Phloretic acid requires the insulin/IGF-1 pathway and autophagy to enhance stress resistance and extend the lifespan of Caenorhabditis elegans.

Objective: In humans, aging is associated with increased susceptibility to most age-related diseases. Phloretic acid (PA), a naturally occurring compound found in Ginkgo biloba and Asparagus, exhibits has potential as an anti-aging agent and possesses antioxidant, anti-inflammatory, and immunomodulatory properties. This study aimed to investigate the effects of PA on longevity and stress resistance in Caenorhabditis elegans (C.elegans) and the mechanisms that underlie its effects. Methods: First, we examined the effects of PA on lifespan and healthspan assay, stress resistance and oxidative analysis, lipofuscin levels. Second, we examined the insulin/insulin-like pathway, mitochondria, autophagy-related proteins, and gene expression to explain the possible mechanism of PA prolonging lifespan. Results: Our findings demonstrated that PA dose-dependently extended the C.elegans lifespan, with 200 µM PA showing the greatest effect and increased the C.elegans lifespan by approximately 16.7%. PA enhanced motility and the pharyngeal pumping rate in senescent C.elegans while reducing the accumulation of aging pigments. Further investigations revealed that daf-16, skn-1, and hsf-1 were required for mediating the lifespan extension effect of PA in C.elegans since its impact was suppressed in mutant strains lacking these genes. This suggests that PA activates these genes, leading to the upregulation of downstream genes involved in stress response and senescence regulation pathways. Furthermore, PA did not extend the lifespan of the RNAi atg-18 and RNAi bec-1 but it attenuated SQST-1 accumulation, augmented autophagosome expression, upregulated autophagy-related gene expression, and downregulated S6K protein levels. These findings suggest that the potential life-extending effect of PA also involves the modulation of the autophagy pathway. Conclusion: These findings results highlight the promising anti-aging effects of PA and warrant further investigation into its pharmacological mechanism and medicinal development prospects.

Clinical efficacy of probiotics in the treatment of alcoholic liver disease: a systematic review and meta-analysis.

Objective: Alcoholic liver disease (ALD) is a liver damage disease caused by long-term heavy drinking. Currently, there is no targeted pharmaceutical intervention available for the treatment of this disease. To address this, this paper evaluates the efficacy and safety of probiotic preparation in treating ALD through conducting a meta-analysis, and provides a valuable insight for clinical decision-making. Methods: A systematic search was conducted across databases, including PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP, Wanfang, and CBM from the inception dates to October 15, 2023, to identify clinical randomized controlled trials on probiotic preparations in the treatment of ALD. After the literature underwent screening, data extraction, and quality assessment, RevMan 5.3 and Stata 14.2 were employed for data analysis and processing. Results: A total of 9 randomized controlled trials fulfilled the inclusion criteria. The results of the meta-analysis showed that probiotic preparation could significantly improve the liver function of patients with alcoholic liver disease compared with the control group. Probiotic intervention led to a significant reduction in the levels of alanine aminotransferase (MD=-13.36,95%CI:-15.80,-10.91;P<0.00001),aspartate aminotransferase (MD=-16.99,95%CI:-20.38,-13.59;P<0.00001),γ-glutamyl transpeptidase (MD=-18.79,95% CI:-28.23,-9.34; P<0.0001). Concurrently, the level of serum albumin (MD=0.19,95% CI:0.02,0.36;P=0.03) was increased. Furthermore, probiotic intervention could also modulate the composition of intestinal flora in patients with alcoholic liver disease, leading to an augmentation in Bifidobacteria and a reduction in Escherichia coli. However, in patients with alcoholic liver disease, probiotic intervention showed no significant effects on total bilirubin (MD=-0.01,95% CI:-0.17,0.15;P=0.91), tumor necrosis factor-α (MD=0.03,95% CI:-0.86,0.92;P=0.94) and interleukin-6 (MD=-5.3,95% CI:-16.04,5.45;P=0.33). Conclusion: The meta-analysis indicates that probiotics can improve liver function in alcoholic liver disease, reduce inflammatory responses, regulate intestinal flora, which have potential value in the treatment of alcoholic liver disease. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023472527.

Dendrobium Nobile Alcohol Extract Extends the Lifespan of Caenorhabditis elegans via hsf-1 and daf-16.

Dendrobium nobile is a traditional Chinese herb with anti-inflammatory, antioxidant, and neuroprotective properties. However, its antiaging effects are unclear. Herein, we studied the aging-related functions and the mechanism of action of the alcohol extract of Dendrobium nobile (DnAE) in the model organism Caenorhabditis elegans. The results indicated that 1 mg/mL DnAE slowed lipofuscin accumulation, decreased the levels of reactive oxygen species, elevated superoxide dismutase activity, enhanced oxidative and heat stress resistance, extended the lifespan of nematodes, protected their dopamine neurons from 6-hydroxydopamine-induced neurodegeneration, and reduced Aß-induced neurotoxicity. DnAE upregulated the mRNA expression of the transcription factors DAF-16 and HSF-1, promoted the nuclear localization of DAF-16, and enhanced the fluorescence intensity of HSP-16.2. However, it had no effect on the lifespan of DAF-16 mutants. Thus, DnAE can significantly extend lifespan, enhance heat stress tolerance, and delay age-related diseases through a DAF-16-dependent pathway.

Nicotine exacerbates diabetic nephropathy through upregulation of Grem1 expression.

BACKGROUND: Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Clinical reports indicate that smoking is a significant risk factor for chronic kidney disease, and the tobacco epidemic exacerbates kidney damage in patients with DN. However, the underlying molecular mechanisms remain unclear. METHOD: In the present study, we used a diabetic mouse model to investigate the molecular mechanisms for nicotine-exacerbated DN. Twelve-week-old female mice were injected with streptozotocin (STZ) to establish a hyperglycemic diabetic model. After four months, the control and hyperglycemic diabetic mice were further divided into four groups (control, nicotine, diabetic mellitus, nicotine + diabetic mellitus) by intraperitoneal injection of nicotine or PBS. After two months, urine and blood were collected for kidney injury assay, and renal tissues were harvested for further molecular assays using RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry. In vitro studies, we used siRNA to suppress Grem1 expression in human podocytes. Then we treated them with nicotine and high glucose to compare podocyte injury. RESULT: Nicotine administration alone did not cause apparent kidney injury, but it significantly increased hyperglycemia-induced albuminuria, BUN, plasma creatinine, and the kidney tissue mRNA expression of KIM-1 and NGAL. Results from RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry analysis revealed that, compared to hyperglycemia or nicotine alone, the combination of nicotine treatment and hyperglycemia significantly increased the expression of Grem1 and worsened DN. In vitro experiments, suppression of Grem1 expression attenuated nicotine-exacerbated podocyte injury. CONCLUSION: Grem1 plays a vital role in nicotine-exacerbated DN. Grem1 may be a potential therapeutic target for chronic smokers with DN.

Basing on the machine learning model to analyse the coronary calcification score and the coronary flow reserve score to evaluate the degree of coronary artery stenosis.

AIM: To obtain the coronary artery calcium score (CACS) for each branch in coronary artery computed tomography angiography (CCTA) examination combined with the flow fraction reserve (FFR) of each branch in the coronary artery detected by CT and apply a machine learning model (ML) to analyse and predict the severity of coronary artery stenosis. METHODS: All patients who underwent coronary computed tomography angiography (CCTA) from January 2019 to April 2022 in the HOSPITAL (T.C.M) AFFILIATED TO SOUTHWEST MEDICAL UNIVERSITY) were retrospectively screened, and their sex, age, characteristics of lipid-containing lesions, coronary calcium score (CACS) and CT-FFR values were collected. Five machine learning models, random forest (RF), k-nearest neighbour algorithm (KNN), kernel logistic regression, support vector machine (SVM) and radial basis function neural network (RBFNN), were used as predictive models to evaluate the severity of coronary stenosis. RESULTS: Among the five machine learning models, the SVM model achieved the best prediction performance, and the prediction accuracy of mild stenosis was up to 90%. Second, age and male sex were important influencing factors of increasing CACS and decreasing CT-FFR. Moreover, the critical CACS value of myocardial ischemia >200.70 was calculated. CONCLUSION: Through computer machine learning model analysis, we prove the importance of CACS and FFR in predicting coronary stenosis, especially the prominent vector machine model, which promotes the application of artificial intelligence computer learning methods in the field of medical analysis.

D-chiro-inositol increases antioxidant capacity and longevity of Caenorhabditis elegans via activating Nrf-2/SKN-1 and FOXO/DAF-16.

D-chiro-inositol (DCI) is an isomer of inositol, abundant in many foods, such as beans and buckwheat, with insulin-sensitizing, anti-inflammatory, and antioxidant effects. DCI has been used to relieve insulin resistance in diabetes and polycystic ovary syndrome in combination with inositol or D-pinitol. Here, we investigated the effect of DCI on aging and stress resistance in C. elegans. We found that DCI could prolong the lifespan of C. elegans by up to 29.6 %. DCI significantly delayed the onset of neurodegenerative diseases in models of C. elegans. DCI decreased the accumulation of Aß1-42, alpha-synuclein, and poly-glutamine, the pathological causes of Alzheimer's, Parkinson's, and Huntington's diseases, respectively. DCI significantly increased the stress resistances against pathogens, oxidants and heat shock. Moreover, D-chiro-inositol reduced the content of ROS and malondialdehyde by increasing the total antioxidant capacity and the activity of superoxide dismutase and catalase. Above effects of DCI requires the transcription factors FOXO/DAF-16 and Nrf-2/SKN-1. DCI also increased the expression of downstream genes regulated by FOXO/DAF-16 and Nrf-2/SKN-1. In conclusion, DCI enhanced the antioxidant capacity and healthy lifespan of C. elegans by activating DAF-16, SKN-1, and HSF-1. Our results showed that DCI could be a promising antiaging agent that is worth further research on the mechanism and health supplemental application of DCI.

Flavonol glycoside complanatoside A requires FOXO/DAF-16, NRF2/SKN-1, and HSF-1 to improve stress resistances and extend the life span of Caenorhabditis elegans.

Aging is associated with the increased risk of most age-related diseases in humans. Complanatoside A (CA) is a flavonoid compound isolated from the herbal medicine Semen Astragali Complanati. CA was reported to have potential anti-inflammatory and anti-oxidative activities. In this study, we investigated whether CA could increase the stress resistance capability and life span of Caenorhabditis elegans. Our results showed that CA could extend the longevity of C. elegans in a dosage-dependent manner, while 50 µM of CA has the best effect and increased the life span of C. elegans by about 16.87%. CA also improved the physiological functions in aging worms, such as enhanced locomotor capacity, and reduced the accumulation of the aging pigment. CA could also reduce the accumulation of toxic proteins (α-synuclein and ß-amyloid) and delay the onset of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, in models of C. elegans. Further investigation has revealed that CA requires DAF-16/FOXO, SKN-1, and HSF-1 to extend the life span of C. elegans. CA could increase the antioxidation and detoxification activities regulated by transcription factor SKN-1 and the heat resistance by activating HSF-1 that mediated the expression of the chaperone heat shock proteins. Our results suggest that CA is a potential antiaging agent worth further research for its pharmacological mechanism and development for pharmaceutical applications.

Altered spontaneous brain activity in major depressive disorder: An activation likelihood estimation meta-analysis.

BACKGROUND: Wide application of resting-state functional magnetic resonance imaging (fMRI) in psychiatric research has revealed that major depressive disorder (MDD) manifest abnormal neural activities in several brain regions involving key resting state networks. However, inconsistent results have hampered our understanding of the exact neuropathology associated with MDD. Therefore, our aim was to conduct a meta-analysis to identify the consistent vulnerable brain regions of MDD in resting state, and to reveal the potential pathogenesis of MDD. METHODS: A systematic review analysis was conducted on studies involving brain resting-state changes in MDD using low-frequency amplitude (ALFF), fractional low-frequency amplitude (fALFF) and regional homogeneity (ReHo) analysis. The meta-analysis was based on the activation likelihood estimation method, using the software of Ginger ALE 2.3. RESULTS: 25 studies (892 MDD and 799 healthy controls) were included. Based on the meta-analysis results of ReHo, we found robust reduction of resting-state spontaneous brain activity in MDD, including the left cuneus and right middle occipital gyrus (cluster size = 216, 256 mm3, uncorrected P < 0.0001), while no increased spontaneous activation in any of the brain regions. We also found reduced ALFF in the left middle occipital gyrus (cluster size = 224 mm3, uncorrected P < 0.0001), and no increased spontaneous brain activation in any regions. CONCLUSION: Our meta-analysis study using the activation likelihood estimation method demonstrated that MDD showed significant abnormalities in spontaneous neural activity, compared with healthy controls, mainly in areas associated with visual processing, such as the cuneus and the middle occipital gyrus. Dysfunction of these brain regions may be one of the pathogenesis of MDD.

Para-Hydroxybenzyl Alcohol Delays the Progression of Neurodegenerative Diseases in Models of Caenorhabditis elegans through Activating Multiple Cellular Protective Pathways.

The traditional Chinese medicine Gastrodia elata (commonly called "Tianma" in Chinese) has been widely used in the treatment of rheumatism, epilepsy, paralysis, headache, and dizziness. Phenolic compounds, such as gastrodin, para-hydroxybenzyl alcohol (HBA), p-hydroxybenzaldehyde, and vanillin are the main bioactive components isolated from Gastrodia elata. These compounds not only are structurally related but also share similar pharmacological activities, such as antioxidative and anti-inflammatory activities, and effects on the treatment of aging-related diseases. Here, we investigated the effect of para-hydroxybenzyl alcohol (HBA) on neurodegenerative diseases and aging in models of Caenorhabditis elegans (C. elegans). Our results showed that HBA effectively delayed the progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease in models of C. elegans. In addition, HBA could increase the average lifespan of N2 worms by more than 25% and significantly improve the age-related physiological functions of worms. Moreover, HBA improved the survival rate of worms under stresses of oxidation, heat, and pathogenic bacteria. Further mechanistic investigation revealed that HBA could activate FOXO/DAF-16 and SKN-1 to regulate antioxidative and xenobiotic metabolism pathway. HBA could also activate HSF-1 to regulate proteostasis maintenance pathway, mitochondrial unfolded stress response, endoplasmic stress response and autophagy pathways. The above results suggest that HBA activated multiple cellular protective pathways to increase stress resistance and protect against aging and aging-related diseases. Overall, our study indicates that HBA is a potential candidate for future development of antiaging pharmaceutical application.

Orientin Prolongs the Longevity of Caenorhabditis elegans and Postpones the Development of Neurodegenerative Diseases via Nutrition Sensing and Cellular Protective Pathways.

Age is the major risk factor for most of the deadliest diseases. Developing small molecule drugs with antiaging effects could improve the health of aged people and retard the onset and progress of aging-associated disorders. Bioactive secondary metabolites from medicinal plants are the main source for development of medication. Orientin is a water-soluble flavonoid monomer compound widely found in many medicinal plants. Orientin inhibits fat production, antioxidation, and anti-inflammatory activities. In this study, we explored whether orientin could affect the aging of C. elegans. We found that orientin improved heat, oxidative, and pathogenic stress resistances through activating stress responses, including HSF-1-mediated heat shock response, SKN-1-mediated xenobiotic and oxidation response, mitochondria unfolded responses, endoplasmic unfolded protein response, and increased autophagy activity. Orientin also could activate key regulators of the nutrient sensing pathway, including AMPK and insulin downstream transcription factor FOXO/DAF-16 to further improve the cellular health status. The above effects of orientin reduced the accumulation of toxic proteins (α-synuclein, ß-amyloid, and poly-Q) and delayed the onset of neurodegenerative disorders in AD, PD, and HD models of C. elegans and finally increased the longevity and health span of C. elegans. Our results suggest that orientin has promising antiaging effects and could be a potential natural source for developing novel therapeutic drugs for aging and its related diseases.

Trigonelline Extends the Lifespan of C. Elegans and Delays the Progression of Age-Related Diseases by Activating AMPK, DAF-16, and HSF-1.

Trigonelline is the main alkaloid with bioactivity presented in fenugreek, which was used in traditional medicine in Asian countries for centuries. It is reported that trigonelline has anti-inflammatory, anti-oxidant, and anti-pathogenic effects. We are wondering whether trigonelline have anti-aging effect. We found that 50 µM of trigonelline had the best anti-aging activity and could prolong the lifespan of Caenorhabditis elegans (C. elegans) by about 17.9%. Trigonelline can enhance the oxidative, heat, and pathogenic stress resistance of C. elegans. Trigonelline could also delay the development of neurodegenerative diseases, such as AD, PD, and HD, in models of C. elegans. Trigonelline could not prolong the lifespan of long-lived worms with loss-of-function mutations in genes regulating energy and nutrition, such as clk-1, isp-1, eat-2, and rsks-1. Trigonelline requires daf-16, hsf-1, and aak-2 to extend the lifespan of C. elegans. Trigonelline can also up-regulate the expression of daf-16 and hsf-1 targeted downstream genes, such as sod-3, gst-4, hsp-16.1, and hsp-12.6. Our results can be the basis for developing trigonelline-rich products with health benefits, as well as for further research on the pharmacological usage of trigonelline.

Fluoxetine ameliorates depressive symptoms by regulating lncRNA expression in the mouse hippocampus.

Depression is a prevalent mental disorder that is associated with aging and contributes to increased mortality and morbidity. The overall prevalence of geriatric depression with clinically significant symptoms is currently on the rise. Recent studies have demonstrated that altered expressions of long non-coding RNAs (lncRNAs) in the brain affect neurodevelopment and manifest modulating functions during the depression. However, most lncRNAs have not yet been studied. Herein, we analyzed the transcriptome of dysregulated lncRNAs to reveal their expressions in a mouse model exhibiting depressive-like behaviors, as well as their corresponding response following antidepressant fluoxetine treatment. A chronic unpredictable mild stress (CUMS) mouse model was applied. A six-week fluoxetine intervention in CUMS-induced mice attenuated depressive-like behaviors. In addition, differential expression analysis of lncRNAs was performed following RNA-sequencing. A total of 282 lncRNAs (134 up-regulated and 148 down-regulated) were differentially expressed in CUMS-induced mice relative to non-stressed counterparts ( P<0.05). Moreover, 370 differentially expressed lncRNAs were identified in CUMS-induced mice after fluoxetine intervention. Gene Ontology (GO) analyses showed an association between significantly dysregulated lncRNAs and protein binding, oxygen binding, and transport activity, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that these dysregulated lncRNAs might be involved in inflammatory response pathways. Fluoxetine effectively ameliorated the symptoms of depression in CUMS-induced mice by regulating the expression of lncRNAs in the hippocampus. The findings herein provide valuable insights into the potential mechanism underlying depression in elderly people.

Inositol polyphosphate multikinase IPMK-1 regulates development through IP3/calcium signaling in Caenorhabditis elegans.

Inositol polyphosphate multikinase (IPMK) is a conserved protein that initiates the production of inositol phosphate intracellular messengers and is critical for regulating a variety of cellular processes. Here, we report that the C. elegans IPMK-1, which is homologous to the mammalian inositol polyphosphate multikinase, plays a crucial role in regulating rhythmic behavior and development. The deletion mutant ipmk-1(tm2687) displays a long defecation cycle period and retarded postembryonic growth. The expression of functional ipmk-1::GFP was detected in the pharyngeal muscles, amphid sheath cells, the intestine, excretory (canal) cells, proximal gonad, and spermatheca. The expression of IPMK-1 in the intestine was sufficient for the wild-type phenotype. The IP3-kinase activity of IPMK-1 is required for defecation rhythms and postembryonic development. The defective phenotypes of ipmk-1(tm2687) could be rescued by a loss-of-function mutation in type I inositol 5-phosphatase homolog (IPP-5) and improved by a supplemental Ca2+ in the medium. Our work demonstrates that IPMK-1 and the signaling molecule inositol triphosphate (IP3) pathway modulate rhythmic behaviors and development by dynamically regulating the concentration of intracellular Ca2+ in C. elegans. Advances in understanding the molecular regulation of Ca2+ homeostasis and regulation of organism development may lead to therapeutic strategies that modulate Ca2+ signaling to enhance function and counteract disease processes. Unraveling the physiological role of IPMK and the underlying functional mechanism in C. elegans would contribute to understanding the role of IPMK in other species, especially in mammals, and benefit further research on the involvement of IPMK in disease.

A Dihydroflavonoid Naringin Extends the Lifespan of C. elegans and Delays the Progression of Aging-Related Diseases in PD/AD Models via DAF-16.

Naringin is a dihydroflavonoid, which is rich in several plant species used for herbal medicine. It has a wide range of biological activities, including antineoplastic, anti-inflammatory, antiphotoaging, and antioxidative activities. So it would be interesting to know if naringin has an effect on aging and aging-related diseases. We examined the effect of naringin on the aging of Caenorhabditis elegans (C. elegans). Our results showed that naringin could extend the lifespan of C. elegans. Moreover, naringin could also increase the thermal and oxidative stress tolerance, reduce the accumulation of lipofuscin, and delay the progress of aging-related diseases in C. elegans models of AD and PD. Naringin could not significantly extend the lifespan of long-lived mutants from genes in insulin/IGF-1 signaling (IIS) and nutrient-sensing pathways, such as daf-2, akt-2, akt-1, eat-2, sir-2.1, and rsks-1. Naringin treatment prolonged the lifespan of long-lived glp-1 mutants, which have decreased reproductive stem cells. Naringin could not extend the lifespan of a null mutant of the fox-head transcription factor DAF-16. Moreover, naringin could increase the mRNA expression of genes regulated by daf-16 and itself. In conclusion, we show that a natural product naringin could extend the lifespan of C. elegans and delay the progression of aging-related diseases in C. elegans models via DAF-16.

Secoisolariciresinol Diglucoside Delays the Progression of Aging-Related Diseases and Extends the Lifespan of Caenorhabditis elegans via DAF-16 and HSF-1.

Secoisolariciresinol diglucoside (SDG) is a phytoestrogen and rich in food flaxseed, sunflower seeds, and sesame seeds. Among the beneficial pharmacological activities of SDG on health, many are age related, such as anticancer, antidiabetes, antioxidant, and neuroprotective effects. Thus, we investigated if SDG had an effect on antiaging in Caenorhabditis elegans (C. elegans). Our results showed that SDG could extend the lifespan of C. elegans by up to 22.0%, delay age-related decline of body movement, reduce the lethality of heat and oxidative stress, alleviate dopamine neurodegeneration induced by 6-hydroxydopamine (6-OHDA), and decrease the toxicity of Aß protein in C. elegans. SDG could increase the expression of the downstream genes of DAF-16, DAF-12, NHR-80, and HSF-1 at mRNA level. SDG could not extend the lifespan of mutants from genes daf-16, hsf-1, nhr-80, daf-12, glp-1, eat-2, and aak-2. The above results suggested that SDG might enhance the stress resistance, delay the progression of aging-related diseases, and extend the lifespan of C. elegans via DAF-16 and HSF-1.

Tectochrysin increases stress resistance and extends the lifespan of Caenorhabditis elegans via FOXO/DAF-16.

Aging is related to the lowered overall functioning and increased risk for various age-related diseases in humans. Tectochrysin is a flavonoid compound and rich in a traditional Chinese Medicine Alpinia oxyphylla Miq., which has antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, anti-diarrhea, hepatoprotective, and neuro-protective effects. Therefore, we tested if tectochrysin had an effect on aging in Caenorhabditis elegans (C. elegans). Our results showed that tectochrysin could extend the lifespan of C. elegans by up to 21.0%, delay the age-related decline of body movement, improve high temperature-stress resistance and anti-infection capacity, and protected worms against Aß1-42-induced toxicity. Tectochrysin could not extend the lifespan of the mutants from genes daf-2, daf-16, eat-2, aak-2, skn-1, and hsf-1. Tectochrysin could increase the expression of DAF-16 regulated genes. The extension of lifespan by tectochrysin requires FOXO/DAF-16 and HSF-1. Overall, our findings suggest that tectochrysin may have a potential effect on extending lifespan and age-related diseases.

EDA2R mediates podocyte injury in high glucose milieu.

EDA2R is a member of the large family of tumor necrosis factor receptor (TNFR). Previous studies suggested that EDA2R expression might be increased in the kidneys of diabetic mice. However, its mRNA and protein expression in kidneys were not analyzed; moreover, its role in the development of diabetic kidney disease was not explored. Here we analyzed the mRNA and protein expressions of EDA2R in diabetic kidneys and examined its role in the podocyte injury in high glucose milieu. By analysis with real-time PCR, Western blotting, we found that both the mRNA and protein levels of EDA2R were increased in the kidneys of diabetic mice. Immunohistochemical studies revealed that EDA2R expression was enhanced in both glomerular and tubular cells of diabetic mice and humans. In vitro studies, high glucose increased EDA2R expression in cultured human podocytes. Overexpression of EDA2R in podocytes promoted podocyte apoptosis and decreased nephrin expression. Moreover, ED2AR increased ROS generation in podocytes, while inhibiting ROS generation attenuates EDA2R-mediated podocyte injury. In addition, EDA2R silencing partially suppressed high glucose-induced ROS generation, apoptosis, and nephrin decrease. Our study demonstrated that high glucose increases EDA2R expression in kidney cells and that EDA2R induces podocyte apoptosis and dedifferentiation in high glucose milieu partially through enhanced ROS generation.

Prophylactic Effects of Bifidobacterium adolescentis on Anxiety and Depression-Like Phenotypes After Chronic Stress: A Role of the Gut Microbiota-Inflammation Axis.

Stress disturbs the balance of the gut microbiota and stimulates inflammation-to-brain mechanisms. Moreover, stress leads to anxiety and depressive disorders. Bifidobacterium adolescentis displays distinct anti-inflammatory effects. However, no report has focused on the anxiolytic and antidepressant effects of B. adolescentis related to the gut microbiome and the inflammation on chronic restraint stress (CRS) in mice. We found that pretreatment with B. adolescentis increased the time spent in the center of the open field apparatus, increased the percentage of entries into the open arms of the elevated plus-maze (EPM) and the percentage of time spent in the open arms of the EPM, and decreased the immobility duration in the tail suspension test as well as the forced swimming test (FST). Moreover, B. adolescentis increased the sequence proportion of Lactobacillus and reduced the sequence proportion of Bacteroides in feces. Furthermore, B. adolescentis markedly reduced the protein expression of interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), p-nuclear factor-kappa B (NF-κB) p65 and Iba1 and elevated brain derived neurotrophic factor (BDNF) expression in the hippocampus. We conclude that the anxiolytic and antidepressant effects of B. adolescentis are related to reducing inflammatory cytokines and rebalancing the gut microbiota.

The Effects of Age and Reproduction on the Lipidome of Caenorhabditis elegans.

Aging is a complex life process, and a unified view is that metabolism plays key roles in all biological processes. Here, we determined the lipidomic profile of Caenorhabditis elegans (C. elegans) using ultraperformance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS). Using a nontargeted approach, we detected approximately 3000 species. Analysis of the lipid metabolic profiles at young adult and ten-day-old ages among wild-type N2, glp-1 defective mutant, and double mutant daf-16;glp-1 uncovered significant age-related differences in the total amount of phosphatidylcholines (PC), sphingomyelins (SM), ceramides (Cer), diglycerides (DG), and triglycerides (TG). In addition, the age-associated lipid profiles were characterized by ratio of polyunsaturated (PUFA) over monounsaturated (MUFA) lipid species. Lipid metabolism modulation plays an important role in reproduction-regulated aging; to identify the variations of lipid metabolites during germ line loss-induced longevity, we investigated the lipidomic profiles of long-lived glp-1/notch receptor mutants, which have reproductive deficiency when grown at nonpermissive temperature. The results showed that there was some age-related lipid variation, including TG 40:2, TG 40:1, and TG 41:1, which contributed to the long-life phenotype. The longevity of glp-1 mutant was daf-16-dependent; the lipidome analysis of daf-16;glp-1 double mutant revealed that the changes of some metabolites in the glp-1 mutant were daf-16-dependent, while other metabolites displayed more complex epistatic patterns. We first conducted a comprehensive lipidome analysis to provide novel insights into the relationships between longevity and lipid metabolism regulated by germ line signals in C. elegans.