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Wendling AL, Ribeiro MGC, Kravchychyn ACP, Hermsdorff HHM. Effect of Nut Consumption on Human Gene Expression: A Systematic Review of Clinical Trials. Nutr Rev 2025; 83:1198-1213. [PMID: 40327757 DOI: 10.1093/nutrit/nuaf023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/08/2025] Open
Abstract
CONTEXT The consumption of nuts has beneficial effects on cardiovascular health, body composition, cognitive functions, the intestinal microbiota, and satiety control, but how nuts and their nutrients impact related gene expression is unclear. OBJECTIVE We analyzed the effects of nut consumption on human gene expression as investigated in controlled clinical trials. DATA SOURCES This systematic review was conducted according to the PRISMA guidelines. The databases used in the search were MEDLINE/PubMed, Embase, and the Cochrane Library. DATA EXTRACTION Randomized and nonrandomized controlled trials conducted to date that evaluated the effect of nut consumption on the mRNA expression of human genes were evaluated according to eligible criteria. Two authors screened and determined the quality of the studies; disagreements were resolved by the third author between May and June 2024. All authors were involved in analyzing the compiled data. DATA ANALYSIS We selected 13 original articles. Most studies evaluated the effects of Brazil nuts, followed by studies using combinations of two or more nuts, with an interventional duration of six weeks to one year. The consumption of hazelnuts and Brazil nuts increased expression in antioxidant-related genes, while beneficial regulation of proinflammatory pathways (tumor necrosis factor - TNF, interleukin-6 - IL-6, and toll-like receptors 2 and 4 - TLR2 and TLR4) was reported after consumption of Brazil nuts. Genes involved in vascular inflammation (eg, ciclooxygenase-2 - COX-2) were downregulated after the consumption of mixed nuts, and the expression of selenoprotein - SELENOP and glutathione peroxidase 1 - GPX1 were regulated according to the presence of single nucleotide polymorphisms after the consumption of Brazil nuts. Finally, pistachio consumption reduced telomere oxidation (telomerase reverse transcriptase - TERT and WD repeat containing antisense to TP53 - WRAP53) and downregulated resistin and IL-6 genes. CONCLUSION The consumption of nuts has beneficial effects on human health, modulating gene expression involved in the progression of chronic diseases, with emphasis on the pathways of inflammation, oxidative stress, and cardiovascular health. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration No. CRD42024505199.
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Affiliation(s)
- Aline Lage Wendling
- Laboratory of Clinical Analysis and Genomics, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
- Laboratory of Energy Metabolism and Body Composition, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
| | - Madalena Geralda Cupertino Ribeiro
- Laboratory of Clinical Analysis and Genomics, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
- Laboratory of Energy Metabolism and Body Composition, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
| | - Ana Claudia Pelissari Kravchychyn
- Laboratory of Clinical Analysis and Genomics, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
- Laboratory of Energy Metabolism and Body Composition, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
| | - Helen Hermana Miranda Hermsdorff
- Laboratory of Clinical Analysis and Genomics, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
- Laboratory of Energy Metabolism and Body Composition, Universidade Federal de Viçosa, Viçosa, Minas Gerais 36570-900, Brazil
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Zhu C, Xu W, Yang J. Causal validation between 179 lipids and hyperparathyroidism: A bidirectional Mendelian randomization combined meta-analysis with mediation factors. Medicine (Baltimore) 2025; 104:e42580. [PMID: 40489840 DOI: 10.1097/md.0000000000042580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/11/2025] Open
Abstract
Hyperparathyroidism, an endocrine disorder linked to hypercalcemia, increases with age, particularly in those over 60. Abnormal lipid metabolism may be closely related to its occurrence and progression. The study used Mendelian randomization (MR) analysis on 179 lipid traits against hyperparathyroidism in the Finngen and UK Biobank (UKB) databases. Meta-analysis of inverse variance weighted results followed, with significance P-values corrected for multiple comparisons. Causal validation was performed between positive lipids and renal failure, and MR analysis examined the link between renal failure and hyperparathyroidism. Reverse causal validation was also conducted between lipids and hyperparathyroidism, positive lipids and renal failure, and renal failure and hyperparathyroidism. The study conducted causal validation between 179 lipid traits and hyperparathyroidism, also exploring intermediary factors. Ultimately, MR analysis was performed on triacylglycerol (52:3) levels with hyperparathyroidism in both Finngen and UKB databases, followed by meta-analysis and multiple corrections. The results showed an odds ratio (OR) of 1.147 (95% confidence interval [CI]: 1.065-1.235, P = .040). The MR results for triacylglycerol (52:3) levels and renal failure indicated an OR of 1.054 (95% CI: 1.004-1.106, P = .032). For the intermediary factor renal failure, MR analysis with hyperparathyroidism in both Finngen and UKB databases followed by meta-analysis showed an OR of 1.336 (95% CI: 1.193-1.495, P = 4.78 × 10-7). Notably, no significant associations were found in the reverse validation of each analysis process. Furthermore, the mediation effect was β12 = 0.0153, and the direct effect was β3 = 0.1207 (0.1183, 0.1230). The mediation effect accounted for 11.25%, while the direct effect accounted for 88.75% of the total effect, Z = 12.5, indicating that the direct effect predominantly influences the overall impact. The research shows that triacylglycerol (52:3) levels can directly increase the risk of hyperparathyroidism. It also raises the risk indirectly by increasing the likelihood of renal failure, an intermediary factor. About one-tenth of the lipid's effect on hyperparathyroidism is mediated through renal failure, while the direct effect constitutes roughly nine-tenths of the total effect.
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Affiliation(s)
- Chongyang Zhu
- Eastern Michigan Joint College of Engineering, Beibu Gulf University, Guangxi, China
| | - Wanxian Xu
- Department of Breast and Thyroid Surgery, First People's Hospital of Kunming City & Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Jingze Yang
- Department of Breast and Thyroid Surgery, First People's Hospital of Kunming City & Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
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Hang L, Zhang Y, Zhang Z, Jiang H, Xia L. Metabolism Serves as a Bridge Between Cardiomyocytes and Immune Cells in Cardiovascular Diseases. Cardiovasc Drugs Ther 2025; 39:661-676. [PMID: 38236378 DOI: 10.1007/s10557-024-07545-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/06/2023] [Indexed: 01/19/2024]
Abstract
Metabolic disorders of cardiomyocytes play an important role in the progression of various cardiovascular diseases. Metabolic reprogramming can provide ATP to cardiomyocytes and protect them during diseases, but this transformation also leads to adverse consequences such as oxidative stress, mitochondrial dysfunction, and eventually aggravates myocardial injury. Moreover, abnormal accumulation of metabolites induced by metabolic reprogramming of cardiomyocytes alters the cardiac microenvironment and affects the metabolism of immune cells. Immunometabolism, as a research hotspot, is involved in regulating the phenotype and function of immune cells. After myocardial injury, both cardiac resident immune cells and heart-infiltrating immune cells significantly contribute to the inflammation, repair and remodeling of the heart. In addition, metabolites generated by the metabolic reprogramming of immune cells can further affect the microenvironment, thereby affecting the function of cardiomyocytes and other immune cells. Therefore, metabolic reprogramming and abnormal metabolite levels may serve as a bridge between cardiomyocytes and immune cells, leading to the development of cardiovascular diseases. Herein, we summarize the metabolic relationship between cardiomyocytes and immune cells in cardiovascular diseases, and the effect on cardiac injury, which could be therapeutic strategy for cardiovascular diseases, especially in drug research.
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Affiliation(s)
- Lixiao Hang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Zhenjiang, 212001, China
- International Genome Center, Jiangsu University, Zhenjiang, 212013, China
| | - Ying Zhang
- Department of Biochemistry and Molecular Biology, School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Zheng Zhang
- International Genome Center, Jiangsu University, Zhenjiang, 212013, China
| | - Haiqiang Jiang
- Department of Laboratory Medicine, Jiangyin Hospital of Traditional Chinese Medicine, No.130 Renmin Middle Road, Wuxi, 214400, Jiangyin, China.
| | - Lin Xia
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, No. 438 Jiefang Road, Zhenjiang, 212001, China.
- Institute of Hematological Disease, Jiangsu University, Zhenjiang, 212001, China.
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Huang L, Zhang F, Wang Y, Wu J, Wang R, Wei S, Li X, Xu N, Wang Y, Li Y. Functional metabolomics combined with network pharmacology reveals the mechanism of alleviating rheumatoid arthritis with Yiyi Fuzi powder. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119842. [PMID: 40268109 DOI: 10.1016/j.jep.2025.119842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/07/2025] [Accepted: 04/18/2025] [Indexed: 04/25/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yiyi Fuzi powder (YYFZ) is a composite formulation consisting of Fuzi and Coix lacryma-jobi seeds. The synergistic application of these exhibits notable anti-inflammatory properties, playing a crucial role in the management of rheumatoid arthritis (RA). However, the therapeutic advantages and potential mechanism of YYFZ in the treatment of RA are still unclear. AIM OF THE STUDY The purpose of this study is to find functional metabolites by metabolomics technology, and to investigate the mechanism of functional metabolites mediating RA inflammation on the basis of collagen-induced arthritis rat fibroblast-like synovial cells (CIA-FLS) model, and to explore the pharmacodynamic material basis of YYFZ. MATERIALS AND METHODS Utilizing untargeted metabolomics in conjunction with UPLC-Q-TOF/MS and GC-MS, we identified potential functional metabolites of YYFZ. In vitro experiments were conducted to determine pyroptosis-related proteins via Western blot, q-PCR and immunofluorescence, thereby exploring functional metabolic pathways. Subsequently, network pharmacology and molecular docking techniques were employed to evaluate the mode of action and mechanisms of "effective components-key targets", elucidating the active components of YYFZ. RESULTS Using untargeted metabolomics, 18 differential metabolites were identified, with palmitic acid (PA) showing high correlation as a potential functional metabolite. MTT experiments revealed that 300 μM PA inhibited CIA-FLS by 50%. Further analysis through in vitro experiments indicated that PA promotes inflammatory factor expression via NLRP3/Caspase-1/GSDMD-N/IL-1β mediated pyroptosis. Network pharmacology and molecular docking of 26 in vitro YYFZ components identified benzoylaconine (BAC), benzoylmesaconine (BMA) and benzoylhypacoitine (BHA) as potential active components. In vitro experiments revealed that these components reduce RA inflammation by targeting pyroptosis. CONCLUSION PA, a functional metabolite, can promote RA inflammatory factors by inducing pyroptosis of NLRP3/Caspase1/GSDMD-N/IL-1β. BAC, BMA and BHA derived from YYFZ have demonstrated efficacy in mitigating the inflammatory damage induced by the functional metabolite PA, suggesting their potential as therapeutic agents for RA. These findings offer valuable insights for the development of targeted therapies for RA and underscore the clinical applicability of YYFZ.
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Affiliation(s)
- Liping Huang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Fangfang Zhang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yuyu Wang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Junke Wu
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Rui Wang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Shuang Wei
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xinyu Li
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Nanjian Xu
- Department of Spine Surgery, No.6 Hospital in Ningbo, Ningbo city, 315040, China.
| | - Yuming Wang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Yubo Li
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
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Zhang C, Simón M, Harder JM, Lim H, Montgomery C, Wang Q, John SWM. TLR4 deficiency does not alter glaucomatous progression in a mouse model of chronic glaucoma. Sci Rep 2025; 15:16852. [PMID: 40374644 PMCID: PMC12081889 DOI: 10.1038/s41598-025-00638-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 04/29/2025] [Indexed: 05/17/2025] Open
Abstract
Glaucoma is a leading cause of irreversible blindness worldwide. Toll-like receptor 4 (TLR4) is a pattern-recognition transmembrane receptor that induces neuroinflammatory processes in response to injury. Tlr4 is highly expressed in ocular tissues and is known to modulate inflammatory processes in both anterior and posterior segment tissues. TLR4 activation can lead to mitochondrial dysfunction and metabolic deficits in inflammatory disorders. Due to its effects on inflammation and metabolism, TLR4 is a candidate to participate in glaucoma pathogenesis. It has been suggested as a therapeutic target based on studies using acute models, such as experimentally raising IOP to ischemia-inducing levels. Nevertheless, its role in chronic glaucoma needs further evaluation. In the current study, we investigated the role of TLR4 in an inherited mouse model of chronic glaucoma, DBA/2J. To do this, we analyzed the effect of Tlr4 knockout (Tlr4-/-) on glaucoma in DBA/2J mice. Our studies found no significant differences in intraocular pressure, iris disease, or glaucomatous progression in Tlr4-/- compared to Tlr4+/+ DBA/2J mice. Our data do not support a role for TLR4 as a treatment target in chronic glaucoma.
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Affiliation(s)
- Chi Zhang
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
| | - Marina Simón
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
| | | | - Haeyn Lim
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
| | - Christa Montgomery
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
| | - Qing Wang
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
| | - Simon W M John
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.
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Hernandez-Reyes M, Oo TT. From receptor to response: dissecting the TLR4 pathway in diabetic neuropathy. Inflammopharmacology 2025:10.1007/s10787-025-01774-2. [PMID: 40347407 DOI: 10.1007/s10787-025-01774-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Accepted: 04/24/2025] [Indexed: 05/12/2025]
Abstract
Diabetic neuropathy (DNP) is a common complication of diabetes that has a significant impact on the patient's quality of life. The primary objectives of clinical treatment for DNP these days are symptomatic pain management and glycemic control. Since there is currently no cure for nerve damage, the only objective is to alleviate discomfort and slow its progression. Pre-clinical research over the last decade has increasingly linked toll-like receptor 4 (TLR4)-mediated neuroinflammation as a major contributor to DNP development. The role of TLR4-mediated neuroinflammation in the pathophysiology of DNP is covered in this review, along with different therapeutic approaches that target TLR4-mediated neuroinflammation in DNP in pre-clinical research. Despite promising pre-clinical results, translating these findings into clinical practice remains a challenge, which we also discuss how to address and overcome in this review.
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Affiliation(s)
- Monserrat Hernandez-Reyes
- College of Advanced Studies Cuautitlan, National Autonomous University of Mexico, 54740, Cuautitlan Izcalli, State of Mexico, Mexico
| | - Thura Tun Oo
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, 53792, USA.
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Dong Z, Zhang S, Zhang H, Zhao D, Pan Z, Wang D. Untargeted metabolomics for acute intra-abdominal infection diagnosis in serum and urine using UHPLC-TripleTOF MS. Front Mol Biosci 2025; 12:1534102. [PMID: 40406622 PMCID: PMC12094940 DOI: 10.3389/fmolb.2025.1534102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 03/12/2025] [Indexed: 05/26/2025] Open
Abstract
Introduction Acute intra-abdominal infection (IAI) is a prevalent and life-threatening condition in general surgery, with significant implications for patient mortality. However, the timely identification of IAI is often hindered by the limitations of current medical laboratory sciences and imaging diagnostics. Methods To address this critical issue, we employed metabolomics to identify early biomarkers for IAI. In this study, we enrolled a cohort of 30 IAI patients and 20 healthy volunteers. Following preliminary experimental processing, all serum and urinary samples were subjected to ultrahigh performance liquid chromatography-triple time-of-flight mass spectrometry analysis. Initial metabolite profiling was conducted using total ion current chromatography and principal component analysis. Differential metabolites were subsequently identified through Student's t-test, partial least squares discriminant analysis, and support vector machine. Hierarchical clustering analysis was then applied to assess the discriminatory power of the selected metabolites. Based on receiver operating characteristic curve analysis, we identified the most promising biomarkers, which were further subjected to enrichment analysis. Additionally, we stratified patients according to the severity and etiology of IAI to explore potential differences among these subgroups. Results Our findings revealed five serum and two urinary metabolites as potential biomarkers for IAI. The serum biomarkers were associated with the Fatty Acid Biosynthesis pathway, while the urinary biomarkers were linked to the Catecholamine Biosynthesis pathway. Notably, no significant differences were observed among the three types of IAI or the seven etiologies studied. Discussion For individuals at risk of IAI, regular screening of these biomarkers could facilitate the early and convenient identification of the condition, thereby improving patient outcomes.
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Affiliation(s)
- Zhenhua Dong
- Gastric and Colorectal Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shaopeng Zhang
- Gastric and Colorectal Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongwei Zhang
- Gastric and Colorectal Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Dingliang Zhao
- Second Urology Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ziwen Pan
- Gastric and Colorectal Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Daguang Wang
- Gastric and Colorectal Surgery Department, The First Hospital of Jilin University, Changchun, Jilin, China
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Wang YX, Kang JQ, Chen ZG, Gao S, Zhao WX, Zhao N, Lan Y, Li YJ. Machine Learning Analysis of Nutrient Associations with Peripheral Arterial Disease: Insights from NHANES 1999-2004. Ann Vasc Surg 2025; 114:154-162. [PMID: 39892831 DOI: 10.1016/j.avsg.2024.12.077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/31/2024] [Accepted: 12/31/2024] [Indexed: 02/04/2025]
Abstract
BACKGROUND Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis, affecting over 200 million people worldwide. The incidence of PAD is increasing due to the aging population. Common risk factors include smoking, diabetes, and hyperlipidemia, but its exact pathogenesis remains unclear. Nutritional intake is associated with the onset and progression of PAD, although relevant studies remain limited. Some studies suggest that certain nutritional elements may influence the development of PAD. This study aims to explore the relationship between nutrition and PAD using machine learning techniques. Unlike traditional statistical methods, machine learning can effectively capture complex, nonlinear relationships, providing a more comprehensive analysis of PAD risk factor. METHODS Data from National Health and Nutrition Examination Survey (NHANES 1999-2004) were analyzed, including demographic, clinical, and dietary information. Nutrient intake was assessed through 24-h dietary recalls using computer-assisted dietary interview system (CADI) and automated multiple pass method (AMPM) methods. PAD was defined as an ankle-brachial index (ABI) < 0.9. Six ML models-extreme gradient boosting (XGBoost), random Forest (RF), naive bayes classifier (NB), support vector machine (SVM), logistic regression (LR), and decision tree (DT)-were trained on a 70/30 train-test split, with missing data imputed and sample imbalance addressed via synthetic minority oversampling technique (SMOTE). Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, specificity, precision, recall, and F1 score. Shapley additive explanations (SHAP) analysis was used to identify key features. In addition, to further enhance the interpretability of the model, we applied SHAP analysis to identify the features that have a significant impact on PAD prediction. This approach allowed us to determine the contribution of different variables to the model's output, providing deeper insights into how each feature influences the prediction of PAD outcomes. RESULTS Of 31,126 participants, 4,520 met the inclusion criteria (mean age 61.2 ± 13.5 years; 48.8% male), and 441 (9.7%) had ABI < 0.9. XGBoost outperformed other models, achieving an AUROC of 0.913 (95% CI, 0.891-0.936) and F1 score of 0.932. With SMOTE, its AUROC improved to 0.926 (95% CI, 0.889-0.936) and F1 score to 0.937. SHAP analysis identified vitamin C, saturated fatty acids, selenium, phosphorus, and protein intake as key predictors of PAD. CONCLUSION This is the first study to apply ML algorithms to examine nutrient intake and PAD in a general population. Vitamin C and phosphorus showed negative correlations with PAD, while saturated fatty acids, protein, and selenium exhibited positive associations.
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Affiliation(s)
- Yi-Xuan Wang
- Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China; Peking University Fifth School of Clinical Medicine, Beijing, China
| | - Jin-Quan Kang
- Beijing Information Science & Technology University, Beijing, China
| | - Zuo-Guan Chen
- Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Shang Gao
- Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Wen-Xin Zhao
- Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ning Zhao
- Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yong Lan
- Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yong-Jun Li
- Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
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Jia F, Wang Y, Chen Z, Jin J, Zeng L, Zhang L, Tang H, Wang Y, Fan P. 10-Hydroxydec-2-enoic acid reduces vascular smooth muscle cell inflammation via interacting with Toll-like receptor 4. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156534. [PMID: 40054182 DOI: 10.1016/j.phymed.2025.156534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 01/09/2025] [Accepted: 02/15/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND 10-Hydroxydec-2-enoic acid (10-HDA), a unique and marker compound in royal jelly, has a wide range of bio-activities. However, its role in regulating inflammation of vascular smooth muscle cell (VSMC), which is essential to a set of vascular diseases, is still unknown. PURPOSE Our study aimed to investigate whether 10-HDA exerts effect on VSMC inflammation via interacting with toll-like receptor 4 (TLR4), a pivotal inflammatory initiator. METHODS A package of proteins, which might participate in TLR4-mediated signaling, influenced by 10-HDA were analyzed in mouse VSMCs with Angiotensin Ⅱ(Ang Ⅱ) or lipopolysaccharide (LPS) stimulation. Accordingly, pro- or anti-inflammatory cytokines, reactive oxygen species (ROS), and anti-oxidants that are closely relevant to inflammatory process were determined. The possible mode for 10-HDA interacting with TLR4 was also characterized. Moreover, involvement of a key miRNA in 10-HDA regulating VSMC inflammation was identified. RESULTS In the presence of Ang Ⅱ, 10-HDA inhibited the TLR4 expression in a dose-dependent manner. In such occasion, 10-HDA hindered the up-regulation of specificity protein 1 (SP1) and serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C), the phosphorylation of extracellular signal-regulated kinase 1/2, TGF-β-activated kinase 1, and nuclear factor-κB p56, as well as the enhancement of myeloid differentiation primary response gene 88. Apart from SP1 and PPP6C, the level change of these proteins by 10-HDA was similar with LPS stimulation. The effect might be resulted from 10-HDA blocking TLR4 through multiple atomic interactions. 10-HDA mitigated the increase of pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-2 (IL-2), and IL-6, as well as increased the anti-inflammatory cytokine IL-10, in the Ang Ⅱ- or LPS-induced VSMCs. Correspondingly, the level of ROS was attenuated and the anti-oxidants such as glutathione and superoxide dismutase were fortified. The data indicated the anti-inflammatory potential of 10-HDA in VSMCs, which was associated with 10-HDA's capability of relieving oxidative stress. Additionally, the expression of miR-17-5p was saved by 10-HDA from Ang Ⅱ- or LPS-treated VSMCs, which might be relevant to SP1 and PPP6C targeting. CONCLUSION The present work of 10-HDA, for the first time, revealed its ability to alleviate VSMC inflammation by targeting TLR4 and therefore modulate the downstream inflammatory participants. Our data will cast light on the utilization of 10-HDA in VSMC inflammation-related vascular disorders.
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MESH Headings
- Toll-Like Receptor 4/metabolism
- Animals
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/metabolism
- Mice
- Lipopolysaccharides/pharmacology
- Inflammation/drug therapy
- Inflammation/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Reactive Oxygen Species/metabolism
- Cytokines/metabolism
- Angiotensin II/pharmacology
- Signal Transduction/drug effects
- Cells, Cultured
- Anti-Inflammatory Agents/pharmacology
- NF-kappa B/metabolism
- Fatty Acids, Monounsaturated
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Affiliation(s)
- Feng Jia
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Yongqing Wang
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Zhiqiang Chen
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Jingxian Jin
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Lei Zeng
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Li Zhang
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Huaijian Tang
- School of Food and Strategic Reserves, Henan University of Technology, Zhengzhou 450001, China
| | - Yanyan Wang
- School of Food and Strategic Reserves, Henan University of Technology, Zhengzhou 450001, China
| | - Pei Fan
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China.
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Zhang A, Zhang Z, Liu R, Zhao Z, Liu L. Human umbilical cord mesenchymal stem cell-derived exosomes inhibit inflammation and fibrotic scar formation after intracerebral hemorrhage. Mol Cell Biochem 2025:10.1007/s11010-025-05259-2. [PMID: 40279088 DOI: 10.1007/s11010-025-05259-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 03/16/2025] [Indexed: 04/26/2025]
Abstract
Human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-ex) have emerged as a promising alternative to whole-cell therapies due to their minimal immunogenicity and tumorigenicity. Pentraxin 3 (PTX3) acts as an inflammatory marker and pattern recognition receptor, playing a critical role in promoting tumor progression and inflammatory diseases. Fibrotic scars resulting from cerebral hemorrhage can impair motor and sensory functions, leading to poor prognosis. This study aimed to investigate whether hUCMSC-ex regulate matrix metalloproteinase-3 (MMP3) expression via the PTX3/Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway, thereby inhibiting inflammation and fibrotic scar formation following intracerebral hemorrhage and ultimately promoting the recovery of nerve function. A stereotactic technique was used to inject type IV collagenase (1 μL) into the striatum of rats, establishing an animal model of hemorrhagic stroke. Concurrently, hUCMSC-ex were administered via the tail vein at a dosage of 200 μg. In vitro, primary astrocytes were treated with hUCMSC-ex and subsequently stimulated with Hemin (20 μmol/mL) to create a cellular model of cerebral hemorrhage. The expression levels of PTX3, TLR4/NF-κB/MMP3 pathway proteins, and inflammatory factors, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-10 (IL-10), were assessed both in vivo and in vitro to investigate the effects of hUCMSC-ex on the inflammatory response and fibroblast migration. Neurological function in rats with cerebral hemorrhage was evaluated on days 1, 3, and 5 using the corner turn test, forelimb placement test, Longa score, and Bederson score. Additionally, real-time PCR was utilized to measure PTX3 mRNA expression following treatment with hUCMSC-ex. hUCMSC-ex inhibited MMP3 expression by downregulating the protein levels of PTX3, TLR4, NF-κB/P65, and p-P65. This action resulted in a reduction of pro-inflammatory cytokines TNF-α and IL-1β while simultaneously increasing the expression of the anti-inflammatory cytokine IL-10. Furthermore, hUCMSC-ex suppressed the inflammatory response, prevented fibroblast migration, and decreased MMP3 expression in the conditioned medium derived from primary astrocytes. Importantly, hUCMSC-ex improved behavioral performance in rats with intracerebral hemorrhage (ICH). hUCMSC-ex modulated the expression of MMP3 through the downregulation of PTX3, TLR4, NF-κB/P65, and p-P65. This regulatory mechanism contributed to a decrease in pro-inflammatory cytokines TNF-α and IL-1β, while concurrently enhancing the expression of the anti-inflammatory cytokine IL-10. Additionally, hUCMSC-ex effectively suppressed the inflammatory response, inhibited fibroblast migration, and reduced MMP3 expression in primary astrocyte-conditioned medium. Overall, hUCMSC-ex significantly improved behavioral performance in rats with ICH.
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Affiliation(s)
- Aobo Zhang
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Zhanzhan Zhang
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Rongge Liu
- Department of Respiratory, The Second Affiliated Hospital of Xingtai Medical College, Xingtai, 054000, China
| | - Zongmao Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Liqiang Liu
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.
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Abu-Amer W, Shorbaji K, Meade R, Pyeatte SR, Belaygorod L, Zaghloul MS, Hafezi S, Penrose A, Arif B, Wu SG, Semenkovich CF, Zayed MA. Serum cFAS Content Correlates with Incidence of Peripheral Arterial Disease. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.04.06.25325325. [PMID: 40297461 PMCID: PMC12036395 DOI: 10.1101/2025.04.06.25325325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Background No reliable serum diagnostic test currently exists for peripheral arterial disease (PAD). We previously observed that serum circulating Fatty Acid Synthase (cFAS) is elevated in individuals with chronic limb threatening ischemia (CLTI). Objectives We hypothesized that cFAS can be an independent diagnostic biomarker for PAD and CLTI. Methods Patients with/without PAD and CLTI were retrospectively reviewed. Total serum cFAS content was evaluated using ELISA and normalized to total protein. Patient demographics and PAD incidence were collected via chart review. Serum cFAS and demographics were compared, and regression analysis was used to determine the correlation between cFAS and PAD incidence, and the impact of co-morbidities on cFAS content. Results A total 347 patients met inclusion criteria. Of these, 34 were healthy controls without PAD (Group 1), 164 had PAD (Group 2), and 149 had CLTI (Group 3). Compared to Group 1, the remaining groups were significantly older, had more males, and had higher incidence of cardiovascular co-morbidities (p<0.001). Compared to Group 1, Groups 2 and 3 had significantly higher serum cFAS content (p=0.007). ROC analysis revealed an optimal cutoff of 340pg/mg protein for cFAS in distinguishing between individuals with or without PAD (p<0.001), and 490pg/mg protein in distinguishing between those with PAD and those with CLTI (p=0.015). Conclusions Our study demonstrates that cFAS is an independent serum-based diagnostic biomarker for PAD, can distinguish between patients with PAD versus CLTI, and may serve as a predictive variable for identifying patients with highest risk of disease progression. CONDENSED ABSTRACT There are currently no reliable serum biomarkers to aid in the diagnosis of peripheral arterial disease (PAD). We hypothesized that circulating Fatty Acid Synthase (cFAS) can be an independent diagnostic biomarker for PAD. Serum cFAS and demographics were compared for patients with and without PAD or CLTI. Patients with PAD or CLTI had significantly higher serum cFAS content. We observed optimal cutoffs for cFAS in distinguishing between individuals with and without PAD or CLTI. Our study demonstrates that cFAS is an independent serum-based diagnostic biomarker for PAD, can distinguish between patients with PAD versus CLTI, and may predict disease severity.
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12
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Li H, Zhang Y, Peh HY. Interferon regulatory factor 3 beyond innate immunity: Regulation in obesity and metabolic disorders. Semin Immunol 2025; 78:101948. [PMID: 40156960 DOI: 10.1016/j.smim.2025.101948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
Interferon regulatory factor 3 (IRF3) is a transcription factor known primarily for its role in antiviral immunity via regulation of type I interferons (IFNs). Recent research has broadened its significance to encompass metabolic disorders, particularly obesity and diabetes. Obesity is characterized by chronic low-grade inflammation, insulin resistance, and metabolic dysfunction, all of which are increasingly found to be associated with immune signaling pathways. IRF3 has emerged as an important regulator in the development of obesity and type 2 diabetes (T2D), predominantly through its regulation of inflammatory cytokines production in various cells in adipose tissue. In obese individuals, IRF3 is activated in the adipocytes and adipose tissue macrophages, to promote the expression of inflammatory cytokines, thereby contributing to chronic inflammation and exacerbating insulin resistance. Moreover, IRF3 has been linked to mitochondrial dysfunction in hepatic disorders, further amplifying metabolic stress and imbalances associated with obesity. The growing evidence suggests that IRF3 is an important mediator in both immune and metabolic pathways, highlighting its potential as a target for the development of therapeutic interventions for obesity-related inflammation and metabolic dysfunction.
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Affiliation(s)
- Heng Li
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore; NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore; NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore.
| | - Hong Yong Peh
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Singapore Lipidomics Incubator, Life Science Institute, National University of Singapore, Singapore 117456, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
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Sharma J, Dey P. Differential modulation of the hepatocellular metabolome, cytoprotective and inflammatory responses due to endotoxemia and lipotoxicity. Mol Omics 2025; 21:152-163. [PMID: 39744997 DOI: 10.1039/d4mo00140k] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2025]
Abstract
The present work aimed to examine the primary mechanisms of liver damage, namely the impact of gut-derived endotoxins along the gut-liver axis and adipose-derived free fatty acids along the adipose-liver axis. These processes are known to play a significant role in the development of hepatic inflammation and steatosis. Although possible overlapping in the pathogenesis was expected, these processes have unique pathophysiological consequences. Therefore, we used HepG2 cells as a model system to investigate the impact of lipopolysaccharides (LPS) and free fatty acid (FFA; albumin conjugated palmitic acid) on the intracellular metabolome. Although both LPS and FFA triggered the expression of nuclear factor κB (NFκB)-dependent inflammation, only LPS treatment was able to trigger a Toll-like receptor 4 (TLR4) dependent response. The intracellular cytoprotective enzymatic levels (catalase, peroxidase, glutathione) were increased due to FFA but lowered due to LPS. The free-radical neutralizing efficacies of cell-free metabolites of FFA-treated cells were better than those of the LPS-treated ones. The use of untargeted metabolomics allowed for the identification of distinct metabolic pathway enrichments, providing further insights into the differential effects of LPS and FFA on the metabolism of hepatocytes. Collectively, the current study highlights the distinct impacts of endotoxemia and lipotoxicity on the metabolome of hepatocytes, hence offering valuable insights into hepatocellular function.
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Affiliation(s)
- Jyoti Sharma
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, Punjab, India.
| | - Priyankar Dey
- Department of Biotechnology, Thapar Institute of Engineering and Technology, Patiala, Punjab, India.
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Hongzhao Z, Dawei Z, Bo Z, Xuesong Y, Huihan L, Qingzhi H, Longyu S. Application of the chocolate balloon (restrictive dilatation technique) in vascular preparation for arterial angioplasty of the lower limbs. Front Surg 2025; 12:1528231. [PMID: 40124529 PMCID: PMC11925876 DOI: 10.3389/fsurg.2025.1528231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 02/24/2025] [Indexed: 03/25/2025] Open
Abstract
Objective This study aims to compare the immediate clinical effects of the chocolate balloon and the conventional balloon in endovascular angioplasty of the lower limbs. Methods Clinical data were retrospectively collected from a single center, including 117 patients with lower limb arterial lesions treated from January to December 2021 and 112 patients treated from January to December 2023 at our center. The comparison focused on the incidence of vascular dissection after balloon dilatation, with secondary endpoints including the stent implantation rate. Results In both groups, the success rate was 100%. Dissection formation rates in the chocolate balloon and conventional balloon groups were 20.5% vs. 17.5%, respectively. Non-flow-limiting dissection formation rates were 14.7% vs. 4.8% (P < 0.05), while severe dissection rates were 5.8% vs. 12.7% (P < 0.05). Stent implantation rates were 9.0% in the chocolate balloon group and 18.3% in the conventional balloon group (P < 0.05). Conclusion The use of chocolate balloons resulted in a lower incidence of severe dissection and reduced the stent implantation rate compared to conventional balloons. It effectively prepares complex multiple lesions of lower limb arteries in real-world scenarios.
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Affiliation(s)
- Zhong Hongzhao
- The First Clinical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Zhang Dawei
- Department of Vascular Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Zhao Bo
- Department of Vascular Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yang Xuesong
- Department of Vascular Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Li Huihan
- Department of Vascular Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Hao Qingzhi
- Department of Vascular Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Song Longyu
- The First Clinical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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15
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Hadjisavva ME, Cooper RL. The Biphasic Effect of Lipopolysaccharide on Membrane Potential. MEMBRANES 2025; 15:74. [PMID: 40137026 PMCID: PMC11943570 DOI: 10.3390/membranes15030074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 03/27/2025]
Abstract
Lipopolysaccharide (LPS) from certain strains of Gram-negative bacteria can induce a rapid (<1 s) hyperpolarization of membrane potential, followed by a gradual depolarization exceeding the initial resting membrane potential. Through overexpression of a Drosophila ORK1 two-pore-domain K+ channel (K2P) in larval muscles and altering the external concentrations of K+ and Na+ ions, it is clear that the hyperpolarization is due to activating K2P channels and the depolarization is due to promoting an inward Na+ leak. When the external Na+ concentration is negligible, the LPS-delayed depolarization is dampened. The hyperpolarization induced by LPS can exceed -100 mV when external K+ and Na+ concentrations are lowered. These results indicate direct action by LPS on ion channels independently of immune responses. Such direct actions may need to be considered when developing clinical treatments for certain forms of bacterial septicemia.
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Affiliation(s)
| | - Robin L. Cooper
- Department of Biology, University of Kentucky, Lexington, KY 40506-0225, USA;
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16
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Campos-Bayardo TI, Román-Rojas D, García-Sánchez A, Cardona-Muñoz EG, Sánchez-Lozano DI, Totsuka-Sutto S, Gómez-Hermosillo LF, Casillas-Moreno J, Andrade-Sierra J, Pazarín-Villaseñor L, Campos-Pérez W, Martínez-López E, Miranda-Díaz AG. The Role of TLRs in Obesity and Its Related Metabolic Disorders. Int J Mol Sci 2025; 26:2229. [PMID: 40076851 PMCID: PMC11900219 DOI: 10.3390/ijms26052229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
Obesity affects the adaptability of adipose tissue (AT), impairing its ability to regulate energy and metabolism. Obesity is associated with many metabolic disorders, including dyslipidemia, hypertension, sleep disorders, non-alcoholic liver disease, and some types of cancer. Toll-like receptors (TLRs) are important in obesity and related metabolic disorders. TLRs are pattern-recognizing receptors (PRRs) involved in the innate immune system and recognize pathogen-associated molecular patterns (PAMPs) and endogenous ligands. TLRs, especially TLR2 and TLR4, are activated by fatty acids, endotoxins, and other ligands. TLR2 and TLR4 activation triggers inflammatory responses. Chronic inflammation driven by TLR activation is a hallmark of obesity and metabolic diseases. The inflammatory response triggered by TLR activation alters insulin signaling, contributing to insulin resistance, a key feature of metabolic syndrome and type 2 diabetes. Modulation of TLR activity through lifestyle changes (diet and exercise), obesity surgery, and pharmacological agents is under study as a possible therapeutic approach to controlling obesity and its complications.
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Affiliation(s)
- Tannia Isabel Campos-Bayardo
- Department of Physiology, University Center of Health Sciences, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico; (T.I.C.-B.); (D.R.-R.); (A.G.-S.); (E.G.C.-M.); (D.I.S.-L.); (S.T.-S.)
| | - Daniel Román-Rojas
- Department of Physiology, University Center of Health Sciences, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico; (T.I.C.-B.); (D.R.-R.); (A.G.-S.); (E.G.C.-M.); (D.I.S.-L.); (S.T.-S.)
| | - Andrés García-Sánchez
- Department of Physiology, University Center of Health Sciences, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico; (T.I.C.-B.); (D.R.-R.); (A.G.-S.); (E.G.C.-M.); (D.I.S.-L.); (S.T.-S.)
| | - Ernesto Germán Cardona-Muñoz
- Department of Physiology, University Center of Health Sciences, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico; (T.I.C.-B.); (D.R.-R.); (A.G.-S.); (E.G.C.-M.); (D.I.S.-L.); (S.T.-S.)
| | - Daniela Itzel Sánchez-Lozano
- Department of Physiology, University Center of Health Sciences, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico; (T.I.C.-B.); (D.R.-R.); (A.G.-S.); (E.G.C.-M.); (D.I.S.-L.); (S.T.-S.)
| | - Sylvia Totsuka-Sutto
- Department of Physiology, University Center of Health Sciences, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico; (T.I.C.-B.); (D.R.-R.); (A.G.-S.); (E.G.C.-M.); (D.I.S.-L.); (S.T.-S.)
| | - Luis Francisco Gómez-Hermosillo
- Department of Laparoscopic Surgery, Hospital Civil de Guadalajara, “Juan I Menchaca”, Guadalajara 44360, Jalisco, Mexico; (L.F.G.-H.); (J.C.-M.)
| | - Jorge Casillas-Moreno
- Department of Laparoscopic Surgery, Hospital Civil de Guadalajara, “Juan I Menchaca”, Guadalajara 44360, Jalisco, Mexico; (L.F.G.-H.); (J.C.-M.)
| | - Jorge Andrade-Sierra
- Department of Nephrology, National Medical Center of the West, Mexican Social Security Institute, Guadalajara 44340, Jalisco, Mexico; (J.A.-S.); (L.P.-V.)
| | - Leonardo Pazarín-Villaseñor
- Department of Nephrology, National Medical Center of the West, Mexican Social Security Institute, Guadalajara 44340, Jalisco, Mexico; (J.A.-S.); (L.P.-V.)
| | - Wendy Campos-Pérez
- Department of Molecular Biology and Genomics, Institute of Nutrigenetics and Translational Nutrigenomics, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico; (W.C.-P.); (E.M.-L.)
| | - Erika Martínez-López
- Department of Molecular Biology and Genomics, Institute of Nutrigenetics and Translational Nutrigenomics, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico; (W.C.-P.); (E.M.-L.)
| | - Alejandra Guillermina Miranda-Díaz
- Department of Physiology, University Center of Health Sciences, University of Guadalajara, Guadalajara 44360, Jalisco, Mexico; (T.I.C.-B.); (D.R.-R.); (A.G.-S.); (E.G.C.-M.); (D.I.S.-L.); (S.T.-S.)
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Wang J, Hu X, Li Y, Li S, Wang T, Wang D, Gao Y, Wang Q, Zhou J, Wan C. Impaired lipid homeostasis and elevated lipid oxidation of erythrocyte membrane in adolescent depression. Redox Biol 2025; 80:103491. [PMID: 39809016 PMCID: PMC11780951 DOI: 10.1016/j.redox.2025.103491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 01/07/2025] [Indexed: 01/16/2025] Open
Abstract
Adolescent depression is a globally concerned mental health issue, the pathophysiological mechanisms of which remain elusive. Membrane lipids play a crucial role in brain development and function, potentially serving as a crossroad for the abnormalities in neurotransmitters, neuroendocrine, inflammation, oxidative stress, and energy metabolism observed in depressed adolescents. The primary aim of this study was to investigate the erythrocyte membrane lipid profile in adolescent depression. A total of 2838 erythrocyte membrane lipids were detected and quantified in 81 adolescents with depression and 67 matched healthy adolescents using ultra-high performance liquid chromatography-mass spectrometry. Depressed adolescents exhibited significantly different membrane lipid characteristics compared to healthy controls. Specifically, the levels of cholesterol, sphingomyelins, and ceramides were increased, while ether lipids were decreased in patients. Moreover, the patients showed reduced polyunsaturated fatty acids and elevated lipophilic index in membrane, suggesting diminished membrane fluidity. The higher oxidized membrane lipids and plasma malondialdehyde were observed in adolescent depression, indicating the presence of oxidative stress. Importantly, membrane lipid damage was associated with more severe depressive symptoms and worse cognitive function in patients. In addition, reduced polyunsaturated fatty acids and membrane fluidity may be partly responsible for the blunted niacin skin flushing response found in depressed adolescents. In conclusion, our results reveal impaired erythrocyte membrane lipid homeostasis in adolescents with depression, which may implicate membrane dysfunction in the brain. These findings offer new insights into the underlying molecular mechanisms of adolescent depression, highlighting the potential of counteracting membrane damage as a promising avenue for future therapeutic interventions.
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Affiliation(s)
- Jinfeng Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
| | - Xiaowen Hu
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
| | - Ya Li
- School of Rehabilitation Medicine, Shandong Second Medical University, Weifang, Shandong, China.
| | - Shuhui Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
| | - Tianqi Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
| | - Dandan Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
| | - Yan Gao
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
| | - Qian Wang
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
| | - Jiansong Zhou
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
| | - Chunling Wan
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China; Shanghai Mental Health Center, Shanghai Key Laboratory of Psychiatry Disorders, Shanghai Jiao Tong University, Shanghai, China.
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Zhang H, Tian Y, Xu C, Chen M, Xiang Z, Gu L, Xue H, Xu Q. Crosstalk between gut microbiotas and fatty acid metabolism in colorectal cancer. Cell Death Discov 2025; 11:78. [PMID: 40011436 DOI: 10.1038/s41420-025-02364-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 01/30/2025] [Accepted: 02/17/2025] [Indexed: 02/28/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy globally and the second leading cause of cancer-related mortality. Its development is a multifactorial and multistage process influenced by a dynamic interplay between gut microbiota, environmental factors, and fatty acid metabolism. Dysbiosis of intestinal microbiota and abnormalities in microbiota-associated metabolites have been implicated in colorectal carcinogenesis, highlighting the pivotal role of microbial and metabolic interactions. Fatty acid metabolism serves as a critical nexus linking dietary patterns with gut microbial activity, significantly impacting intestinal health. In CRC patients, reduced levels of short-chain fatty acids (SCFAs) and SCFA-producing bacteria have been consistently observed. Supplementation with SCFA-producing probiotics has demonstrated tumor-suppressive effects, while therapeutic strategies aimed at modulating SCFA levels have shown potential in enhancing the efficacy of radiation therapy and immunotherapy in both preclinical and clinical settings. This review explores the intricate relationship between gut microbiota, fatty acid metabolism, and CRC, offering insights into the underlying mechanisms and their potential translational applications. Understanding this interplay could pave the way for novel diagnostic, therapeutic, and preventive strategies in the management of CRC.
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Affiliation(s)
- Hao Zhang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Yuan Tian
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Chunjie Xu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Miaomiao Chen
- Department of Radiology, Huashan Hospital, National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200040, PR China
| | - Zeyu Xiang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China
| | - Lei Gu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
| | - Hanbing Xue
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Qing Xu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
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Li J, Ge Z, Li C, Ran H, Zhang Y, Xiang Y. METRNL exerts cytoprotective effects on EPCs via regulation of the E2F1-TXNIP axis in obese limb ischemia. Cell Signal 2025; 126:111528. [PMID: 39603439 DOI: 10.1016/j.cellsig.2024.111528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 11/10/2024] [Accepted: 11/22/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Obesity increases cardiovascular disease risk by impairing angiogenesis, primarily through dysfunction of endothelial progenitor cells (EPCs). METRNL, a recently identified secreted protein, exhibits diverse biological activities. However, its impact on EPC function and its role in obesity-related microvascular dysfunction remain unclear. This study aims to investigate the effects of METRNL on EPC function and its potential therapeutic mechanisms for promoting angiogenesis. METHOD In vitro, human EPCs derived from peripheral and umbilical cord blood were treated with recombinant METRNL protein (rMETRNL) and exposed to palmitic acid (PA). EPC proliferation, migration, and tube formation were assessed. Apoptosis and pyroptosis levels were evaluated using Western blotting, flow cytometry, scanning electron microscopy (SEM), immunofluorescence (IF), and enzyme-linked immunosorbent assay (ELISA). RNA sequencing, ChIP, and dual-luciferase assays were performed to investigate the regulatory mechanisms. In vivo, an obese mouse model with hind limb ischemia received local injections of METRNL-overexpressing EPCs in the ischemic muscle. Blood flow recovery was monitored using laser Doppler flowmetry and CD31 immunofluorescence. RESULTS Replenishment of METNRL alleviated PA-induced apoptosis and pyroptosis of EPCs, while simultaneously enhancing their proliferation, migration, and tube formation. Mechanistically, RNA sequencing revealed that rMETRNL restoration downregulated E2F1 expression, and the protective effects of METRNL were partially reversed by E2F1 overexpression. Further, E2F1 was found to bind the TXNIP promoter region, promoting TXNIP transcription. Elevated TXNIP levels counteracted the beneficial effects of rMETRNL on EPC function in the presence of PA. In vivo, the transplantation of METRNL-overexpressing EPCs into the ischemic hind limbs of obese mice promoted angiogenesis, as evidenced by improved blood flow recovery and increased CD31 immunofluorescence in the ischemic tissues. CONCLUSION Our research emphasizes the potential of METRNL in reducing EPC cellular pyroptosis and promoting angiogenesis by inhibiting the E2F1-TXNIP signaling pathway. METRNL shows promise in treating obesity-related cardiovascular diseases through angiogenic therapy.
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Affiliation(s)
- Jing Li
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai 200000, China
| | - Zhuowang Ge
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai 200000, China
| | - Chengsi Li
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai 200000, China
| | - Hui Ran
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai 200000, China
| | - Yachen Zhang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai 200000, China.
| | - Yin Xiang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai 200000, China.
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Ribeiro MGC, Kravchychyn ACP, Bressan J, Hermsdorff HHM. Adiposity and inflammation markers explain mostly part of the plasma zonulin variation in Brazilian adults with overweight/obesity: A cross-sectional analysis from Brazilian nuts study. Clin Nutr 2025; 45:22-30. [PMID: 39731881 DOI: 10.1016/j.clnu.2024.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 11/26/2024] [Accepted: 12/16/2024] [Indexed: 12/30/2024]
Abstract
OBJECTIVE This study evaluated intestinal permeability according to plasma zonulin and its association with adiposity, inflammation, cardiometabolic risk, liver function, and intestinal health markers in adults with overweight/obesity. METHODOLOGY This study is a cross-sectional analysis using baseline data from the Brazilian Nut Study, which involved 123 participants (93 women, age 33.2 ± 8.58 years, BMI 33.9 ± 4.30kg/m2). Subjects were divided into quartiles according to plasma zonulin, assessed by Elisa. Cytokines were assessed by flow cytometry; anthropometric measurements were collected by standard procedure and body composition was assessed by DXA. SCFA analysis was performed by high-performance liquid chromatography, and fecal pH, by a pH meter. Linear regression models were performed (α<5 %). RESULTS Participants included in the last quartile of plasma zonulin had higher values of body fat (%), pro-inflammatory cytokines (CRP, IL-1). According to the multivariate regression model, each one-unit increased in body fat, CRP, IL-12p70, IL-6 and IL-8 resulted correspondingly in an increment of 0.42, 0.14, 0.192, 0.250 and 0.312 ng/ml in plasma zonulin, respectively. Conversely, a one-unit decreased in IL-10 led to an increase of 0.40 ng/ml in plasma zonulin. CONCLUSION Intestinal permeability assessed by plasma zonulin is associated with adiposity, subclinical inflammation and reduced serum HDL levels adults with overweight/obesity, while adiposity and inflammation markers are independent factors for plasma zonulin variation.
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Affiliation(s)
- Madalena Geralda Cupertino Ribeiro
- Laboratory of Clinical Analysis and Genomics, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, MG, Brazil; Laboratory of Energy Metabolism and Body Composition, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, MG, Brazil.
| | - Ana Claudia Pelissari Kravchychyn
- Laboratory of Clinical Analysis and Genomics, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, MG, Brazil; Laboratory of Energy Metabolism and Body Composition, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, MG, Brazil
| | - Josefina Bressan
- Laboratory of Clinical Analysis and Genomics, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, MG, Brazil; Laboratory of Energy Metabolism and Body Composition, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, MG, Brazil
| | - Helen Hermana Miranda Hermsdorff
- Laboratory of Clinical Analysis and Genomics, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, MG, Brazil; Laboratory of Energy Metabolism and Body Composition, Department of Nutrition and Health, Universidade Federal de Viçosa, Viçosa, MG, Brazil
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Bakhtiari S, Asri N, Jahdkaran M, Rezaei-Tavirani M, Jahani-Sherafat S, Rostami-Nejad M. The connection between fatty acids and inflammation in celiac disease; a deep exploring. Tissue Barriers 2025; 13:2342619. [PMID: 38618691 PMCID: PMC11875481 DOI: 10.1080/21688370.2024.2342619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/09/2024] [Accepted: 04/09/2024] [Indexed: 04/16/2024] Open
Abstract
The interplay between fatty acids (FAs) and celiac disease (CD) is a burgeoning field of research with significant implications for understanding the pathophysiology and potential therapeutic avenues for this autoimmune disorder. CD, triggered by gluten consumption in susceptible individuals, presents with a range of intestinal and extra-intestinal symptoms impacting various bodily functions. The disruption of intestinal tight junctions (TJs) by gluten proteins leads to increased gut permeability and subsequent inflammatory responses mediated by T-cells. FAs, crucial components of cell membranes, play diverse roles in inflammation and immune regulation. In fact, FAs have been shown to modulate inflammatory processes through various mechanisms. Studies have highlighted alterations in FA profiles in individuals with CD, indicating potential implications for disease pathogenesis and micronutrient deficiencies. Moreover, the exploration of FAs as biomarkers for CD diagnosis offers promising avenues for future research and therapeutic interventions. Understanding the intricate relationship between FAs and CD could lead to novel approaches in managing this complex autoimmune disorder. Therefore, this review article aims to provide an overview of the connection between FAs and inflammation in CD.
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Affiliation(s)
- Sajjad Bakhtiari
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nastaran Asri
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahtab Jahdkaran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Somayeh Jahani-Sherafat
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Xie H, Halimulati M, Dou Y, Zhang H, Jiang X, Peng L. Systemic immune-inflammation states in US adults with seropositivity to infectious pathogens: A nutrient-wide association study. JPEN J Parenter Enteral Nutr 2025; 49:94-102. [PMID: 39380423 DOI: 10.1002/jpen.2695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/19/2024] [Accepted: 09/21/2024] [Indexed: 10/10/2024]
Abstract
BACKGROUND Limited understanding exists regarding the association between daily total dietary nutrient intakes and immune-inflammation states in US adults exposed to various pathogens. This study sought to examine the correlation between nutrient intakes and immune-inflammation indicators and to assess their performance in distinguishing immune-inflammation states. METHODS This study was derived from the National Health and Nutrition Examination Survey (NHANES), which included 33,804 participants aged 20 years or older between 2005 and 2018. Multivariable linear regression and restricted cubic spline regression were conducted to evaluate the association between nutrient intakes and immune-inflammation indicators. Receiver operating characteristic curve analysis was performed to evaluate the discriminatory performance of identified nutrients for various immune-inflammation states measured by the systemic immune-inflammation index (SII). RESULTS Ten key nutrients were significantly associated with immune-inflammation responses, including calcium, saturated fatty acid (SFA) 4:0, SFA 6:0, SFA 12:0, SFA 14:0, SFA 16:0, vitamin B2, total SFAs, retinol, and lutein + zeaxanthin, which show potential as dietary indicators. The area under the curve for discriminating various immune-inflammation states was improved by at least 0.03 compared with a model that included only covariates, with all P values <0.05 in the Delong tests, indicating a significant enhancement in model performance. CONCLUSIONS Ten nutrients, including calcium, various SFAs, vitamin B2, retinol, and lutein + zeaxanthin, exhibit significant association with SII and potential as dietary indicators for distinguishing between different immune-inflammation states in US adults with seropositivity to various viruses.
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Affiliation(s)
- He Xie
- Department of Preventive Health Care, Bazhong Central Hospital, Bazhong, Sichuan, China
| | - Mairepaiti Halimulati
- Department of Nutrition Science, the University of Texas at Austin, Austin, Texas, USA
| | - Yuqi Dou
- Health Systems and Equity, Eastern Health Clinical School, Monash University, Boxhill, Victoria, Australia
| | - Hanyue Zhang
- Research Unit for Dietary Studies, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
- Section for General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Xiaowen Jiang
- Department of Epidemiology, School of Clinical Oncology, Peking University, Beijing, China
| | - Lei Peng
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
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23
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Correa-da-Silva F, Yi CX. Neuroglia in eating disorders (obesity, Prader-Willi syndrome and anorexia nervosa). HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:313-324. [PMID: 40148052 DOI: 10.1016/b978-0-443-19102-2.00019-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
The hypothalamus is widely recognized as one of the most extensively studied brain regions involved in the central regulation of energy homeostasis. Within the hypothalamus, peptidergic neurons play a crucial role in monitoring peripheral concentrations of metabolites and hormones, and they finely adjust the sensing of these factors, leading to the activation of either anorexigenic (appetite-suppressing) or orexigenic (appetite-stimulating) pathways. While cortical innervation of the hypothalamus does influence these processes, it is generally considered of secondary importance. Eating-related disorders, such as obesity and anorexia nervosa, are strongly associated with imbalances in energy intake and expenditure. The phenotypes of these disorders can be attributed to dysfunctions in the hypothalamus. Traditionally, it has been believed that hypothalamic dysfunction in these disorders primarily stems from defects in neural pathways. However, recent evidence challenges this perception, highlighting the active participation of neuroglial cells in shaping both physiologic and behavioral characteristics. This review aims to provide an overview of the latest insights into glial biology in three specific eating disorders: obesity, Prader-Willi syndrome, and anorexia. In these disorders, neural dysfunction coincides with glial malfunction, suggesting that neuroglia actively contribute to the development and progression of various neurologic disorders. These findings underscore the importance of glial cells and open up potential new avenues for therapeutic interventions.
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Affiliation(s)
- Felipe Correa-da-Silva
- Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands; Laboratory of Endocrinology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands; Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
| | - Chun-Xia Yi
- Department of Endocrinology and Metabolism, Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands; Laboratory of Endocrinology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands; Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
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24
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Kumar S, Sharma V, Yadav S. TLR4 Targeting: A Promising Therapeutic Approach Across Multiple Human Diseases. Curr Protein Pept Sci 2025; 26:241-258. [PMID: 39722483 DOI: 10.2174/0113892037324425241018061548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/31/2024] [Accepted: 09/23/2024] [Indexed: 12/28/2024]
Abstract
TLR4 stands at the forefront of innate immune responses, recognizing various pathogen- associated molecular patterns and endogenous ligands, thus serving as a pivotal mediator in the immune system's defense against infections and tissue damage. Beyond its canonical role in infection, emerging evidence highlights TLR4's involvement in numerous non-infectious human diseases, ranging from metabolic disorders to neurodegenerative conditions and cancer. Targeting TLR4 signaling pathways presents a promising therapeutic approach with broad applicability across these diverse pathological states. In metabolic disorders such as obesity and diabetes, dysregulated TLR4 activation contributes to chronic low-grade inflammation and insulin resistance, driving disease progression. In cardiovascular diseases, TLR4 signaling promotes vascular inflammation and atherogenesis, implicating its potential as a therapeutic target to mitigate cardiovascular risk. Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, exhibit aberrant TLR4 activation linked to neuroinflammation and neuronal damage, suggesting TLR4 modulation as a strategy to attenuate neurodegeneration. Additionally, in cancer, TLR4 signaling within the tumor microenvironment promotes tumor progression, metastasis, and immune evasion, underscoring its relevance as a target for anticancer therapy. Advances in understanding TLR4 signaling cascades and their contributions to disease pathogenesis have spurred the development of various pharmacological agents targeting TLR4. These agents range from small molecule inhibitors to monoclonal antibodies, with some undergoing preclinical and clinical evaluations. Furthermore, strategies involving TLR4 modulation through dietary interventions and microbiota manipulation offer additional avenues for therapeutic exploration. Hence, targeting TLR4 holds significant promise as a therapeutic strategy across a spectrum of human diseases, offering the potential to modulate inflammation, restore immune homeostasis, and impede disease progression.
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Affiliation(s)
- Sakshi Kumar
- Department of Pharmacy, Galgotias College, Greater Noida, Uttar Pradesh, 201310, India
| | - Vikram Sharma
- Department of Pharmacy, Galgotias College, Greater Noida, Uttar Pradesh, 201310, India
| | - Shikha Yadav
- School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, 201310, India
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25
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Zhang Z, Liu J, Wang Y, Zhang L, Zhou T, Huang Y, Zhu T. Toll-like Receptor 4 Signaling Mediates Gastritis and Gastric Cancer. Curr Mol Med 2025; 25:388-398. [PMID: 38204278 DOI: 10.2174/0115665240276139231206071742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/02/2023] [Accepted: 10/25/2023] [Indexed: 01/12/2024]
Abstract
The stomach is a crucial digestive organ in the human body, highly susceptible to inflammation or pathogen invasion, which can lead to various gastric diseases, including gastric cancer. Toll-like receptors (TLRs) are the first line of defense against pathogen invasion. TLR4, a member of the TLRs family, recognizes pathogen and danger-related molecular patterns to induce inflammatory responses. Helicobacter pylori (H. pylori) is a significant factor in gastric health, and TLR4 recognizes H. pylori -LPS to trigger an inflammatory response. Downstream TLR4 signaling generates proinflammatory cytokines that initiate inflammation in the gastric mucosa. In addition, TLR4 gene polymorphisms can increase health risks. This study aims to investigate the contribution of TLR4 to the inflammatory response in gastric diseases and the relation between TLR4 and H. pylori, TLR4 gene polymorphisms, and how TLR4 affects gastric diseases' possible pathways to provide further insight for future prevention and clinical treatment strategies.
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Affiliation(s)
- Zepeng Zhang
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Ju Liu
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Yi Wang
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Lei Zhang
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Tong Zhou
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Yu Huang
- Department of pharmacy, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, China
| | - Tongtong Zhu
- Department of pharmacy, Kunshan Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, China
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26
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Zhu J, Huang Y, Ye C, Deng X, Zou Y, Yuan E, Chen Q. The Effect Components and Mechanisms of Action of Cimicifugae Rhizoma in the Treatment of Acute Pneumonia. J Inflamm Res 2024; 17:11757-11787. [PMID: 39749001 PMCID: PMC11694570 DOI: 10.2147/jir.s489691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 12/14/2024] [Indexed: 01/04/2025] Open
Abstract
Objective The main objective of this study was to elucidate the effector material basis of Cimicifugae Rhizoma (CR) for the treatment of acute pneumonia (AP) and to explore the potential mechanisms underlying the anti-AP effects of these active components in a lipopolysaccharide (LPS)-induced inflammation model of lung epithelial cells. Methods Chemical components were identified using ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UPLC-TOF-MS), and a CR component library was subsequently established based on a combination of databases and available literature. Bioinformatics techniques were used to construct "component-target" and "protein-protein interaction (PPI)" networks, and the potential active components and core targets screened according to degree value, followed by molecular docking and in vitro experiments for verification. Inflammation was induced in normal human lung epithelial cells using lipopolysaccharide (LPS) to mimic the occurrence of AP. Results In total, 122 CR components were identified. The therapeutic effects of potential active components against AP were associated with 147 targets involving 165 signaling pathways. Molecular docking experiments revealed the strong affinity of N-cis- feruloyltyramine, ferulic acid, cimifugin, and isoferulic acid for core AP-associated targets. In vitro cellular experiments showed that the above compounds and CR alcoholic extracts inhibited the expression of inflammatory factors in the following order: isoferulic acid > cimifugin > CR alcoholic extract > N-cis-feruloyltyramine > ferulic acid. Conclusion N-cis- feruloyltyramine, ferulic acid, cimifugin, and isoferulic acid were the effector components of CR with activity against AP. These compounds potentially co-regulate the IL-6/JAK/STAT3 and TLR4/IL-1β-IRAK pathways through the inhibition of cytokines such as IL-6, TNF-α, and IL-1β, and downregulation of P-STAT3, TLR4, PIK3CA, and NF-κB involved in TLR4/IL-1β-IRAK/NF-κB and PI3K-Akt signaling pathways to exert therapeutic effects on AP.
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Affiliation(s)
- Jing Zhu
- Research Center for Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
| | - Yiming Huang
- Research Center for Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
| | - Chao Ye
- The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
| | - Xiaoxia Deng
- Research Center for Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
| | - Yuxuan Zou
- Research Center for Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
| | - En Yuan
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
| | - Qi Chen
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China
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Sullivan JP, Jones MK. The Multifaceted Impact of Bioactive Lipids on Gut Health and Disease. Int J Mol Sci 2024; 25:13638. [PMID: 39769399 PMCID: PMC11728145 DOI: 10.3390/ijms252413638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
Bioactive lipids have a multifaceted role in health and disease and are recognized to play an important part in gut immunity and disease conditions such as inflammatory bowel disease and colon cancer. Advancements in lipidomics, enabled by mass spectrometry and chromatographic techniques, have enhanced our understanding of lipid diversity and functionality. Bioactive lipids, including short-chain fatty acids, saturated fatty acids, omega-3 fatty acids, and sphingolipids, exhibit diverse effects on inflammation and immune regulation. Short-chain fatty acids like butyrate demonstrate anti-inflammatory properties, enhancing regulatory T cell function, gut barrier integrity, and epigenetic regulation, making them promising therapeutic targets for inflammatory bowel disease and colon cancer. Conversely, saturated fatty acids promote inflammation by disrupting gut homeostasis, triggering oxidative stress, and impairing immune regulation. Omega-3 lipids counteract these effects, reducing inflammation and supporting immune balance. Sphingolipids exhibit complex roles, modulating immune cell trafficking and inflammation. They can exert protective effects or exacerbate colitis depending on their source and context. Additionally, eicosanoids can also prevent pathology through prostaglandin defense against damage to epithelial barriers. This review underscores the importance of dietary lipids in shaping gut health and immunity and also highlights the potential use of lipids as therapeutic strategies for managing inflammatory conditions and cancer.
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Affiliation(s)
| | - Melissa K. Jones
- Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611, USA;
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Zhou B, Zhang B, Han J, Zhang J, Li J, Dong W, Zhao X, Zhang Y, Zhang Q. Role of Acyl-CoA Thioesterase 7 in Regulating Fatty Acid Metabolism and Its Contribution to the Onset and Progression of Bovine Clinical Mastitis. Int J Mol Sci 2024; 25:13046. [PMID: 39684757 DOI: 10.3390/ijms252313046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
Clinical mastitis (CM) is a prevalent and severe inflammatory disease in dairy cows affecting the mammary glands. Fatty acid (FA) metabolism and associated enzymes are crucial for many physiological and pathological processes in dairy cows. However, the relationships among FA metabolism, FA-associated enzymes, and CM, as well as the mechanisms underlying their interactions, in dairy cows are not fully understood. The aim of this study was to characterize biological process (BP) terms, pathways, and differentially expressed proteins (DEPs) related to FA metabolism from our previous data-independent acquisition proteomic study. Six BPs involving 14 downregulated and 20 upregulated DEPs, and four pathways involving 10 downregulated and 11 upregulated DEPs related to FA synthesis and metabolism were systematically identified. Associated analysis suggested that 12 candidate DEPs obtained from BPs and pathways, especially acyl-CoA thioesterase 7 (ACOT7), regulate long-chain FA (LCFA) elongation and the biosynthesis of unsaturated FAs. Immunohistochemical and immunofluorescence staining results showed that ACOT7 was present mainly in the cytoplasm of mammary epithelial cells. The qRT-PCR and Western blotting results showed that ACOT7 mRNA and protein levels in the mammary glands of the CM group were significantly upregulated compared to those in the healthy group. This evidence indicates that ACOT7 is positively correlated with CM onset and progression in Holstein cows. These findings offer novel insights into the role of FA metabolism and related enzymes in CM and offer potential targets for the development of therapeutic strategies and biomarkers for the prevention and treatment of CM in dairy cows.
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Affiliation(s)
- Bin Zhou
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Bohao Zhang
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Jiangyuan Han
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
| | - Junjun Zhang
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Jianfu Li
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Weitao Dong
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Xingxu Zhao
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Yong Zhang
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Quanwei Zhang
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
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29
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Bakhtiari S, Asri N, Nikzamir A, Ahmadipour S, Rostami-Nejad M, Ciacci C. Exploring fatty acid effects in celiac disease: potential therapeutic avenues. Tissue Barriers 2024. [DOI: 10.1080/21688370.2024.2435552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 11/20/2024] [Accepted: 11/24/2024] [Indexed: 01/05/2025] Open
Affiliation(s)
- Sajjad Bakhtiari
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nastaran Asri
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolrahim Nikzamir
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shokoufeh Ahmadipour
- Department of Pediatric, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Mohammad Rostami-Nejad
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Carolina Ciacci
- Department of Medicine, Surgery, Dentistry, University of Salerno, Fisciano, Italy
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Yahya MA, Alshammari GM, Osman MA, Al-Harbi LN, Alotaibi SN. Isoliquiritigenin Prevents the Development of Nephropathy by an HFD in Rats Through the Induction of Antioxidant Production and Inhibition of the MD-2/TLR4/NF-κB Pathway. BIOLOGY 2024; 13:984. [PMID: 39765652 PMCID: PMC11727570 DOI: 10.3390/biology13120984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 01/15/2025]
Abstract
This study tested the ISL against renal damage induced by a high-fat diet (HFD) and explored its underlying mechanisms. Adult male rats were assigned to four groups: (1) control on a standard diet (STD), (2) ISL on STD (30 mg/kg), (3) HFD, and (4) HFD + ISL (30 mg/kg). After 12 weeks of dietary intervention, ISL treatment led to significant reductions in body weight gain, visceral fat, and glucose and insulin levels in HFD-fed rats. Notably, ISL decreased serum urea and creatinine, increased serum albumin, and improved urinary profiles by lowering the urinary albumin and the albumin/creatinine ratio. Histological analyses revealed that ISL enhanced the glomerular structure and mitigated tubular damage, as evidenced by reduced urinary excretion of the kidney injury markers NGAL and KIM-1. Additionally, ISL significantly lowered cholesterol, triglycerides, and free fatty acids in both the control and HFD groups while also decreasing oxidized low-density lipoproteins (ox-LDLs) and malondialdehyde (MDA). Importantly, ISL enhanced renal antioxidant levels, increasing glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Moreover, ISL downregulated mRNA levels of MD-2, Toll-like receptor-4 (TLR-4), and NF-κB, leading to reduced NF-κB p65 levels in renal tissues. In conclusion, ISL offers substantial protection against HFD-induced renal toxicity through mechanisms that attenuate metabolic stress, enhance antioxidant defenses, and inhibit the MD-2/TLR4/NF-κB inflammatory pathway.
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Affiliation(s)
| | - Ghedeir M. Alshammari
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh 11451, Saudi Arabia; (M.A.Y.); (M.A.O.); (L.N.A.-H.); (S.N.A.)
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31
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Huwart SJP, Fayt C, Gangarossa G, Luquet S, Cani PD, Everard A. TLR4-dependent neuroinflammation mediates LPS-driven food-reward alterations during high-fat exposure. J Neuroinflammation 2024; 21:305. [PMID: 39580436 PMCID: PMC11585241 DOI: 10.1186/s12974-024-03297-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/13/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Obesity has become a global pandemic, marked by significant shifts in both the homeostatic and hedonic/reward aspects of food consumption. While the precise causes are still under investigation, recent studies have identified the role of gut microbes in dysregulating the reward system within the context of obesity. Unravelling these gut-brain connections is crucial for developing effective interventions against eating and metabolic disorders, particularly in the context of obesity. This study explores the causal role of LPS, as a key relay of microbiota component-induced neuroinflammation in the dysregulation of the reward system following exposure to high-fat diet (HFD). METHODS Through a series of behavioural paradigms related to food-reward events and the use of pharmacological agents targeting the dopamine circuit, we investigated the mechanisms associated with the development of reward dysregulation during HFD-feeding in male mice. A Toll-like receptor 4 (TLR4) full knockout model and intraventricular lipopolysaccharide (LPS) diffusion at low doses, which mimics the obesity-associated neuroinflammatory phenotype, were used to investigate the causal roles of gut microbiota-derived components in neuroinflammation and reward dysregulation. RESULTS Our study revealed that short term exposure to HFD (24 h) tended to affect food-seeking behaviour, and this effect became significant after 1 week of HFD. Moreover, we found that deletion of TLR4 induced a partial protection against HFD-induced neuroinflammation and reward dysregulation. Finally, chronic brain diffusion of LPS recapitulated, at least in part, HFD-induced molecular and behavioural dysfunctions within the reward system. CONCLUSIONS These findings highlight a link between the neuroinflammatory processes triggered by the gut microbiota components LPS and the dysregulation of the reward system during HFD-induced obesity through the TLR4 pathway, thus paving the way for future therapeutic approaches.
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Affiliation(s)
- Sabrina J P Huwart
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 Box B1.73.11, Brussels, B-1200, Belgium
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Avenue Pasteur, 6, Wavre, Belgium
| | - Clémence Fayt
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 Box B1.73.11, Brussels, B-1200, Belgium
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Avenue Pasteur, 6, Wavre, Belgium
| | - Giuseppe Gangarossa
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, F-75013, France
- Institut Universitaire de France (IUF), Paris, France
| | - Serge Luquet
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, F-75013, France
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 Box B1.73.11, Brussels, B-1200, Belgium
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Avenue Pasteur, 6, Wavre, Belgium
- Institute of Experimental and Clinical Research (IREC), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Amandine Everard
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 Box B1.73.11, Brussels, B-1200, Belgium.
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Avenue Pasteur, 6, Wavre, Belgium.
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Maher S, Rajapakse J, El-Omar E, Zekry A. Role of the Gut Microbiome in Metabolic Dysfunction-Associated Steatotic Liver Disease. Semin Liver Dis 2024; 44:457-473. [PMID: 39389571 DOI: 10.1055/a-2438-4383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-previously described as nonalcoholic fatty liver disease-continues to rise globally. Despite this, therapeutic measures for MASLD remain limited. Recently, there has been a growing interest in the gut microbiome's role in the pathogenesis of MASLD. Understanding this relationship may allow for the administration of therapeutics that target the gut microbiome and/or its metabolic function to alleviate MASLD development or progression. This review will discuss the interplay between the gut microbiome's structure and function in relation to the development of MASLD, assess the diagnostic yield of gut microbiome-based signatures as a noninvasive tool to identify MASLD severity, and examine current and emerging therapies targeting the gut microbiome-liver axis.
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Affiliation(s)
- Salim Maher
- Department of Gastroenterology and Hepatology, St George Hospital, Sydney, Australia
- School of Clinical Medicine, UNSW Medicine & Health, St George & Sutherland Clinical Campuses
| | - Jayashi Rajapakse
- School of Clinical Medicine, UNSW Medicine & Health, St George & Sutherland Clinical Campuses
| | - Emad El-Omar
- Department of Gastroenterology and Hepatology, St George Hospital, Sydney, Australia
- School of Clinical Medicine, UNSW Medicine & Health, St George & Sutherland Clinical Campuses
| | - Amany Zekry
- Department of Gastroenterology and Hepatology, St George Hospital, Sydney, Australia
- School of Clinical Medicine, UNSW Medicine & Health, St George & Sutherland Clinical Campuses
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Seo YJ, Park JH, Byun JH. Therapeutic Potential of Stearoyl-CoA Desaturase1 (SCD1) in Modulating the Effects of Fatty Acids on Osteoporosis. Cells 2024; 13:1781. [PMID: 39513888 PMCID: PMC11544805 DOI: 10.3390/cells13211781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 10/19/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Osteoporosis is a common skeletal disease, primarily associated with aging, that results from decreased bone density and bone volume. This reduction significantly increases the risk of fractures in osteoporosis patients compared to individuals with normal bone density. Additionally, the bone regeneration process in these patients is slow, making complete healing difficult. Along with the decline in bone volume and density, osteoporosis is characterized by an increase in marrow adipose tissue (MAT), which is fat within the bone. In this altered bone microenvironment, osteoblasts are influenced by various factors secreted by adipocytes. Notably, saturated fatty acids promote osteoclast activity, inhibit osteoblast differentiation, and induce apoptosis, further reducing osteoblast formation. In contrast, monounsaturated fatty acids inhibit osteoclast formation and mitigate the apoptosis caused by saturated fatty acids. Leveraging these properties, we aimed to investigate the effects of overexpressing stearoyl-CoA desaturase 1 (SCD1), an enzyme that converts saturated fatty acids into monounsaturated fatty acids, on osteogenic differentiation and bone regeneration in both in vivo and in vitro models. Through this novel approach, we seek to develop a stem cell-based therapeutic strategy that harnesses SCD1 to improve bone regeneration in the adipocyte-rich osteoporotic environment.
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Affiliation(s)
- Young-Jin Seo
- Department of Oral and Maxillofacial Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Institute of Medical Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea;
- Department of Convergence Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea
| | - Jin-Ho Park
- Department of Nutritional Science, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA;
| | - June-Ho Byun
- Department of Oral and Maxillofacial Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Institute of Medical Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea;
- Department of Convergence Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea
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Alexander SN, Green AR, Debner EK, Ramos Freitas LE, Abdelhadi HMK, Szabo-Pardi TA, Burton MD. The influence of sex on neuroimmune communication, pain, and physiology. Biol Sex Differ 2024; 15:82. [PMID: 39439003 PMCID: PMC11494817 DOI: 10.1186/s13293-024-00660-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.
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Affiliation(s)
- Shevon N Alexander
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Audrey R Green
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Emily K Debner
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Lindsey E Ramos Freitas
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Hanna M K Abdelhadi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Thomas A Szabo-Pardi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Michael D Burton
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA.
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Liu K, Gu Y, Pan X, Chen S, Cheng J, Zhang L, Cao M. Behenic acid alleviates inflammation and insulin resistance in gestational diabetes mellitus by regulating TLR4/NF-κB signaling pathway. iScience 2024; 27:111019. [PMID: 39429784 PMCID: PMC11490720 DOI: 10.1016/j.isci.2024.111019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/13/2024] [Accepted: 09/20/2024] [Indexed: 10/22/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is a distinct form of diabetes that poses a significant threat to the health of both pregnant women and fetuses. The objective of this study was to investigate the impact of behenic acid (BA) on glucose metabolism, inflammation, and insulin resistance in GDM mice, and to elucidate the underlying molecular mechanism. Here, we demonstrated that daily administration of 10 mg/mL BA during pregnancy effectively ameliorated abnormal glucose metabolism in GDM mice and their offspring and improved birth outcomes in the offspring. Moreover, BA promoted the proliferation of islet β cells, restored their normal function, and augmented glucose uptake by skeletal muscle cells. Mechanistically, BA mitigated inflammation and insulin resistance in GDM mice by inhibiting activation of the TLR4/NF-κB signaling pathway. Our study provides compelling evidence supporting the efficacy of BA in improving GDM, suggesting its potential use as a dietary supplement for preventing and treating GDM.
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Affiliation(s)
- Kerong Liu
- Department of Endocrinology, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Wuxi 214023, Jiangsu, China
| | - Ying Gu
- Department of Obstetrics and Gynecology, Affiliated Women’s Hospital of Jiangnan University (Wuxi Maternity and Child Health Care Hospital), Wuxi 214002, Jiangsu, China
| | - Xingnan Pan
- Department of Pediatric, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Wuxi 214023, Jiangsu, China
| | - Sha Chen
- Department of Obstetrics and Gynecology, Affiliated Women’s Hospital of Jiangnan University (Wuxi Maternity and Child Health Care Hospital), Wuxi 214002, Jiangsu, China
| | - Jie Cheng
- Center for Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
| | - Le Zhang
- Department of Neonatology, Affiliated Children’s Hospital of Jiangnan University (Wuxi Children’s Hospital), Wuxi 214023, Jiangsu, China
| | - Minkai Cao
- Department of Obstetrics and Gynecology, Affiliated Women’s Hospital of Jiangnan University (Wuxi Maternity and Child Health Care Hospital), Wuxi 214002, Jiangsu, China
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Guarner-Lans V, Soria-Castro E, Cano-Martínez A, Rubio-Ruiz ME, Zarco G, Carreón-Torres E, Grimaldo O, Castrejón-Téllez V, Pérez-Torres I. Rats Exposed to Excess Sucrose During a Critical Period Develop Inflammation and Express a Secretory Phenotype of Vascular Smooth Muscle Cells. Metabolites 2024; 14:555. [PMID: 39452936 PMCID: PMC11509398 DOI: 10.3390/metabo14100555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 10/04/2024] [Accepted: 10/15/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Neonatal rats that receive sucrose during a critical postnatal period (CP, days 12 to 28) develop hypertension by the time they reach adulthood. Inflammation might contribute to changes during this period and could be associated with variations in the vascular smooth muscle (VSMC) phenotype. OBJECTIVE We studied changes in inflammatory pathways that could underlie the expression of the secretory phenotype in the VSMC in the thoracic aorta of rats that received sucrose during CP. METHODS We analyzed histological changes in the aorta and the expression of the COX-2, TLR4, iNOS, eNOS, MMP-2 and -9, and β- and α-actin, the quantities of TNF-α, IL-6, and IL-1β using ELISA, and the levels of fatty acids using gas chromatography. RESULTS The aortic wall presented disorganization, decellularization, and wavy elastic fibers and an increase in the lumen area. The α- and β-actin expressions were decreased, while COX-2, TLR4, TNF-α, and the activity of IL-6 were increased. Oleic acid was increased in CP in comparison to the control group. CONCLUSIONS There is transient hypertension at the end of the CP that is accompanied by inflammation and a change in the phenotype of VSMC to the secretory phenotype. The inflammatory changes could act as epigenetic signals to determine the development of hypertension when animals reach adulthood.
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Affiliation(s)
- Verónica Guarner-Lans
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (V.G.-L.); (A.C.-M.); (M.E.R.-R.)
| | - Elizabeth Soria-Castro
- Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico;
| | - Agustina Cano-Martínez
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (V.G.-L.); (A.C.-M.); (M.E.R.-R.)
| | - María Esther Rubio-Ruiz
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (V.G.-L.); (A.C.-M.); (M.E.R.-R.)
| | - Gabriela Zarco
- Department of Pharmacology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico
| | - Elizabeth Carreón-Torres
- Department of Molecular Biology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico;
| | - Oscar Grimaldo
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (V.G.-L.); (A.C.-M.); (M.E.R.-R.)
| | - Vicente Castrejón-Téllez
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (V.G.-L.); (A.C.-M.); (M.E.R.-R.)
| | - Israel Pérez-Torres
- Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico;
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Korzun T, Moses AS, Jozic A, Grigoriev V, Newton S, Kim J, Diba P, Sattler A, Levasseur PR, Le N, Singh P, Sharma KS, Goo YT, Mamnoon B, Raitmayr C, Souza APM, Taratula OR, Sahay G, Taratula O, Marks DL. Lipid Nanoparticles Elicit Reactogenicity and Sickness Behavior in Mice Via Toll-Like Receptor 4 and Myeloid Differentiation Protein 88 Axis. ACS NANO 2024; 18:24842-24859. [PMID: 39186628 PMCID: PMC11916992 DOI: 10.1021/acsnano.4c05088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/28/2024]
Abstract
mRNA therapeutics encapsulated in lipid nanoparticles (LNPs) offer promising avenues for treating various diseases. While mRNA vaccines anticipate immunogenicity, the associated reactogenicity of mRNA-loaded LNPs poses significant challenges, especially in protein replacement therapies requiring multiple administrations, leading to adverse effects and suboptimal therapeutic outcomes. Historically, research has primarily focused on the reactogenicity of mRNA cargo, leaving the role of LNPs understudied in this context. Adjuvanticity and pro-inflammatory characteristics of LNPs, originating at least in part from ionizable lipids, may induce inflammation, activate toll-like receptors (TLRs), and impact mRNA translation. Knowledge gaps remain in understanding LNP-induced TLR activation and its impact on induction of animal sickness behavior. We hypothesized that ionizable lipids in LNPs, structurally resembling lipid A from lipopolysaccharide, could activate TLR4 signaling via MyD88 and TRIF adaptors, thereby propagating LNP-associated reactogenicity. Our comprehensive investigation utilizing gene ablation studies and pharmacological receptor manipulation proves that TLR4 activation by LNPs triggers distinct physiologically meaningful responses in mice. We show that TLR4 and MyD88 are essential for reactogenic signal initiation, pro-inflammatory gene expression, and physiological outcomes like food intake and body weight─robust metrics of sickness behavior in mice. The application of the TLR4 inhibitor TAK-242 effectively reduces the reactogenicity associated with LNPs by mitigating TLR4-driven inflammatory responses. Our findings elucidate the critical role of the TLR4-MyD88 axis in LNP-induced reactogenicity, providing a mechanistic framework for developing safer mRNA therapeutics and offering a strategy to mitigate adverse effects through targeted inhibition of this pathway.
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Affiliation(s)
- Tetiana Korzun
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
- Department of Biomedical Engineering, Oregon Health & Science University, 3303 S.W. Bond Avenue, Portland, Oregon, 97239, USA
- Medical Scientist Training Program, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, USA
| | - Abraham S. Moses
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Antony Jozic
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Vladislav Grigoriev
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Samuel Newton
- Papé Family Pediatric Research Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code L481 Portland, Oregon, 97239, USA
| | - Jeonghwan Kim
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Parham Diba
- Medical Scientist Training Program, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239, USA
- Papé Family Pediatric Research Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code L481 Portland, Oregon, 97239, USA
| | - Ariana Sattler
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, 2720 S Moody Ave, Portland, OR 97201
| | - Peter R. Levasseur
- Papé Family Pediatric Research Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code L481 Portland, Oregon, 97239, USA
| | - Ngoc Le
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Prem Singh
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Kongbrailatpam Shitaljit Sharma
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Yoon Tae Goo
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Babak Mamnoon
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Constanze Raitmayr
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Ana Paula Mesquita Souza
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Olena R. Taratula
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Gaurav Sahay
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
| | - Oleh Taratula
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, 2730 SW Moody Avenue, Portland, Oregon, 97201, USA
- Department of Biomedical Engineering, Oregon Health & Science University, 3303 S.W. Bond Avenue, Portland, Oregon, 97239, USA
| | - Daniel L. Marks
- Endevica Bio, 1935 Techny Rd, Northbrook, Illinois, 60062, USA
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Mu J, Lin Q, Chen Y, Wang J, Yu X, Huang F, Liu X, Fang Y, Li Y, Zhu B, Liang Y. Rice bran active peptide (RBAP) inhibited macrophage differentiation to foam cell and atherosclerosis in mice via regulating cholesterol efflux. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155864. [PMID: 39032281 DOI: 10.1016/j.phymed.2024.155864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/11/2024] [Accepted: 07/08/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND Atherosclerosis is a long-lasting inflammatory condition affecting the walls of arteries, marked by the buildup of fats, plaque formation, and vascular remodeling. Recent findings highlight the significance of cholesterol removal pathways in influencing atherosclerosis, yet the connection between cholesterol removal and regulation of macrophage inflammation remains poorly understood. RBAP could serve as an anti-inflammatory agent; however, its role in atherosclerosis and the mechanism behind it are still not well understood. PURPOSE The objective of this research is to explore how RBAP impacts cholesterol efflux, which is a considerable element in the advancement of atherosclerosis. METHODS An atherosclerosis mouse model was established by using an ApoE KO strain mouse on a high-fat diet (HFD) to assess the effects of RBAP, conducted either orally or through injection. Additionally, in vitro experiments were conducted where the induction of THP-1 cells was conducted for the differentiation towards macrophages, and along with mouse RAW264.7 cells, were challenged with ox-LDL to evaluate the impact of RBAP. RESULTS In this study, RBAP was found to reduce the production and downregulate TNF-α, IL-1β, and IL-6 levels and inhibited the activation of the TLR4/MyD88/NF-κB signaling in atherosclerosis model mice, as well as in ox-LDL-challenged THP-1 cells and mouse RAW264.7 macrophages. RBAP's effectiveness also improved the enhancement of reverse cholesterol transport (RCT) and cholesterol removal to HDL and apoA1 by increasing the activity of genes related to cholesterol removal PPARγ/LXRα/ABCA1/ABCG1, both in ApoE-/- mice and in THP-1 cells and mouse RAW264.7 macrophages. Notably, RBAP exerted similar effects on atherosclerosis model mice and macrophages to those of TAK-242, an inhibitor of the TLR4 signaling. When RBAP and TAK-242 were applied simultaneously, the improvement was not enhanced compared with either RBAP or TAK-242 treatment alone. CONCLUSION These findings suggest that RBAP, as a TLR4 inhibitor, has anti-atherosclerotic effects by improving inflammation and promoting cholesterol effection, indicating its therapeutic potential in intervening atherosclerosis.
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Affiliation(s)
- Jianfei Mu
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China
| | - Qinlu Lin
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China
| | - Yajuan Chen
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China
| | - Jianqiang Wang
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China
| | - Xudong Yu
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China
| | - Fang Huang
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China
| | - Xinxin Liu
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China
| | - Yong Fang
- College of Food Science and Engineering, Nanjing University of Finance and Economics/Collaborative Innovation Center for Modern Grain Circulation and Safety, Nanjing, Jiangsu 210023, PR China
| | - Yusheng Li
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China; Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Beiwei Zhu
- National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning 116034, PR China.
| | - Ying Liang
- Molecular Nutrition Branch, National Engineering Research Center of Rice and By-product Deep Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China.
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Rajamanickam V, Desouza CV, Castillo RT, Saraswathi V. Blocking Thromboxane-Prostanoid Receptor Signaling Attenuates Lipopolysaccharide- and Stearic Acid-Induced Inflammatory Response in Human PBMCs. Cells 2024; 13:1320. [PMID: 39195211 PMCID: PMC11352481 DOI: 10.3390/cells13161320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/06/2024] [Accepted: 08/06/2024] [Indexed: 08/29/2024] Open
Abstract
Inflammation is implicated in the etiology of obesity-related diseases. Thromboxane-prostanoid receptor (TPR) is known to play a role in mediating an inflammatory response in a variety of cells. Gut-derived lipopolysaccharide (LPS), a TLR4 agonist, is elevated in obesity. Moreover, free fatty acids (FFAs) are important mediators of obesity-related inflammation. However, the role and mechanisms by which TPR regulates the inflammatory response in human immune cells remain unclear. We sought to determine the link between TPR and obesity and the role/mechanisms by which TPR alters LPS- or stearic acid (SA)-induced inflammatory responses in PBMCs. Cells were pre-treated with agents blocking TPR signaling, followed by treatment with LPS or stearic acid (SA). Our findings showed that TPR mRNA levels are higher in PBMCs from individuals with obesity. Blockade of TPR as well as ROCK, which acts downstream of TPR, attenuated LPS- and/or SA-induced pro-inflammatory responses. On the other hand, TPR activation using its agonist enhanced the pro-inflammatory effects of LPS and/or SA. Of note, the TPR agonist by itself elicits an inflammatory response, which was attenuated by blocking TPR or ROCK. Our data suggest that TPR plays a key role in promoting an inflammatory response in human PBMCs, and this effect is mediated via TLR4 and/or ROCK signaling.
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Affiliation(s)
- Vinothkumar Rajamanickam
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (V.R.); (C.V.D.); (R.T.C.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Cyrus V. Desouza
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (V.R.); (C.V.D.); (R.T.C.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Romilia T. Castillo
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (V.R.); (C.V.D.); (R.T.C.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Viswanathan Saraswathi
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (V.R.); (C.V.D.); (R.T.C.)
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
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Lim JJ, Lim SW, Reginald K, Say Y, Liu MH, Chew FT. Association of frequent intake of trans fatty acids and saturated fatty acids in diets with increased susceptibility of atopic dermatitis exacerbation in young Chinese adults: A cross-sectional study in Singapore/Malaysia. SKIN HEALTH AND DISEASE 2024; 4:e330. [PMID: 39104637 PMCID: PMC11297457 DOI: 10.1002/ski2.330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 11/17/2023] [Accepted: 12/24/2023] [Indexed: 08/07/2024]
Abstract
Background & Objective Numerous evidence has attributed diets with a high fatty acids (FAs) intake to be associated with atopic dermatitis (AD) development. Therefore, this study investigated the association between intake frequencies of five dietary FAs and AD exacerbations among young Chinese adults from Singapore and Malaysia. Methods A validated International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was investigator-administered to 13,561 subjects to collect information on socioeconomic, anthropometric, dietary and lifestyles habits, and personal/family medical histories. Six novel dietary indices were derived to analyse the associations between total FAs, trans fatty acids (TFAs), saturated fatty acids (SFAs), monounsaturated fatty acids, linoleic acids, and alpha-linolenic acids in diets and AD exacerbation. Synergy factor (SF) analysis was used to identify interactions between the dietary FAs to influence disease susceptibility. Results In our multivariable model adjusted for age, gender, BMI, parental eczema, and lifestyle factors, a diet high in total estimated FAs was strongly associated with AD (Adjusted Odds Ratio (AOR): 1.227; 95% Confidence Interval (CI): 1.054-1.429; adjusted p-value <0.01). Particularly, high estimated total TFAs and SFAs were significantly associated with AD exacerbations including chronic and current moderate-to-severe AD. The association between TFAs and AD remained strong even controlled for the total FAs in diets and false discovery rate corrected (AOR: 1.516; 95% CI: 1.094-2.097; adjusted p-value <0.05). Similarly, having a high SFAs in diets was associated with AD (AOR: 1.581; 95% CI: 1.106-2.256; adjusted p-value <0.05) independently on the total FAs in diets. FAs in diets do not interact to influence AD. Conclusion Overall, these results highlighted an association between high dietary TFAs and SFAs and AD exacerbations in an Asian population.
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Affiliation(s)
- Jun Jie Lim
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
| | - Sing Wei Lim
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
| | - Kavita Reginald
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
- Department of Biological SciencesSchool of Medicine and Life SciencesSunway UniversityPetaling JayaMalaysia
| | - Yee‐How Say
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
- Department of Biological SciencesSchool of Medicine and Life SciencesSunway UniversityPetaling JayaMalaysia
- Department of Biomedical ScienceFaculty of ScienceUniversiti Tunku Abdul Rahman (UTAR)KamparMalaysia
| | - Mei Hui Liu
- Department of Food Science & TechnologyFaculty of ScienceNational University of SingaporeSingaporeSingapore
| | - Fook Tim Chew
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
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Zhang Y, Huang F, Wu Y, Jiao L, Wang Y, Ding T. Protective effect of rubber seed oil on human endothelial cells. J Mol Histol 2024; 55:589-598. [PMID: 38890233 PMCID: PMC11306359 DOI: 10.1007/s10735-024-10198-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 05/01/2024] [Indexed: 06/20/2024]
Abstract
OBJECTIVE This study was conducted to characterize the antioxidant and anti-inflammatory properties of Rubber Seed Oil (RSO) against atherosclerosis (AS) through the study of the protective effects and mechanisms on human umbilical vein endothelial cells (HUVECs) injury induced by oxidized low-density lipoprotein (ox-LDL). METHODS HUVECs were treated with RSO, ox-LDL, RSO + ox-LDL, respectively, followed by cell activity testing, levels of IL-1β, IL-6, IL-10, TNF-α, ROS, NO, the mRNA expression of eNOS and protein expression of MCP-1, VCAM-1, eNOS, TLR4, NF-κB p65、p-NF-κB p65. RESULTS Compared with the ox-LDL group, cell viability, NO level and the expression of eNOS mRNA significantly increased. and the levels of pro-inflammatory factors such as IL-1β, IL-6, TNF-α, IL-10, ROS were significantly decreased, which was accompanied by decreases in TLR4 mRNA, TLR4, MCP-1, VCAM-1 protein expression, as well as the ratio of NF-κB p-p65/p65 in the group treated with 250 μg/ml ox-LDL + 50 μg/ml RSO, 250 μg/ml ox-LDL + 100 μg/ml RSO, 250 μg/ml ox-LDL + 150 μg/ml RSO. CONCLUSIONS RSO can reduce the expression of pro-inflammatory mediators, oxidative factors involved in injured vascular endothelial cells, exhibiting anti-inflammatory and antioxidant properties HUVECs exposed to ox-LDL. In addition, it may alleviate endothelial cell damage by inhibiting the TLR4/NF-κB signaling pathway.
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Affiliation(s)
- Yujie Zhang
- The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wuhua District, Kunming, Yunnan, China
| | - Fuchuan Huang
- The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wuhua District, Kunming, Yunnan, China
| | - Yiran Wu
- The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wuhua District, Kunming, Yunnan, China
| | - Linmei Jiao
- The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wuhua District, Kunming, Yunnan, China
| | - Yun Wang
- Xishuangbanna Huakun Biotechnology Co., Ltd, Xishuangbanna Dai Autonomous Prefecture, Jinghong, Yunnan, China
| | - Tao Ding
- The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Road, Wuhua District, Kunming, Yunnan, China.
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Bai H, Zhang H, Wang C, Lambo MT, Li Y, Zhang Y. Effects of altering the ratio of C16:0 and cis-9 C18:1 in rumen bypass fat on growth performance, lipid metabolism, intestinal barrier, cecal microbiota, and inflammation in fattening bulls. J Anim Sci Biotechnol 2024; 15:94. [PMID: 38971799 PMCID: PMC11227724 DOI: 10.1186/s40104-024-01052-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 05/20/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND C16:0 and cis-9 C18:1 may have different effects on animal growth and health due to unique metabolism in vivo. This study was investigated to explore the different effects of altering the ratio of C16:0 and cis-9 C18:1 in fat supplements on growth performance, lipid metabolism, intestinal barrier, cecal microbiota, and inflammation in fattening bulls. Thirty finishing Angus bulls (626 ± 69 kg, 21 ± 0.5 months) were divided into 3 treatments according to the randomized block design: (1) control diet without additional fat (CON), (2) CON + 2.5% palmitic acid calcium salt (PA, 90% C16:0), and (3) CON + 2.5% mixed fatty acid calcium salt (MA, 60% C16:0 + 30% cis-9 C18:1). The experiment lasted for 104 d, after which all the bulls were slaughtered and sampled for analysis. RESULTS MA tended to reduce 0-52 d dry matter intake compared to PA (DMI, P = 0.052). Compared with CON and MA, PA significantly increased 0-52 d average daily gain (ADG, P = 0.027). PA tended to improve the 0-52 d feed conversion rate compared with CON (FCR, P = 0.088). Both PA and MA had no significant effect on 52-104 days of DMI, ADG and FCR (P > 0.05). PA tended to improve plasma triglycerides compared with MA (P = 0.077), significantly increased plasma cholesterol (P = 0.002) and tended to improve subcutaneous adipose weight (P = 0.066) when compared with CON and MA. Both PA and MA increased visceral adipose weight compared with CON (P = 0.021). Only PA increased the colonization of Rikenellaceae, Ruminococcus and Proteobacteria in the cecum, and MA increased Akkermansia abundance (P < 0.05). Compared with CON, both PA and MA down-regulated the mRNA expression of Claudin-1 in the jejunum (P < 0.001), increased plasma diamine oxidase (DAO, P < 0.001) and lipopolysaccharide (LPS, P = 0.045). Compared with CON and MA, PA down-regulated the ZO-1 in the jejunum (P < 0.001) and increased plasma LPS-binding protein (LBP, P < 0.001). Compared with CON, only PA down-regulated the Occludin in the jejunum (P = 0.013). Compared with CON, PA and MA significantly up-regulated the expression of TLR-4 and NF-κB in the visceral adipose (P < 0.001) and increased plasma IL-6 (P < 0.001). Compared with CON, only PA up-regulated the TNF-α in the visceral adipose (P = 0.01). Compared with CON and MA, PA up-regulated IL-6 in the visceral adipose (P < 0.001), increased plasma TNF-α (P < 0.001), and reduced the IgG content in plasma (P = 0.035). Compared with CON, PA and MA increased C16:0 in subcutaneous fat and longissimus dorsi muscle (P < 0.05), while more C16:0 was also deposited by extension and desaturation into C18:0 and cis-9 C18:1. However, neither PA nor MA affected the content of cis-9 C18:1 in longissimus dorsi muscle compared with CON (P > 0.05). CONCLUSIONS MA containing 30% cis-9 C18:1 reduced the risk of high C16:0 dietary fat induced subcutaneous fat obesity, adipose tissue and systemic low-grade inflammation by accelerating fatty acid oxidative utilization, improving colonization of Akkermansia, reducing intestinal barrier damage, and down-regulating NF-κB activation.
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Affiliation(s)
- Haixin Bai
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, China
| | - Haosheng Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, China
| | - Congwen Wang
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming, 650500, China
| | - Modinat Tolani Lambo
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, China
| | - Yang Li
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, China.
| | - Yonggen Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, China.
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Hao J, Jin X, Li Z, Zhu Y, Wang L, Jiang X, Wang D, Qi L, Jia D, Gao B. Anti-Obesity Activity of Sanghuangporus vaninii by Inhibiting Inflammation in Mice Fed a High-Fat Diet. Nutrients 2024; 16:2159. [PMID: 38999906 PMCID: PMC11243596 DOI: 10.3390/nu16132159] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 06/29/2024] [Accepted: 07/01/2024] [Indexed: 07/14/2024] Open
Abstract
Obesity is an unhealthy condition associated with various diseases characterized by excess fat accumulation. However, in China, the prevalence of obesity is 14.1%, and it remains challenging to achieve weight loss or resolve this issue through clinical interventions. Sanghuangpours vaninii (SPV) is a nutritional fungus with multiple pharmacological activities and serves as an ideal dietary intervention for combating obesity. In this study, a long-term high-fat diet (HFD) was administered to induce obesity in mice. Different doses of SPV and the positive drug simvastatin (SV) were administered to mice to explore their potential anti-obesity effects. SPV regulated weight, serum lipids, and adipocyte size while inhibiting inflammation and hepatic steatosis. Compared with the vehicle-treated HFD-fed mice, the lowest decreases in total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) were 9.72%, 9.29%, and 12.29%, respectively, and the lowest increase in high-density lipoprotein cholesterol (HDL-C) was 5.88% after treatment with different doses of SPV. With SPV treatment, the analysis of gut microbiota and serum lipids revealed a significant association between lipids and inflammation-related factors, specifically sphingomyelin. Moreover, Western blotting results showed that SPV regulated the toll-like receptor (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway in HFD-diet mice, which is related to inflammation and lipid metabolism. This research presents empirical proof of the impact of SPV therapy on obesity conditions.
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Affiliation(s)
- Jie Hao
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.H.); (X.J.); (Z.L.); (Y.Z.); (L.W.); (D.W.)
| | - Xinghui Jin
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.H.); (X.J.); (Z.L.); (Y.Z.); (L.W.); (D.W.)
| | - Zhige Li
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.H.); (X.J.); (Z.L.); (Y.Z.); (L.W.); (D.W.)
| | - Yanfeng Zhu
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.H.); (X.J.); (Z.L.); (Y.Z.); (L.W.); (D.W.)
| | - Lu Wang
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.H.); (X.J.); (Z.L.); (Y.Z.); (L.W.); (D.W.)
| | - Xue Jiang
- College of Life Science and Technology, Changchun University of Science and Technology, Changchun 130022, China;
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.H.); (X.J.); (Z.L.); (Y.Z.); (L.W.); (D.W.)
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun 130118, China
| | - Liangliang Qi
- Microbiology Research Institute, Guangxi Academy of Agricultural Sciences, Nanning 530007, China;
| | - Dongxu Jia
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.H.); (X.J.); (Z.L.); (Y.Z.); (L.W.); (D.W.)
| | - Bo Gao
- School of Life Sciences, Jilin University, Changchun 130012, China; (J.H.); (X.J.); (Z.L.); (Y.Z.); (L.W.); (D.W.)
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Zhang C, Simón M, Harder JM, Lim H, Montgomery C, Wang Q, John SW. TLR4 deficiency does not alter glaucomatous progression in a mouse model of chronic glaucoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.07.597951. [PMID: 38895321 PMCID: PMC11185798 DOI: 10.1101/2024.06.07.597951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Glaucoma is a leading cause of irreversible blindness worldwide. Toll-like receptor 4 (TLR4) is a pattern-recognition transmembrane receptor that induces neuroinflammatory processes in response to injury. Tlr4 is highly expressed in ocular tissues and is known to modulate inflammatory processes in both anterior and posterior segment tissues. TLR4 activation can lead to mitochondrial dysfunction and metabolic deficits in inflammatory disorders. Due to its effects on inflammation and metabolism, TLR4 is a candidate to participate in glaucoma pathogenesis. It has been suggested as a therapeutic target based on studies using acute models, such as experimentally raising IOP to ischemia-inducing levels. Nevertheless, its role in chronic glaucoma needs further evaluation. In the current study, we investigated the role of TLR4 in an inherited mouse model of chronic glaucoma, DBA/2J. To do this, we analyzed the effect of Tlr4 knockout (Tlr4 -/-) on glaucoma-associated phenotypes in DBA/2J mice. Our studies found no significant differences in intraocular pressure, iris disease, or glaucomatous progression in Tlr4 -/- compared to Tlr4 +/+ DBA/2J mice. These data do not identify a role for TLR4 in this chronic glaucoma, but further research is warranted to understand its role in other glaucoma models and different genetic contexts.
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Affiliation(s)
- Chi Zhang
- Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY
| | - Marina Simón
- Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY
| | | | - Haeyn Lim
- Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY
| | - Christa Montgomery
- Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY
| | - Qing Wang
- Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY
| | - Simon W.M. John
- Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY
- Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY
- The Jackson Laboratory, Bar Harbor, ME
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Sun M, Zhan H, Long X, Alsayed AM, Wang Z, Meng F, Wang G, Mao J, Liao Z, Chen M. Dehydrocostus lactone alleviates irinotecan-induced intestinal mucositis by blocking TLR4/MD2 complex formation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155371. [PMID: 38518649 DOI: 10.1016/j.phymed.2024.155371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/08/2024] [Accepted: 01/15/2024] [Indexed: 03/24/2024]
Abstract
BACKGROUND Irinotecan (CPT-11) is used as chemotherapeutic drug for treatment of colorectal cancer. However, without satisfactory treatments, its gastrointestinal toxicities such as diarrhea and intestinal inflammation severely restrained its clinical application. Roots of Aucklandia lappa Decne. are used as traditional Chinese medicine to relieve gastrointestinal dysfunction and dehydrocostus lactone (DHL) is one of its main active components. Nevertheless, the efficacy and mechanism of DHL against intestinal mucositis remains unclear. PURPOSE The present study aimed to investigate the protective effects of DHL on CPT-11-induced intestinal mucositis and its underlying mechanisms. METHODS The protective effect of DHL was investigated in CPT-11-induced mice and lipopolysaccharide (LPS)+CPT-11 induced THP-1 macrophages. Body weight, diarrhea score, survival rate, colon length, and histopathological changes in mice colon and jejunum were analyzed to evaluate the protective effect of DHL in vivo. And DHL on reducing inflammatory response and regulating TLR4/NF-κB/NLRP3 pathway in vivo and in vitro were explored. Moreover, DHL on the interaction between TLR4 and MD2 was investigated. And silencing TLR4 targeted by siRNA was performed to validate the mechanisms of DHL on regulating the inflammation. RESULTS DHL prevented CPT-11-induced intestinal damage, represented by reducing weight loss, diarrhea score, mortality rate and the shortening of the colon. Histological analysis confirmed that DHL prevented intestinal epithelial injury and improved the intestinal barrier function in CPT-11 induced mice. Besides, DHL significantly downregulated the level of inflammatory cytokines by inhibiting TLR4/NF-κB/NLRP3 signaling pathway in CPT-11-induced mice and LPS+CPT-11-induced THP-1 macrophages. In addition, DHL blocked TLR4/MD2 complex formation. Molecular docking combined with SIP and DARTS assay showed that DHL could bind to TLR4/MD2 and occludes the hydrophobic pocket of MD2. Furthermore, Silencing TLR4 abrogated the effect of DHL on LPS+CPT-11 induced inflammatory response in THP-1 macrophages. Additionally, DHL ameliorate the CPT-11-induced intestinal mucositis without affecting the anti-tumor efficacy of CPT-11 in the tumor xenograft mice. CONCLUSION This study found that DHL exhibited the anti-inflammatory effects in CPT-11-induced intestinal mucositis by inhibiting the formation of TLR4/MD2 complex and then regulation of NF-κB/NLRP3 signaling pathway. DHL is potentially served as a novel strategy of combined medication with CPT-11.
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Affiliation(s)
- Miaomiao Sun
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Honghong Zhan
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Xiaoliang Long
- School of Life Sciences, Integrative Science Center of Germplasm Creation in Western China (Chongqing) Science City and Southwest University, TAAHC-SWU Medicinal Plant Joint R&D Centre, Southwest University, Chongqing 400715, China
| | - Ali M Alsayed
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Zhe Wang
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Fancheng Meng
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Guowei Wang
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
| | - Jingxin Mao
- Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Zhihua Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Min Chen
- Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China; Chongqing Key Laboratory of High Active Traditional Chinese Drug Delivery System, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China.
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Sun Y, Yin Y, Yang S, Ai D, Qin H, Xia X, Xu X, Song J. Lipotoxicity: The missing link between diabetes and periodontitis? J Periodontal Res 2024; 59:431-445. [PMID: 38419425 DOI: 10.1111/jre.13242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 01/10/2024] [Accepted: 01/14/2024] [Indexed: 03/02/2024]
Abstract
Lipotoxicity refers to the accumulation of lipids in tissues other than adipose tissue (body fat). It is one of the major pathophysiological mechanisms responsible for the progression of diabetes complications such as non-alcoholic fatty liver disease and diabetic nephropathy. Accumulating evidence indicates that lipotoxicity also contributes significantly to the toxic effects of diabetes on periodontitis. Therefore, we reviewed the current in vivo, in vitro, and clinical evidence of the detrimental effects of lipotoxicity on periodontitis, focusing on its molecular mechanisms, especially oxidative and endoplasmic reticulum stress, inflammation, ceramides, adipokines, and programmed cell death pathways. By elucidating potential therapeutic strategies targeting lipotoxicity and describing their associated mechanisms and clinical outcomes, including metformin, statins, liraglutide, adiponectin, and omega-3 PUFA, this review seeks to provide a more comprehensive and effective treatment framework against diabetes-associated periodontitis. Furthermore, the challenges and future research directions are proposed, aiming to contribute to a more profound understanding of the impact of lipotoxicity on periodontitis.
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Affiliation(s)
- Yu Sun
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Yuanyuan Yin
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Sihan Yang
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Dongqing Ai
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Han Qin
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Xuyun Xia
- Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiaohui Xu
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Jinlin Song
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
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Zou Y, Wang Y, Zhou W, Pei J. Banxia Xiexin decoction combined with 5-ASA protects against CPT-11-induced intestinal dysfunction in rats via inhibiting TLR4/NF-κB signaling pathway. Immun Inflamm Dis 2024; 12:e1208. [PMID: 38860759 PMCID: PMC11165681 DOI: 10.1002/iid3.1208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 10/24/2023] [Accepted: 02/17/2024] [Indexed: 06/12/2024] Open
Abstract
BACKGROUND Banxia Xiexin decoction (BXD) can control irinotecan (CPT-11)-caused delayed diarrhea, but the corresponding mechanism remains undefined. AIMS This paper aimed to uncover the mechanism of BXD in regulating CPT-11-caused delayed diarrhea. MATERIALS & METHODS Sprague-Dawley (SD) rats were assigned into the control, model, BXD low-dose (BXD-L, 5 g/kg), BXD medium-dose (BXD-M, 10 g/kg), BXD high-dose (BXD-H, 15 g/kg), 5-aminosalicylic acid (5-ASA, 10 mL/kg), and BXD-M + 5-ASA groups. Rats were injected intraperitoneally with 150 mg/kg CPT-11 at Day 4 and Day 5 to induce delayed diarrhea, and later treated with various doses (low, medium, and high) of BXD and 5-ASA for 9 days, except for rats in control group. The body weight of rats was measured. The rat colon tissue injury, inflammatory cytokine levels, and the activation of toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway were detected. RESULTS BXD (5, 10, or 15 g/kg) or 5-ASA (10 mL/kg) alleviated body weight loss and colon tissue injury, decreased levels of inflammatory cytokines, and inactivated TLR4/NF-κB signaling pathway in CPT-11-induced model rats. BXD at 10 g/kg (the optimal concentration) could better treat CPT-11-induced intestinal dysfunction, as evidenced by the resulting approximately 50% reduction on injury score of model rats. Moreover, BXD-M (10 g/kg) synergistic with 5-ASA (10 mL/kg) further strengthened the inhibition on rat body weight loss, colon tissue injury, inflammatory cytokine levels, and TLR4/NF-κB signaling pathway. CONCLUSION To sum up, BXD has a protective effect against CPT-11-induced intestinal dysfunction by inhibiting inflammation through inactivation TLR4/NF-κB signaling pathway. In particular, the combined use of BXD and 5-ASA holds great promise for treating CPT-11-induced delayed diarrhea.
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Affiliation(s)
- Yuanyuan Zou
- Department of GastroenterologyXiaoshan Hospital of Traditional Chinese MedicineHangzhouChina
| | - Yakun Wang
- Department of Critical Care MedicineHangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical UniversityHangzhouChina
| | - Wenying Zhou
- Department of GastroenterologyXiaoshan Hospital of Traditional Chinese MedicineHangzhouChina
| | - Jingbo Pei
- Department of GastroenterologyXiaoshan Hospital of Traditional Chinese MedicineHangzhouChina
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Zhang Y, Ren X, Zhang L, Sun X, Li W, Chen Y, Tian Y, Chu Z, Wei Y, Yao G, Wang Y. Hydrogen gas inhalation ameliorates LPS-induced BPD by inhibiting inflammation via regulating the TLR4-NFκB-IL6/NLRP3 signaling pathway in the placenta. Eur J Med Res 2024; 29:285. [PMID: 38745325 PMCID: PMC11092067 DOI: 10.1186/s40001-024-01874-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 04/28/2024] [Indexed: 05/16/2024] Open
Abstract
INTRODUCTION Hydrogen (H2) is regarded as a novel therapeutic agent against several diseases owing to its inherent biosafety. Bronchopulmonary dysplasia (BPD) has been widely considered among adverse pregnancy outcomes, without effective treatment. Placenta plays a role in defense, synthesis, and immunity, which provides a new perspective for the treatment of BPD. This study aimed to investigate if H2 reduced the placental inflammation to protect the neonatal rat against BPD damage and potential mechanisms. METHODS We induced neonatal BPD model by injecting lipopolysaccharide (LPS, 1 µg) into the amniotic fluid at embryonic day 16.5 as LPS group. LPS + H2 group inhaled 42% H2 gas (4 h/day) until the samples were collected. We primarily analyzed the neonatal outcomes and then compared inflammatory levels from the control group (CON), LPS group and LPS + H2 group. HE staining was performed to evaluate inflammatory levels. RNA sequencing revealed dominant differentially expressed genes. Bioinformatics analysis (GO and KEGG) of RNA-seq was applied to mine the signaling pathways involved in protective effect of H2 on the development of LPS-induced BPD. We further used qRT-PCR, Western blot and ELISA methods to verify differential expression of mRNA and proteins. Moreover, we verified the correlation between the upstream signaling pathways and the downstream targets in LPS-induced BPD model. RESULTS Upon administration of H2, the inflammatory infiltration degree of the LPS-induced placenta was reduced, and infiltration significantly narrowed. Hydrogen normalized LPS-induced perturbed lung development and reduced the death ratio of the fetus and neonate. RNA-seq results revealed the importance of inflammatory response biological processes and Toll-like receptor signaling pathway in protective effect of hydrogen on BPD. The over-activated upstream signals [Toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), Caspase1 (Casp1) and NLR family pyrin domain containing 3 (NLRP3) inflammasome] in LPS placenta were attenuated by H2 inhalation. The downstream targets, inflammatory cytokines/chemokines [interleukin (IL)-6, IL-18, IL-1β, C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1)], were decreased both in mRNA and protein levels by H2 inhalation in LPS-induced placentas to rescue them from BPD. Correlation analysis displayed a positive association of TLR4-mediated signaling pathway both proinflammatory cytokines and chemokines in placenta. CONCLUSION H2 inhalation ameliorates LPS-induced BPD by inhibiting excessive inflammatory cytokines and chemokines via the TLR4-NFκB-IL6/NLRP3 signaling pathway in placenta and may be a potential therapeutic strategy for BPD.
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Affiliation(s)
- Yafang Zhang
- Department of Neonatology and NICU, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Xianhui Ren
- Medical Imaging Center, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Linli Zhang
- Department of Neonatology and NICU, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Xinliu Sun
- Central Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Wenjing Li
- Department of Ultrasound, Taian Traditional Chinese Medicine Hospital, Taian, Shandong, China
| | - Yunxi Chen
- Research Center for Translational Medicine, Tongji University Affiliated East Hospital, Shanghai, China
| | - Yan Tian
- Research Center for Translational Medicine, Tongji University Affiliated East Hospital, Shanghai, China
| | - Zhongxia Chu
- Department of Neonatology and NICU, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Youzhen Wei
- Central Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China
| | - Guo Yao
- Department of Neonatology and NICU, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China.
| | - Yan Wang
- Department of Neonatology and NICU, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong, China.
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Meng S, Wang Z, Liu X, Shen K, Gu Y, Yu B, Wang L. Uptake of ox-LDL by binding to LRP6 mediates oxidative stress-induced BMSCs senescence promoting obesity-related bone loss. Cell Signal 2024; 117:111114. [PMID: 38387686 DOI: 10.1016/j.cellsig.2024.111114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/10/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Obesity has long been thought to be a main cause of hyperlipidemia. As a systemic disease, the impact of obesity on organs, tissues and cells is almost entirely negative. However, the relationship between obesity and bone loss is highly controversial. On the one hand, obesity has long been thought to have a positive effect on bone due to increased mechanical loading on the skeleton, conducive to increasing bone mass to accommodate the extra weight. On the other hand, obesity-related metabolic oxidative modification of low-density lipoprotein (LDL) in vivo causes a gradual increase of oxidized LDL (ox-LDL) in the bone marrow microenvironment. We have reported that low-density lipoprotein receptor-related protein 6 (LRP6) acts as a receptor of ox-LDL and mediates the bone marrow stromal cells (BMSCs) uptake of ox-LDL. We detected elevated serum ox-LDL in obese mice. We found that ox-LDL uptake by LRP6 led to an increase of intracellular reactive oxygen species (ROS) in BMSCs, and N-acetyl-L-cysteine (NAC) alleviated the cellular senescence and impairment of osteogenesis induced by ox-LDL. Moreover, LRP6 is a co-receptor of Wnt signaling. We found that LRP6 preferentially binds to ox-LDL rather than dickkopf-related protein 1 (DKK1), both inhibiting Wnt signaling and promoting BMSCs senescence. Mesoderm development LRP chaperone (MESD) overexpression inhibits ox-LDL binding to LRP6, attenuating oxidative stress and BMSCs senescence, eventually rescuing bone phenotype.
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Affiliation(s)
- Senxiong Meng
- Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhuan Wang
- Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xiaonan Liu
- Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ke Shen
- Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuan Gu
- Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bin Yu
- Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Lei Wang
- Division of Orthopedics and Traumatology, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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Yuri G, Cifuentes M, Cisternas P, Paredes A, Ormazabal P. Effect of Lampaya medicinalis Phil. (Verbenaceae) and Palmitic Acid on Insulin Signaling and Inflammatory Marker Expression in Human Adipocytes. Pharmaceuticals (Basel) 2024; 17:566. [PMID: 38794136 PMCID: PMC11123923 DOI: 10.3390/ph17050566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Aging and obesity are associated with insulin resistance (IR) and low-grade inflammation. Molecularly, IR is characterized by a reduction in glucose uptake and insulin signaling (IRS-1/Akt/AS160 pathway), while inflammation may result from upregulated NF-κB pathway after low Tyr-IκBα phosphorylation. Upregulated phosphatase activity of PTP1B is associated with impaired insulin signaling and increased inflammation. Plasma levels of palmitic acid (PA) are elevated in obesity, triggering inflammation and disruption of insulin signaling. Traditional medicine in Northern Chile uses oral infusions of Lampaya medicinalis Phil. (Verbenaceae) to treat inflammatory conditions. Significant amounts of flavonoids are found in the hydroethanolic extract of Lampaya (HEL), which may account for its biological activity. The aim of this work was to study the effect of HEL and PA on insulin signaling and glucose uptake as well as inflammatory marker expression in human adipocytes. METHODS We studied HEL effects on PA-induced impairment on insulin signaling, glucose uptake and inflammatory marker content in human SW872 adipocytes. HEL cytotoxicity was assessed in adipocytes at different concentrations (0.01 to 10 g/mL). Adipocytes were incubated or not with PA (0.4 mM, 24 h) with or without HEL (2 h pre-incubation), and then stimulated with insulin (10 min, 100 mM) or a vehicle. Phospho-IRS-1, phospho-Akt, phospho-AS160, phospho-NF-κB and phospho-IκBα, as well as protein levels of PTP1B, were assessed using Western blotting, and glucose uptake was evaluated using the 2-NBDG analogue. RESULTS At the assessed HEL concentrations, no cytotoxic effects were observed. PA decreased insulin-stimulated phospho-Akt and glucose uptake, while co-treatment with HEL increased such markers. PA decreased phospho-IRS-1 and phospho-Tyr-IκBα. On the other hand, incubation with HEL+PA decreased phospho-AS160 and phospho-NF-κB compared with cells treated with PA alone. CONCLUSION Our results suggest a beneficial effect of HEL by improving PA-induced impairment on molecular markers of insulin signaling, glucose uptake and inflammation in adipocytes. Further studies are necessary to elucidate whether lampaya may constitute a preventive strategy for people whose circulating PA levels contribute to IR and inflammation during aging and obesity.
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Affiliation(s)
- Gabriela Yuri
- Institute of Health Sciences, Universidad de O’Higgins, Av. Libertador Bernardo O’Higgins 611, Rancagua 2820000, Chile; (G.Y.); (P.C.)
- Laboratory of Obesity and Metabolism in Geriatrics and Adults (OMEGA), Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Av. El Líbano 5524, Macul, Santiago 7830490, Chile;
| | - Mariana Cifuentes
- Laboratory of Obesity and Metabolism in Geriatrics and Adults (OMEGA), Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Av. El Líbano 5524, Macul, Santiago 7830490, Chile;
- Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380453, Chile
| | - Pedro Cisternas
- Institute of Health Sciences, Universidad de O’Higgins, Av. Libertador Bernardo O’Higgins 611, Rancagua 2820000, Chile; (G.Y.); (P.C.)
| | - Adrián Paredes
- Laboratorio de Química Biológica, Instituto Antofagasta (IA) and Departamento de Química, Facultad de Ciencias Básicas, Universidad de Antofagasta, Av. Angamos 601, Antofagasta 1240000, Chile;
| | - Paulina Ormazabal
- Escuela de Obstetricia, Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebastián, Santiago 8330106, Chile
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