activation and modulated osteoblast differentiation. PENVs increased the proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells and osteoblasts from mouse bone marrow cultures. Notably, PENVs elevated the expression of osteoblastic transcription factors and osteoblast differentiation marker proteins in MC3T3-E1 cells. Higher levels of phosphorylated BMP-2, p38, JNK, and smad1 proteins were detected in PENV-treated MC3T3-E1 cells. Additionally, the number of TRAP-positive cells was significantly decreased in PENV-treated osteoclasts isolated from osteoblasts from mouse bone marrow cultures. Importantly, osteoclastogenesis of marker proteins such as PPAR-gamma, NFATc1, and c-Fos were suppressed by treatment with PENVs (50 µg/mL). Taken together, these results demonstrate that PENVs can be used as therapeutic targets for treating bone-related diseases by improving osteoblast differentiation and inhibiting osteoclast activation for the first time.
Subject(s)
Bone Diseases , Exosomes , Prunus domestica , Animals , Mice , Osteoclasts , Osteoblasts , Cell DifferentiationABSTRACT
Glioblastoma (GBM) is the most lethal intracranial tumor. Sequencing technologies have supported personalized therapy for precise diagnosis and optimal treatment of GBM by revealing clinically actionable molecular characteristics. Although accumulating sequence data from brain tumors and matched normal tissues have facilitated a comprehensive understanding of genomic features of GBM, these in silico evaluations could gain more biological credibility when they are verified with in vitro and in vivo models. From this perspective, GBM cell lines with whole exome sequencing (WES) datasets of matched tumor tissues and normal blood are suitable biological platforms to not only investigate molecular markers of GBM but also validate the applicability of druggable targets. Here, we provide a complete WES dataset of 26 GBM patient-derived cell lines along with their matched tumor tissues and blood to demonstrate that cell lines can mostly recapitulate genomic profiles of original tumors such as mutational signatures and copy number alterations.
Subject(s)
Brain Neoplasms , Cell Line, Tumor , Genes, Neoplasm , Glioblastoma , Humans , Brain Neoplasms/genetics , Genomics , Glioblastoma/genetics , MutationABSTRACT
Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of the digestive tract that causes pain and weight loss and also increases the risk of colon cancer. Inspired by the benefits of plant-derived nanovesicles and aloe, we herein report aloe-derived nanovesicles, including aloe vera-derived nanovesicles (VNVs), aloe arborescens-derived nanovesicles (ANVs), and aloe saponaria-derived nanovesicles (SNVs) and evaluate their therapeutic potential and molecular mechanisms in a dextran sulfate sodium (DSS)-induced acute experimental colitis mouse model. Aloe-derived nanovesicles not only facilitate markedly reduced DSS-induced acute colonic inflammation, but also enable the restoration of tight junction (TJ) and adherent junction (AJ) proteins to prevent gut permeability in DSS-induced acute colonic injury. These therapeutic effects are ascribed to the anti-inflammatory and anti-oxidant effects of aloe-derived nanovesicles. Therefore, aloe-derived nanovesicles are a safe treatment option for IBD.
Subject(s)
Aloe , Colitis , Inflammatory Bowel Diseases , Mice , Animals , Aloe/metabolism , Tight Junction Proteins/metabolism , Colitis/chemically induced , Colitis/drug therapy , Inflammation/drug therapy , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/chemically induced , Disease Models, Animal , Dextran Sulfate , Mice, Inbred C57BLABSTRACT
Background: Amyloid ß (Aß) is a hallmark of Alzheimer's disease (AD). Insufficient sleep duration and poor sleep quality have been found to be a risk factor of developing AD because sleep may involve regulating Aß. However, the magnitude of the relationship between sleep duration and Aß is still unclear. This systematic review examines the relationship between sleep duration and Aß in later-life adults. Methods: We screened 5,005 published articles searched from relevant electronic databases (i.e., PubMed, CINAHL, Embase, and PsycINFO) and reviewed 14 articles for the qualitative synthesis and 7 articles for the quantitative synthesis. Results: Mean ages of the samples ranged from 63 to 76. Studies measured Aß using cerebrospinal fluid, serum, and positron emission tomography scans with two tracers: Carbone 11-labeled Pittsburgh compound B or fluorine 18-labeled. Sleep duration was subjectively measured using interviews, questionnaires, or using objective measures such as polysomnography or actigraphy. The studies accounted for demographic and lifestyle factors in their analyses. Five of the 14 studies reported a statistically significant association between sleep duration and Aß. Using seven eligible articles, our quantitative synthesis demonstrated that the average association between sleep duration and Aß was not statistically significant (Fisher's Z = -0.006, 95% CI= -0.065 ~ 0.054). Conclusion: This review suggests that caution should be taken when considering sleep duration as the primary factor for Aß levels. More studies are needed using a longitudinal design, comprehensive sleep metrics, and larger sample sizes to advance our understanding of the optimal sleep duration and AD prevention.
ABSTRACT
Plants-releasing exosome-like nanovesicles (PENs) contain miRNA, bioactive lipids, mRNAs, and proteins to exert antioxidant, anti-inflammatory, and regenerative activity. Substances extracted from yams have been reported to promote osteoblast growth in bone regeneration, which prevent weak and brittle bones in osteoporosis. Herein, we describe the beneficial effects of yam-derived exosome-like nanovesicles (YNVs) on promoting differentiation and mineralization of osteoblasts for bone regeneration in ovariectomized (OVX)-induced osteoporotic mice. YNVs were successfully isolated and characterized. YNVs stimulate the proliferation, differentiation, and mineralization of osteoblasts with increased bone differentiation markers (OPN, ALP, and COLI). Interestingly, YNVs do not contain saponins including diosgenin and dioscin known to mainly exert osteogenic activity of yams. Instead, the osteogenic activity of YNVs was revealed to be resulted from activation of the BMP-2/p-p38-dependent Runx2 pathway. As a result, YNVs promote longitudinal bone growth and mineral density of the tibia in the OVX-induced osteoporotic mice in vivo, and these results positively correlate the significant increases in osteoblast-related parameters. In addition, the orally administered YNVs were transported through the GI tract and absorbed through the small intestine. These results showed an excellent systemic biosafety determined by histological analysis and liver/kidney toxicity tests. Taken together, YNVs can serve as a safe and orally effective agent in the treatment of osteoporosis.
Subject(s)
Dioscorea , Exosomes , Osteoporosis , Mice , Animals , Exosomes/metabolism , Osteoblasts/metabolism , Osteoporosis/drug therapy , Osteoporosis/prevention & control , Osteoporosis/metabolism , Osteogenesis , Cell DifferentiationABSTRACT
Osteoporosis is characterized by low bone mass and elevated structural deterioration of the bone tissue, resulting in bone weakness with an increased risk of fracture. Considering biological activities of various phytochemicals extracted from apples, we herein demonstrated the potential antiosteoporotic effects of apple-derived nanovesicles (apple NVs) using osteoblastic MC3T3-E1 cells. Apple NVs significantly stimulated the growth of MC3T3-E1 cells. The cellular alkaline phosphatase (ALP) activity was significantly upregulated in the 5 µg/mL apple NVs-treated group. In addition, the concentrarion of mineralized nodules was significantly increased in the apple NVs-treated groups. Furthermore, apple NVs increased the expression of the genes and proteins associated with osteoblast growth and differentiation, such as Runx2, ALP, OPN, and BMP2/4, which further activated ERK- and JNK-related mitogen-activated protein kinase signaling. These results demonstrate that apple NVs have a potential to prevent osteoporosis by promoting osteoblastogenesis in osteoblastic MC3T3-E1 cells through regulating the BMP2/Smad1 pathways.
Subject(s)
Malus , Osteoporosis , Bone Morphogenetic Protein 2/genetics , Bone Morphogenetic Protein 2/metabolism , Cell Differentiation , JNK Mitogen-Activated Protein Kinases/metabolism , Malus/metabolism , Osteoblasts , Osteoporosis/drug therapy , Osteoporosis/metabolism , Signal Transduction , Animals , MiceABSTRACT
BACKGROUND: Gastric cancer (GC) is a common malignancy worldwide, with a major attribution to Helicobacter pylori. Interleukin (IL)-17A has been reported to be up-regulated in serum and tumor of GC patients, but the precise mechanisms underlying its involvement in gastric tumorigenesis are yet to be established. Here, we investigated the roles of IL-17A in the pathogenesis of H. pylori-induced GC. METHODS: GC was induced in IL-17A knockout (KO) and wild-type (WT) mice via N-methyl-N-nitrosourea (MNU) treatment and H. pylori infection. At 50 weeks after treatment, gastric tissues were examined by histopathology, immunohistochemistry, and immunoblot analyses. In vitro experiments on the human GC cell lines were additionally performed to elucidate the underlying mechanisms. RESULTS: Deletion of IL-17A suppressed MNU and H. pylori-induced gastric tumor development accompanied by a decrease in gastric epithelial cell growth, oxidative stress, and expression of gastric epithelial stem cells markers. In AGS cells, recombinant human IL-17A (rhIL-17A) inhibited apoptosis and G1/S phase transition arrest while promoting reactive oxygen species production, sphere formation ability of cancer stem cells (CSC), and expression of stemness-related genes. In addition, rhIL-17A induced expression of IL-17RC, leading to NF-κB activation and increased NADPH oxidase 1 (NOX1) levels. Inhibition of NOX1 with GKT136901 attenuated rhIL-17A-mediated elevation of GC cell growth, ROS generation, and CSC stemness. Clinically, IL-17RC expressions were significantly upregulated in human GC compared with normal gastric tissues. CONCLUSION: Our results suggest that IL-17A promotes gastric carcinogenesis, in part, by regulating IL-17RC/NF-κB/NOX1 pathway, supporting its potential as a target in human GC therapy.