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He JM, Yang Y. Association between neutrophil-lymphocyte ratio and all-cause and cardiovascular mortality in patients with diabetes or prediabetes with comorbid obstructive sleep apnea symptoms: evidence from NHANES 2005-2008 and 2015-2018. Front Endocrinol (Lausanne) 2025; 16:1512621. [PMID: 40331136 PMCID: PMC12052538 DOI: 10.3389/fendo.2025.1512621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/25/2025] [Indexed: 05/08/2025] Open
Abstract
Objective The neutrophil-lymphocyte ratio (NLR) is a hematological marker to assess systemic inflammation and immune status. The relationship between NLR and the risk of mortality in individuals with diabetes mellitus or pre-diabetes mellitus who have comorbid symptoms of obstructive sleep apnea is unknown. Our study aims to evaluate the association between NLR and all-cause and cardiovascular mortality in this population. Methods Our research enrolled 5432 patients from the National Health and Nutrition Examination Surveys (2005-2008 and 2015-2018) diagnosed with diabetes or prediabetes combined with symptoms of OSA. Mortality outcomes were ascertained by linkage to the National Death Index (NDI) records for December 31, 2019. The association between NLR and mortality was tested using multivariate Cox regression models. The non-linear relationship was analyzed based on restricted cubic spline curves (RCS). Kaplan-Meier (K-M) survival analysis and time-dependent subject operating characteristic curve (ROC) analysis were performed to assess the predictive value of NLR on patient survival. Results In a median follow-up period of 52 months, study participants experienced 632 deaths from all causes and 143 deaths due to cardiovascular disease. According to Cox regression analysis, the fourth quartile was associated with higher all-cause mortality (HR=1.76, 95% CI 1.25-2.49) and cardiovascular mortality (HR=3.08, 95% CI 1.54-6.18) compared with the first quartile under the fully adjusted model. Meanwhile, K-M survival curves showed that all-cause and cardiovascular mortality increased with increasing NLR levels, with the highest mortality in the fourth quartile group. In addition, the areas under the curve (AUC) of the 3, 5and 10year survival were 0.67, 0.63, and 0.74 for all-cause mortality, respectively. Meanwhile, the AUC values for cardiovascular mortality were 0.73, 0.56, and 0.69. Conclusion For individuals with diabetes and OSA symptoms, elevated NLR can serve as a prognostic indicator for all-cause and cardiovascular mortality.
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Affiliation(s)
- Jin-Mao He
- Department of the Central Laboratory, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, China
- Department of the Cardiac Ultrasound Department, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yi Yang
- Department of the Central Laboratory, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, China
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Zhang Y, Zhang Z, Tu C, Chen X, He R. Advanced Glycation End Products in Disease Development and Potential Interventions. Antioxidants (Basel) 2025; 14:492. [PMID: 40298887 PMCID: PMC12024296 DOI: 10.3390/antiox14040492] [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: 03/06/2025] [Revised: 04/09/2025] [Accepted: 04/16/2025] [Indexed: 04/30/2025] Open
Abstract
Advanced glycation end products (AGEs) are a group of compounds formed through non-enzymatic reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs can be generated in the body or introduced through dietary sources and smoking. Recent clinical and animal studies have highlighted the significant role of AGEs in various health conditions. These compounds accumulate in nearly all mammalian tissues and are associated with a range of diseases, including diabetes and its complications, cardiovascular disease, and neurodegeneration. This review summarizes the major diseases linked to AGE accumulation, presenting both clinical and experimental evidence. The pathologies induced by AGEs share common mechanisms across different organs, primarily involving oxidative stress, chronic inflammation, and direct protein cross-linking. Interventions targeting AGE-related diseases focus on inhibiting AGE formation using synthetic or natural antioxidants, as well as reducing dietary AGE intake through lifestyle modifications. AGEs are recognized as significant risk factors that impact health and accelerate aging, particularly in individuals with hyperglycemia. Monitoring AGE level and implementing nutritional interventions can help maintain overall health and reduce the risk of AGE-related complications.
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Affiliation(s)
- Yihan Zhang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou Higher Education Mega Center, Panyu District, Guangzhou 510006, China; (Y.Z.); (Z.Z.)
- BYHEALTH Institute of Nutrition & Health, No. 916, Huangpu Avenue East, Huangpu District, Guangzhou 510799, China; (C.T.); (X.C.)
| | - Zhen Zhang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou Higher Education Mega Center, Panyu District, Guangzhou 510006, China; (Y.Z.); (Z.Z.)
- BYHEALTH Institute of Nutrition & Health, No. 916, Huangpu Avenue East, Huangpu District, Guangzhou 510799, China; (C.T.); (X.C.)
| | - Chuyue Tu
- BYHEALTH Institute of Nutrition & Health, No. 916, Huangpu Avenue East, Huangpu District, Guangzhou 510799, China; (C.T.); (X.C.)
| | - Xu Chen
- BYHEALTH Institute of Nutrition & Health, No. 916, Huangpu Avenue East, Huangpu District, Guangzhou 510799, China; (C.T.); (X.C.)
| | - Ruikun He
- BYHEALTH Institute of Nutrition & Health, No. 916, Huangpu Avenue East, Huangpu District, Guangzhou 510799, China; (C.T.); (X.C.)
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Yadegar A, Mohammadi F, Seifouri K, Mokhtarpour K, Yadegar S, Bahrami Hazaveh E, Seyedi SA, Rabizadeh S, Esteghamati A, Nakhjavani M. Surrogate markers of insulin resistance and coronary artery disease in type 2 diabetes: U-shaped TyG association and insights from machine learning integration. Lipids Health Dis 2025; 24:96. [PMID: 40089748 PMCID: PMC11910848 DOI: 10.1186/s12944-025-02526-5] [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: 01/28/2025] [Accepted: 03/11/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Surrogate insulin resistance (IR) indices are simpler and more practical alternatives to insulin-based IR indicators for clinical use. This study explored the association between surrogate IR indices, including triglyceride-glucose index (TyG), triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist circumference (TyG-WC), triglyceride glucose-waist to height ratio (TyG-WHtR), metabolic score for insulin resistance (METS-IR), and the triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) ratio, and coronary artery disease (CAD) in patients with type 2 diabetes (T2D). METHODS Patients with T2D were enrolled in this study and divided into two groups, matched for age and diabetes duration: those with CAD and those without CAD. The association between surrogate IR indices and CAD was evaluated using restricted cubic spline (RCS) and multivariable logistic regression and their discriminative ability was assessed via Receiver operating characteristic (ROC) curve analysis. Additionally, machine learning models, including Logistic Regression, Random Forest, eXtreme Gradient Boosting (XGBoost), Light Gradient Boosting Machine (LightGBM), and Support Vector Machine (SVM), were employed to predict CAD presence using multiple surrogate IR indices and their components. RESULTS All surrogate IR indices exhibited non-linear associations with CAD. TyG demonstrated a U-shaped relationship, where both extremely low and high levels were associated with higher odds of CAD compared to intermediate levels. The surrogate IR indices showed a relatively strong discriminative ability for CAD, with AUC values exceeding 0.708 across all indices. The TG/HDL-C ratio displayed the highest AUC (0.721), accuracy (68%), and sensitivity (71%), whereas TyG-WC showed the highest specificity (78%). Machine learning algorithms (except logistic regression) demonstrated greater discriminative power than individual IR indices. Random forest and XGBoost revealed the best performance when using either multiple surrogate IR indices or their components. CONCLUSIONS Surrogate IR indices could be used as valuable tools for evaluating cardiometabolic risk in patients with T2D, who are at high risk for CAD. Integrating machine learning models further improved CAD prediction, underscoring their potential for better risk stratification. The observed association between these indices and CAD in T2D may help clarify the complex pathophysiology of CAD and offer insights for future research.
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Affiliation(s)
- Amirhossein Yadegar
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Mohammadi
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Kiana Seifouri
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Kiavash Mokhtarpour
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Yadegar
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Bahrami Hazaveh
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Arsalan Seyedi
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Soghra Rabizadeh
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Esteghamati
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Baek S, Hong S, Kim E, Park S, Lee M, Park J, Cho Y, Yoon H, Kim D, Yun Y, Kim Y, Choi Y, Kang K, Jung S, Kim JP, Kim E, Seo SW, Jung Y, Jo D. A Novel RAGE Modulator Induces Soluble RAGE to Reduce BACE1 Expression in Alzheimer's Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2407812. [PMID: 39755927 PMCID: PMC11848596 DOI: 10.1002/advs.202407812] [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] [Received: 07/10/2024] [Revised: 11/12/2024] [Indexed: 01/06/2025]
Abstract
β-secretase (BACE1) is instrumental in amyloid-β (Aβ) production, with overexpression noted in Alzheimer's disease (AD) neuropathology. The interaction of Aβ with the receptor for advanced glycation endproducts (RAGE) facilitates cerebral uptake of Aβ and exacerbates its neurotoxicity and neuroinflammation, further augmenting BACE1 expression. Given the limitations of previous BACE1 inhibition efforts, the study explores reducing BACE1 expression to mitigate AD pathology. The research reveals that the anticancer agent 6-thioguanosine (6-TG) markedly diminishes BACE1 expression without eliciting cytotoxicity while enhancing microglial phagocytic activity, and ameliorate cognitive impairments with reducing Aβ accumulation in AD mice. Leveraging advanced deep learning-based tool for target identification, and corroborating with surface plasmon resonance assays, it is elucidated that 6-TG directly interacts with RAGE, modulating BACE1 expression through the JAK2-STAT1 pathway and elevating soluble RAGE (sRAGE) levels in the brain. The findings illuminate the therapeutic potential of 6-TG in ameliorating AD manifestations and advocate for small molecule strategies to increase brain sRAGE levels, offering a strategic alternative to the challenges posed by the complexity of AD.
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Affiliation(s)
- Seung‐Hyun Baek
- School of PharmacySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Suji Hong
- School of PharmacySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Eunae Kim
- School of PharmacySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Sunyoung Park
- School of PharmacySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Minyoung Lee
- Department of Molecular Science and TechnologyAjou UniversitySuwon16499Republic of Korea
| | - Jinsu Park
- School of PharmacySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Yoonsuk Cho
- School of PharmacySungkyunkwan UniversitySuwon16419Republic of Korea
| | | | | | - Youngkwang Yun
- School of PharmacySungkyunkwan UniversitySuwon16419Republic of Korea
| | - Youbin Kim
- School of Biological SciencesSeoul National UniversitySeoul08826Republic of Korea
| | | | - Keunsoo Kang
- Deargen Inc.Daejeon34051Republic of Korea
- Department of MicrobiologyCollege of Science and TechnologyDankook UniversityCheonan31116Republic of Korea
| | - Sangyong Jung
- Department of Medical ScienceCollege of MedicineCHA UniversitySeongnam13496Republic of Korea
| | - Jun Pyo Kim
- Department of NeurologySamsung Medical CenterSungkyunkwan University School of MedicineSeoul06355Republic of Korea
| | - Eunha Kim
- Department of Molecular Science and TechnologyAjou UniversitySuwon16499Republic of Korea
| | - Sang Won Seo
- Department of NeurologySamsung Medical CenterSungkyunkwan University School of MedicineSeoul06355Republic of Korea
- Alzheimer's Disease Convergence Research CenterSamsung Medical CenterSeoul06351Republic of Korea
- Neuroscience CenterSamsung Medical CenterSeoul06351Republic of Korea
| | - Yong‐Keun Jung
- School of Biological SciencesSeoul National UniversitySeoul08826Republic of Korea
| | - Dong‐Gyu Jo
- School of PharmacySungkyunkwan UniversitySuwon16419Republic of Korea
- Biomedical Institute for Convergence at SKKU (BICS)Suwon16419Republic of Korea
- Department of Health Sciences and TechnologySAIHSTSungkyunkwan UniversitySeoul06355Republic of Korea
- Institute of Quantum BiophysicsSungkyunkwan UniversitySuwon16419Republic of Korea
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Baumann S, Sewing L, Traechslin C, Verhagen-Kamerbeek W, Grize L, Kraenzlin M, Meier C. Serum Pentosidine in Relation to Obesity in Patients with Type 2 Diabetes and Healthy Controls. Calcif Tissue Int 2025; 116:25. [PMID: 39777548 PMCID: PMC11706925 DOI: 10.1007/s00223-024-01338-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025]
Abstract
Pentosidine (PEN), a surrogate marker of advanced glycation end-product formation, reflects increased non-enzymatic cross-linking in bone collagen, which is thought to be an important determinant of bone fragility in type 2 diabetes mellitus (T2DM). We aimed to investigate serum concentrations of PEN in patients with T2DM and controls without T2DM and to examine its relationship with bone parameters and metabolic state such as glycaemic control, insulin resistance and body weight. In a cross-sectional study-design, data from postmenopausal women and men with T2DM (n = 110) and controls without T2DM (n = 111) were evaluated. Serum PEN was measured using an ELISA-based assay (CSB-E09415h, Cusabio). In addition, biochemical markers of glucose metabolism and bone turnover markers were measured. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry. After adjustment for age, gender and body mass index (BMI), serum PEN was significantly higher in patients with T2DM compared to controls (p = 0.02) and most prominently in women with T2DM (p = 0.09). We found a strong association of serum PEN concentrations with BMI in the entire study population (R = 0.43, p < 0.001) as well as in patients with T2DM (R = 0.28, p < 0.01). While bone turnover markers were significantly decreased, and BMD increased in patients with T2DM, only weak or no associations were observed between these skeletal surrogate markers and serum PEN. We conclude that serum PEN is strongly associated with BMI with highest levels in obese women with T2DM. Adjustment for patient's weight is needed when evaluating serum PEN levels in patients with T2DM.Clinical Trial Information: NCT02551315.
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Affiliation(s)
- Sandra Baumann
- Division of Endocrinology and Diabetes, Spital Emmental, Burgdorf, Switzerland
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland
| | - Lilian Sewing
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland
| | - Cyril Traechslin
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland
| | - Wilma Verhagen-Kamerbeek
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland
| | - Leticia Grize
- Swiss Tropical and Public Health Institute and University of Basel, Basel, Switzerland
| | | | - Christian Meier
- Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Aeschenvorstadt 57, 4051, Basel, Switzerland.
- Endocrine Clinic and Laboratory, Basel, Switzerland.
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Hashiesh HM, Azimullah S, Nagoor Meeran MF, Saraswathiamma D, Arunachalam S, Jha NK, Sadek B, Adeghate E, Sethi G, Albawardi A, Al Marzooqi S, Ojha S. Cannabinoid 2 Receptor Activation Protects against Diabetic Cardiomyopathy through Inhibition of AGE/RAGE-Induced Oxidative Stress, Fibrosis, and Inflammasome Activation. J Pharmacol Exp Ther 2024; 391:241-257. [PMID: 38955492 DOI: 10.1124/jpet.123.002037] [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: 11/21/2023] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/04/2024] Open
Abstract
Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)-receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms. SIGNIFICANCE STATEMENT: BCP, a CB2R agonist, shows protection against DCM. BCP attenuates oxidative stress, inflammation, and fibrosis in DCM via activating CB2Rs. BCP mediating CB2R activation favorably modulates AGE/RAGE, PI3K/AKT/Nrf2β and TGF-β/Smad and (NLRP3) inflammasome in diabetic cardiomyopathy.
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Affiliation(s)
- Hebaallah Mamdouh Hashiesh
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Sheikh Azimullah
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Mohamed Fizur Nagoor Meeran
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Dhanya Saraswathiamma
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Seenipandi Arunachalam
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Niraj Kumar Jha
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Bassem Sadek
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Ernest Adeghate
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Gautam Sethi
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Alia Albawardi
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Saeeda Al Marzooqi
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
| | - Shreesh Ojha
- Departments of Pharmacology and Therapeutics (H.M.H., Sh.A., M.F.N.M., Se.A., B.S., S.O.), Pathology (D.S., A.A., S.A.M.), and Anatomy (E.A.), College of Medicine and Health Sciences, and Zayed Bin Sultan Center for Health Sciences (S.O.), United Arab Emirates University, Al Ain, United Arab Emirates; Department of Pharmacology and Toxicology, Helwan University, Cairo, Egypt (H.M.H.); Department of Pharmaceutical Biosciences, Research; Drug Safety and Toxicology, Uppsala Biomedicines Centrum BMC, UPPSALA, Sweden (Sh.A.); Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India (N.K.J.); School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India (N.K.J.); and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (G.S.)
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7
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Liu C, Xue Q, Zhang Y, Zhang D, Li Y. Anti-hypertensive effect and potential mechanism of gastrodia-uncaria granules based on network pharmacology and experimental validation. J Clin Hypertens (Greenwich) 2024; 26:1024-1038. [PMID: 38990083 PMCID: PMC11488320 DOI: 10.1111/jch.14833] [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] [Revised: 04/18/2024] [Accepted: 05/05/2024] [Indexed: 07/12/2024]
Abstract
Hypertension has become a major contributor to the morbidity and mortality of cardiovascular diseases worldwide. Despite the evidence of the anti-hypertensive effect of gastrodia-uncaria granules (GUG) in hypertensive patients, little is known about its potential therapeutic targets as well as the underlying mechanism. GUG components were sourced from TCMSP and HERB, with bioactive ingredients screened. Hypertension-related targets were gathered from DisGeNET, OMIM, GeneCards, CTD, and GEO. The STRING database constructed a protein-protein interaction network, visualized by Cytoscape 3.7.1. Core targets were analyzed via GO and KEGG using R package ClusterProfiler. Molecular docking with AutodockVina 1.2.2 revealed favorable binding affinities. In vivo studies on hypertensive mice and rats validated network pharmacology findings. GUG yielded 228 active ingredients and 1190 targets, intersecting with 373 hypertension-related genes. PPI network analysis identified five core genes: AKT1, TNF-α, GAPDH, IL-6, and ALB. Top enriched GO terms and KEGG pathways associated with the anti-hypertensive properties of GUG were documented. Molecular docking indicated stable binding of core components to targets. In vivo study showed that GUG could improve vascular relaxation, alleviate vascular remodeling, and lower blood pressure in hypertensive animal models possibly through inhibiting inflammatory factors such as AKT1, mTOR, and CCND1. Integrated network pharmacology and in vivo experiment showed that GUG may exert anti-hypertensive effects by inhibiting inflammation response, which provides some clues for understanding the effect and mechanisms of GUG in the treatment of hypertension.
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Affiliation(s)
- Chu‐Hao Liu
- Department of Cardiovascular MedicineShanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Qi‐Qi Xue
- Department of Cardiovascular MedicineShanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Yi‐Qing Zhang
- Department of Cardiovascular MedicineShanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Dong‐Yan Zhang
- Department of Cardiovascular MedicineShanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Yan Li
- Department of Cardiovascular MedicineShanghai Institute of Hypertension, Shanghai Key Laboratory of Hypertension, National Research Centre for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
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8
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Wang T, Li X, Tao Y, Wang X, Li L, Liu J. METTL3-mediated NDUFB5 m6A modification promotes cell migration and mitochondrial respiration to promote the wound healing of diabetic foot ulcer. J Transl Med 2024; 22:643. [PMID: 38982516 PMCID: PMC11234709 DOI: 10.1186/s12967-024-05463-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 07/02/2024] [Indexed: 07/11/2024] Open
Abstract
BACKGROUND Diabetic foot ulcer (DFU) is the most devastating complication of diabetes mellitus (DM) and plays a major role in disability and death in DM patients. NADH: ubiquinone oxidoreductase subunit B5 (NDUFB5) plays an important role in maintaining mitochondrial respiration, but whether it is involved in regulating the progression of advanced glycation end products (AGEs)-mediated DFU is still unclear. METHODS Firstly, the role of AGEs on cell viability, migration, and mitochondrial respiration in human umbilical vein endothelial cells (HUVECs) was explored in vitro. Next, NDUFB5 expression was detected in human samples and AGEs-treated HUVECs, and NDUFB5's effect on AGEs-induced HUVECs injury and skin wound in diabetic mice was further clarified. In addition, the role of m6A modification mediated by methyltransferase-like 3 (METTL3) in regulating NDUFB5 expression and AGEs-induced HUVECs injury was investigated. RESULTS NDUFB5 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs, whereas mitochondrial fusion promoter M1 facilitated cell viability, migration, and mitochondrial oxiadative respiration in NDUFB5 knockdown HUVECs. Meanwhile, NDUFB5 promotes skin wound healing in diabetic mice. Besides, METTL3-mediated m6A modification and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) enhanced NDUFB5 expression in HUVECs. Furthermore, METTL3 promoted cell viability, migration, and mitochondrial respiration in AGEs-treated HUVECs by increasing NDUFB5. CONCLUSION METTL3-mediated NDUFB5 m6A modification inhibits AGEs-induced cell injury in HUVECs. METTL3 and NDUFB5 might serve as potential targets for DFU therapy in the future.
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Affiliation(s)
- Tao Wang
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, affiliated to Fudan University, 1158 East Park Road, Qingpu District, Shanghai, 201700, China
| | - Xu Li
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, affiliated to Fudan University, 1158 East Park Road, Qingpu District, Shanghai, 201700, China
| | - Yue Tao
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, affiliated to Fudan University, 1158 East Park Road, Qingpu District, Shanghai, 201700, China
| | - Xiaojun Wang
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, affiliated to Fudan University, 1158 East Park Road, Qingpu District, Shanghai, 201700, China
| | - Limeng Li
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, affiliated to Fudan University, 1158 East Park Road, Qingpu District, Shanghai, 201700, China
| | - Jianjun Liu
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, affiliated to Fudan University, 1158 East Park Road, Qingpu District, Shanghai, 201700, China.
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9
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Xiang M, Pan Z, Hong S, Cao G, Feng B. Association of dietary zinc consumption with periodontitis in diabetes mellitus patients: A cross-sectional study of national health and nutrition examination surveys database (2009-2014). J Dent Sci 2024; 19:952-960. [PMID: 38618104 PMCID: PMC11010600 DOI: 10.1016/j.jds.2023.07.025] [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: 07/10/2023] [Revised: 07/18/2023] [Indexed: 04/16/2024] Open
Abstract
Background/purpose Periodontitis is an independent risk factor for diabetes mellitus (DM), and DM patients had an increased risk in susceptibility to periodontitis. And serum zinc (Zn) levels were low in patients with periodontitis combined with DM. Herein, this study aimed to explore the association between dietary Zn intake and the risk of periodontitis in DM patients, in order to provide some scientific references for the prevention and treatment for periodontitis clinically. Materials and methods Demographic and clinical data of DM patients were extracted from the National Health and Nutrition Examination Surveys (NHANES) database in 2009-2014 in this cross-sectional study. Weighted univariate logistic regression and backward regression analyses were used for covariates screening. Weighted univariate and multivariate logistic regression analyses were used to explore the association between Zn and periodontitis with odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses of age and gender were also performed. Results Of the eligible participants, 1281 had moderate or severe periodontitis. After adjusting for the covariates, we found that comparing to DM patients who had not reach the recommended Zn intake level, those who reached had low odds for periodontitis [OR = 0.76, 95% CI: (0.58-0.99)]. In patients who aged ≥65 years old [OR = 0.59, 95% CI: (0.36-0.97)] and were female [OR = 0.71, 95% CI: (0.51-0.99)], reaching the recommended level of Zn intake was related to low odds of periodontitis. Conclusion Sufficient dietary Zn intake antagonized the risk of periodontitis, which may provide some references for diet management in DM patients to reduce the risk of periodontitis.
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Affiliation(s)
- Mingdi Xiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Zhiwen Pan
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Siqian Hong
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Guifen Cao
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, PR China
| | - Bin Feng
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, PR China
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10
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Balczon R, Lin MT, Voth S, Nelson AR, Schupp JC, Wagener BM, Pittet JF, Stevens T. Lung endothelium, tau, and amyloids in health and disease. Physiol Rev 2024; 104:533-587. [PMID: 37561137 PMCID: PMC11281824 DOI: 10.1152/physrev.00006.2023] [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: 02/02/2023] [Revised: 06/26/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023] Open
Abstract
Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule-associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta-amyloid is produced during infection. Beta-amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection.
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Affiliation(s)
- Ron Balczon
- Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama, United States
- Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States
| | - Mike T Lin
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama, United States
- Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States
| | - Sarah Voth
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine, Monroe, Louisiana, United States
| | - Amy R Nelson
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama, United States
- Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States
| | - Jonas C Schupp
- Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University, New Haven, Connecticut, United States
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- German Center for Lung Research (DZL), Hannover, Germany
| | - Brant M Wagener
- Department of Anesthesiology and Perioperative Medicine, University of Alabama-Birmingham, Birmingham, Alabama, United States
| | - Jean-Francois Pittet
- Department of Anesthesiology and Perioperative Medicine, University of Alabama-Birmingham, Birmingham, Alabama, United States
| | - Troy Stevens
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama, United States
- Department of Internal Medicine, University of South Alabama, Mobile, Alabama, United States
- Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States
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11
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Ong C, Li M, Xu D. Targeting the heparan sulfate-binding site of RAGE with monoclonal antibodies. Glycobiology 2024; 34:cwae001. [PMID: 38181393 PMCID: PMC10987294 DOI: 10.1093/glycob/cwae001] [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: 11/13/2023] [Revised: 12/26/2023] [Accepted: 12/29/2023] [Indexed: 01/07/2024] Open
Abstract
Heparan sulfate (HS) plays its biological functions by interacting with hundreds of secreted extracellular and transmembrane proteins. Interaction with HS has been shown to be required for the normal function of many HS-binding proteins. Receptor for advanced glycation end-product (RAGE) is such a protein, whose activation requires HS-induced oligomerization. Using RAGE as an exemplary protein, we show here the workflow of a simple method of developing and characterizing mAbs that targets the HS-binding site. We found that HS-binding site of RAGE is quite immunogenic as 18 out of 94 anti-RAGE mAbs target various epitopes within the HS-binding site. Sequence analysis found that a common feature of anti-HS-binding site mAbs is the presence of abundant acidic residues (range between 6 to 11) in the complementarity determining region, suggesting electrostatic interaction plays an important role in promoting antigen-antibody interaction. Interestingly, mAbs targeting different epitopes within the HS-binding site blocks HS-RAGE interaction to different degrees, and the inhibitory effect is highly consistent among mAbs that target the same epitope. Functional assay revealed that anti-HS-binding site mAbs show different potency in inhibiting osteoclastogenesis, and the inhibitory potency does not have a simple correlation with the affinity and the epitope. Our study demonstrates that developing HS-binding site targeting mAbs should be applicable to most HS-binding proteins. By targeting this unique functional site, these mAbs might find therapeutic applications in treating various human diseases.
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Affiliation(s)
- Chihyean Ong
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, 3435 Main Street, Buffalo, NY 14214, United States
| | - Miaomiao Li
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, 3435 Main Street, Buffalo, NY 14214, United States
| | - Ding Xu
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, 3435 Main Street, Buffalo, NY 14214, United States
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12
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Lei T, Yang Z, Li H, Qin M, Gao H. Interactions between nanoparticles and pathological changes of vascular in Alzheimer's disease. Adv Drug Deliv Rev 2024; 207:115219. [PMID: 38401847 DOI: 10.1016/j.addr.2024.115219] [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: 10/30/2023] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 02/26/2024]
Abstract
Emerging evidence suggests that vascular pathological changes play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The dysfunction of the cerebral vasculature occurs in the early course of AD, characterized by alterations in vascular morphology, diminished cerebral blood flow (CBF), impairment of the neurovascular unit (NVU), vasculature inflammation, and cerebral amyloid angiopathy. Vascular dysfunction not only facilitates the influx of neurotoxic substances into the brain, triggering inflammation and immune responses but also hampers the efflux of toxic proteins such as Aβ from the brain, thereby contributing to neurodegenerative changes in AD. Furthermore, these vascular changes significantly impact drug delivery and distribution within the brain. Therefore, developing targeted delivery systems or therapeutic strategies based on vascular alterations may potentially represent a novel breakthrough in AD treatment. This review comprehensively examines various aspects of vascular alterations in AD and outlines the current interactions between nanoparticles and pathological changes of vascular.
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Affiliation(s)
- Ting Lei
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zixiao Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hanmei Li
- School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
| | - Meng Qin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Huile Gao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University, Chengdu 610041, China.
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13
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Wang J, Zhao Z, Yang K, Bai Y. Research progress in cell therapy for oral diseases: focus on cell sources and strategies to optimize cell function. Front Bioeng Biotechnol 2024; 12:1340728. [PMID: 38515628 PMCID: PMC10955105 DOI: 10.3389/fbioe.2024.1340728] [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: 11/20/2023] [Accepted: 02/23/2024] [Indexed: 03/23/2024] Open
Abstract
In recent years, cell therapy has come to play an important therapeutic role in oral diseases. This paper reviews the active role of mesenchymal stem cells, immune cell sources, and other cells in oral disorders, and presents data supporting the role of cell therapy in oral disorders, including bone and tooth regeneration, oral mucosal disorders, oral soft tissue defects, salivary gland dysfunction, and orthodontic tooth movement. The paper will first review the progress of cell optimization strategies for oral diseases, including the use of hormones in combination with stem cells, gene-modified regulatory cells, epigenetic regulation of cells, drug regulation of cells, cell sheets/aggregates, cell-binding scaffold materials and hydrogels, nanotechnology, and 3D bioprinting of cells. In summary, we will focus on the therapeutic exploration of these different cell sources in oral diseases and the active application of the latest cell optimization strategies.
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Affiliation(s)
| | | | | | - Yuxing Bai
- Department of Orthodontics, School of Stomatology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
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14
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Ravi R, Nagarajan H, Muralikumar S, Vetrivel U, Subramaniam Rajesh B. Unveiling the therapeutic potential of a mutated paraoxonase 2 in diabetic retinopathy: Defying glycation, mitigating oxidative stress, ER stress and inflammation. Int J Biol Macromol 2024; 258:128899. [PMID: 38141706 DOI: 10.1016/j.ijbiomac.2023.128899] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 11/20/2023] [Accepted: 12/18/2023] [Indexed: 12/25/2023]
Abstract
Paraoxonase 2 (PON2) is an intracellular anti-oxidant protein ubiquitously expressed in all cells and reduces reactive oxygen species, endoplasmic reticulum (ER) stress, further improves mitochondrial function and thereby shows anti-apoptotic function. In diabetes and its complications this PON gets glycated and becomes in effective. The PON activity is reported to be reduced in diabetic retinopathy and we have earlier showed Carboxy methyl lysine (AGE) decreased PON2 expression and activity in Human retinal endothelial cells (HREC) . In this study, we have designed and developed a mutated PON2 by in silico and in vitro approach which can resist glycation. Where in glycation-prone residues in PON2 was predicted using in silico analyses and a mutated PON2 was developed using in vitro site directed mutagenesis (SDM) assay mPON2 (mutant PON2-PON2-K70A) and its efficacy was compared with wPON2 (wild type PON2). CML glycated wPON2 and reduced its activity when compared with mPON2 in HREC confirmed by immunoprecipitation and in vitro experiments. Additionally, mPON2 interaction efficiency with its substrates was higher than wPON2 by insilico assay and demonstrated enhanced inhibition against CML-induced oxidative stress, ER stress, pro-inflammation, and mitochondrial fission than wPON2 by invitro assay. Further mPON2 showed increased inhibition of phosphorylation of NFĸB induced by CML. Our investigation establishes that the over expression of mPON2 in HREC can defy glycation and therefore mitigate ER stress and inflammation against CML than endogenous wPON2. These findings imply that mPON2 can be a beneficial therapeutic target against diabetic retinopathy.
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Affiliation(s)
- Ramya Ravi
- R.S. Mehta Jain Department of Biochemistry and Cell Biology, KBIRVO, Vision Research Foundation, Sankara Nethralaya, Chennai 600006, India; School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, India
| | - Hemavathy Nagarajan
- Centre for Bioinformatics, KBIRVO, Vision Research Foundation, Sankara Nethralaya, Chennai 600006, India
| | - Shalini Muralikumar
- Centre for Bioinformatics, KBIRVO, Vision Research Foundation, Sankara Nethralaya, Chennai 600006, India
| | - Umashankar Vetrivel
- Centre for Bioinformatics, KBIRVO, Vision Research Foundation, Sankara Nethralaya, Chennai 600006, India; Department of Bioinformatics, ICMR-National Institute of Traditional Medicine, Nehru Nagar, Belagavi, Karnataka 590 010, India
| | - Bharathidevi Subramaniam Rajesh
- R.S. Mehta Jain Department of Biochemistry and Cell Biology, KBIRVO, Vision Research Foundation, Sankara Nethralaya, Chennai 600006, India.
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15
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Shrivastav D, Singh DD. Emerging roles of microRNAs as diagnostics and potential therapeutic interest in type 2 diabetes mellitus. World J Clin Cases 2024; 12:525-537. [PMID: 38322458 PMCID: PMC10841963 DOI: 10.12998/wjcc.v12.i3.525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/18/2023] [Accepted: 01/03/2024] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a metabolic disease of impaired glucose utilization. Uncontrolled high sugar levels lead to advanced glycation end products (AGEs), which affects several metabolic pathways by its receptor of advanced glycation end products (RAGE) and causes diabetic complication. MiRNAs are small RNA molecules which regulate genes linked to diabetes and affect AGEs pathogenesis, and target tissues, influencing health and disease processes. AIM To explore miRNA roles in T2DM's metabolic pathways for potential therapeutic and diagnostic advancements in diabetes complications. METHODS We systematically searched the electronic database PubMed using keywords. We included free, full-length research articles that evaluate the role of miRNAs in T2DM and its complications, focusing on genetic and molecular disease mechanisms. After assessing the full-length papers of the shortlisted articles, we included 12 research articles. RESULTS Several types of miRNAs are linked in metabolic pathways which are affected by AGE/RAGE axis in T2DM and its complications. miR-96-5p, miR-7-5p, miR-132, has_circ_0071106, miR-143, miR-21, miR-145-5p, and more are associated with various aspects of T2DM, including disease risk, diagnostic markers, complications, and gene regulation. CONCLUSION Targeting the AGE/RAGE axis, with a focus on miRNA regulation, holds promise for managing T2DM and its complications. MiRNAs have therapeutic potential as they can influence the metabolic pathways affected by AGEs and RAGE, potentially reducing inflammation, oxidative stress, and vascular complications. Additionally, miRNAs may serve as early diagnostic biomarkers for T2DM. Further research in this area may lead to innovative therapeutic strategies for diabetes and its associated complications.
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Affiliation(s)
| | - Desh Deepak Singh
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur 303002, India
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16
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Liu X, Ren J, Zhou R, Wen Z, Wen Z, Chen Z, He S, Zhang H. Construction of iron metabolism-related prognostic features of gastric cancer based on RNA sequencing and TCGA database. BMC Cancer 2023; 23:1106. [PMID: 37957566 PMCID: PMC10644585 DOI: 10.1186/s12885-023-11569-9] [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: 06/29/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Researches have manifested that the disorder of iron metabolism is participated in Gastric cancer (GC), but whether iron metabolism-relevant genes (IMRGs) is related to the survival outcome of GC remain unknown. METHODS Eleven tumor as well as nine adjacent normal tissues from GC patients were underwent mRNA sequencing, and the The Cancer Genome Atlas Stomach Cancer (TCGA-STAD) datasets were acquired from the TCGA database. Cox analyses and least absolute shrinkage and selection operator (LASSO) regression were applied to build a IMRGs signature. The relationship between signature genes and the infiltration profiling of 24 immune cells were investigated using single-sample GSEA (ssGSEA). Meanwhile, the potential biological significance, genes that act synergistically with signature genes, and the upstream regulatory targets were predicted. Finally, the abundance of the signature genes were measured via the quantitative real-time PCR (qRT-PCR). RESULTS A IMRGs signature was constructed according to the expression and corresponding coefficient of DOHH, P4HA3 and MMP1 (The Schoenfeld individual test showed risk score was not significant with P values = 0.83). The prognostic outcome of patients in the high-risk group was terrible (p < 0.05). Receiver operating characteristic (ROC) curves confirmed that the IMRGs signature presented good efficiency for predicting GC prognosis (AUC > 0.6). The nomogram was performed well for clinical utilize (C-index = 0.60), and the MMP1 expression significantly increased in the cohorts at age > 60 and Stage II-IV (p < 0.05). The positive correlation of P4HA3 and MMP1 expression as well as the negative correlation of DOHH expression with risk score (p < 0.0001) and worse prognosis (p < 0.05) were detected as well. Furthermore, 11 differential immune cells were associated with these signature genes (most p < 0.01). Finally, qRT-PCR revealed that the abundance of DOHH, P4HA3 and MMP1 were high in tumor cases, indicating the complex mechanism between the high expression of DOHH as a protective factor and the high expression of P4HA3 and MMP1 as the risk factors in the development of GC. CONCLUSION An iron metabolism-related signature was constructed and has significant values for foretelling the OS of GC.
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Affiliation(s)
- Xihong Liu
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Junyu Ren
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ruize Zhou
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhengqi Wen
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhengwei Wen
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zihao Chen
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Shanshan He
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hongbin Zhang
- Department of Pediatric Surgery First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, P. R. China.
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17
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Bansal S, Burman A, Tripathi AK. Advanced glycation end products: Key mediator and therapeutic target of cardiovascular complications in diabetes. World J Diabetes 2023; 14:1146-1162. [PMID: 37664478 PMCID: PMC10473940 DOI: 10.4239/wjd.v14.i8.1146] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/21/2023] [Accepted: 05/22/2023] [Indexed: 08/11/2023] Open
Abstract
The incidence of type 2 diabetes mellitus is growing in epidemic proportions and has become one of the most critical public health concerns. Cardiovascular complications associated with diabetes are the leading cause of morbidity and mortality. The cardiovascular diseases that accompany diabetes include angina, myocardial infarction, stroke, peripheral artery disease, and congestive heart failure. Among the various risk factors generated secondary to hyperglycemic situations, advanced glycation end products (AGEs) are one of the important targets for future diagnosis and prevention of diabetes. In the last decade, AGEs have drawn a lot of attention due to their involvement in diabetic patho-physiology. AGEs can be derived exogenously and endogenously through various pathways. These are a non-homogeneous, chemically diverse group of compounds formed non-enzymatically by condensation between carbonyl groups of reducing sugars and free amino groups of protein, lipids, and nucleic acid. AGEs mediate their pathological effects at the cellular and extracellular levels by multiple pathways. At the cellular level, they activate signaling cascades via the receptor for AGEs and initiate a complex series of intracellular signaling resulting in reactive oxygen species generation, inflammation, cellular proliferation, and fibrosis that may possibly exacerbate the damaging effects on cardiac functions in diabetics. AGEs also cause covalent modifications and cross-linking of serum and extracellular matrix proteins; altering their structure, stability, and functions. Early diagnosis of diabetes may prevent its progression to complications and decrease its associated comorbidities. In the present review, we recapitulate the role of AGEs as a crucial mediator of hyperglycemia-mediated detrimental effects in diabetes-associated complications. Furthermore, this review presents an overview of future perspectives for new therapeutic interventions to ameliorate cardiovascular complications in diabetes.
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Affiliation(s)
- Savita Bansal
- Department of Biochemistry, Institute of Home Sciences, University of Delhi, New Delhi 110016, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi 110016, India
| | - Asok Kumar Tripathi
- Department of Biochemistry, University College of Medical Sciences, University of Delhi, New Delhi 110095, India
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18
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Pujals M, Mayans C, Bellio C, Méndez O, Greco E, Fasani R, Alemany-Chavarria M, Zamora E, Padilla L, Mitjans F, Nuciforo P, Canals F, Nonell L, Abad M, Saura C, Tabernero J, Villanueva J. RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer. Oncogene 2023; 42:2610-2628. [PMID: 37468678 DOI: 10.1038/s41388-023-02778-4] [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: 02/15/2023] [Revised: 06/29/2023] [Accepted: 07/07/2023] [Indexed: 07/21/2023]
Abstract
Epithelial/Mesenchymal (E/M) plasticity plays a fundamental role both in embryogenesis and during tumorigenesis. The receptor for advanced glycation end products (RAGE) is a driver of cell plasticity in fibrotic diseases; however, its role and molecular mechanism in triple-negative breast cancer (TNBC) remains unclear. Here, we demonstrate that RAGE signaling maintains the mesenchymal phenotype of aggressive TNBC cells by enforcing the expression of SNAIL1. Besides, we uncover a crosstalk mechanism between the TGF-β and RAGE pathways that is required for the acquisition of mesenchymal traits in TNBC cells. Consistently, RAGE inhibition elicits epithelial features that block migration and invasion capacities. Next, since RAGE is a sensor of the tumor microenvironment, we modeled acute acidosis in TNBC cells and showed it promotes enhanced production of RAGE ligands and the activation of RAGE-dependent invasive properties. Furthermore, acute acidosis increases SNAIL1 levels and tumor cell invasion in a RAGE-dependent manner. Finally, we demonstrate that in vivo inhibition of RAGE reduces metastasis incidence and expands survival, consistent with molecular effects that support the relevance of RAGE signaling in E/M plasticity. These results uncover new molecular insights on the regulation of E/M phenotypes in cancer metastasis and provide rationale for pharmacological intervention of this signaling axis.
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Affiliation(s)
- Mireia Pujals
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Carla Mayans
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat de Barcelona, Barcelona, Spain
| | - Chiara Bellio
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Olga Méndez
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Emanuela Greco
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Roberta Fasani
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Mercè Alemany-Chavarria
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Esther Zamora
- Medical Oncology Service, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain
| | - Laura Padilla
- LEITAT Technological Center, 08028, Barcelona, Spain
| | | | - Paolo Nuciforo
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Francesc Canals
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Lara Nonell
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - María Abad
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Altos Labs Cambridge Institute of Science, Cambridge, UK
| | - Cristina Saura
- Medical Oncology Service, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain
| | - Josep Tabernero
- Medical Oncology Service, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
- IOB Institute of Oncology, Quiron Group (Quiron-IOB), Barcelona, Spain
- University of Vic-Central University of Catalonia (UVic-UCC), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Josep Villanueva
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
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19
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Abstract
The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Moreover, studies in mouse models indicate a causal role of inflammasomes and IL-1β in atherosclerosis. However, recent studies have led to a more granular view of the role of inflammasomes in atherosclerosis. Studies in hyperlipidemic mouse models suggest that prominent activation of the NLRP3 inflammasome requires a second hit such as defective cholesterol efflux, defective DNA repair, clonal hematopoiesis or diabetes. Similarly in humans some mutations promoting clonal hematopoiesis increase coronary artery disease risk in part by promoting inflammasome activation. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2) inflammasome in promoting cardiovascular disease including in some forms of clonal hematopoiesis and diabetes. These developments suggest a precision medicine approach in which treatments targeting inflammasomes or IL-1β might be best employed in clinical settings involving increased inflammasome activation.
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Affiliation(s)
- Alan R Tall
- Division of Molecular Medicine, Department of Medicine, Columbia University Irving Medical Center, New York (A.R.T.)
| | - Karin E Bornfeldt
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington, Seattle (K.E.B.)
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20
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Ma J, Li Y, Yang X, Liu K, Zhang X, Zuo X, Ye R, Wang Z, Shi R, Meng Q, Chen X. Signaling pathways in vascular function and hypertension: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023; 8:168. [PMID: 37080965 PMCID: PMC10119183 DOI: 10.1038/s41392-023-01430-7] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/03/2023] [Accepted: 03/31/2023] [Indexed: 04/22/2023] Open
Abstract
Hypertension is a global public health issue and the leading cause of premature death in humans. Despite more than a century of research, hypertension remains difficult to cure due to its complex mechanisms involving multiple interactive factors and our limited understanding of it. Hypertension is a condition that is named after its clinical features. Vascular function is a factor that affects blood pressure directly, and it is a main strategy for clinically controlling BP to regulate constriction/relaxation function of blood vessels. Vascular elasticity, caliber, and reactivity are all characteristic indicators reflecting vascular function. Blood vessels are composed of three distinct layers, out of which the endothelial cells in intima and the smooth muscle cells in media are the main performers of vascular function. The alterations in signaling pathways in these cells are the key molecular mechanisms underlying vascular dysfunction and hypertension development. In this manuscript, we will comprehensively review the signaling pathways involved in vascular function regulation and hypertension progression, including calcium pathway, NO-NOsGC-cGMP pathway, various vascular remodeling pathways and some important upstream pathways such as renin-angiotensin-aldosterone system, oxidative stress-related signaling pathway, immunity/inflammation pathway, etc. Meanwhile, we will also summarize the treatment methods of hypertension that targets vascular function regulation and discuss the possibility of these signaling pathways being applied to clinical work.
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Affiliation(s)
- Jun Ma
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Yanan Li
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xiangyu Yang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Kai Liu
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xin Zhang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xianghao Zuo
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Runyu Ye
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Ziqiong Wang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Rufeng Shi
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Qingtao Meng
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Xiaoping Chen
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China.
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21
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Tsirebolos G, Tsoporis JN, Drosatos IA, Izhar S, Gkavogiannakis N, Sakadakis E, Triantafyllis AS, Parker TG, Rallidis LS, Rizos I. Emerging markers of inflammation and oxidative stress as potential predictors of coronary artery disease. Int J Cardiol 2023; 376:127-133. [PMID: 36758863 DOI: 10.1016/j.ijcard.2023.02.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/20/2023] [Accepted: 02/03/2023] [Indexed: 02/11/2023]
Abstract
BACKGROUND AND AIMS The multi-ligand receptor for advanced glycation end products (RAGE) and its ligands AGEs and S100/calgranulin proteins are important mediators of inflammation and oxidative stress whereas the soluble form of RAGE (sRAGE) by acting as a decoy and the antioxidant PARK7/DJ-1 exert antiatherogenic effects. We examined whether sRAGE and its ligands AGEs, S100A8/A9, S100B, S100A12 and DJ-1 are associated with the presence of angiographic coronary artery disease (CAD) in asymptomatic patients with and without diabetes. METHODS AND RESULTS Plasma levels of RAGE ligands, sRAGE and DJ-1 were determined in 50 patients with angiographically proven CAD and in 50 age-matched healthy controls. In the whole cohort, lower levels of sRAGE and higher levels of interleukin-6 (IL-6), the RAGE ligands S100B, S100A12 and the AGEs/sRAGE ratio were associated with CAD. In patients without diabetes (n = 72), lower levels of sRAGE and DJ-1 and higher levels of IL-6 and AGEs/sRAGE ratio were associated with CAD. In multivariable analysis, AGEs/sRAGE ratio was an independent predictor of CAD both in the whole cohort (p = 0.034, OR = 1.247, [95%CI: 1.024, 1.0519]) and in the subgroup of patients without diabetes (p = 0.021, OR = 1.363, 95%CI [1.048, 1.771]) on top of established cardiovascular risk factors. CONCLUSION Alterations in plasma RAGE axis inflammatory mediators are associated with atherosclerosis, and higher levels of AGEs/sRAGE ratio are independently associated with CAD in asymptomatic patients and may act as a novel biomarker for predicting CAD. DJ-1 emerges as promising marker of oxidative stress in CAD patients without diabetes, a finding that deserves further study.
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Affiliation(s)
- George Tsirebolos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 401 General Military Hospital of Athens, Athens, Greece
| | - James N Tsoporis
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Ontario, Canada.
| | - Ioannis-Alexandros Drosatos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 414 Military Hospital, P.Penteli, Athens, Greece
| | - Shehla Izhar
- Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, University of Toronto, Ontario, Canada
| | - Nikolaos Gkavogiannakis
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece; Department of Cardiology, 401 General Military Hospital of Athens, Athens, Greece
| | | | | | - Thomas G Parker
- Department of Cardiology, 414 Military Hospital, P.Penteli, Athens, Greece
| | | | - Ioannis Rizos
- Second Department of Cardiology, Attikon University Hospital, Athens, Greece
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22
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Birben E, Şahiner ÜM, Kalaycı CÖ. Determination of the effects of advanced glycation end products receptor polymorphisms and its activation on structural cell responses and inflammation in asthma. Turk J Med Sci 2023; 53:160-170. [PMID: 36945930 PMCID: PMC10387853 DOI: 10.55730/1300-0144.5569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 11/30/2022] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Advanced glycation end products receptor (RAGE) is a pattern recognition receptor which attracted attention in chronic airway diseases recently. This study aimed to determine the association of RAGE with asthma and the cellular responses resulting from RAGE signaling pathway activation. METHODS Asthmatic (n = 362) and healthy (n = 134) children were genotyped by PCR-RFLP. Plasma sRAGE levels were determined by ELISA. Lung structural cells were stimulated with AGEs (advanced glycation end products) and control BSA. Expressions of cytokines and protein levels were determined by real-time PCR and ELISA. RESULTS : Gly82Ser and -374 T/A polymorphisms in RAGE gene were associated with lower plasma sRAGE levels (p < 0.001 and p < 0.025, respectively). AGE stimulation increased the expression of RAGE (p = 0.002), ICAM-1 (p = 0.010) and VCAM-1 (p = 0.002) in endothelial cells; TIMP-1 (p = 0.003) and MCP-1 (p = 0.005) in fibroblasts. AGE stimulation increased protein levels of IL-6 (p < 0.001) in endothelial cells; VEGF (p = 0.025) and IL-8 (p < 0.001) in fibroblasts; IL-1b (p < 0.001) and VEGF (p = 0.007) in epithelial cells. DISCUSSION Activation of RAGE pathway may contribute to asthma pathogenesis by increasing the expression of several asthmarelated genes. These findings suggest that suppression of RAGE signaling may be an alternative candidate for treating asthma.
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Affiliation(s)
- Esra Birben
- Department of Biology, Faculty of Science, Hacettepe University, Ankara, Turkey
| | - Ümit Murat Şahiner
- Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Can Ömer Kalaycı
- Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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23
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The Role of Advanced Glycation End Products on Dyslipidemia. Metabolites 2023; 13:metabo13010077. [PMID: 36677002 PMCID: PMC9862879 DOI: 10.3390/metabo13010077] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/28/2022] [Accepted: 12/29/2022] [Indexed: 01/05/2023] Open
Abstract
Disorders of lipoprotein metabolism and glucose homeostasis are common consequences of insulin resistance and usually co-segregate in patients with metabolic syndrome and type 2 diabetes mellitus (DM). Insulin-resistant subjects are characterized by atherogenic dyslipidemia, a specific lipid pattern which includes hypertriglyceridemia, reduced high-density lipoprotein cholesterol level, and increased proportion of small, dense low-density lipoprotein (LDL). Chronic hyperglycemia favors the processes of non-enzymatic glycation, leading to the increased production of advanced glycation end products (AGEs). Apart from direct harmful effects, AGEs are also potent inducers of oxidative stress and inflammation. In addition, increased AGEs' production may induce further qualitative modifications of small, dense LDL particles, converting them to glycated LDLs. These particles are even more atherogenic and may confer an increased cardiovascular risk. In this narrative review, we summarize the available evidence of the pathophysiological role and clinical importance of circulating AGEs and glycated LDLs in patients with dyslipidemia, particularly those with DM and related complications. In addition, we discuss recent advances and the issues that should be improved regarding laboratory assessment of AGEs and glycated LDLs, as well as the possibilities for their therapeutic modulation.
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24
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Rao Y, Wang Y, Lin Z, Zhang X, Ding X, Yang Y, Liu Z, Zhang B. Comparative efficacy and pharmacological mechanism of Chinese patent medicines against anthracycline-induced cardiotoxicity: An integrated study of network meta-analysis and network pharmacology approach. Front Cardiovasc Med 2023; 10:1126110. [PMID: 37168657 PMCID: PMC10164985 DOI: 10.3389/fcvm.2023.1126110] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 04/04/2023] [Indexed: 05/13/2023] Open
Abstract
Background This study aimed to evaluate the efficacy of Chinese patent medicines (CPMs) combined with dexrazoxane (DEX) against anthracycline-induced cardiotoxicity (AIC) and further explore their pharmacological mechanism by integrating the network meta-analysis (NMA) and network pharmacology approach. Methods We searched for clinical trials on the efficacy of DEX + CPMs for AIC until March 10, 2023 (Database: PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, China Science and Technology Journal and China Online Journals). The evaluating outcomes were cardiac troponin I (cTnI) level, creatine kinase MB (CK-MB) level, left ventricular ejection fraction (LVEF) value, and electrocardiogram (ECG) abnormal rate. Subsequently, the results of NMA were further analyzed in combination with network pharmacology. Results We included 14 randomized controlled trials (RCTs) and 1 retrospective cohort study (n = 1,214), containing six CPMs: Wenxinkeli (WXKL), Cinobufotalin injection (CI), Shenqifuzheng injection (SQFZ), Shenmai injection (SM), Astragalus injection (AI) and AI + CI. The NMA was implemented in Stata (16.0) using the mvmeta package. Compared with using DEX only, DEX + SM displayed the best effective for lowering cTnI level (MD = -0.44, 95%CI [-0.56, -0.33], SUCRA 93.4%) and improving LVEF value (MD = 14.64, 95%CI [9.36, 19.91], SUCRA 98.4%). DEX + SQFZ showed the most effectiveness for lowering CK-MB level (MD = -11.57, 95%CI [-15.79, -7.35], SUCRA 97.3%). And DEX + AI + CI has the highest effectiveness for alleviating ECG abnormalities (MD = -2.51, 95%CI [-4.06, -0.96], SUCRA 96.8%). So that we recommended SM + DEX, SQFZ + DEX, and DEX + AI + CI as the top three effective interventions against AIC. Then, we explored their pharmacological mechanism respectively. The CPMs' active components and AIC-related targets were screened to construct the component-target network. The potential pathways related to CPMs against AIC were determined by KEGG. For SM, we identified 118 co-targeted genes of active components and AIC, which were significantly enriched in pathways of cancer pathways, EGFR tyrosine kinase inhibitor resistance and AGE-RAGE signaling pathway in diabetic complications. For SQFZ, 41 co-targeted genes involving pathways of microRNAs in cancer, Rap1 signaling pathway, MAPK signaling pathway, and lipid and atherosclerosis. As for AI + CI, 224 co-targeted genes were obtained, and KEGG analysis showed that the calcium signaling pathway plays an important role except for the consistent pathways of SM and SQFZ in anti-AIC. Conclusions DEX + CPMs might be positive efficacious interventions from which patients with AIC will derive benefits. DEX + SM, DEX + SQFZ, and DEX + AI + CI might be the preferred intervention for improving LVEF value, CK-MB level, and ECG abnormalities, respectively. And these CPMs play different advantages in alleviating AIC by targeting multiple biological processes.
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Affiliation(s)
- Yifei Rao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yu Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhijian Lin
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- Center for Pharmacovigilance and Rational Use of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaomeng Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- Center for Pharmacovigilance and Rational Use of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xueli Ding
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Ying Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zeyu Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Bing Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- Center for Pharmacovigilance and Rational Use of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Correspondence: Bing Zhang
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25
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Ye N, Miao L, Wang F, Wu S, Wu B, Zhou Y, Wang C, Sun G. Cathepsin D Attenuates the Proliferation of Vascular Smooth Muscle Cells Induced by the AGE/RAGE Pathway by Suppressing the ERK Signal. Curr Pharm Des 2023; 29:2387-2395. [PMID: 37855363 DOI: 10.2174/0113816128261894231012144719] [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: 05/11/2023] [Revised: 08/21/2023] [Accepted: 09/21/2023] [Indexed: 10/20/2023]
Abstract
BACKGROUND In this study, we aimed to clarify the role and mechanism by which Cathepsin D (CTSD) mediates the advanced glycation end products (AGEs)-induced proliferation of vascular smooth muscle cells (VSMCs). METHODS We conducted a Western blotting assay and co-immunoprecipitation assay to detect the expression of target proteins and the interaction between different proteins. Cell Counting Kit-8 (CCK-8) assay and 5- ethynyl-2'-deoxyuridine (EdU) were used to evaluate the proliferation. RESULTS AGEs significantly promoted phenotypic switching and proliferation of VSMCs in a concentration-dependent manner. This effect of AGEs was accompanied by inhibition of CTSD. Both the proliferation of VSMCs and inhibition of CTSD induced by AGEs could be attenuated by the specific inhibitor of the receptor for advanced glycation end products (RAGE), FPS-ZM1. Overexpression of CTSD significantly alleviated these effects of AGEs on VSMCs. The mechanism of CTSD action in VSMCs was also explored. Overexpression of CTSD reduced the activation of p-ERK caused by AGEs. By contrast, the knockdown of CTSD, elicited using a plasmid containing short hairpin RNA (shRNA) against CTSD, further increased the activation of p-ERK compared to AGEs alone. Additionally, co-immunoprecipitation studies revealed an endogenous interaction between CTSD, a protease, and p-ERK, its potential substrate. CONCLUSION It has been demonstrated that CTSD downregulates the level of phosphorylated ERK by degrading its target, and this interaction plays a critical role in the proliferation of VSMCs induced by the AGE/RAGE axis. These results provide a novel insight into the prevention and treatment of vascular complications in diabetes.
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Affiliation(s)
- Ning Ye
- Department of Cardiovascular Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Linlin Miao
- Department of Cardiovascular Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Fengzhi Wang
- Department of Neurology, People's Hospital of Liaoning Province, People's Hospital of China Medical University, Shenyang, Liaoning 110016, China
| | - Shaojun Wu
- Department of Cardiovascular Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Boquan Wu
- Department of Cardiovascular Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Ying Zhou
- Department of Cardiovascular Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Chang Wang
- Department of Cardiovascular Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Guozhe Sun
- Department of Cardiovascular Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
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A Study on the Protective Effect of sRAGE-MSCs in a Rodent Reperfusion Model of Myocardial Infarction. Int J Mol Sci 2022; 23:ijms232415630. [PMID: 36555270 PMCID: PMC9779272 DOI: 10.3390/ijms232415630] [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: 10/25/2022] [Revised: 11/30/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Acute myocardial infarction (AMI) is one of the major leading causes of death in humans globally. Recently, increased levels of recruited macrophages and AGE-albumin were observed in the hearts of humans and animals with acute myocardial infarction. Thus, the purposes of this study were to investigate whether the elevated levels of AGE-albumin from activated macrophage cells are implicated in ischemia-induced cardiomyocyte death and to develop therapeutic strategies for AMI based on its underlying molecular mechanisms with respect to AGEs. The present study demonstrated that activated macrophages and AGE-albumin were observed in heart tissues obtained from humans and rats with AMI incidences. In the cellular model of AMI, it was found that increased expression of AGE-albumin was shown to be co-localized with macrophages, and the presence of AGE-albumin led to increased expression of RAGE through the mitogen-activated protein kinase pathway. After revealing cardiomyocyte apoptosis induced by toxicity of the AGE-RAGE system, sRAGE-secreting MSCs were generated using the CRISPR/Cas9 platform to investigate the therapeutic effects of sRAGE-MSCs in an AMI rat model. Gene-edited sRAGE-MSCs showed greater therapeutic effects against AMI pathogenesis in rat models compared to mock MSCs, and promising results of the functional improvement of stem cells could result in significant improvements in the clinical management of cardiovascular diseases.
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27
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RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice. Clin Immunol 2022; 245:109165. [DOI: 10.1016/j.clim.2022.109165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/21/2022]
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Lai SWT, Lopez Gonzalez EDJ, Zoukari T, Ki P, Shuck SC. Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease. Chem Res Toxicol 2022; 35:1720-1746. [PMID: 36197742 PMCID: PMC9580021 DOI: 10.1021/acs.chemrestox.2c00160] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Metabolism is an essential part of life that provides energy for cell growth. During metabolic flux, reactive electrophiles are produced that covalently modify macromolecules, leading to detrimental cellular effects. Methylglyoxal (MG) is an abundant electrophile formed from lipid, protein, and glucose metabolism at intracellular levels of 1-4 μM. MG covalently modifies DNA, RNA, and protein, forming advanced glycation end products (MG-AGEs). MG and MG-AGEs are associated with the onset and progression of many pathologies including diabetes, cancer, and liver and kidney disease. Regulating MG and MG-AGEs is a potential strategy to prevent disease, and they may also have utility as biomarkers to predict disease risk, onset, and progression. Here, we review recent advances and knowledge surrounding MG, including its production and elimination, mechanisms of MG-AGEs formation, the physiological impact of MG and MG-AGEs in disease onset and progression, and the latter in the context of its receptor RAGE. We also discuss methods for measuring MG and MG-AGEs and their clinical application as prognostic biomarkers to allow for early detection and intervention prior to disease onset. Finally, we consider relevant clinical applications and current therapeutic strategies aimed at targeting MG, MG-AGEs, and RAGE to ultimately improve patient outcomes.
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Affiliation(s)
- Seigmund Wai Tsuen Lai
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Edwin De Jesus Lopez Gonzalez
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Tala Zoukari
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Priscilla Ki
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Sarah C Shuck
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
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29
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Yang R, Zhang X. A potential new pathway for heparin treatment of sepsis-induced lung injury: inhibition of pulmonary endothelial cell pyroptosis by blocking hMGB1-LPS-induced caspase-11 activation. Front Cell Infect Microbiol 2022; 12:984835. [PMID: 36189354 PMCID: PMC9519888 DOI: 10.3389/fcimb.2022.984835] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Abstract
Sepsis is a significant cause of mortality in critically ill patients. Acute lung injury (ALI) is a leading cause of death in these patients. Endothelial cells exposed to the bacterial endotoxin lipopolysaccharide (LPS) can progress into pyroptosis, a programmed lysis of cell death triggered by inflammatory caspases. It is characterized by lytic cell death induced by the binding of intracellular LPS to caspases 4/5 in human cells and caspase-11 in mouse cells. In mice,caspase-11-dependent pyroptosis plays an important role in endotoxemia. HMGB1 released into the plasma binds to LPS and is internalized into lysosomes in endothelial cells via the advanced glycation end product receptor. In the acidic lysosomal environment, HMGB1 permeates the phospholipid bilayer, which is followed by the leakage of LPS into the cytoplasm and the activation of caspase-11. Heparin is an anticoagulant widely applied in the treatment of thrombotic disease. Previous studies have found that heparin could block caspase-11-dependent inflammatory reactions, decrease sepsis-related mortality, and reduce ALI, independent of its anticoagulant activity. Heparin or modified heparin with no anticoagulant property could inhibit the alarmin HMGB1-LPS interactions, minimize LPS entry into the cytoplasm, and thus blocking caspase-11 activation. Heparin has been studied in septic ALI, but the regulatory mechanism of pulmonary endothelial cell pyroptosis is still unclear. In this paper, we discuss the potential novel role of heparin in the treatment of septic ALI from the unique mechanism of pulmonary endothelial cell pyroptosis.
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Songjang W, Nensat C, Nernpermpisooth N, Seenak P, Pankhong P, Jumroon N, Kumphune S, Jiraviriyakul A. Tumor-Promoting Activity and Proteomic Profiling of Cisplatin/Oxaliplatin-Derived DAMPs in Cholangiocarcinoma Cells. Int J Mol Sci 2022; 23:ijms231810540. [PMID: 36142453 PMCID: PMC9502173 DOI: 10.3390/ijms231810540] [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: 08/08/2022] [Revised: 09/03/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022] Open
Abstract
Damage-associated molecular patterns (DAMPs) are well recognized as the molecular signature of immunogenic cell death (ICD). The efficacy of drug-induced ICD function may be impacted by the precise ratio between immunostimulatory and immunoinhibitory DAMPs. Tumor-derived DAMPs can activate tumor-expressed TLRs for the promotion of tumor cell motility, invasion, metastatic spread and resistance to chemotherapeutic treatment. Herein, drug-induced DAMPs’ expression and their role in tumor progression are utilized as one crucial point of evaluation regarding chemotherapeutic treatment efficacy in our study. Cisplatin and oxaliplatin, the conventional anticancer chemotherapy drugs, are emphasized as a cause of well-known DAMPs’ release from cholangiocarcinoma (CCA) cells (e.g., HSP family, S100, CRT and HMGB1), whereby they trigger Akt, ERK and Cyclin-D1 to promote tumor activities. These findings strengthen the evidence that DAMPs are not only involved in immunomodulation but also in tumor promotion. Therefore, DAMP molecules should be considered as either targets of cancer treatment or biomarkers to evaluate treatment efficacy and tumor recurrence.
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Affiliation(s)
- Worawat Songjang
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Chatchai Nensat
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani 12120, Thailand
| | - Nitirut Nernpermpisooth
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Porrnthanate Seenak
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Panyupa Pankhong
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Noppadon Jumroon
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Sarawut Kumphune
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Biomedical Engineering Institute (BMEI), Chiang Mai University, Chiang Mai 50200, Thailand
| | - Arunya Jiraviriyakul
- Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand
- Correspondence:
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Wang Q, Lu M, Zhu X, Gu X, Zhang T, Xia C, Yang L, Xu Y, Zhou M. The role of microglia immunometabolism in neurodegeneration: Focus on molecular determinants and metabolic intermediates of metabolic reprogramming. Biomed Pharmacother 2022; 153:113412. [DOI: 10.1016/j.biopha.2022.113412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 11/16/2022] Open
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Bai R, Zhang T, Gao Y, Shu T, Zhou Y, Wang F, Chang X, Tang W, Zhu Y, Han X. Rab31, a receptor of advanced glycation end products (RAGE) interacting protein, inhibits AGE induced pancreatic β-cell apoptosis through the pAKT/BCL2 pathway. Endocr J 2022; 69:1015-1026. [PMID: 35314532 DOI: 10.1507/endocrj.ej21-0594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Receptor of advanced glycation end products (RAGE) mediates diverse signal transduction following ligand stimulation and plays an important role in diabetes complications and aging associated disease. We have previously verified that advanced glycation end products (AGE) bind to RAGE to cause pancreatic β-cell apoptosis through the mitochondrial pathway. However, the direct interacting protein(s) of RAGE in β cells has never been appreciated. In the present study, we utilized GST pull-down assay combined with mass spectrometry to identify the interacting proteins of the RAGE intracellular domain (C-terminal 43 amino acid of RAGE). Overall four RAGE interacting proteins, including Rab31, were identified with scores over 160. Rab31 was detected in three β-cell lines and confirmed to have interacted with RAGE via co-immunoprecipitation and immunostaining assays. This interaction was further enhanced by glycation-serum (GS) stimulation due to membrane distribution of Rab31 following treatment with GS. We further confirmed that Rab31 promoted RAGE endocytosis and inhibited GS-induced β-cell apoptosis through the pAKT/BCL2 pathway. These findings reveal a new RAGE interaction protein Rab31 that prevents AGE/RAGE-induced pancreatic β-cell apoptosis. Rab31 is therefore a promising therapeutic target for preserving functional β cells under diabetes conditions.
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Affiliation(s)
- Rongjie Bai
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Tao Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Yan Gao
- Institute of Suzhou Biobank, Suzhou Center for Disease Prevention and Control, Suzhou 215004, China
- Suzhou Institute of Advanced Study in Public Health, Gusu School, Nanjing Medical University, Suzhou 215004, China
| | - Tingting Shu
- Department of Endocrinology, Geriatric Hospital of Nanjing Medical University, Nanjing 210024, China
| | - Yuncai Zhou
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Fuqiang Wang
- Analysis Center, Nanjing Medical University, Nanjing 210029, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Wei Tang
- Department of Endocrinology, Geriatric Hospital of Nanjing Medical University, Nanjing 210024, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
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Santonocito S, Polizzi A, Marchetti E, Dalessandri D, Migliorati M, Lupi SM, Cicciù M, Isola G. Impact of Periodontitis on Glycemic Control and Metabolic Status in Diabetes Patients: Current Knowledge on Early Disease Markers and Therapeutic Perspectives. Mediators Inflamm 2022; 2022:4955277. [PMID: 35996409 PMCID: PMC9392618 DOI: 10.1155/2022/4955277] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/15/2022] [Accepted: 07/20/2022] [Indexed: 11/18/2022] Open
Abstract
Diabetes mellitus and periodontitis are two of the most common chronic diseases affecting the world's population, and they are intimately linked. For several years, in fact, it has been known that there is an interdependent relationship between the two diseases: Diabetes promotes the destruction of periodontal tissues, and periodontal disease negatively affects glycemic control. In relation to the control of dental plaque and oral dysbiosis responsible for periodontal disease, both nonsurgical and surgical therapy associated with proper home hygiene procedures have emerged as essential for good glycemic control. Moreover, several evidences suggest the essential role played by the control of periodontal disease in preventing the onset of the most common complications of diabetes: cardiovascular diseases, retinopathies, and other systemic diseases. The aim of this study is to update the current knowledge on the bi-univocal relationship between diabetes and periodontitis and the impact of therapy in the optimal management of these two disorders. From the information found in the literature, it has emerged that the correct treatment of periodontal disease in diabetic patients represents one of the main mechanisms and means currently established and valid to control periodontal disease and glucose metabolism and prevent the onset or development of diabetic complications.
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Affiliation(s)
- Simona Santonocito
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 78, 95124 Catania, Italy
| | - Alessandro Polizzi
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 78, 95124 Catania, Italy
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Enrico Marchetti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Domenico Dalessandri
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Marco Migliorati
- Dental School, Department of Surgery, University of Genova, Italy
| | - Saturnino Marco Lupi
- Unit of Oral Surgery and Implantology, Section of Dentistry, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
| | - Marco Cicciù
- Department of Biomedical and Dental Sciences, Morphological and Functional Images, University of Messina, Messina, Italy
| | - Gaetano Isola
- Department of General Surgery and Surgical-Medical Specialties, School of Dentistry, University of Catania, Via S. Sofia 78, 95124 Catania, Italy
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De Masi R, Orlando S. GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review. Int J Mol Sci 2022; 23:7373. [PMID: 35806376 PMCID: PMC9266668 DOI: 10.3390/ijms23137373] [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: 05/13/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022] Open
Abstract
Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc3Man9GlcNAc2 highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.
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Affiliation(s)
- Roberto De Masi
- Complex Operative Unit of Neurology, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy;
- Laboratory of Neuroproteomics, Multiple Sclerosis Centre, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy
| | - Stefania Orlando
- Laboratory of Neuroproteomics, Multiple Sclerosis Centre, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy
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Gerber KS, Alvarez G, Alamian A, Behar-Zusman V, Downs CA. Biomarkers of Neuroinflammation in Traumatic Brain Injury. Clin Nurs Res 2022; 31:1203-1218. [PMID: 35770330 DOI: 10.1177/10547738221107081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Traumatic brain injury (TBI) is characterized by neuroinflammation and structural damage leading to symptoms and altered brain function. Biomarkers are useful in understanding neuroinflammation and correlations with TBI sequalae. The purpose of this paper is to identify and discuss biomarkers of neuroinflammation used to study TBI and its sequalae. A systematic review was conducted using PubMed, CINAHL, Embase, and Web of Science. A total of 350 articles met criteria; 70 used biomarkers. PRISMA criteria were used for Quality Assessment. Articles included reviews (n = 17), case-control (n = 25), cross-sectional (n = 25) studies, and randomized controlled trials (n = 3). Twenty-seven biomarkers were identified, including inflammasomes, cytokines, neuropeptides, complement complexes, miRNA and exosomes, and glial cell-specific proteins. Biomarkers aid in predicting morbidity and mortality and advance our understanding of neuroinflammation in TBI. This systematic review advances our understanding of the neuroinflammatory response to better enable nurses and clinicians to provide informed care of TBI patients.
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Affiliation(s)
- Kathryn S Gerber
- University of Miami School of Nursing and Health Studies, Coral Gables, FL, USA
| | - Gema Alvarez
- University of Miami Miller School of Medicine, FL, USA
| | - Arsham Alamian
- University of Miami School of Nursing and Health Studies, Coral Gables, FL, USA
| | | | - Charles A Downs
- University of Miami School of Nursing and Health Studies, Coral Gables, FL, USA
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Krychtiuk KA, Vrints C, Wojta J, Huber K, Speidl WS. Basic mechanisms in cardiogenic shock: part 1-definition and pathophysiology. EUROPEAN HEART JOURNAL. ACUTE CARDIOVASCULAR CARE 2022; 11:356-365. [PMID: 35218350 DOI: 10.1093/ehjacc/zuac021] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 01/17/2022] [Accepted: 02/07/2022] [Indexed: 05/23/2023]
Abstract
Cardiogenic shock mortality rates remain high despite significant advances in cardiovascular medicine and the widespread uptake of mechanical circulatory support systems. Except for early invasive angiography and percutaneous coronary intervention of the infarct-related artery, the most widely used therapeutic measures are based on low-quality evidence. The grim prognosis and lack of high-quality data warrant further action. Part 1 of this two-part educational review defines cardiogenic shock and discusses current treatment strategies. In addition, we summarize current knowledge on basic mechanisms in the pathophysiology of cardiogenic shock, focusing on inflammation and microvascular disturbances, which may ultimately be translated into diagnostic or therapeutic approaches to improve the outcome of our patients.
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Affiliation(s)
- Konstantin A Krychtiuk
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Duke Clinical Research Institute, Durham, NC, USA
| | - Christiaan Vrints
- Research Group Cardiovascular Diseases, Department GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital (UZA), Edegem, Belgium
| | - Johann Wojta
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria
- Core Facilities, Medical University of Vienna, Vienna, Austria
| | - Kurt Huber
- Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria
- 3rd Department of Internal Medicine, Cardiology and Intensive Care Unit, Wilhelminenhospital, Vienna, Austria
- Medical School, Sigmund Freud University, Vienna, Austria
| | - Walter S Speidl
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria
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Therapeutic Potential of Phlorotannin-Rich Ecklonia cava Extract on Methylglyoxal-Induced Diabetic Nephropathy in In Vitro Model. Mar Drugs 2022; 20:md20060355. [PMID: 35736158 PMCID: PMC9229597 DOI: 10.3390/md20060355] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 11/22/2022] Open
Abstract
Advanced glycation end-products (AGEs) play a vital role in the pathogenesis of diabetic complications. Methylglyoxal (MGO), one of the major precursors of AGEs, is a highly reactive dicarbonyl compound that plays an important role in the pathogenesis of diabetic nephropathy. This study was designed to evaluate the therapeutic potential of phlorotannin-rich Ecklonia cava extract (ECE) on MGO-induced diabetic nephropathy in in vitro models using mouse glomerular mesangial cells. ECE showed anti-glycation activity via breaking of AGEs-collagen cross-links and inhibition of AGEs formation and AGE-collagen cross-linking formation. The renoprotective effects were determined by assessing intracellular reactive oxygen species (ROS) and MGO accumulation, cell apoptosis, and the Nrf-2/ARE signaling pathway. MGO-induced renal damage, intracellular ROS production level, and MGO-protein adduct accumulation were significantly decreased by pretreating ECE. Moreover, ECE pretreatment exhibited preventive properties against MGO-induced dicarbonyl stress via activation of the Nrf2/ARE signaling pathway and reduction of RAGE protein expression in mouse glomerular mesangial cells. Collectively, these results indicated potential anti-glycation properties and prominent preventive effects of ECE against MGO-induced renal damage. Additionally, ECE may be utilized for the management of AGE-related diabetic nephropathy.
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Vargas-George S, Dave KR. Models of cerebral amyloid angiopathy-related intracerebral hemorrhage. BRAIN HEMORRHAGES 2022. [DOI: 10.1016/j.hest.2022.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives. Biomolecules 2022; 12:biom12040542. [PMID: 35454131 PMCID: PMC9030615 DOI: 10.3390/biom12040542] [Citation(s) in RCA: 349] [Impact Index Per Article: 116.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/28/2022] [Accepted: 03/31/2022] [Indexed: 02/06/2023] Open
Abstract
Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications.
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Li M, Ong CY, Langouët-Astrié CJ, Tan L, Verma A, Yang Y, Zhang X, Shah DK, Schmidt EP, Xu D. Heparan sulfate-dependent RAGE oligomerization is indispensable for pathophysiological functions of RAGE. eLife 2022; 11:e71403. [PMID: 35137686 PMCID: PMC8863369 DOI: 10.7554/elife.71403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 02/01/2022] [Indexed: 12/13/2022] Open
Abstract
RAGE, a druggable inflammatory receptor, is known to function as an oligomer but the exact oligomerization mechanism remains poorly understood. Previously we have shown that heparan sulfate (HS) plays an active role in RAGE oligomerization. To understand the physiological significance of HS-induced RAGE oligomerization in vivo, we generated RAGE knock-in mice (AgerAHA/AHA) by introducing point mutations to specifically disrupt HS-RAGE interaction. The RAGE mutant demonstrated normal ligand-binding but impaired capacity of HS-binding and oligomerization. Remarkably, AgerAHA/AHA mice phenocopied Ager-/- mice in two different pathophysiological processes, namely bone remodeling and neutrophil-mediated liver injury, which demonstrates that HS-induced RAGE oligomerization is essential for RAGE signaling. Our findings suggest that it should be possible to block RAGE signaling by inhibiting HS-RAGE interaction. To test this, we generated a monoclonal antibody that targets the HS-binding site of RAGE. This antibody blocks RAGE signaling in vitro and in vivo, recapitulating the phenotype of AgerAHA/AHA mice. By inhibiting HS-RAGE interaction genetically and pharmacologically, our work validated an alternative strategy to antagonize RAGE. Finally, we have performed RNA-seq analysis of neutrophils and lungs and found that while Ager-/- mice had a broad alteration of transcriptome in both tissues compared to wild-type mice, the changes of transcriptome in AgerAHA/AHA mice were much more restricted. This unexpected finding suggests that by preserving the expression of RAGE protein (in a dominant-negative form), AgerAHA/AHA mouse might represent a cleaner genetic model to study physiological roles of RAGE in vivo compared to Ager-/- mice.
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Affiliation(s)
- Miaomiao Li
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Chih Yean Ong
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Christophe J Langouët-Astrié
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Lisi Tan
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
- Department of Periodontics, School of Stomatology, China Medical UniversityShenyangChina
| | - Ashwni Verma
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Yimu Yang
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Xiaoxiao Zhang
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Dhaval K Shah
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New YorkBuffaloUnited States
| | - Eric P Schmidt
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical CampusAuroraUnited States
| | - Ding Xu
- Department of Oral Biology, University at Buffalo, State University of New YorkBuffaloUnited States
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Lee CH, Lee SW. Vasculopathy in Diabetic Foot. DIABETIC FOOT RECONSTRUCTION 2022:11-23. [DOI: 10.1007/978-981-16-9816-3_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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Rojas A, Lindner C, Schneider I, Gonzàlez I, Araya H, Morales E, Gómez M, Urdaneta N, Araya P, Morales MA. Diabetes mellitus contribution to the remodeling of the tumor microenvironment in gastric cancer. World J Gastrointest Oncol 2021; 13:1997-2012. [PMID: 35070037 PMCID: PMC8713306 DOI: 10.4251/wjgo.v13.i12.1997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/10/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial contribution of diabetes mellitus (DM) as a risk factor associated with increased cancer incidence and mortality in many human neoplasms, including gastric cancer (GC). DM is considered a systemic inflammatory disease and therefore, this inflammatory status may have profound effects on the tumor microenvironment (TME), particularly by driving many molecular mechanisms to generate a more aggressive TME. DM is an active driver in the modification of the behavior of many cell components of the TME as well as altering the mechanical properties of the extracellular matrix (ECM), leading to an increased ECM stiffening. Additionally, DM can alter many cellular signaling mechanisms and thus favoring tumor growth, invasion, and metastatic potential, as well as key elements in regulating cellular functions and cross-talks, such as the microRNAs network, the production, and cargo of exosomes, the metabolism of cell stroma and resistance to hypoxia. In the present review, we intend to highlight the mechanistic contributions of DM to the remodeling of TME in GC.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Cristian Lindner
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Iván Schneider
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Ileana Gonzàlez
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Hernan Araya
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Erik Morales
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Anatomía Patologica, Hospital Regional de Talca, Talca 34600000, Chile
| | - Milibeth Gómez
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Nelson Urdaneta
- Department of Clinical Sciences, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
- Servicio de Oncología, Hospital Regional de Talca, Talca 34600000, Chile
| | - Paulina Araya
- Biomedical Research Lab., Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Miguel Angel Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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Gerber KS, De Santis JP, Cianelli R. Psychological Trauma in the Context of Intimate Partner Violence: A Concept Analysis. Issues Ment Health Nurs 2021; 42:1104-1113. [PMID: 33960875 DOI: 10.1080/01612840.2021.1920651] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
A comprehensive understanding of psychological trauma in the context of intimate partner violence (IPV) is relevant for nurses and other healthcare providers to provide better care for individuals and families confronting this issue. A concept analysis based on Walker and Avant was conducted to fully understand this concept and its impact on physical and mental health. This concept analysis demonstrates that psychological trauma in the IPV context is an intricate multi-faceted concept that can have a significant long-term effect on individuals who have experienced IPV. The concept's attributes, antecedents, and consequences identified in this concept analysis will contribute to guiding practice, research, education, and policy development aimed to address the trauma affecting individuals and families in the context of IPV.
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Affiliation(s)
- Kathryn S Gerber
- School of Nursing and Health Studies, University of Miami, Coral Gables, Florida, USA
| | - Joseph P De Santis
- School of Nursing and Health Studies, University of Miami, Coral Gables, Florida, USA
| | - Rosina Cianelli
- School of Nursing and Health Studies, University of Miami, Coral Gables, Florida, USA
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Leu JG, Su WH, Chen YC, Liang YJ. Hydralazine attenuates renal inflammation in diabetic rats with ischemia/reperfusion acute kidney injury. Eur J Pharmacol 2021; 910:174468. [PMID: 34478692 DOI: 10.1016/j.ejphar.2021.174468] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/24/2021] [Accepted: 08/30/2021] [Indexed: 01/23/2023]
Abstract
Acute kidney injury (AKI) is one of the major complications with increased oxidative stress and inflammation in diabetic patients. Hyperglycemia stimulates the formation of advanced glycation end products (AGEs). However, hyperglycemia directly triggers the interaction between AGEs and transmembrane AGEs receptors (RAGE), which enhances oxidative stress and increases the production of inflammatory substances. Therefore, diabetes plays a pivotal role in kidney injury. Hydralazine, a vasodilator and antihypertensive drug, was found to have the ability to reduce ROS, oxidative stress, and inflammation. We applied Hydralazine co-culture with AGEs in rat mesangial cells (RMC) and to renal ischemia/reperfusion(I/R) injury models in streptozotocin-induced diabetic rats. Hydralazine significantly decreased AGEs-induced RAGE, iNOS, and COX-2 expressions in RMC. Compared to the diabetic with AKI group, hydralazine decreased inflammation-related protein, and JAK2, STAT3 signaling in rat kidney tissue. Our studies indicate that Hydralazine has the potential to become a beneficial drug in the treatment of diabetic acute kidney injury.
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Affiliation(s)
- Jyh-Gang Leu
- Fu-Jen Catholic University School of Medicine, New Taipei City, Taiwan, ROC; Division of Nephrology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC; Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Hsiang Su
- Department and Institute of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan, ROC
| | - Yu-Cheng Chen
- Division of Nephrology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC; Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yao-Jen Liang
- Department and Institute of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan, ROC.
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Mocanu CA, Fuior EV, Voicu G, Rebleanu D, Safciuc F, Deleanu M, Fenyo IM, Escriou V, Manduteanu I, Simionescu M, Calin M. P-selectin targeted RAGE-shRNA lipoplexes alleviate atherosclerosis-associated inflammation. J Control Release 2021; 338:754-772. [PMID: 34530051 DOI: 10.1016/j.jconrel.2021.09.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/03/2021] [Accepted: 09/10/2021] [Indexed: 12/19/2022]
Abstract
The receptor for advanced glycation end products (RAGE) plays a central role in the chronic inflammatory process associated with atherosclerosis development. We aimed to develop lipoplexes carrying RAGE-short hairpin (sh) RNA, targeted to the adhesion molecule P-selectin, selectively expressed on the surface of activated endothelium (Psel-lipo/shRAGE) to down-regulate RAGE expression as a therapeutic strategy for atherosclerosis. In vitro, Psel-lipo/shRAGE lipoplexes were efficiently taken up by activated endothelial cells (EC), decreased the expression of RAGE protein, and proved to be functional by reducing the monocyte adhesion to activated EC. In ApoE-deficient mice, the targeted lipoplexes accumulated specifically and efficiently transfected the aorta. The repeated administration of Psel-lipo/shRAGE lipoplexes, twice per week for one month: i) reduced the expression of RAGE protein in the aorta by decreasing the expression of NF-kB and TNF-α; ii) diminished the plasma levels of TNF-α, IL6, IL-1β, and MCP-1; iii) inhibited the atherosclerotic plaque development and iv) had no significant adverse effects. In conclusion, the newly developed Psel-lipo/shRAGE lipoplexes reduce the inflammatory processes associated with RAGE signaling and the progression of atherosclerosis in ApoE-deficient mice. Downregulation of RAGE employing these lipoplexes may represent a promising new targeted therapy to block atherosclerosis progression.
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Affiliation(s)
- Cristina Ana Mocanu
- "Medical and Pharmaceutical Bionanotechnologies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | - Elena Valeria Fuior
- "Medical and Pharmaceutical Bionanotechnologies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | - Geanina Voicu
- "Medical and Pharmaceutical Bionanotechnologies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | - Daniela Rebleanu
- "Medical and Pharmaceutical Bionanotechnologies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | - Florentina Safciuc
- "Medical and Pharmaceutical Bionanotechnologies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | - Mariana Deleanu
- "Liquid and Gas Chromatography" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | - Ioana Madalina Fenyo
- "Gene Regulation and Molecular Therapies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | | | - Ileana Manduteanu
- "Medical and Pharmaceutical Bionanotechnologies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | - Maya Simionescu
- "Medical and Pharmaceutical Bionanotechnologies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania
| | - Manuela Calin
- "Medical and Pharmaceutical Bionanotechnologies" Laboratory, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 050568 Bucharest, Romania.
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Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice. Sci Rep 2021; 11:17851. [PMID: 34497344 PMCID: PMC8426400 DOI: 10.1038/s41598-021-97361-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/24/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.
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Yoon JK, Kim J, Shah Z, Awasthi A, Mahajan A, Kim Y. Advanced Human BBB-on-a-Chip: A New Platform for Alzheimer's Disease Studies. Adv Healthc Mater 2021; 10:e2002285. [PMID: 34075728 PMCID: PMC8349886 DOI: 10.1002/adhm.202002285] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/17/2021] [Indexed: 12/14/2022]
Abstract
The blood-brain barrier (BBB) is a unique vascular structure that serves as a molecular transport gateway for the maintenance of brain homeostasis. Chronic disruption or breakdown of the BBB reportedly leads to neurodegenerative diseases. Nonetheless, research on human BBB pathophysiology and drug development remains highly dependent on studies using inherently different animals. Moreover, more studies have shown that animal models are not appropriate in modeling Alzheimer's disease (AD), underlining the importance of in vitro models of the human BBB with physiological relevance. In this review, recent advances in human BBB-on-a-chip technologies are highlighted and their potential for pathogenesis studies and drug prescreening for AD treatment are discussed.
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Affiliation(s)
- Jeong-Kee Yoon
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Jaehoon Kim
- Mepsgen Co. Ltd., Seoul, 05836, Republic of Korea
| | - Zachary Shah
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Ashi Awasthi
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Advay Mahajan
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - YongTae Kim
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
- Mepsgen Co. Ltd., Seoul, 05836, Republic of Korea
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
- Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332, USA
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Volpina OM, Koroev DO, Serebryakova MV, Volkova TD, Kamynina AV, Bobkova NV. Proteolytic degradation patterns of the receptor for advanced glycation end products peptide fragments correlate with their neuroprotective activity in Alzheimer's disease models. Drug Dev Res 2021; 82:1217-1226. [PMID: 34060112 DOI: 10.1002/ddr.21836] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 11/10/2022]
Abstract
The receptor for advanced glycation end products (RAGE) plays an essential role in Alzheimer's disease (AD). We previously demonstrated that a fragment (60-76) of RAGE improved the memory of olfactory bulbectomized (OBX) and Tg 5 × FAD mice - animal models of AD. The peptide analog (60-76) with protected N- and C-terminal groups was more active than the free peptide in Tg 5 × FAD mice. This study investigated proteolytic cleavage of the RAGE fragment (60-76) and its C- and N-terminally modified analog by blood serum using HPLC and mass spectrometry. The modified peptide was proteolyzed slower than the free peptide. Degrading the protected analog resulted in shortened fragments with memory-enhancing effects, whereas the free peptide yielded inactive fragments. After administering the different peptides to OBX mice, their performance in a spatial memory task revealed that the effective dose of the modified peptide was five times lower than that of the free peptide. HPLC and mass spectrometry analysis of the proteolytic products allowed us to clarify the differences in the neuroprotective activity conferred by administering these two peptides to AD animal models. The current study suggests that the modified RAGE fragment is more promising for the development of anti-AD therapy than its free analog.
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Affiliation(s)
- Olga M Volpina
- Department of Molecular Neurobiology, Laboratory of Synthetic Vaccines, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (RAS), Moscow, Russia
| | - Dmitriy O Koroev
- Department of Molecular Neurobiology, Laboratory of Synthetic Vaccines, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (RAS), Moscow, Russia
| | - Marina V Serebryakova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Tatyana D Volkova
- Department of Molecular Neurobiology, Laboratory of Synthetic Vaccines, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (RAS), Moscow, Russia
| | - Anna V Kamynina
- Department of Molecular Neurobiology, Laboratory of Synthetic Vaccines, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry (RAS), Moscow, Russia.,Research Center for Molecular Mechanisms of Aging and Age Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Natalia V Bobkova
- Laboratory of Cellular Mechanisms of Memory Pathology, Institute of Cell Biophysics (RAS), Pushchino, Russia
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Hitsumoto T. Clinical Significance of the Cardio-Ankle Vascular Index in Postmenopausal Women With Hypercholesterolemia. J Clin Med Res 2021; 13:276-282. [PMID: 34104279 PMCID: PMC8166294 DOI: 10.14740/jocmr4509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 05/04/2021] [Indexed: 12/21/2022] Open
Abstract
Background The cardio-ankle vascular index (CAVI) is a physiological indicator of arterial elasticity. However, limited information regarding the clinical significance of the CAVI in patients with hypercholesterolemia is available. This cross-sectional study aimed to elucidate the clinical significance of the CAVI for the primary prevention of cardiovascular disease (CVD) among postmenopausal women with hypercholesterolemia. Methods A total of 168 untreated postmenopausal hypercholesterolemic women (low-density lipoprotein cholesterol levels ≥ 140 mg/dL, mean age ± standard deviation, 63 ± 10 years) with no history of CVD events were enrolled. The CAVI was measured using commercial devices, after which, its relationships with various clinical parameters, such as carotid artery ultrasonography findings and CVD biomarkers, were examined. Results A significant positive correlation was observed between the CAVI and maximum intima-media thickness of the common carotid artery (max-C-IMT), which was evaluated using carotid artery ultrasonography (r = 0.49, P < 0.001). Regarding CVD biomarkers, the CAVI was significantly correlated with estimated glomerular filtration rate (r = -0.18, P < 0.001), high-sensitivity C-reactive protein (r = 0.36, P < 0.001), whole blood passage time as a marker of blood rheology (r = 0.41, P < 0.001), and skin autofluorescence as a marker of advanced glycation end products in tissues (r = 0.46, P < 0.001), although no significant correlation was noted between serum lipid parameters and the CAVI. Multiple regression analysis identified max-C-IMT (β = 0.35, P < 0.001), whole blood passage time (β = 0.18, P = 0.007), skin autofluorescence (β = 0.17, P = 0.011), and age (β = 0.16, P = 0.018) as variables independently associated with CAVI. Conclusion The present study indicated that the CAVI is an essential CVD risk factor among postmenopausal women with hypercholesterolemia. Moreover, impaired blood rheology and increase of skin autofluorescence were associated with elevated CAVI in such patients.
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Affiliation(s)
- Takashi Hitsumoto
- Hitsumoto Medical Clinic, 2-7-7, Takezakicyou, Shimonoseki City, Yamaguchi 750-0025, Japan.
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50
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Rojas A, Lindner C, Gonzàlez I, Morales MA. Advanced-glycation end-products axis: A contributor to the risk of severe illness from COVID-19 in diabetes patients. World J Diabetes 2021; 12:590-602. [PMID: 33995847 PMCID: PMC8107984 DOI: 10.4239/wjd.v12.i5.590] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/29/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products (RAGE) in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus (DM). During the coronavirus disease 2019 (COVID-19) pandemic, many clinical reports have pointed out that DM increases the risk of COVID-19 complications, hospitalization requirements, as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate. In the present review, we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype, as well as the contribution of RAGE signaling in lung inflammation, may then lead to the increased mortality risk of COVID-19 in these patients. Additionally, the cross-talk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection, as well as the role of this multi-ligand receptor on the obesity-associated low-grade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19, are also discussed.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Cristian Lindner
- Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Ileana Gonzàlez
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca 3460000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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