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Religiosity of baby-boomers in young adulthood: Associations with psychological well-being over the life course

ADVANCES IN LIFE COURSE RESEARCH 2022年 52卷 100477页

作者： Hwang, Woosang Cheng, Kent Jason Brown, Maria T. Silverstein, Merril Syracuse Univ Aging Studies Inst Syracuse NY USA Syracuse Univ Social Sci PhD Program Syracuse NY USA Syracuse Univ Sch Social Work Syracuse NY USA Syracuse Univ Dept Human Dev & Family Sci Syracuse NY USA Syracuse Univ Dept Sociol Syracuse NY USA Syracuse Univ Aging Studies Inst 307B Lyman Hall Syracuse NY 13244 USA

Although several studies have discovered positive relationships between religion and various aspects of mental health, less is known about longitudinal associations between religiosity and psychological well-being over the life course. We examined how religious latent classes during the transition to adulthood are associated with trajectories of psychological well-being over 45 years. We selected 798 young-adults baby-boomers from the 1971 wave of the Longitudinal Study of Generation (mean age: 19 years) and tracked their psychological wellbeing over nine waves up to the 2016 wave (mean age: 64 years). Latent class analysis focused on four religiosity domains (religious service attendance, religious intensity, civic value of religion, literal beliefs) identified four distinct latent religious classes: strongly religious, weakly religious, liberally religious, and privately religious. Results of latent growth curve modeling showed that strongly religious baby-boomers during the transition to adulthood generally reported better psychological well-being than weakly religious baby-boomers at the same stage in life. In addition, psychological well-being in strongly, liberally, and privately religious baby-boomers followed a consistently upward trend across the life course, whereas among weakly religious baby-boomers psychological well-being followed an inverted u-curve (increased until mid-40s and decreased thereafter). Findings suggest that earlier religiosity may serve as a significant predictor affecting psychological well-being throughout the adult life course.

关键词： Baby-boomers Religiosity Psychological well-being Life course Latent class analysis

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Prostate cancer cells elevate glycolysis and G6PD in response to caffeic acid phenethyl ester-induced growth inhibition

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BMC CANCER 2025年第1期25卷 1-12页

作者： Lin, Tzu-Ping Chen, Pei-Chun Lin, Ching-Yu Wang, Bi-Juan Kuo, Ying-Yu Yeh, Chien-Chih Tseng, Jen-Chih Huo, Chieh Kao, Cheng-Li Shih, Li-Jane Chen, Jen-Kun Li, Chia-Yang Hour, Tzyh-Chyuan Chuu, Chih-Pin Natl Yang Ming Chiao Tung Univ Inst Electroopt Engn Hsinchu 30010 Taiwan Taipei Vet Gen Hosp Dept Urol Taipei City 11217 Taiwan Natl Hlth Res Inst Inst Cellular & Syst Med Zhunan 35053 Miaoli County Taiwan Taipei Med Univ Ph D Program Canc Mol Biol & Drug Discovery Taipei City Taiwan Taoyuan Armed Forces Gen Hosp Dept Internal Med Taoyuan City 325208 Taiwan Triserv Gen Hosp Natl Def Med Ctr Dept Surg Div Colon & Rectal Surg Taipei City 114202 Taiwan Natl Hlth Res Inst Immunol Res Ctr Zhunan Miaoli Taiwan Triserv Gen Hosp Natl Def Med Ctr Dept Obstet & Gynecol Taipei City 114202 Taiwan Armed Forces Taoyuan Gen Hosp Dept Surg Div Urol Taoyuan Taiwan Natl Def Med Ctr Grad Inst Med Sci Taipei City 114202 Taiwan Natl Hlth Res Inst Inst Biomed Engn & Nanomed Zhunan 35053 Miaoli Taiwan Kaohsiung Med Univ Grad Inst Med Coll Med Kaohsiung 80708 Taiwan Kaohsiung Med Univ Hosp Dept Med Res Kaohsiung 80708 Taiwan Kaohsiung Med Univ Neurosci Res Ctr Kaohsiung 80708 Taiwan Kaohsiung Med Univ Coll Med Dept Biochem Kaohsiung 80708 Taiwan Kaohsiung Med Univ Hosp Dept Med Res Kaohsiung 80708 Taiwan China Med Univ PhD Program Aging Taichung 40402 Taiwan Natl Chung Hsing Univ Biotechnol Ctr Taichung 40227 Taiwan Natl Cent Univ Dept Life Sci Taoyuan City 320317 Taiwan

BackgroundCaffeic acid phenethyl ester (CAPE) is the main bioactive component of poplar type propolis. We previously reported that treatment with caffeic acid phenethyl ester (CAPE) suppressed the cell proliferation, tumor growth, as well as migration and invasion of prostate cancer (PCa) cells via inhibition of signaling pathways of AKT, c-Myc, Wnt and EGFR. We also demonstrated that combined treatment of CAPE and docetaxel altered the genes involved in glycolysis and tricarboxylic acid (TCA) cycle. We therefore suspect that CAPE treatment may interfere glucose metabolism in PCa *** Bioenergetics platform was applied to analyzed the extra cellular acidification rate (ECAR) and oxygen consumption rate (OCR) of PCa cells under CAPE treatment. UPLC-MSMS with Multiple Reaction Monitoring (MRM), PCR, and western blot were used to analyze the effects of CAPE on metabolites, genes, and proteins involved in glycolysis, TCA cycle and pentose phosphate pathway in PCa cells. Flow cytometry and ELISA were used to determine the level of reactive oxygen species in PCa cells being treated with *** Bioenergetics analysis revealed that ECAR, glycolysis, OCR, and ATP production were elevated in C4-2B cells under CAPE treatment. Protein levels of glucose-6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (PGD), glutaminase (GLS), phospho-AMPK Thr172 as well as abundance of pyruvate, lactate, ribulose-5-phosphate, and sedoheptulose-7-phosphate were increased in CAPE-treated C4-2B cells. ROS level decreased 48 h after treatment with CAPE. Co-treatment of AMPK inhibitor with CAPE exhibited additive growth inhibition on PCa *** study indicated that PCa cells attempted to overcome the CAPE-induced stress by upregulation of glycolysis and G6PD but failed to impede the growth inhibition caused by CAPE. Concurrent treatment of CAPE and inhibitors targeting glycolysis may be effective therapy for advanced PCa.

关键词： Caffeic acid phenethyl ester Prostate cancer Glycolysis G6PD Pyruvate Lactate

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Non-genomic rewiring of vitamin D receptor to p53 as a key to Alzheimer's disease

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aging CELL 2021年第12期20卷 e13509-e13509页

作者： Lai, Rai-Hua Hsu, Yueh-Ying Shie, Feng-Shiun Huang, Che-Ching Chen, Mei-Hsin Juang, Jyh-Lyh Natl Hlth Res Inst Inst Mol & Genom Med Zhunan Taiwan Natl Hlth Res Inst Div Mental Hlth & Addict Med Zhunan Taiwan Natl Tsing Hua Univ Dept Life Sci Grad Program Biotechnol Med NTHU Hsinchu Taiwan Natl Tsing Hua Univ NHRI Hsinchu Taiwan China Med Univ PhD Program Aging Taichung Taiwan

Observational epidemiological studies have associated vitamin D deficiency with Alzheimer's disease (AD). However, whether vitamin D deficiency would result in some impacts on the vitamin D binding receptor (VDR) remains to be characterized in AD. Vitamin D helps maintain adult brain health genomically through binding with and activating a VDR/retinoid X receptor (RXR) transcriptional complex. Thus, we investigated the role of VDR in AD using postmortem human brains, APP/PS1 mice, and cell cultures. Intriguingly, although vitamin D was decreased in AD patients and mice, hippocampal VDR levels were inversely increased. The abnormally increased levels of VDR were found to be colocalized with A beta plaques, gliosis and autophagosomes, implicating a non-genomic activation of VDR in AD pathogenesis. Mechanistic investigation revealed that A beta upregulated VDR without its canonical ligand vitamin D and switched its heterodimer binding-partner from RXR to p53. The VDR/p53 complex localized mostly in the cytosol, increased neuronal autophagy and apoptosis. Chemically inhibiting p53 switched VDR back to RXR, reversing amyloidosis and cognitive impairment in AD mice. These results suggest a non-genomic rewiring of VDR to p53 is key for the progression of AD, and thus VDR/p53 pathway might be targeted to treat people with AD.

关键词： Alzheimer's disease autophagy non-genomic vitamin D receptor p53 vitamin D

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Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations

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NATURE METABOLISM 2025年 1-10页

作者： Chang, Hsuan-Chia Tsai, Chung-Ying Hsu, Cheng-Lung Tai, Tzong-Shyuan Cheng, Mei-Ling Chuang, Yu-Ming Tang, Hsiang-Yu Lin, Kun-Ju Chen, Jia-Jin Chang, Szu-Han Ko, Yi-Ching Chi, Yu-Wen Liu, Hsuan Tan, Bertrand Chin-Ming Shen, Chia-Rui Yang, Chih-Wei Ho, Ping-Chih Yang, Huang-Yu Chang Gung Univ Grad Inst Biomed Sci Coll Med Taoyuan Taiwan Chang Gung Univ Chang Gung Mem Hosp Coll Med Kidney Res Ctr Taoyuan Taiwan Chang Gung Univ Chang Gung Mem Hosp Coll Med Dept Nephrol Taoyuan Taiwan Chang Gung Univ Chang Gung Mem Hosp Dept Internal Med Div Hematol Oncol Taoyuan Taiwan Chang Gung Univ Sch Med Taoyuan Taiwan Chang Gung Mem Hosp Adv Immunol Lab Taoyuan Taiwan Chang Gung Univ Coll Med Dept Biomed Sci Taoyuan Taiwan Chang Gung Mem Hosp Clin Metabol Core Lab Taoyuan Taiwan Chang Gung Univ Hlth Aging Res Ctr Metabol Core Lab Taoyuan Taiwan Univ Lausanne Dept Oncol Lausanne Switzerland Univ Lausanne Ludwig Inst Canc Res Epalinges Switzerland Chang Gung Univ Coll Med Hlth Aging Res Ctr Dept Med Imaging & Radiol Sci Taoyuan Taiwan Chang Gung Mem Hosp Dept Nucl Med Taoyuan Taiwan Chang Gung Mem Hosp Mol Imaging Ctr Taoyuan Taiwan Chang Gung Univ Mol Med Res Ctr Taoyuan Taiwan Chang Gung Univ Coll Med Dept Cell & Mol Biol Taoyuan Taiwan Chang Gung Mem Hosp Lin Kou Med Ctr Div Colon & Rectal Surg Taoyuan Taiwan Chang Gung Univ Res Ctr Emerging Viral Infect Taoyuan Taiwan Chang Gung Mem Hosp Lin Kou Med Ctr Dept Neurosurg Taoyuan Taiwan Chang Gung Univ Coll Med PhD Program Biotechnol Ind Taoyuan Taiwan Chang Gung Univ Ctr Mol & Clin Immunol Taoyuan Taiwan Linkou Chang Gung Mem Hosp Dept Ophthalmol Taoyuan Taiwan Johns Hopkins Bloomberg Sch Publ Hlth Dept Hlth Policy & Management Baltimore MD USA

Preclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of l-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The use of l-asparaginase notably enhances immune-checkpoint blockade therapy in patients by strengthening CD8+T cell fitness. Our study shows that this combination is a promising avenue for clinical application and provides further mechanistic insight into how asparagine restriction rewires T cell metabolism.

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Disturbed Gastrointestinal Contractility in a Polycystic Ovary Syndrome Rat Model

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DIGESTIVE DISEASES AND SCIENCES 2020年第10期65卷 2834-2843页

作者： Wang, Kai-Lee Hsia, Shih-Min Wang, Paulus S. Lin, Po-Han Ching Kuo Inst Management & Hlth Dept Nursing 336 Fuxsin Rd Keelung 20301 Taiwan Natl Yang Ming Univ Sch Med Dept Physiol Taipei Taiwan Taipei Med Univ Sch Nutr & Hlth Sci Taipei 11031 Taiwan Taipei Vet Gen Hosp Dept Med Res & Educ Taipei Taiwan China Med Univ Coll Med PhD Program Aging Taichung Taiwan Asia Univ Dept Biotechnol Taichung Taiwan

Background Polycystic ovary syndrome (PCOS), a common hormonal disorder in women, affects 4-18% of women of reproductive age worldwide. A higher prevalence of irritable bowel syndrome was found in women with PCOS. However, the effects and mechanism of PCOS on stomach and colon contractility remain unclear. Aims This study aims to evaluate the correlation between PCOS and gastrointestinal disorder. Methods Four-week-old female rats were subcutaneously implanted with pellets containing 7.5 mg of dihydrotestosterone for 13 weeks to create PCOS rat models. After vaginal smears, the estrus cycle stage was evaluated. Oral glucose tolerance test was performed after 90 days of treatment. All animals were killed at 17 weeks. The rats were fasted overnight and then anesthetized before decapitation, and the stomach fundus and colon were surgically removed and cultured in oxygenated Krebs solution. Acetylcholine and carbachol were used to evaluate the cholinergic system on contractility. Results The basal and stomach fundus responded with a reduced frequency and contractility in response to acetylcholine in the PCOS group. Moreover, no difference was found in the spontaneous stomach contractility induced by carbachol in both groups. Lower maximal colon muscle contractility was also found in response to acetylcholine stimulation in PCOS rats. Furthermore, lower maximal muscle contractility was found in response to extracellular calcium levels. MLC20 phosphorylation was also reduced in the gastrointestinal tissue in PCOS rats. Conclusions PCOS induces gastroparesis and reduces gastrointestinal muscle contractility. This effect is, at least partly, through reducing the responsiveness of acetylcholine and MLC20 phosphorylation.

关键词： Polycystic ovary syndrome Gastrointestinal contraction Acetylcholine Carbachol Muscle contractility

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Reduced mortality with antimicrobial stewardship guided by BioFire FilmArray Blood Culture Identification 2 panel in critically ill patients with bloodstream infection: A retrospective propensity score-matched study

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INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS 2024年第4期64卷 107300-107300页

作者： Tseng, How-Yang Chen, Chieh-Lung Chen, Wei-Cheng Kuo, Yu-Chu Liang, Shinn-Jye Tu, Chih-Yen Lin, Yu-Chao Hsueh, Po-Ren China Med Univ China Med Univ Hosp Dept Internal Med Div Pulm & Crit Care Med Taichung Taiwan China Med Univ Sch Chinese Med Taichung Taiwan China Med Univ Grad Inst Biomed Sci Taichung Taiwan China Med Univ Coll Med Sch Med Taichung Taiwan China Med Univ Hosp Dept Educ Taichung Taiwan China Med Univ China Med Univ Hosp Dept Lab Med Taichung Taiwan China Med Univ China Med Univ Hosp Dept Internal Med Taichung Taiwan China Med Univ Sch Med PhD Program Aging Taichung Taiwan China Med Univ Sch Med Dept Lab Med Taichung Taiwan

Objectives: To investigate whether using the BioFire (R) FilmArray (R) Blood Culture Identification 2 panel (BCID2) leads to timely antimicrobial therapy and improves patient outcomes in critically ill patients with bloodstream infections (BSIs). Methods: This retrospective observational study included patients with BSIs admitted to the intensive care unit from July 1, 2021, to August 31, 2023. Patients were divided into groups receiving appropriate or inappropriate antimicrobial therapy. Those receiving inappropriate therapy underwent adjustments using standard-of-care (SOC) testing or BCID2. Propensity score matching (PSM) was performed on the original cohort (Model 1) and a time-window bias-adjusted cohort (Model 2). Clinical impact of BCID2-guided antimicrobial adjustment was analysed in both models. Results: A total of 181 patients received inappropriate antimicrobial therapy, with 33 undergoing BCID2 testing and 148 undergoing SOC testing. Following PSM and time-window bias adjustment, 66 patients were analysed in Model 1 and 46 patients in Model 2. BCID2 significantly reduced the median time to appropriate antimicrobial therapy (40.8 vs. 74.0 h in Model 1;42.8 vs. 68.9 h in Model 2) and the day-28 mortality rate (27.8% vs. 77.1%, P < 0.001 in Model 1;23.5% vs. 58.6%, P = 0.021 in Model 2). In multivariate regression analysis, BCID2-guided antimicrobial adjustment was an independent prognostic factor for day-28 mortality (adjusted odds ratio [aOR] 0.07 in Model 1 and aOR 0.12 in Model 2). Conclusion: BCID2-guided antimicrobial stewardship was associated with a shorter time to appropriate antimicrobial therapy and reduced day-28 mortality in critically ill patients with BSIs receiving inappropriate antimicrobial therapy. (c) 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Antimicrobial stewardship Bloodstream infection Critically ill Intensive care unit Multiplex polymerase chain reaction Outcomes

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Associations of Plasma Folate and Vitamin B6 With Blood DNA Methylation Age: An Analysis of One-Carbon Metabolites in the VA Normative aging Study

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JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES 2021年第5期76卷 760-769页

作者： Nwanaji-Enwerem, Jamaji C. Colicino, Elena Gao, Xu Wang, Cuicui Vokonas, Pantel Boyer, Edward W. Baccarelli, Andrea A. Schwartz, Joel Harvard TH Chan Sch Publ Hlth Dept Environm Hlth Boston MA USA Harvard Med Sch MD PhD Program Boston MA 02115 USA Icahn Sch Med Mt Sinai Dept Environm Med & Publ Hlth New York NY 10029 USA Columbia Mailman Sch Publ Hlth Dept Environm Hlth Sci New York NY USA Vet Affairs Boston Healthcare Syst VA Normat Aging Study Boston MA USA Boston Univ Sch Med Dept Med Boston MA 02118 USA Harvard Med Sch Brigham & Womens Hosp Dept Emergency Med Div Med Toxicol Boston MA 02115 USA

One-carbon metabolism is an important contributor to aging-related diseases;nevertheless, relationships of one-carbon metabolites with novel DNA methylation-based measures of biological aging remain poorly characterized. We examined relationships of one-carbon metabolites with 3 DNA methylation-based measures of biological aging: DNAm Age, Grim Age, and Pheno Age. We measured plasma levels of 4 common one-carbon metabolites (vitamin B-6 vitamin B-12, folate, and homocysteine) in 715 VA Normative aging Study participants with at least 1 visit between 1999 and 2008 (observations = 1153). DNA methylation age metrics were calculated using the Human Methylation 450 Bead Chip. We utilized Bayesian Kernel Machine Regression models adjusted for chronological age, lifestyle factors, age-related diseases, and study visits to determine metabolites important to the aging outcomes. Bayesian Kernel Machine Regression models allowed for the estimation of the relationships of single metabolites and the cumulative metabolite mixture with methylation age. Log vitamin B(6 )was selected as important to PhenoAge (beta = -1.62 years, 95% CI: -2.28, -0.96). Log folate was selected as important to GrimAge (beta = 0.75 years, 95% CI: 0.41, 1.09) and PhenoAge (beta = 1.62 years, 95% CI: 0.95, 2.29). Compared to a model where each metabolite in the mixture is set to its 50th percentile, the log cumulative mixture with each metabolite at its 30th (beta = -0.13 years, 95% CI: -0.26, -0.005) and 40th percentile (beta = -0.06 years, 95% CI: -0.11, -0.005) was associated with decreased GrimAge. Our results provide novel characterizations of the relationships between one-carbon metabolites and DNA methylation age in a human population study. Further research is required to confirm these findings and establish their generalizability.

关键词： DNA methylation age Epigenetic clock Folate One-carbon metabolism Vitamin B-6

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Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

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NEURON 2024年第23期112卷 3877-3896.e8页

作者： Carling, Gillian K. Fan, Li Foxe, Nessa R. Norman, Kendra Wong, Man Ying Zhu, Daphne Corona, Carlo Razzoli, Agnese Yu, Fangmin Yarahmady, Allan Ye, Pearly Chen, Hao Huang, Yige Amin, Sadaf Sereda, Rebecca Lopez-Lee, Chloe Zacharioudakis, Emmanouil Chen, Xiaoying Xu, Jielin Cheng, Feixiong Gavathiotis, Evripidis Cuervo, Ana Maria Holtzman, David M. Mok, Sue-Ann Sinha, Subhash C. Sidoli, Simone Ratan, Rajiv R. Luo, Wenjie Gong, Shiaoching Gan, Li Weill Cornell Med Helen & Robert Appel Alzheimers Dis Inst Feil Family Brain & Mind Res Inst New York NY 10065 USA Weill Cornell Med Neurosci Grad Program New York NY 10065 USA Weill Cornell Med Burke Neurol Inst White Plains NY 10605 USA Azienda USL IRCCS Reggio Emilia Transfus Med Unit I-42122 Reggio Emilia Italy Univ Modena & Reggio Emilia Clin & Expt PhD Program I-41121 Modena Italy Univ Alberta Dept Biochem Edmonton AB T6G 2H7 Canada Weill Cornell Med Cell Biol Dev Biol & Mol Biol Grad Program Biochem Struct Biol New York NY 10065 USA Inst Aging Res Albert Einstein Coll Med Dept Dev & Mol Biol New York NY 10461 USA Inst Aging Res Albert Einstein Coll Med Montefiore Einstein Comprehens Canc Ctr Dept BiochemDept Med New York NY 10461 USA Washington Univ Hope Ctr Neurol Disorders Knight Alzheimers Dis Res Ctr Dept NeurolSch Med St Louis MO 63110 USA Cleveland Clin Genome Ctr Cleveland OH 44106 USA Cleveland Clin Genom Med Inst Lerner Res Inst Cleveland OH 44106 USA

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the epsilon 4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H ( R47H ) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9-to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H ( APOE4-R47H ) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)stimulator of interferon genes (STING) signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

关键词： Alzheimer’s disease APOE TREM2 R47H tau microglia inflammation interferon cGAS senescence

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IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury

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JOURNAL OF NEUROINFLAMMATION 2023年第1期20卷 248-248页

作者： Vincent, Jonathan C. Garnett, Colleen N. Watson, James B. Higgins, Emma K. Macheda, Teresa Sanders, Lydia Roberts, Kelly N. Shahidehpour, Ryan K. Blalock, Eric M. Qaun, Ning Bachstetter, Adam D. Univ Kentucky Dept Neurosci 741 S Limestone St Lexington KY 40536 USA Univ Kentucky Spinal Cord & Brain Injury Res Ctr Lexington KY USA Univ Kentucky Sanders Brown Ctr Aging Lexington KY USA Univ Kentucky MD PhD Program Lexington KY USA Univ Alabama Birmingham Dept Cell Dev & Integrat Biol Birmingham AL USA Univ Kentucky Dept Pharmacol & Nutr Sci Lexington KY USA Florida Atlantic Univ Charles E Schmidt Coll Med Dept Biomed Sci Jupiter FL USA Florida Atlantic Univ Brain Inst Jupiter FL USA

Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood-brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, Ncorpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnf alpha. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health.

关键词： Neuroinflammation Interleukin-1 Interleukin-1 receptor-1 Astrocyte Microglia Traumatic brain injury

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Aspalathin-rich unfermented Aspalathus linearsis extract mitigates vascular endothelial inflammation by inhibiting the TNF-α/Hexokinase 2/NF-κB signaling pathway

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JOURNAL OF AGRICULTURE AND FOOD RESEARCH 2025年 21卷

作者： Wang, Ya-Pei Wang, Bi-Juan Lu, Hsin-Ying Muller, Christo J. F. Kuo, Ying-Yu Huo, Chieh Lai, Chih-Jen Huang, Shih-Han Joubert, Elizabeth Chuu, Chih-Pin Natl Hlth Res Inst Inst Cellular & Syst Med 35 Keyan Rd Zhunan 350 Miaoli Taiwan Taipei Med Univ Coll Med Sch Med Dept Surg Taipei City 11031 Taiwan Taipei Med Univ Wan Fang Hosp Dept Surg Div Cardiovasc Surg Taipei City 11031 Taiwan South African Med Res Council Biomed Res & Innovat Platform BRIP ZA-7505 Tygerberg South Africa Stellenbosch Univ Fac Med & Hlth Sci Ctr Cardiometab Res Afr CARMA Div Med Physiol ZA-7505 Tygerberg South Africa Univ Zululand Dept Biochem & Microbiol ZA-3886 Kwa Dlangezwa South Africa Natl Sun Yat Sen Univ Inst BioPharmaceut Sci Kaohsiung 80424 Taiwan Agr Res Council ARC Plant Bioact Grp Postharvest & Agroproc Technol Infruitec Nietvoorbij ZA-7599 Stellenbosch South Africa Stellenbosch Univ Dept Food Sci ZA-7599 Stellenbosch South Africa China Med Univ PhD Program Aging Taichung 40402 Taiwan China Med Univ Grad Inst Basic Med Sci Taichung 40402 Taiwan Natl Chung Hsing Univ Biotechnol Ctr Taichung 40227 Taiwan Natl Cent Univ Dept Life Sci Taoyuan City 32001 Taiwan

Inflammation of vascular endothelium initiates cardiovascular diseases. We investigated if unfermented green Aspalathus linearis (rooibos) extract (GRT) and its main flavonoid aspalathin may suppress inflammation in cardiovascular endothelial cells. Human coronary artery endothelial cells (HCAEC) and human umbilical vein endothelial cells (HUVEC) were used as cell models, while beta-aminopropionitrile (BAPN)-induced inflammation in mice was used as animal models. Tube formation assay, transwell migration assay, wound healing assay and monolayer permeability assay were used to examine the inflammatory effects on vascular endothelial cells, while cytokine array, qRT-PCR, ELISA, reporter gene assay, fluorescent microscopy, western blot, IHC staining and Seahorse mitochondrial analyzer were used to dissect the molecular mechanisms lying underneath. TNF-alpha decreased angiogenesis and VE-cadherin expression but increased cellular migration, monolayer permeability, secretion of inflammation cytokines IL-6 and IL-8, as well as NF-kappa B activity in HCAEC and HUVEC cells. Treatment with GRT or aspalathin reversed these TNF-alpha-induced inflammatory effects. We discovered that hexokinase 2 (HK2) was essential in regulation of TNF-alpha-induced inflammation in vascular endothelial cells, but was inhibited by GRT or aspalathin. Overexpression of HK2 induced NF-kappa B phosphorylation, activity and inflammatory effects. However, these phenomenon was repressed by GRT, aspalathin or HK2 knockdown. GRT or aspalathin reversed the TNF-alpha-enhanced interaction between HK2 and YB-1, vimentin or drebrin. Gavage of GRT repressed the expression of IL-6 and HK-2 in aortic tissues in BAPN-induced inflammation murine model. Our study demonstrated that GRT or aspalathin can suppress the TNF-alpha-induced inflammation in human vascular endothelial cells via inhibition of TNF-alpha/HK2/NF-kappa B signaling axis.

关键词： Aspalathus linearis Aspalathin Vascular endothelial cells NF-kappa B HK2 Inflammation

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