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Alemu BK, Tommasi S, Hulin JA, Meyers J, Mangoni AA. Current knowledge on the mechanisms underpinning vasculogenic mimicry in triple negative breast cancer and the emerging role of nitric oxide. Biomed Pharmacother 2025; 186:118013. [PMID: 40147105 DOI: 10.1016/j.biopha.2025.118013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/13/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025] Open
Abstract
Vasculogenic mimicry (VM) is the process by which cancer cells form vascular-like channels to support their growth and dissemination. These channels lack endothelial cells and are instead lined by the tumour cells themselves. VM was first reported in uveal melanomas but has since been associated with other aggressive solid tumours, such as triple-negative breast cancer (TNBC). In TNBC patients, VM is associated with tumour aggressiveness, drug resistance, metastatic burden, and poor prognosis. The lack of effective targeted therapies for TNBC has stimulated research on the mechanisms underpinning VM in order to identify novel druggable targets. In recent years, studies have highlighted the role of nitric oxide (NO), the NO synthesis inhibitor, asymmetric dimethylarginine (ADMA), and dimethylarginine dimethylaminohydrolase 1 (DDAH1), the key enzyme responsible for ADMA metabolism, in regulating VM. Specifically, NO inhibition through downregulation of DDAH1 and consequent accumulation of ADMA appears to be a promising strategy to suppress VM in TNBC. This review discusses the current knowledge regarding the molecular pathways underpinning VM in TNBC, anti-VM therapies under investigation, and the emerging role of NO regulation in VM.
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Affiliation(s)
- Belete Kassa Alemu
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia; Injibara University, College of Medicine and Health Sciences, Department of Pharmacy, Injibara, Ethiopia
| | - Sara Tommasi
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia; Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, Australia
| | - Julie-Ann Hulin
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Jai Meyers
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Arduino A Mangoni
- Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, South Australia, Australia; Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, Australia.
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Sural S, Tekten T, Gungor H. The Relationship Between Neutrophil/Lymphocyte Ratio Before Coronary Angiography and Coronary Collateral Development. Cureus 2025; 17:e78739. [PMID: 39926621 PMCID: PMC11807405 DOI: 10.7759/cureus.78739] [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] [Accepted: 02/08/2025] [Indexed: 02/11/2025] Open
Abstract
OBJECTIVE The aim of this study was to determine the relationship between the neutrophil/lymphocyte ratio (NLR) measured before coronary angiography and coronary collateral (CC) development. METHOD This retrospective descriptive study was carried out between January 2012 and June 2013 in the cardiology outpatient clinic of a university hospital in Aydın, with 165 patients who were diagnosed with acute coronary syndrome or stable angina pectoris and who had 95% or more stenosis in at least one coronary artery according to angiography. Coronary artery stenosis was determined by Gensini scoring. The classification of CC was performed by the Rentrop method, and patients were divided into two groups: Rentrop stages 0 and 1 (poor CC filling (group 1)) and Rentrop stages 2 and 3 (good CC filling (group 2)). The data were analyzed using appropriate statistical analyses. Multivariate logistic regression was used to determine the predictors of CC level, and receiver operating characteristic (ROC) curve analysis was performed to calculate the predictive value of predictors. RESULTS When the groups were compared, the mean age (p=0.023), Gensini score (p<0.001), smoking status (p=0.012), creatinine level (p=0.032), and aspartate aminotransferase level (p=0.032) of the patients in group 1 were significantly lower than those in group 2, while their total cholesterol (p=0.006) and low-density lipoprotein (LDL) levels (p=0.020) were higher. Neutrophils (p=0.016) and NLR (p<0.001) were significantly higher in group 2 patients. A significant positive correlation was found between CC level and neutrophils (p=0.035) and NLR (p=0.011). In regression analysis, high NLR, high Gensini score, and smoking were predictors of good CC filling. According to ROC curve analysis, the sensitivity and specificity of NLR ≥3.53 at the time of presentation to the clinic for predicting good CC filling were 37.6% and 85%, respectively. CONCLUSION This study showed that NLR was significantly associated with the development of good CC filling; as NLR increased, the development of good CC filling increased in patients.
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Affiliation(s)
- Sefa Sural
- Cardiology, Istinye University, Istanbul, TUR
| | | | - Hasan Gungor
- Cardiology, Adnan Menderes University, Aydın, TUR
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Wei X, Li M, You J, Luo J, Zhai J, Zhang J, Feng J, Wang H, Zhou Y. A Procedural Overview of the Involvement of Small Molecules in the Nervous System in the Regulation of Bone Healing. Int J Nanomedicine 2025; 20:1263-1284. [PMID: 39906525 PMCID: PMC11792627 DOI: 10.2147/ijn.s505677] [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: 11/21/2024] [Accepted: 01/14/2025] [Indexed: 02/06/2025] Open
Abstract
Clinically, a multitude of factors can contribute to the development of bone defects. In the process of bone healing, the nervous system plays a vital role in bone regeneration. Small molecules from the nervous system, such as neurotrophic factors and neuropeptides, have been found to stimulate osteoblast proliferation and differentiation by activating signaling pathways associated with bone calcification and angiogenesis. These small molecules play a crucial regulatory role at various stages of bone healing. The systematic release mechanism of small molecules within the nervous system through diverse bone tissue engineering materials holds significant clinical implications for the controlled regulation of the bone healing process. This review provides an overview of the involvement of various nervous system small molecules at different stages of bone healing and discusses their regulatory mechanisms, aiming to establish a theoretical foundation for programmed regulation in bone regeneration and design of replacement materials in bone tissue engineering.
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Affiliation(s)
- Xuyan Wei
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Mucong Li
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiaqian You
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiaxin Luo
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jingjie Zhai
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jiameng Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jian Feng
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Hanchi Wang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Yanmin Zhou
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
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Wang Y, Bai M, Peng Q, Li L, Tian F, Guo Y, Jing C. Angiogenesis, a key point in the association of gut microbiota and its metabolites with disease. Eur J Med Res 2024; 29:614. [PMID: 39710789 DOI: 10.1186/s40001-024-02224-5] [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: 10/09/2024] [Accepted: 12/15/2024] [Indexed: 12/24/2024] Open
Abstract
The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood-brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy.
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Affiliation(s)
- Yan Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Mingshuai Bai
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Qifan Peng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Feng Tian
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Ying Guo
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
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Yen PC, Geng JH, Wu PY, Huang JC, Hu HM, Kuo CH, Chen SC. Secondhand smoke is associated with peptic ulcer disease and gastroesophageal reflux disease in non-smokers in a large Taiwanese population study. Front Public Health 2024; 12:1450481. [PMID: 39435406 PMCID: PMC11491381 DOI: 10.3389/fpubh.2024.1450481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/27/2024] [Indexed: 10/23/2024] Open
Abstract
Background Active smokers are known to be at an increased risk of both gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD), however the role of passive smoking remains unclear. In this study, we aimed to examine whether secondhand smoke (SHS) is associated with PUD and GERD. Methods In this population-based study, we conducted a large-scale analysis with 88,297 never-smokers (male: 18,595; female: 69,702; mean age 50.1 ± 11.0 years) from the Taiwan Biobank. The exposure group was comprised of those who had been exposed to SHS, and the no exposure group as those without SHS exposure. According to the frequency of exposure, we further divided the participants into "no exposure," "<1 h per week," and "≥1 h per week" groups. A cutoff point of 1 h per week was chosen according to the median exposure time in our participants. Associations between SHS and SHS frequency with PUD and GERD were assessed. Results Of the 88,297 enrolled participants, 11,909 (13.5%) had PUD and 76,388 (86.5%) did not. In addition, 11,758 (13.3%) had GERD and 76,539 (86.7%) did not. Multivariable analysis showed a significant association between SHS with PUD (odds ratio [OR] = 1.166; 95% confidence interval [CI] = 1.084-1.254; p < 0.001), and GERD (OR = 1.131; 95% CI = 1.053-1.216; p = 0.001). Furthermore, those exposed to SHS ≥ 1 h per week (vs. no exposure) were associated with higher risks of PUD (OR = 1.232; 95% CI = 1.121-1.355; p < 0.001) and GERD (OR = 1.200; 95% CI = 1.093-1.319; p < 0.001). Conclusion SHS was significantly associated with PUD and GERD. Furthermore, exposure to SHS ≥ 1 h per week (vs. no exposure) was associated with a 1.23-fold higher risk of PUD and 1.20-fold higher risk of GERD. This study represents the largest population-based investigation to explore the association between SHS with PUD and GERD in Taiwanese never-smokers.
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Affiliation(s)
- Pei-Chi Yen
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jiun-Hung Geng
- Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Yu Wu
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jiun-Chi Huang
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Huang-Ming Hu
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Hung Kuo
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Szu-Chia Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Munkhjargal U, Fukuda D, Maeda J, Hara T, Okamoto S, Bavuu O, Yamamoto T, Sata M. LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Ameliorates Endothelial Dysfunction in Diabetic C57BL/6 Mice. J Atheroscler Thromb 2024; 31:1333-1340. [PMID: 38616113 PMCID: PMC11374559 DOI: 10.5551/jat.64468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 02/18/2024] [Indexed: 04/16/2024] Open
Abstract
AIMS LCZ696 (sacubitril/valsartan) exerts cardioprotective effects. Recent studies have suggested that it improves the endothelial function; however, the underlying mechanisms have not been thoroughly investigated. We investigated whether LCZ696 ameliorates diabetes-induced endothelial dysfunction. METHODS Diabetes was induced using streptozotocin in 8-week-old male C57BL/6 mice. Diabetic mice were randomly assigned to receive LCZ696 (100 mg/kg/day), valsartan (50 mg/kg/day), or a vehicle for three weeks. The endothelium-dependent and endothelium-independent vascular responses of the aortic segments were determined based on the response to acetylcholine and sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVEC) and aortic segments obtained from C57BL/6 mice were used to perform in vitro and ex vivo experiments, respectively. RESULTS LCZ696 and valsartan reduced the blood pressure in diabetic mice (P＜0.05). The administration of LCZ696 (P＜0.001) and valsartan (P＜0.01) ameliorated endothelium-dependent vascular relaxation, but not endothelium-independent vascular relaxation, under diabetic conditions. LCZ696, but not valsartan, increased eNOSSer1177 (P=0.06) and Akt (P＜0.05) phosphorylation in the aorta. In HUVEC, methylglyoxal (MGO), a major precursor of advanced glycation end products, decreased eNOSSer1177 phosphorylation (P＜0.05) and increased eNOSThr495 phosphorylation (P＜0.001). However, atrial natriuretic peptide (ANP) reversed these effects. ANP also ameliorated the MGO-induced impairment of endothelium-dependent vascular relaxation in the aortic segments (P＜0.05), although L-NAME completely blocked this effect (P＜0.001). CONCLUSION LCZ696 ameliorated diabetes-induced endothelial dysfunction by increasing the bioavailability of ANP. Our findings suggest that LCZ696 has a vascular protective effect in a diabetic model and highlight that it may be more effective than valsartan.
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Affiliation(s)
- Uugantsetseg Munkhjargal
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Daiju Fukuda
- Department of Cardiovascular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Juri Maeda
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Tomoya Hara
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Shintaro Okamoto
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Oyunbileg Bavuu
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
- Department of Cardiovascular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Takayuki Yamamoto
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
- Department of Cardiovascular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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Song JH, Hwang B, Lyea Park S, Kim H, Jung S, Choi C, Myung Lee H, Yun SJ, Hyun Choi Y, Cha EJ, Patterson C, Kim WJ, Moon SK. IL-28A/IL-10Rβ axis promotes angiogenesis via eNOS/AKT signaling and AP-1/NF-κB/MMP-2 network by regulating HSP70-1 expression. J Adv Res 2024:S2090-1232(24)00356-4. [PMID: 39127098 DOI: 10.1016/j.jare.2024.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 08/06/2024] [Accepted: 08/07/2024] [Indexed: 08/12/2024] Open
Abstract
INTRODUCTION Angiogenesis plays a significant role in the development of tumor progression and inflammatory diseases. The role of IL-28A in angiogenesis and its precise regulatory mechanisms remain rarely elucidated. OBJECTIVES We report the novel regulatory role of IL-28A in physiological angiogenesis. The study aimed to elucidate the regulatory mechanisms involved in IL-28A-mediated angiogenesis and identify key genes associated with IL-28A-induced angiogenic responses. METHODS To know the effect of IL-28A on angiogenesis, HUVECs were applied to perform proliferation, migration, invasion, tube formation, immunoblot, and EMSA. Gene expression changes in HUVECs following IL-28A treatment were analyzed by NGS. The functional role of HSP70-1 and IL-10Rβ in IL-28A-induced angiogenic responses was evaluated using PCR and siRNA knockdown. Animal studies were conducted by aortic ring ex vivo assays, Matrigel plug in vivo assays, and immunochemistry using HSP70-1 knockout and transgenic mice models. The efficacy of IL-28A in angiogenesis was confirmed in a hind-limb ischemia model. RESULTS Autocrine/paracrine actions in HUVECs regulated IL-28A protein expression. Exogenous IL-28A increased the proliferation of HUVECs via eNOS/AKT and ERK1/2 signaling. IL-28A treatment promoted migration, invasion, and capillary tube formation of HUVECs through induction of the AP-1/NF-κB/MMP-2 network, which was associated with eNOS/AKT and ERK1/2 signaling. The efficacy of IL-28A-induced angiogenic potential was confirmed by aortic ring and Matrigel plug assay. HSP70-1 was identified as an IL-28A-mediated angiogenic effector gene using bioinformatics. Knockdown of HSP70-1 abolished angiogenic responses and eNOS/AKT signaling in IL-28A-treated HUVECs. IL-28A-induced microvessel sprouting formation was testified in HSP70-1-deficient and HSP70-1 transgenic mice. Flow recovery in hind-limb ischemia mice was accelerated by IL-28A injection. Finally, ablation of the IL-10Rβ gene impeded the angiogenic responses and eNOS/AKT signaling stimulated by IL-28A in HUVECs. CONCLUSION HSP70-1 drives the progression of angiogenesis by the IL-28A/IL-10Rβ axis via eNOS/AKT signaling and the AP-1/NF-κB/MMP-2 network.
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Affiliation(s)
- Jun-Hui Song
- Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea
| | - Byungdoo Hwang
- Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea
| | - Sung Lyea Park
- Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea
| | - Hoon Kim
- Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea
| | - Soontag Jung
- Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea
| | - Changsun Choi
- Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea
| | - Hwan Myung Lee
- Department of Cosmetic Science, Hoseo University, Asan-si 31499, Republic of Korea
| | - Seok-Joong Yun
- Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, South Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-052, South Korea
| | - Eun-Jong Cha
- Department of Biomedical Engineering, Chungbuk National University, Cheongju 361-763, Korea
| | - Cam Patterson
- University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Wun-Jae Kim
- Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju, Chungbuk 361-763, South Korea; Institute of Urotech, Cheongju, Chungcheongbuk-do 361-763, Korea
| | - Sung-Kwon Moon
- Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Korea.
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Tripathy S, Londhe S, Patra CR. Nitroprusside and metal nitroprusside nano analogues for cancer therapy. Biomed Mater 2024; 19:032001. [PMID: 38387050 DOI: 10.1088/1748-605x/ad2c18] [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: 09/18/2023] [Accepted: 02/22/2024] [Indexed: 02/24/2024]
Abstract
Sodium nitroprusside (SNP), U.S approved drug has been used in clinical emergency as a hypertensive drug for more than a decade. It is well established for its various biomedical applications such as angiogenesis, wound healing, neurological disorders including anti-microbial applications etc. Apart from that, SNP have been considered as excellent biomedical materials for its use as anti-cancer agent because of its behavior as NO-donor. Recent reports suggest that incorporation of metals in SNP/encapsulation of SNP in metal nanoparticles (metal nitroprusside analogues) shows better therapeutic anti-cancer activity. Although there are numerous reports available regarding the biological applications of SNP and metal-based SNP analogue nanoparticles, unfortunately there is not a single comprehensive review which highlights the anti-cancer activity of SNP and its derivative metal analogues in detail along with the future perspective. To this end, the present review article focuses the recent development of anti-cancer activity of SNP and metal-based SNP analogues, their plausible mechanism of action, current status. Furthermore, the future perspectives and challenges of these biomedical materials are also discussed. Overall, this review article represents a new perspective in the area of cancer nanomedicine that will attract a wider spectrum of scientific community.
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Affiliation(s)
- Sanchita Tripathy
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, 500007 Telangana, India
- Academy of Scientific and Innovative Research (AcSIR), Gaziabad, 201002 U.P, India
| | - Swapnali Londhe
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, 500007 Telangana, India
- Academy of Scientific and Innovative Research (AcSIR), Gaziabad, 201002 U.P, India
| | - Chitta Ranjan Patra
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, 500007 Telangana, India
- Academy of Scientific and Innovative Research (AcSIR), Gaziabad, 201002 U.P, India
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Zheng Y, Yang D, Gao B, Huang S, Tang Y, Wa Q, Dong Y, Yu S, Huang J, Huang S. A DNA-inspired injectable adhesive hydrogel with dual nitric oxide donors to promote angiogenesis for enhanced wound healing. Acta Biomater 2024; 176:128-143. [PMID: 38278340 DOI: 10.1016/j.actbio.2024.01.026] [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: 09/29/2023] [Revised: 01/17/2024] [Accepted: 01/18/2024] [Indexed: 01/28/2024]
Abstract
Chronic diabetic wounds are a severe complication of diabetes, often leading to high treatment costs and high amputation rates. Numerous studies have revealed that nitric oxide (NO) therapy is a promising option because it favours wound revascularization. Here, base-paired injectable adhesive hydrogels (CAT) were prepared using adenine- and thymine-modified chitosan (CSA and CST). By further introducing S-nitrosoglutathione (GSNO) and binary l-arginine (bArg), we obtained a NO sustained-release hydrogel (CAT/bArg/GSON) that was more suitable for the treatment of chronic wounds. The results showed that the expression of HIF-1α and VEGF was upregulated in the CAT/bArg/GSON group, and improved blood vessel regeneration was observed, indicating an important role of NO. In addition, the research findings revealed that following treatment with the CAT/bArg/GSON hydrogel, the viability of Staphylococcus aureus and Escherichia coli decreased to 14 ± 2 % and 6 ± 1 %, respectively. Moreover, the wound microenvironment was improved, as evidenced by a 60 ± 1 % clearance of DPPH. In particular, histological examination and immunohistochemical staining results showed that wounds treated with CAT/bArg/GSNO exhibited denser neovascularization, faster epithelial tissue regeneration, and thicker collagen deposition. Overall, this study proposes an effective strategy to prepare injectable hydrogel dressings with dual NO donors. The functionality of CAT/bArg/GSON has been thoroughly demonstrated in research on chronic wound vascular regeneration, indicating that CAT/bArg/GSON could be a potential option for promoting chronic wound healing. STATEMENT OF SIGNIFICANCE: This article prepares a chitosan hydrogel utilizing the principle of complementary base pairing, which offers several advantages, including good adhesion, biocompatibility, and flow properties, making it a good material for wound dressings. Loaded GSNO and bArg can steadily release NO and l-arginine through the degradation of the gel. Then, the released l-arginine not only possesses antioxidant properties but can also continue to generate a small amount of NO under the action of NOS. This design achieves a sustained and stable supply of NO at the wound site, maximizing the angiogenesis-promoting and antibacterial effects of NO. More neovascularization and abundant collagen were observed in the regenerated tissues. This study provides an effective repair hydrogel material for diabetic wound.
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Affiliation(s)
- Yongsheng Zheng
- Department of Orthopedics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Dong Yang
- Department of Orthopedics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Botao Gao
- Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510632, China
| | - Shuai Huang
- Department of Orthopedics, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
| | - Yubo Tang
- Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Qingde Wa
- Department of Orthopedics, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Yong Dong
- Department of Oncology, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, 523106, China
| | - Shan Yu
- Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510632, China
| | - Jun Huang
- Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou 510632, China.
| | - Sheng Huang
- Department of Orthopedics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
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10
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Sulakhiya K, Soni P, Tembhre MK, Kungumaraj HJ, Paliwal R, Kumar S. Physiology and pharmacology of wounds. NANOTECHNOLOGICAL ASPECTS FOR NEXT-GENERATION WOUND MANAGEMENT 2024:21-54. [DOI: 10.1016/b978-0-323-99165-0.00011-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Parsamanesh N, Poudineh M, Siami H, Butler AE, Almahmeed W, Sahebkar A. RNA interference-based therapies for atherosclerosis: Recent advances and future prospects. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 204:1-43. [PMID: 38458734 DOI: 10.1016/bs.pmbts.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Atherosclerosis represents a pathological state that affects the arterial system of the organism. This chronic, progressive condition is typified by the accumulation of atheroma within arterial walls. Modulation of RNA molecules through RNA-based therapies has expanded the range of therapeutic options available for neurodegenerative diseases, infectious diseases, cancer, and, more recently, cardiovascular disease (CVD). Presently, microRNAs and small interfering RNAs (siRNAs) are the most widely employed therapeutic strategies for targeting RNA molecules, and for regulating gene expression and protein production. Nevertheless, for these agents to be developed into effective medications, various obstacles must be overcome, including inadequate binding affinity, instability, challenges of delivering to the tissues, immunogenicity, and off-target toxicity. In this comprehensive review, we discuss in detail the current state of RNA interference (RNAi)-based therapies.
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Affiliation(s)
- Negin Parsamanesh
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Haleh Siami
- School of Medicine, Islamic Azad University of Medical Science, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Kargl CK, Jia Z, Shera DA, Sullivan BP, Burton LC, Kim KH, Nie Y, Hubal MJ, Shannahan JH, Kuang S, Gavin TP. Angiogenic potential of skeletal muscle derived extracellular vesicles differs between oxidative and glycolytic muscle tissue in mice. Sci Rep 2023; 13:18943. [PMID: 37919323 PMCID: PMC10622454 DOI: 10.1038/s41598-023-45787-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 10/24/2023] [Indexed: 11/04/2023] Open
Abstract
Skeletal muscle fibers regulate surrounding endothelial cells (EC) via secretion of numerous angiogenic factors, including extracellular vesicles (SkM-EV). Muscle fibers are broadly classified as oxidative (OXI) or glycolytic (GLY) depending on their metabolic characteristics. OXI fibers secrete more pro-angiogenic factors and have greater capillary densities than GLY fibers. OXI muscle secretes more EV than GLY, however it is unknown whether muscle metabolic characteristics regulate EV contents and signaling potential. EVs were isolated from primarily oxidative or glycolytic muscle tissue from mice. MicroRNA (miR) contents were determined and endothelial cells were treated with OXI- and GLY-EV to investigate angiogenic signaling potential. There were considerable differences in miR contents between OXI- and GLY-EV and pathway analysis identified that OXI-EV miR were predicted to positively regulate multiple endothelial-specific pathways, compared to GLY-EV. OXI-EV improved in vitro angiogenesis, which may have been mediated through nitric oxide synthase (NOS) related pathways, as treatment of endothelial cells with a non-selective NOS inhibitor abolished the angiogenic benefits of OXI-EV. This is the first report to show widespread differences in miR contents between SkM-EV isolated from metabolically different muscle tissue and the first to demonstrate that oxidative muscle tissue secretes EV with greater angiogenic signaling potential than glycolytic muscle tissue.
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Affiliation(s)
- Christopher K Kargl
- Department of Health and Kinesiology, Max E. Wastl Human Performance Laboratory, Purdue University, West Lafayette, IN, USA
| | - Zhihao Jia
- Department of Animal Sciences, Purdue University, West Lafayette, IN, USA
| | - Deborah A Shera
- School of Health Sciences, Purdue University, West Lafayette, IN, USA
| | - Brian P Sullivan
- Department of Health and Kinesiology, Max E. Wastl Human Performance Laboratory, Purdue University, West Lafayette, IN, USA
| | - Lundon C Burton
- Department of Health and Kinesiology, Max E. Wastl Human Performance Laboratory, Purdue University, West Lafayette, IN, USA
| | - Kun Ho Kim
- Department of Animal Sciences, Purdue University, West Lafayette, IN, USA
| | - Yaohui Nie
- Department of Health and Kinesiology, Max E. Wastl Human Performance Laboratory, Purdue University, West Lafayette, IN, USA
| | - Monica J Hubal
- Department of Kinesiology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | | | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN, USA
| | - Timothy P Gavin
- Department of Health and Kinesiology, Max E. Wastl Human Performance Laboratory, Purdue University, West Lafayette, IN, USA.
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13
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Aktar A, Heit B. Role of the pioneer transcription factor GATA2 in health and disease. J Mol Med (Berl) 2023; 101:1191-1208. [PMID: 37624387 DOI: 10.1007/s00109-023-02359-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 08/04/2023] [Accepted: 08/14/2023] [Indexed: 08/26/2023]
Abstract
The transcription factor GATA2 is involved in human diseases ranging from hematopoietic disorders, to cancer, to infectious diseases. GATA2 is one of six GATA-family transcription factors that act as pioneering transcription factors which facilitate the opening of heterochromatin and the subsequent binding of other transcription factors to induce gene expression from previously inaccessible regions of the genome. Although GATA2 is essential for hematopoiesis and lymphangiogenesis, it is also expressed in other tissues such as the lung, prostate gland, gastrointestinal tract, central nervous system, placenta, fetal liver, and fetal heart. Gene or transcriptional abnormalities of GATA2 causes or predisposes patients to several diseases including the hematological cancers acute myeloid leukemia and acute lymphoblastic leukemia, the primary immunodeficiency MonoMAC syndrome, and to cancers of the lung, prostate, uterus, kidney, breast, gastric tract, and ovaries. Recent data has also linked GATA2 expression and mutations to responses to infectious diseases including SARS-CoV-2 and Pneumocystis carinii pneumonia, and to inflammatory disorders such as atherosclerosis. In this article we review the role of GATA2 in the etiology and progression of these various diseases.
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Affiliation(s)
- Amena Aktar
- Department of Microbiology and Immunology; the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, ON, N6A 5C1, Canada
| | - Bryan Heit
- Department of Microbiology and Immunology; the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, ON, N6A 5C1, Canada.
- Robarts Research Institute, London, ON, N6A 3K7, Canada.
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14
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Iqbal I, Wilairatana P, Saqib F, Nasir B, Wahid M, Latif MF, Iqbal A, Naz R, Mubarak MS. Plant Polyphenols and Their Potential Benefits on Cardiovascular Health: A Review. Molecules 2023; 28:6403. [PMID: 37687232 PMCID: PMC10490098 DOI: 10.3390/molecules28176403] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/26/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Fruits, vegetables, and other food items contain phytochemicals or secondary metabolites which may be considered non-essential nutrients but have medicinal importance. These dietary phytochemicals exhibit chemopreventive and therapeutic effects against numerous diseases. Polyphenols are secondary metabolites found in vegetables, fruits, and grains. These compounds exhibit several health benefits such as immune modulators, vasodilators, and antioxidants. This review focuses on recent studies on using dietary polyphenols to treat cardiovascular disorders, atherosclerosis, and vascular endothelium deficits. We focus on exploring the safety of highly effective polyphenols to ensure their maximum impact on cardiac abnormalities and discuss recent epidemiological evidence and intervention trials related to these properties. Kaempferol, quercetin, and resveratrol prevent oxidative stress by regulating proteins that induce oxidation in heart tissues. In addition, polyphenols modulate the tone of the endothelium of vessels by releasing nitric oxide (NO) and reducing low-density lipoprotein (LDL) oxidation to prevent atherosclerosis. In cardiomyocytes, polyphenols suppress the expression of inflammatory markers and inhibit the production of inflammation markers to exert an anti-inflammatory response. Consequently, heart diseases such as strokes, hypertension, heart failure, and ischemic heart disease could be prevented by dietary polyphenols.
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Affiliation(s)
- Iram Iqbal
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (I.I.); (M.W.); (M.F.L.); (R.N.)
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
| | - Fatima Saqib
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;
| | - Bushra Nasir
- Department of Pharmaceutics, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan;
| | - Muqeet Wahid
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (I.I.); (M.W.); (M.F.L.); (R.N.)
| | - Muhammad Farhaj Latif
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (I.I.); (M.W.); (M.F.L.); (R.N.)
| | - Ahmar Iqbal
- Department of General Surgery, Shanxi Medical University, Jinzhong 030600, China;
| | - Rabia Naz
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (I.I.); (M.W.); (M.F.L.); (R.N.)
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Malektaj H, Nour S, Imani R, Siadati MH. Angiogenesis induction as a key step in cardiac tissue Regeneration: From angiogenic agents to biomaterials. Int J Pharm 2023; 643:123233. [PMID: 37460050 DOI: 10.1016/j.ijpharm.2023.123233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 07/02/2023] [Accepted: 07/14/2023] [Indexed: 07/23/2023]
Abstract
Cardiovascular diseases are the leading cause of death worldwide. After myocardial infarction, the vascular supply of the heart is damaged or blocked, leading to the formation of scar tissue, followed by several cardiac dysfunctions or even death. In this regard, induction of angiogenesis is considered as a vital process for supplying nutrients and oxygen to the cells in cardiac tissue engineering. The current review aims to summarize different approaches of angiogenesis induction for effective cardiac tissue repair. Accordingly, a comprehensive classification of induction of pro-angiogenic signaling pathways through using engineered biomaterials, drugs, angiogenic factors, as well as combinatorial approaches is introduced as a potential platform for cardiac regeneration application. The angiogenic induction for cardiac repair can enhance patient treatment outcomes and generate economic prospects for the biomedical industry. The development and commercialization of angiogenesis methods often involves collaboration between academic institutions, research organizations, and biomedical companies.
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Affiliation(s)
- Haniyeh Malektaj
- Department of Materials and Production, Aalborg University, Fibigerstraede 16, Aalborg 9220, Denmark
| | - Shirin Nour
- Department of Biomedical Engineering, Graeme Clark Institute, The University of Melbourne, VIC 3010, Australia; Department of Chemical Engineering, The University of Melbourne, VIC 3010, Australia
| | - Rana Imani
- Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran.
| | - Mohammad H Siadati
- Materials Science and Engineering Faculty, K. N. Toosi University of Technology, Tehran, Iran
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16
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Zhang J, Li C, Zhang Y, Wu J, Huang Z. Therapeutic potential of nitric oxide in vascular aging due to the promotion of angiogenesis. Chem Biol Drug Des 2023; 102:395-407. [PMID: 37062588 DOI: 10.1111/cbdd.14248] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/20/2023] [Accepted: 04/04/2023] [Indexed: 04/18/2023]
Abstract
The decrease in angiogenesis that occurs with aging significantly contributes to the higher incidence and mortality of cardiovascular diseases among the elderly. This decline in angiogenesis becomes more pronounced with increasing age and is closely linked to abnormal function and senescence of endothelial cells. Enhancing angiogenesis in aging and targeting senescent endothelial cells have gained considerable attention. Nitric oxide (NO) has been thoroughly investigated for its function in regulating angiogenesis and is an important factor that can counteract endothelial cell senescence. This review summarizes the mechanisms of reduced angiogenesis during aging and therapeutic strategies targeting senescent cells. We also discuss the potential of combining the current approaches with NO in promoting angiogenesis in aging vessels.
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Affiliation(s)
- Jiaming Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
| | - Cunrui Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
| | - Yihua Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
| | - Jianbing Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
| | - Zhangjian Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing, China
- School of Pharmacy, Xinjiang Medical University, China
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17
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Gao X, Bayraktutan U. Substance P reversibly compromises the integrity and function of blood-brain barrier. Peptides 2023:171048. [PMID: 37390897 DOI: 10.1016/j.peptides.2023.171048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/15/2023] [Accepted: 06/26/2023] [Indexed: 07/02/2023]
Abstract
BACKGROUND Substance P (SP) plays a role in vasodilatation and tissue integrity through its receptor, neurokinin 1 (NK1R). However, its specific effect on blood-brain barrier (BBB) remains unknown. METHODS The impact of SP on the integrity/function of human BBB model in vitro, composed of brain microvascular endothelial cells (BMECs), astrocytes and pericytes, was assessed by measurements of transendothelial electrical resistance and paracellular flux of sodium fluorescein (NaF), respectively in the absence/presence of specific inhibitors targeting NK1R (CP96345), Rho-associated protein kinase (ROCK; Y27632) and nitric oxide synthase (NOS; N(G)-nitro-L-arginine methyl ester). Sodium nitroprusside (SNP), a NO donor, was employed as a positive control. The levels of tight junction proteins, zonula occludens-1, occludin and claudin-5 alongside RhoA/ROCK/myosin regulatory light chain-2 (MLC2) and extracellular signal‑regulated protein kinase (Erk1/2) proteins were detected by western analyses. Subcellular localisations of F-actin and tight junction proteins were visualized by immunocytochemistry. Flow cytometry was used to detect transient calcium release. RESULTS Exposure to SP increased RhoA, ROCK2 and phosphorylated serine-19 MLC2 protein levels and Erk1/2 phosphorylation in BMECs which were abolished by CP96345. These increases were independent of the changes in intracellular calcium availability. SP perturbed BBB in a time-dependent fashion through induction of stress fibres. Changes in tight junction protein dissolution or relocalisation were not involved in SP-mediated BBB breakdown. Inhibition of NOS, ROCK and NK1R mitigated the effect of SP on BBB characteristics and stress fibre formation. CONCLUSION SP promoted a reversible decline in BBB integrity independent of tight junction proteins expression or localisation.
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Affiliation(s)
- Xin Gao
- Academic Unit of Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham, UK
| | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham, UK.
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18
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Jiao L, Xu T, Du X, Chen X, Jiao Q, Jiang H. The Inhibition Effects of Sodium Nitroprusside on the Survival of Differentiated Neural Stem Cells through the p38 Pathway. Brain Sci 2023; 13:brainsci13030438. [PMID: 36979248 PMCID: PMC10046126 DOI: 10.3390/brainsci13030438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/25/2023] [Accepted: 02/28/2023] [Indexed: 03/08/2023] Open
Abstract
Nitric oxide (NO) is a crucial factor in regulating neuronal development. However, certain effects of NO are complex under different physiological conditions. In this study, we used differentiated neural stem cells (NSCs), which contained neural progenitor cells, neurons, astrocytes, and oligodendrocytes, to observe the physiological effects of sodium nitroprusside (SNP) on the early developmental stage of the nervous system. After SNP treatment for 24 h, the results showed that SNP at 100 μM, 200 μM, 300 μM, and 400 μM concentrations resulted in reduced cell viability and increased cleaved caspase 3 levels, while no significant changes were found at 50 μM. There were no effects on neuronal differentiation in the SNP-treated groups. The phosphorylation of p38 was also significantly upregulated with SNP concentrations of 100 μM, 200 μM, 300 μM, and 400 μM, with no changes for 50 μM concentration in comparison with the control. We also observed that the levels of phosphorylation increased with the increasing concentration of SNP. To further explore the possible role of p38 in SNP-regulated survival of differentiated NSCs, SB202190, the antagonist of p38 mitogen-activated protein kinase, at a concentration of 10 mM, was pretreated for 30 min, and the ratio of phosphorylated p38 was found to be decreased after treatment with SNP. Survival and cell viability increased in the SB202190 and SNP co-treated group. Taken together, our results suggested that p38 is involved in the cell survival of NSCs, regulated by NO.
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Affiliation(s)
- Lingling Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Tongying Xu
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Xi Chen
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, School of Basic Medicine, Qingdao University, Qingdao 266071, China
| | - Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, School of Basic Medicine, Qingdao University, Qingdao 266071, China
- Correspondence:
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, State Key Disciplines: Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, School of Basic Medicine, Qingdao University, Qingdao 266071, China
- College of Health and Life Science, University of Health and Rehabilitation Sciences, Qingdao 266071, China
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19
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Vascularized Tissue Organoids. Bioengineering (Basel) 2023; 10:bioengineering10020124. [PMID: 36829618 PMCID: PMC9951914 DOI: 10.3390/bioengineering10020124] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/19/2023] Open
Abstract
Tissue organoids hold enormous potential as tools for a variety of applications, including disease modeling and drug screening. To effectively mimic the native tissue environment, it is critical to integrate a microvasculature with the parenchyma and stroma. In addition to providing a means to physiologically perfuse the organoids, the microvasculature also contributes to the cellular dynamics of the tissue model via the cells of the perivascular niche, thereby further modulating tissue function. In this review, we discuss current and developing strategies for vascularizing organoids, consider tissue-specific vascularization approaches, discuss the importance of perfusion, and provide perspectives on the state of the field.
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20
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da Silva FC, de Araújo BJ, Cordeiro CS, Arruda VM, Faria BQ, Guerra JFDC, Araújo TGD, Fürstenau CR. Endothelial dysfunction due to the inhibition of the synthesis of nitric oxide: Proposal and characterization of an in vitro cellular model. Front Physiol 2022; 13:978378. [PMID: 36467706 PMCID: PMC9714775 DOI: 10.3389/fphys.2022.978378] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 11/02/2022] [Indexed: 08/13/2023] Open
Abstract
The vascular endothelium plays a pivotal role in the maintenance of vascular homeostasis, mediated by vasoactive molecules produced by endothelial cells. The balance between vasoconstrictor and vasodilator biomolecules is what guarantees this equilibrium. Therefore, an increase in the bioavailability of vasoconstrictors along with a reduction in vasodilators may indicate a condition known as endothelial dysfunction. Endothelial dysfunction is marked by an inflammatory process and reduced activity of vasoprotective enzymes, being characterized by some factors like the reduction of the bioavailability of nitric oxide (NO) and increase in the production of reactive oxygen species (ROS), pro-inflammatory and vasoconstrictor molecules. This condition is a predictive marker of several cardiovascular diseases (e.g., atherosclerosis, hypertension, and diabetes). Research is affected by the scarcity of suitable in vitro models that simulate endothelial dysfunction. The goal of this study was to induce an in vitro condition to mimic endothelial dysfunction by inhibiting NO synthesis in cells. Thymus-derived endothelial cells (tEnd.1) were treated with different concentrations of L-NAME (from 1 to 1,000 μM) for different times (12, 24, 48, 72, 96, and 120 h without and with retreatment every 24 h). Cell viability, nitrite concentration, p22phox, NOX2, NOX4, IL-6, and ACE genes expression and lipid peroxidation were evaluated. The results indicate that the treatment with 100 μM L-NAME for 72 h without retreatment reduced NO concentration and NOX4 gene expression while increasing ACE expression, thus mimicking reduced vascular protection and possibly increased vasoconstriction. On the other hand, treatment with 100 μM L-NAME for 96 h with retreatment reduced the concentration of NO and the expression of the p22phox gene while increasing the expression of the IL-6 and ACE genes, mimicking the increase in inflammation and vasoconstriction parameters. Based on these results, we thus propose that both 100 μM L-NAME for 72 h without retreatment and 100 μM L-NAME for 96 h with retreatment may be used as models for in vitro endothelial dysfunction according to the purpose of the study to be conducted.
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Affiliation(s)
- Fernanda Cardoso da Silva
- Animal Cell Culture Laboratory, Institute of Biotechnology, Federal University of Uberlândia, Patos de Minas, MG, Brazil
- Laboratory of Vascular Biochemistry, Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo André, SP, Brazil
| | - Bruna Juber de Araújo
- Animal Cell Culture Laboratory, Institute of Biotechnology, Federal University of Uberlândia, Patos de Minas, MG, Brazil
- Laboratory of Vascular Biochemistry, Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo André, SP, Brazil
| | - Carina Santos Cordeiro
- Animal Cell Culture Laboratory, Institute of Biotechnology, Federal University of Uberlândia, Patos de Minas, MG, Brazil
| | - Vinícius Marques Arruda
- Animal Cell Culture Laboratory, Institute of Biotechnology, Federal University of Uberlândia, Patos de Minas, MG, Brazil
| | - Bruno Quintanilha Faria
- Animal Cell Culture Laboratory, Institute of Biotechnology, Federal University of Uberlândia, Patos de Minas, MG, Brazil
| | - Joyce Ferreira Da Costa Guerra
- Animal Cell Culture Laboratory, Institute of Biotechnology, Federal University of Uberlândia, Patos de Minas, MG, Brazil
| | - Thaise Gonçalves De Araújo
- Animal Cell Culture Laboratory, Institute of Biotechnology, Federal University of Uberlândia, Patos de Minas, MG, Brazil
| | - Cristina Ribas Fürstenau
- Laboratory of Vascular Biochemistry, Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo André, SP, Brazil
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21
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Yokomizo S, Roessing M, Morita A, Kopp T, Ogawa E, Katagiri W, Feil S, Huang PL, Atochin DN, Kashiwagi S. Near-infrared II photobiomodulation augments nitric oxide bioavailability via phosphorylation of endothelial nitric oxide synthase. FASEB J 2022; 36:e22490. [PMID: 35929438 PMCID: PMC9382775 DOI: 10.1096/fj.202101890r] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 07/05/2022] [Accepted: 07/25/2022] [Indexed: 11/11/2022]
Abstract
There is solid evidence of the beneficial effect of photobiomodulation (PBM) with low-power near-infrared (NIR) light in the NIR-I window in increasing bioavailable nitric oxide (NO). However, it is not established whether this effect can be extended to NIR-II light, limiting broader applications of this therapeutic modality. Since we have demonstrated PBM with NIR laser in the NIR-II window, we determined the causal relationship between NIR-II irradiation and its specific biological effects on NO bioavailability. We analyzed the impact of NIR-II irradiation on NO release in cultured human endothelial cells using a NO-sensitive fluorescence probe and single-cell live imaging. Two distinct wavelengths of NIR-II laser (1064 and 1270 nm) and NIR-I (808 nm) at an irradiance of 10 mW/cm2 induced NO release from endothelial cells. These lasers also enhanced Akt phosphorylation at Ser 473, endothelial nitric oxide synthase (eNOS) phosphorylation at Ser 1177, and endothelial cell migration. Moreover, the NO release and phosphorylation of eNOS were abolished by inhibiting mitochondrial respiration, suggesting that Akt activation caused by NIR-II laser exposure involves mitochondrial retrograde signaling. Other inhibitors that inhibit known Akt activation pathways, including a specific inhibitor of PI3K, Src family PKC, did not affect this response. These two wavelengths of NIR-II laser induced no appreciable NO generation in cultured neuronal cells expressing neuronal NOS (nNOS). In short, NIR-II laser enhances bioavailable NO in endothelial cells. Since a hallmark of endothelial dysfunction is suppressed eNOS with concomitant NO deficiency, NIR-II laser technology could be broadly used to restore endothelial NO and treat or prevent cardiovascular diseases.
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Affiliation(s)
- Shinya Yokomizo
- Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, 149 13 Street, Charlestown, MA, 02129, USA
- Department of Radiological Science, Tokyo Metropolitan University, 7-2-10 Higashi-Ogu, Arakawa, Tokyo 116-8551, Japan
| | - Malte Roessing
- Interfaculty Institute of Biochemistry (IFIB), University of Tübingen, Auf der Morgenstelle 34, Tübingen 72076, Germany
- Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, 149 13 Street, Charlestown, MA 02129, USA
| | - Atsuyo Morita
- Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, 149 13 Street, Charlestown, MA 02129, USA
| | - Timo Kopp
- Interfaculty Institute of Biochemistry (IFIB), University of Tübingen, Auf der Morgenstelle 34, Tübingen 72076, Germany
- Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, 149 13 Street, Charlestown, MA 02129, USA
| | - Emiyu Ogawa
- School of Allied Health Science, Kitasato University, 1-15-1 Kitasato Minami-ku Sagamihara, Kanagawa, Japan
| | - Wataru Katagiri
- Graduate School of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
| | - Susanne Feil
- Interfaculty Institute of Biochemistry (IFIB), University of Tübingen, Auf der Morgenstelle 34, Tübingen 72076, Germany
| | - Paul L. Huang
- Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, 149 13 Street, Charlestown, MA 02129, USA
| | - Dmitriy N. Atochin
- Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, 149 13 Street, Charlestown, MA 02129, USA
| | - Satoshi Kashiwagi
- Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, 149 13 Street, Charlestown, MA, 02129, USA
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22
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Sharma P, Kumar A, Agarwal T, Dey AD, Moghaddam FD, Rahimmanesh I, Ghovvati M, Yousefiasl S, Borzacchiello A, Mohammadi A, Yella VR, Moradi O, Sharifi E. Nucleic acid-based therapeutics for dermal wound healing. Int J Biol Macromol 2022; 220:920-933. [PMID: 35987365 DOI: 10.1016/j.ijbiomac.2022.08.099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/02/2022] [Accepted: 08/14/2022] [Indexed: 02/06/2023]
Abstract
Non-healing wounds have long been the subject of scientific and clinical investigations. Despite breakthroughs in understanding the biology of delayed wound healing, only limited advances have been made in properly treating wounds. Recently, research into nucleic acids (NAs) such as small-interfering RNA (siRNA), microRNA (miRNA), plasmid DNA (pDNA), aptamers, and antisense oligonucleotides (ASOs) has resulted in the development of a latest therapeutic strategy for wound healing. In this regard, dendrimers, scaffolds, lipid nanoparticles, polymeric nanoparticles, hydrogels, and metal nanoparticles have all been explored as NA delivery techniques. However, the translational possibility of NA remains a substantial barrier. As a result, different NAs must be identified, and their distribution method must be optimized. This review explores the role of NA-based therapeutics in various stages of wound healing and provides an update on the most recent findings in the development of NA-based nanomedicine and biomaterials, which may offer the potential for the invention of novel therapies for this long-term condition. Further, the challenges and potential for miRNA-based techniques to be translated into clinical applications are also highlighted.
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Affiliation(s)
- Preety Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India; Government Pharmacy College Kangra, Nagrota Bhagwan, Himachal Pradesh, India
| | - Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Tarun Agarwal
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation, Vaddeswaram, AP, India
| | - Asmita Deka Dey
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Farnaz Dabbagh Moghaddam
- Institute for Photonics and Nanotechnologies, National Research Council, Via Fosso del Cavaliere, 100, 00133 Rome, Italy
| | - Ilnaz Rahimmanesh
- Applied Physiology Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan 8174673461, Iran
| | - Mahsa Ghovvati
- Department of Radiological Sciences, David Geffen School of Medicine, University of California - Los Angeles, Los Angeles, CA 90095, USA
| | - Satar Yousefiasl
- School of Dentistry, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Assunta Borzacchiello
- Institute for Polymers, Composites, and Biomaterials (IPCB), National Research Council (CNR), Naples 80125, Italy
| | - Abbas Mohammadi
- Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran
| | - Venkata Rajesh Yella
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation, Vaddeswaram, AP, India
| | - Omid Moradi
- Department of Chemistry, Shahr-e-Qods Branch, Islamic Azad University, 374-37515 Tehran, Iran
| | - Esmaeel Sharifi
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran.
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Farnesyl diphosphate synthase regulated endothelial proliferation and autophagy during rat pulmonary arterial hypertension induced by monocrotaline. Mol Med 2022; 28:94. [PMID: 35962329 PMCID: PMC9373289 DOI: 10.1186/s10020-022-00511-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/13/2022] [Indexed: 11/10/2022] Open
Abstract
Background The proliferation ability and autophagy level of pulmonary artery endothelial cells (PAECs) play an important role in promoting the development of pulmonary artery hypertension (PAH), and there is still no effective treatment for PAH. Farnesyl diphosphate synthase (FDPS) is a key enzyme in the mevalonate pathway. The intermediate metabolites of this pathway are closely related to the activity of autophagy-associated small G proteins, including Ras-related C3 botulinum toxin substrate 1 (Rac1). Studies have shown that the mevalonate pathway affects the activation levels of different small G proteins, autophagy signaling pathways, vascular endothelial function, and so on. However, the exact relationship between them is still unclear in PAH. Method In vitro, western blotting and mRFP-GFP-LC3 puncta formation assays were used to observe the expression of FDPS and the level of autophagy in PAECs treated with monocrotaline pyrrole (MCTP). In addition, cell proliferation and migration assays were used to assess the effect of FDPS on endothelial function, and Rac1 activity assays were used to evaluate the effect of Rac1 activation on PAEC autophagy via the PI3K/AKT/mTOR signaling pathway. In vivo, the right heart catheterization method, hematoxylin and eosin (H&E) staining and western blotting were used to determine the effect of FDPS on PAEC autophagy and monocrotaline (MCT)-induced PAH. Results We show that the expression of FDPS is increased in the PAH module in vitro and in vivo, concomitant with the induction of autophagy and the activation of Rac1. Our data demonstrate that inhibition of FDPS ameliorates endothelial function and decreases MCT-induced autophagy levels. Mechanistically, we found that FDPS promotes autophagy, Rac1 activity and endothelial disfunction through the PI3K/AKT/mTOR signaling pathway. Conclusion Our study suggests that FDPS contributes to active small G protein-induced autophagy during MCT-induced PAH, which may serve as a potential therapeutic target against PAH. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00511-7.
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24
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Sun R, Bai L, Yang Y, Ding Y, Zhuang J, Cui J. Nervous System-Driven Osseointegration. Int J Mol Sci 2022; 23:ijms23168893. [PMID: 36012155 PMCID: PMC9408825 DOI: 10.3390/ijms23168893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
Implants are essential therapeutic tools for treating bone fractures and joint replacements. Despite the in-depth study of osseointegration for more than fifty years, poor osseointegration caused by aseptic loosening remains one of the leading causes of late implant failures. Osseointegration is a highly sophisticated and spatiotemporal process in vivo involving the immune response, angiogenesis, and osteogenesis. It has been unraveled that the nervous system plays a pivotal role in skeletal health via manipulating neurotrophins, neuropeptides, and nerve cells. Herein, the research related to nervous system-driven osseointegration was systematically analyzed and reviewed, aiming to demonstrate the prominent role of neuromodulation in osseointegration. Additionally, it is indicated that the implant design considering the role of neuromodulation might be a promising way to prevent aseptic loosening.
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Affiliation(s)
- Ruoyue Sun
- Key Laboratory for Ultrafine Materials of Ministry of Education, College of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Long Bai
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, China
- Correspondence: (J.C.); (L.B.)
| | - Yaru Yang
- College of Materials and Textile Engineering, Jiaxing University, Jiaxing 314001, China
| | - Yanshu Ding
- Key Laboratory for Ultrafine Materials of Ministry of Education, College of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Jingwen Zhuang
- Key Laboratory for Ultrafine Materials of Ministry of Education, College of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Jingyuan Cui
- Key Laboratory for Ultrafine Materials of Ministry of Education, College of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, China
- Correspondence: (J.C.); (L.B.)
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25
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Won JE, Kim WJ, Ryu JJ, Shim JS. Guided Bone Regeneration with a Nitric-Oxide Releasing Polymer Inducing Angiogenesis and Osteogenesis in Critical-Sized Bone Defects. Macromol Biosci 2022; 22:e2200162. [PMID: 35895972 DOI: 10.1002/mabi.202200162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/09/2022] [Indexed: 11/07/2022]
Abstract
Synthetic scaffolds, as bone grafts, provide a favorable environment for the repair and growth of new bone tissue at defect sites. However, the lack of angio- and osteo-induction limits the usefulness of artificial scaffolds for bone regeneration. Nitric oxide (NO) performs essential roles in healing processes, such as regulating inflammation and addressing incomplete revascularization. In this study, we developed a polymer capable of controlled NO release to promote the osteogenic capacity in artificial scaffolds. The biological efficiency of the NO compound was assessed by its effect on pre-osteoblasts and macrophages in vitro and the extent of vascularization and bone formation in the calvaria defect model in vivo. The compound did not inhibit cell adhesion or proliferation. NO treatment significantly increased both alkaline phosphatase activity and mineralization in pre-osteoblasts. Macrophages treated with NO secreted high levels of anti-inflammatory factors and adopted the pro-regenerative M2 phenotype. In the critical-sized defect model, the collagen scaffold containing the NO compound enhanced neovascularization and bone formation. The developed NO-releasing system promoted osteogenesis and regeneration of damaged bone tissue. As the multiple functions of NO involve macrophage modulation and angiogenesis, such release systems may be valuable for guiding bone regeneration in critical-sized defects. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Jong-Eun Won
- Institute for Clinical Dental Research, Department of Dentistry, Korea University Guro Hospital, Seoul, 08308, Republic of Korea
| | - Won Jong Kim
- Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang-si, 37673, Republic of Korea
| | - Jae Jun Ryu
- Department of Dentistry, Korea University Anam Hospital, Seoul, 02841, Republic of Korea
| | - Ji Suk Shim
- Institute for Clinical Dental Research, Department of Dentistry, Korea University Guro Hospital, Seoul, 08308, Republic of Korea
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26
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Modulating the tachykinin: Role of substance P and neurokinin receptor expression in ocular surface disorders. Ocul Surf 2022; 25:142-153. [PMID: 35779793 DOI: 10.1016/j.jtos.2022.06.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/21/2022] [Accepted: 06/24/2022] [Indexed: 01/19/2023]
Abstract
Substance P (SP) is a tachykinin expressed by various cells in the nervous and immune systems. SP is predominantly released by neurons and exerts its biological and immunological effects through the neurokinin receptors, primarily the neurokinin-1 receptor (NK1R). SP is essential for maintaining ocular surface homeostasis, and its reduced levels in disorders like diabetic neuropathy disrupt the corneal tissue. It also plays an essential role in promoting corneal wound healing by promoting the migration of keratocytes. In this review, we briefly discuss the structure, expression, and function of SP and its principal receptor NK1R. In addition, SP induces pro-inflammatory effects through autocrine or paracrine action on the immune cells in various ocular surface pathologies, including dry eye disease, herpes simplex virus keratitis, and Pseudomonas keratitis. We provide an in-depth review of the pathogenic role of SP in various ocular surface diseases and several new approaches developed to counter the immune-mediated effects of SP either through modulating its production or blocking its target receptor.
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27
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Role of puerarin in pathological cardiac remodeling: A review. Pharmacol Res 2022; 178:106152. [DOI: 10.1016/j.phrs.2022.106152] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 12/22/2022]
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28
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Methods for vascularization and perfusion of tissue organoids. Mamm Genome 2022; 33:437-450. [PMID: 35333952 DOI: 10.1007/s00335-022-09951-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 03/10/2022] [Indexed: 12/17/2022]
Abstract
Tissue organoids or "mini organs" can be invaluable tools for understanding health and disease biology, modeling tissue dynamics, or screening potential drug candidates. Effective vascularization of these models is critical for truly representing the in vivo tissue environment. Not only is the formation of a vascular network, and ultimately a microcirculation, essential for proper distribution and exchange of oxygen and nutrients throughout larger organoids, but vascular cells dynamically communicate with other cells to modulate overall tissue behavior. Additionally, interstitial fluid flow, mediated by a perfused microvasculature, can have profound influences on tissue biology. Thus, a truly functionally and biologically relevant organoid requires a vasculature. Here, we review existing strategies for fabricating and incorporating vascular elements and perfusion within tissue organoids.
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29
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Beneficial Effects of Caffeic Acid Phenethyl Ester on Wound Healing in a Diabetic Mouse: Role of VEGF and NO. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12052320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Cutaneous wound healing is delayed in patients with diabetes. Caffeic acid phenethyl ester (CAPE) has been identified as an effective constituent of propolis with improved wound healing abilities via an oxidative stress decrease. However, its impact on wound healing in diabetic models and its underlying mechanisms remain unclear. Determining the vascular endothelial growth factor (VEGF) contents in a human vascular smooth muscle cell (VSMC)-conditioned medium was assessed using human VEGF immunoassay and vascular reactivity using porcine coronary artery rings. Later, C57BL/6 or db/db mice were anesthetized, after which a 6-mm biopsy punch was manipulated for perforation via the back skin. Subsequently, CAPE was applied to the wound and changed daily. Furthermore, the injury in each mouse was digitally photographed, and the wound area was quantified. We observed that CAPE increased VEGF levels in human VSMC-conditioned medium, improved endothelium-dependent nitric oxide (NO)-mediated vasorelaxation, inhibited U46619-induced vasoconstriction porcine coronary artery, and enhanced cutaneous wound healing in the diabetic mouse model. Hence, we propose that CAPE improves wound healing in diabetic mice, which is aided by increased VEGF and NO expression.
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30
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Modabber A, Winnand P, Goloborodko E, Möhlhenrich SC, Kniha K, Tolba R, Jockenhoevel S, Hermanns-Sachweh B, Hölzle F, Heitzer M. Biodegradation and Immunological Parameters of Polyurethane-based Tissue Adhesive in Arterial Microvascular Anastomoses - a Long-term in Vivo Study. Macromol Biosci 2022; 22:e2100451. [PMID: 35080346 DOI: 10.1002/mabi.202100451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/16/2022] [Indexed: 11/07/2022]
Abstract
In microsurgical anastomosis, non-synthetic fibrin-based adhesives have predominantly shown superior properties to synthetic cyanoacrylates, but they have hardly any clinical application. This study aimed to investigate the local and systemic effects of synthetically produced biodegradable adhesive VIVO when used in microsurgical anastomosis. VIVO was used in two different anastomosis procedures in the common carotid artery in a rat model: VIVO in addition to a temporary catheter (VIVO TC) and VIVO with a custom-shaped memory nitinol stent (VIVO SM). Conventionally sutured anastomoses served as controls (C). Tissue response was assessed by in vivo fluorescence imaging and histological examination. The systemic effects of biodegradation were measured using hematologic parameters and serum levels of transaminase activity and lactate dehydrogenase. Finally, the degree of local adhesion of the different anastomotic procedures was evaluated. Fluorescence imaging showed reduced inflammatory blood flow in the VIVO TC group. Histological analysis of the anastomosed vessels also revealed significantly more inflammation in C than in the two adhesive groups. The severity of VIVO adhesions proved acceptable, and no histotoxic effects of VIVO were detected. The data demonstrated that the synthetic tissue adhesive VIVO is a reliable and- compared to sutures-tissue-friendly adhesive for microsurgical anastomoses. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Ali Modabber
- Department of Oral and Maxillofacial Surgery, University Hospital of Aachen, Pauwelsstraße 30, Aachen, 52074, Germany.,Head & Chairman Univ. Prof. Dr. med. Dr. med. dent. Frank Hölzle
| | - Philipp Winnand
- Department of Oral and Maxillofacial Surgery, University Hospital of Aachen, Pauwelsstraße 30, Aachen, 52074, Germany.,Head & Chairman Univ. Prof. Dr. med. Dr. med. dent. Frank Hölzle
| | - Evgeny Goloborodko
- Department of Oral and Maxillofacial Surgery, University Hospital of Aachen, Pauwelsstraße 30, Aachen, 52074, Germany.,Head & Chairman Univ. Prof. Dr. med. Dr. med. dent. Frank Hölzle
| | - Stephan Christian Möhlhenrich
- Department of Oral and Maxillofacial Surgery, University Hospital of Aachen, Pauwelsstraße 30, Aachen, 52074, Germany.,Head & Chairman Univ. Prof. Dr. med. Dr. med. dent. Frank Hölzle.,Department of Orthodontics, University of Witten/Herdecke, Alfred-Herrhausen Str. 45, Witten, 58455, Germany.,Head & Chairman Univ.-Prof. Dr. med. dent. Golamreza Danesh
| | - Kristian Kniha
- Department of Oral and Maxillofacial Surgery, University Hospital of Aachen, Pauwelsstraße 30, Aachen, 52074, Germany.,Head & Chairman Univ. Prof. Dr. med. Dr. med. dent. Frank Hölzle
| | - René Tolba
- Institute of Laboratory Animal Science and Experimental Surgery of RWTH-Aachen, Pauwelsstraße 30, Aachen, 52074, Germany.,Head & Chairman Univ.-Prof. Dr. med. René H. Tolba
| | - Stefan Jockenhoevel
- Department of Biohybrid and Medical Textiles (BioTex), AME-Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, 52074, Germany
| | - Benita Hermanns-Sachweh
- Implant Pathology ZBMT, Campus Melaten, Pauwelsstraße 17, Aachen, 52074.,Prof. Dr. med. Benita Hermanns-Sachweh
| | - Frank Hölzle
- Department of Oral and Maxillofacial Surgery, University Hospital of Aachen, Pauwelsstraße 30, Aachen, 52074, Germany.,Head & Chairman Univ. Prof. Dr. med. Dr. med. dent. Frank Hölzle
| | - Marius Heitzer
- Department of Oral and Maxillofacial Surgery, University Hospital of Aachen, Pauwelsstraße 30, Aachen, 52074, Germany.,Head & Chairman Univ. Prof. Dr. med. Dr. med. dent. Frank Hölzle
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Weng T, Wang J, Yang M, Zhang W, Wu P, You C, Han C, Wang X. Nanomaterials for the delivery of bioactive factors to enhance angiogenesis of dermal substitutes during wound healing. BURNS & TRAUMA 2022; 10:tkab049. [PMID: 36960274 PMCID: PMC8944711 DOI: 10.1093/burnst/tkab049] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/14/2021] [Indexed: 11/14/2022]
Abstract
Dermal substitutes provide a template for dermal regeneration and reconstruction. They constitutes an ideal clinical treatment for deep skin defects. However, rapid vascularization remains as a major hurdle to the development and application of dermal substitutes. Several bioactive factors play an important regulatory role in the process of angiogenesis and an understanding of the mechanism of achieving their effective delivery and sustained function is vital. Nanomaterials have great potential for tissue engineering. Effective delivery of bioactive factors (including growth factors, peptides and nucleic acids) by nanomaterials is of increasing research interest. This paper discusses the process of dermal substitute angiogenesis and the roles of related bioactive factors in this process. The application of nanomaterials for the delivery of bioactive factors to enhance angiogenesis and accelerate wound healing is also reviewed. We focus on new systems and approaches for delivering bioactive factors for enhancing angiogenesis in dermal substitutes.
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Affiliation(s)
- Tingting Weng
- Department of Burns & Wound Care Centre, the Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310002, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou 310002,China
| | - Jialiang Wang
- Department of Burns & Wound Care Centre, the Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310002, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou 310002,China
| | - Min Yang
- Department of Burns & Wound Care Centre, the Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310002, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou 310002,China
| | - Wei Zhang
- Department of Burns & Wound Care Centre, the Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310002, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou 310002,China
| | - Pan Wu
- Department of Burns & Wound Care Centre, the Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310002, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou 310002,China
| | - Chuangang You
- Department of Burns & Wound Care Centre, the Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310002, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou 310002,China
| | - Chunmao Han
- Department of Burns & Wound Care Centre, the Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou 310002, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou 310002,China
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Nutrition and Metabolism: Foundations for Animal Growth, Development, Reproduction, and Health. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1354:1-24. [PMID: 34807434 DOI: 10.1007/978-3-030-85686-1_1] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Consumption of high-quality animal protein plays an important role in improving human nutrition, growth, development, and health. With an exponential growth of the global population, demands for animal-sourced protein are expected to increase by 60% between 2021 and 2050. In addition to the production of food protein and fiber (wool), animals are useful models for biomedical research to prevent and treat human diseases and serve as bioreactors to produce therapeutic proteins. For a high efficiency to transform low-quality feedstuffs and forages into high-quality protein and highly bioavailable essential minerals in diets of humans, farm animals have dietary requirements for energy, amino acids, lipids, carbohydrates, minerals, vitamins, and water in their life cycles. All nutrients interact with each other to influence the growth, development, and health of mammals, birds, fish, and crustaceans, and adequate nutrition is crucial for preventing and treating their metabolic disorders (including metabolic diseases) and infectious diseases. At the organ level, the small intestine is not only the terminal site for nutrient digestion and absorption, but also intimately interacts with a diverse community of intestinal antigens and bacteria to influence gut and whole-body health. Understanding the species and metabolism of intestinal microbes, as well as their interactions with the intestinal immune systems and the host intestinal epithelium can help to mitigate antimicrobial resistance and develop prebiotic and probiotic alternatives to in-feed antibiotics in animal production. As abundant sources of amino acids, bioactive peptides, energy, and highly bioavailable minerals and vitamins, animal by-product feedstuffs are effective for improving the growth, development, health, feed efficiency, and survival of livestock and poultry, as well as companion and aquatic animals. The new knowledge covered in this and related volumes of Adv Exp Med Biol is essential to ensure sufficient provision of animal protein for humans, while helping reduce greenhouse gas emissions, minimize the urinary and fecal excretion of nitrogenous and other wastes to the environment, and sustain animal agriculture (including aquaculture).
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Jung S, Park K, Park S, Heo J, Choi W, Hong J. Unraveling the Structured Solvation Shell of Zwitterion Nanoparticles for Controlled Release of Nitric Oxide. ACS APPLIED MATERIALS & INTERFACES 2021; 13:54363-54374. [PMID: 34730330 DOI: 10.1021/acsami.1c15701] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Zwitterions have been attracting emerging attention as an anti-fouling polymer. However, the relationship between structured solvation shells and controlled drug release induced by deceleration of water molecule's translational and vibrational motions of zwitterions is an uncharted territory. Herein, sulfobetaine zwitterion nanoparticles (ZWNPs) were designed as a stable nitric oxide (NO)-delivering carrier. The condensed water structure of the solvation shell at its isoelectric point (PI) and the loose structure of water under different pH conditions were investigated through rheological and thermodynamical analyses. The ZWNPs showed a sustained-release profile at the PI, which presented a structured solvation barrier. On the other hand, NO-loaded ZWNPs showed different release profiles with the burst release at pH 5.5. Notably, an increased cell proliferation rate and a decreased antibacterial effect were observed at the same concentration depending on solvation shell's characteristics.
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Affiliation(s)
- Sungwon Jung
- School of Chemical & Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Kyungtae Park
- School of Chemical & Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Sohyeon Park
- School of Chemical & Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Jiwoong Heo
- School of Chemical & Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Woojin Choi
- School of Chemical & Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Jinkee Hong
- School of Chemical & Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
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Workman CD, Hopkins S, Pant J, Goudie M, Handa H. Covalently Bound S-Nitroso- N-Acetylpenicillamine to Electrospun Polyacrylonitrile Nanofibers for Multifunctional Tissue Engineering Applications. ACS Biomater Sci Eng 2021; 7:5279-5287. [PMID: 34695358 DOI: 10.1021/acsbiomaterials.1c00907] [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] [Indexed: 01/22/2023]
Abstract
Attachment of a nitric oxide (NO) donor to an electrospun polymer has the potential to improve its proliferative and antimicrobial capabilities. This study presents the novel, covalent attachment of S-nitroso-N-acetylpenicillamine (SNAP) to polyacrylonitrile (PAN) fibers. By attaching the NO donor to the polymer, rather than blending it, leaching is reduced to maintain a NO flux within the physiologically relevant range for a longer duration, while limiting any cytotoxic effects. The synthesized fibers were characterized using a variety of techniques such as scanning electron microscopy, 1H NMR, and drop shape analysis. Due to the antimicrobial activity of NO, the SNAP-PAN fibers demonstrated a 2-log reduction of S. aureus adhesion. Furthermore, the extended zone of inhibition of S. aureus by SNAP-PAN demonstrates the ability of NO to impact the environment surrounding the material, in addition to the environment in direct contact with it. The combination of NO release, hydrophilicity of PAN, and the fibrous network led to increased fibroblast proliferation and attachment, potentially expanding the fibers as an improved cell scaffolding platform. The results from this study demonstrate a novel preparation and design of NO-releasing fibers to provide multiple benefits for a variety of biomedical applications.
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Affiliation(s)
- Christina D Workman
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, 220 Riverbend Road, Athens, Georgia 30602, United States
| | - Sean Hopkins
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, 220 Riverbend Road, Athens, Georgia 30602, United States
| | - Jitendra Pant
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, 220 Riverbend Road, Athens, Georgia 30602, United States
| | - Marcus Goudie
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, 220 Riverbend Road, Athens, Georgia 30602, United States
| | - Hitesh Handa
- School of Chemical, Materials and Biomedical Engineering, College of Engineering, University of Georgia, 220 Riverbend Road, Athens, Georgia 30602, United States.,Pharmaceutical and Biomedical Sciences Department, College of Pharmacy, University of Georgia, 220 Riverbend Road, Athens, Georgia 30602, United States
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35
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Kim KJ, Kim E, Kang WS, Jeon M, Choi H, Lee KH, Kim MH, Kim JS, Na CS, Kim S. SR-5, the specific ratio of Korean multi-herbal formula: An evaluation of antiulcerogenic effects on experimentally induced gastric ulcers in mice. Dose Response 2021; 19:15593258211044329. [PMID: 34690616 PMCID: PMC8532236 DOI: 10.1177/15593258211044329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 01/30/2023] Open
Abstract
Purpose Previously, we demonstrated that the specific ratio of Korean multi-herbal formula (SR-5) exhibits hepatoprotective properties against ethanol-induced hepatic damage in rats. Chronic and excessive alcohol consumption is a major etiological factor involved in gastric disease and ulcer development induced by the inflammatory response and oxidative stress. Methods The present study evaluated the gastroprotective effects of SR-5 (100, 150, and 200 mg/kg) against hydrochloride acid/ethanol (HCl/EtOH)-induced and indomethacin/hydrochloride acid (INDO/HCl)-induced gastritis in a mouse model and the mechanisms involved. Results All the tested doses of SR-5 significantly inhibited gastric lesions in the HCl/EtOH-induced ulcer model mice. Similarly, all the tested doses of SR-5 significantly inhibited gastric lesions in the INDO/HCl-induced ulcer model mice. Furthermore, mice pretreated with SR-5 had significantly increased gastric levels of enzymatic and nonenzymatic antioxidants, namely, catalase (CAT) and glutathione (GSH), with concomitant reductions in malondialdehyde (MDA) and reactive oxygen species (ROS) levels compared with those in the HCl/EtOH or INDO/HCl group. SR-5 suppressed the expression of nuclear factor-kappa B (NF-κB)/p65, inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) to their normal values. Conclusion These findings are the first to demonstrate the powerful protective effect of SR-5 against gastric injury development and provide hope for clinical application.
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Affiliation(s)
- Kyeong Jo Kim
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
| | - Eun Kim
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
| | - Wan Seok Kang
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
| | - Mijin Jeon
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
| | - Hakjoon Choi
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
| | - Ki Hoon Lee
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
| | - Mi-Hyeon Kim
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
| | - Jin Seok Kim
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
| | - Chang-Su Na
- College of Korean Medicine, Dongshin University, Naju, Republic of Korea
| | - Sunoh Kim
- Central R&D Center, B&Tech Co., Ltd, Gwangju, Republic of Korea
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36
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Farhad AR, Razavi F, Razavi SM, Saatchi M, Manshaei M. Histological assessment of the local effect of different concentrations of aminoguanidine hydrochloride on bone healing in rats. Dent Res J (Isfahan) 2021; 18:63. [PMID: 34584641 PMCID: PMC8428281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 05/11/2020] [Accepted: 10/21/2020] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Nitric oxide (NO) has several functions in bone healing and affects bone metabolism. Selective inducible NO synthase (iNOS) inhibitors can be used to assess the efficacy of NO for healing of bone defects. This study sought to assess the local effect of different concentrations of aminoguanidine hydrochloride (AG), a selective iNOS inhibitor, on bone healing in rats. MATERIALS AND METHODS In this animal experimental study, 72 rats were divided into six groups of control, placebo, 5% AG, 10% AG, 15% AG, and 20% AG. A bone defect measuring 5 mm × 5 mm was created in the femur. The defect remained empty in the control group. In the placebo group, neutral gel was placed in the bone defect, and in the remaining four AG groups, different concentrations of AG were applied to the defects. Bone healing was assessed histologically. The healing score in the six groups was analyzed by the Kruskal-Wallis test. A P < 0.05 was considered statistically significant. RESULTS The healing score in 20%, 15%, 10%, and 5% AG groups was significantly higher than that in the neutral gel and control groups (P < 0.01). Among the four groups of AG, 20% concentration showed better results, but the difference was not significant. CONCLUSION Four concentrations of AG caused greater bone healing compared to the other two groups. Selective iNOS inhibitors such as AG can be used to promote local bone healing.
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Affiliation(s)
- Ali Reza Farhad
- Dental Research Center, Department of Endodontics, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fahimeh Razavi
- Department of Endodontics, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran,Address for correspondence: Dr. Fahimeh Razavi, Department of Endodontics, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran. E-mail:
| | - Sayed Mohammad Razavi
- Dental Implant Research Center, Department of Oral and Maxillofacial Pathology, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Masoud Saatchi
- Dental Research Center, Department of Endodontics, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maziar Manshaei
- Dental Research Center, Dental Research Institute, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran
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Kandhwal M, Behl T, Kumar A, Arora S. Understanding the Potential Role and Delivery Approaches of Nitric Oxide in Chronic Wound Healing Management. Curr Pharm Des 2021; 27:1999-2014. [PMID: 33106138 DOI: 10.2174/1381612826666201026152209] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 09/22/2020] [Indexed: 11/22/2022]
Abstract
Nitric oxide (NO) is a promising pharmaceutical component that has vasodilator, anti-bacterial, and wound healing activities. Chronic ulcers are non-healing disorders that are generally associated with distortion of lower limbs. Among the severe consequence derivatives of these diseases are the problems of chronic wound progression. NO, which is categorized as the smallest gaseous neurotransmitter, has beneficial effects in different phases of chronic inflammation. The defensive mechanism of NO is found useful in several severe conditions, such as gestational healing, gastrointestinal healing, and diabetic healing. The current review presents an updated collection of literature about the role of NO in chronic ulcers due to the prevalence of diabetes, DPN, and diabetic foot ulcers, and because of the lack of available effective treatments to directly address the pathology contributing to these conditions, novel treatments are being sought. This review also collects information about deficiency of NO synthase in diabetic patients, leading to a lack of vascularization of the peripheral nerves, which causes diabetic neuropathy, and this could be treated with vasodilators such as nitric oxide. Apart from the pharmacological mechanism of NO, the article also reviewed and analyzed to elucidate the potential of transdermal delivery of NO for the treatment of chronic ulcers.
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Affiliation(s)
- Mimansa Kandhwal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Arun Kumar
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sandeep Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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38
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Bencze N, Schvarcz C, Kriszta G, Danics L, Szőke É, Balogh P, Szállási Á, Hamar P, Helyes Z, Botz B. Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth via Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer. Front Oncol 2021; 11:685297. [PMID: 34336669 PMCID: PMC8317060 DOI: 10.3389/fonc.2021.685297] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/18/2021] [Indexed: 11/13/2022] Open
Abstract
There is growing interest in the role of nerve-driven mechanisms in tumorigenesis and tumor growth. Capsaicin-sensitive afferents have been previously shown to possess antitumoral and immune-regulatory properties, the mechanism of which is currently poorly understood. In this study, we have assessed the role of these terminals in the triple negative 4T1 orthotopic mouse model of breast cancer. The ultrapotent capsaicin-analogue resiniferatoxin (RTX) was used for the selective, systemic desensitization of capsaicin-sensitive afferents. Growth and viability of orthotopically implanted 4T1 tumors were measured by caliper, in vivo MRI, and bioluminescence imaging, while tumor vascularity and protease enzyme activity were assessed using fluorescent in vivo imaging. The levels of the neuropeptides Calcitonin Gene-Related Peptide (CGRP), Substance P (SP), and somatostatin were measured from tumor tissue homogenates using radioimmunoassay, while tumor structure and peritumoral inflammation were evaluated by conventional use of CD31, CD45 and CD3 immunohistology. RTX-pretreated mice demonstrated facilitated tumor growth in the early phase measured using a caliper, which was coupled with increased tumor vascular leakage demonstrated using fluorescent vascular imaging. The tumor size difference dissipated by day seven. The MRI tumor volume was similar, while the intratumoral protease enzyme activity measured by fluorescence imaging was also comparable in RTX-pretreated and non-pretreated animals. Tumor viability or immunohistopathological profile was measured using CD3, CD31, and CD45 stains and did not differ significantly from the non-pretreated control group. Intratumoral somatostatin, CGRP, and SP levels were similar in both groups. Our results underscore the beneficial, antitumoral properties of capsaicin sensitive nerve terminals in this aggressive model of breast cancer, which is presumed to be due to the inhibition of tumor vascular bed disruption. The absence of any difference in intratumoral neuropeptide levels indicates non-neural sources playing a substantial part in their expression.
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Affiliation(s)
- Noémi Bencze
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - Csaba Schvarcz
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Gábor Kriszta
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - Lea Danics
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Éva Szőke
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - Péter Balogh
- Department of Immunology and Biotechnology, University of Pécs Medical School, Pécs, Hungary
| | - Árpád Szállási
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Péter Hamar
- Institute of Translational Medicine, Semmelweis University, Budapest, Hungary.,Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary
| | - Bálint Botz
- János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.,Department of Medical Imaging, University of Pécs, Medical School, Pécs, Hungary
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Miyazaki T, Miyazaki A. Hypercholesterolemia and Lymphatic Defects: The Chicken or the Egg? Front Cardiovasc Med 2021; 8:701229. [PMID: 34250049 PMCID: PMC8262609 DOI: 10.3389/fcvm.2021.701229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/28/2021] [Indexed: 12/23/2022] Open
Abstract
Lymphatic vessels are necessary for maintaining tissue fluid balance, trafficking of immune cells, and transport of dietary lipids. Growing evidence suggest that lymphatic functions are limited under hypercholesterolemic conditions, which is closely related to atherosclerotic development involving the coronary and other large arteries. Indeed, ablation of lymphatic systems by Chy-mutation as well as depletion of lymphangiogenic factors, including vascular endothelial growth factor-C and -D, in mice perturbs lipoprotein composition to augment hypercholesterolemia. Several investigations have reported that periarterial microlymphatics were attracted by atheroma-derived lymphangiogenic factors, which facilitated lymphatic invasion into the intima of atherosclerotic lesions, thereby modifying immune cell trafficking. In contrast to the lipomodulatory and immunomodulatory roles of the lymphatic systems, the critical drivers of lymphangiogenesis and the details of lymphatic insults under hypercholesterolemic conditions have not been fully elucidated. Interestingly, cholesterol-lowering trials enable hypercholesterolemic prevention of lymphatic drainage in mice; however, a causal relationship between hypercholesterolemia and lymphatic defects remains elusive. In this review, the contribution of aberrant lymphangiogenesis and lymphatic cholesterol transport to hypercholesterolemic atherosclerosis was highlighted. The causal relationship between hypercholesterolemia and lymphatic insults as well as the current achievements in the field were discussed.
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Affiliation(s)
- Takuro Miyazaki
- Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
| | - Akira Miyazaki
- Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
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40
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Tummanapalli SS, Kuppusamy R, Yeo JH, Kumar N, New EJ, Willcox MDP. The role of nitric oxide in ocular surface physiology and pathophysiology. Ocul Surf 2021; 21:37-51. [PMID: 33940170 DOI: 10.1016/j.jtos.2021.04.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 12/31/2022]
Abstract
Nitric oxide (NO) has a wide array of biological functions including the regulation of vascular tone, neurotransmission, immunomodulation, stimulation of proinflammatory cytokine expression and antimicrobial action. These functions may depend on the type of isoform that is responsible for the synthesis of NO. NO is found in various ocular tissues playing a pivotal role in physiological mechanisms, namely regulating vascular tone in the uvea, retinal blood circulation, aqueous humor dynamics, neurotransmission and phototransduction in retinal layers. Unregulated production of NO in ocular tissues may result in production of toxic superoxide free radicals that participate in ocular diseases such as endotoxin-induced uveitis, ischemic proliferative retinopathy and neurotoxicity of optic nerve head in glaucoma. However, the role of NO on the ocular surface in mediating physiology and pathophysiological processes is not fully understood. Moreover, methods used to measure levels of NO in the biological samples of the ocular surface are not well established due to its rapid oxidation. The purpose of this review is to highlight the role of NO in the physiology and pathophysiology of ocular surface and propose suitable techniques to measure NO levels in ocular surface tissues and tears. This will improve the understanding of NO's role in ocular surface biology and the development of new NO-based therapies to treat various ocular surface diseases. Further, this review summarizes the biochemistry underpinning NO's antimicrobial action.
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Affiliation(s)
| | - Rajesh Kuppusamy
- School of Optometry & Vision Science, University of New South Wales, Australia; School of Chemistry, University of New South Wales, Australia
| | - Jia Hao Yeo
- The University of Sydney, School of Chemistry, NSW, 2006, Australia
| | - Naresh Kumar
- School of Chemistry, University of New South Wales, Australia
| | - Elizabeth J New
- The University of Sydney, School of Chemistry, NSW, 2006, Australia; The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, NSW, 2006, Australia
| | - Mark D P Willcox
- School of Optometry & Vision Science, University of New South Wales, Australia
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41
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Studying Angiogenesis in the Rabbit Corneal Pocket Assay. Methods Mol Biol 2021. [PMID: 32754813 DOI: 10.1007/978-1-0716-0916-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
The rabbit corneal micropocket assay uses the avascular cornea as a substrate to study angiogenesis in vivo. The continuous monitoring of neovascular growth in the same animal allows for the evaluation of drugs acting as suppressors or stimulators of angiogenesis. Through the use of standardized slow-release pellets, a predictable angiogenic response can be quantified over the course of 1-2 weeks. Uniform slow-release pellets are prepared by mixing purified angiogenic growth factors such as basic fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF) and a synthetic polymer to allow for their slow release. A micropocket is surgically created in the cornea thickness under anesthesia and in sterile conditions. The angiogenesis stimulus (growth factor but also tissue fragment or cell suspension) is placed into the pocket in order to induce vascular outgrowth from the limbal capillaries where vessels are preexisting. On the following days, the neovascular development and progression are measured and qualified using a slit lamp, as well as the concomitant vascular phenotype or inflammatory features. The results of the assay allow to assess the ability of potential therapeutic molecules to modulate angiogenesis in vivo, both when released locally or given by ocular formulations or through systemic treatment. In this chapter the experimental details of the avascular rabbit cornea assay, the technical challenges, advantages, and limitations are discussed.
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Ciccone V, Genah S, Morbidelli L. Endothelium as a Source and Target of H 2S to Improve Its Trophism and Function. Antioxidants (Basel) 2021; 10:antiox10030486. [PMID: 33808872 PMCID: PMC8003673 DOI: 10.3390/antiox10030486] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/13/2021] [Accepted: 03/16/2021] [Indexed: 12/18/2022] Open
Abstract
The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.
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43
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Distaffen HE, Jones CW, Abraham BL, Nilsson BL. Multivalent display of chemical signals on
self‐assembled
peptide scaffolds. Pept Sci (Hoboken) 2021. [DOI: 10.1002/pep2.24224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Kurakula K, Smolders VFED, Tura-Ceide O, Jukema JW, Quax PHA, Goumans MJ. Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence? Biomedicines 2021; 9:biomedicines9010057. [PMID: 33435311 PMCID: PMC7827874 DOI: 10.3390/biomedicines9010057] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/30/2020] [Accepted: 01/03/2021] [Indexed: 12/11/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH.
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Affiliation(s)
- Kondababu Kurakula
- Department of Cell and Chemical Biology, Laboratory for CardioVascular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
| | - Valérie F. E. D. Smolders
- Department of Surgery, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.F.E.D.S.); (P.H.A.Q.)
| | - Olga Tura-Ceide
- Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain;
- Department of Pulmonary Medicine, Dr. Josep Trueta University Hospital de Girona, Santa Caterina Hospital de Salt and the Girona Biomedical Research Institut (IDIBGI), 17190 Girona, Catalonia, Spain
- Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), 28029 Madrid, Spain
| | - J. Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
| | - Paul H. A. Quax
- Department of Surgery, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (V.F.E.D.S.); (P.H.A.Q.)
| | - Marie-José Goumans
- Department of Cell and Chemical Biology, Laboratory for CardioVascular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
- Correspondence:
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Costa TJ, Barros PR, Arce C, Santos JD, da Silva-Neto J, Egea G, Dantas AP, Tostes RC, Jiménez-Altayó F. The homeostatic role of hydrogen peroxide, superoxide anion and nitric oxide in the vasculature. Free Radic Biol Med 2021; 162:615-635. [PMID: 33248264 DOI: 10.1016/j.freeradbiomed.2020.11.021] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/08/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023]
Abstract
Reactive oxygen and nitrogen species are produced in a wide range of physiological reactions that, at low concentrations, play essential roles in living organisms. There is a delicate equilibrium between formation and degradation of these mediators in a healthy vascular system, which contributes to maintaining these species under non-pathological levels to preserve normal vascular functions. Antioxidants scavenge reactive oxygen and nitrogen species to prevent or reduce damage caused by excessive oxidation. However, an excessive reductive environment induced by exogenous antioxidants may disrupt redox balance and lead to vascular pathology. This review summarizes the main aspects of free radical biochemistry (formation, sources and elimination) and the crucial actions of some of the most biologically relevant and well-characterized reactive oxygen and nitrogen species (hydrogen peroxide, superoxide anion and nitric oxide) in the physiological regulation of vascular function, structure and angiogenesis. Furthermore, current preclinical and clinical evidence is discussed on how excessive removal of these crucial responses by exogenous antioxidants (vitamins and related compounds, polyphenols) may perturb vascular homeostasis. The aim of this review is to provide information of the crucial physiological roles of oxidation in the endothelium, vascular smooth muscle cells and perivascular adipose tissue for developing safer and more effective vascular interventions with antioxidants.
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Affiliation(s)
- Tiago J Costa
- Pharmacology Department, Ribeirao Preto Medical School, University of São Paulo, Brazil.
| | | | - Cristina Arce
- Department of Biomedical Sciences, University of Barcelona School of Medicine and Health Sciences, Barcelona, Spain; Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Barcelona, Spain; Institut de Nanociencies i Nanotecnologia (IN2UB), University of Barcelona, Barcelona, Spain
| | | | - Júlio da Silva-Neto
- Pharmacology Department, Ribeirao Preto Medical School, University of São Paulo, Brazil
| | - Gustavo Egea
- Department of Biomedical Sciences, University of Barcelona School of Medicine and Health Sciences, Barcelona, Spain; Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Barcelona, Spain; Institut de Nanociencies i Nanotecnologia (IN2UB), University of Barcelona, Barcelona, Spain
| | - Ana Paula Dantas
- Institut Clínic del Tòrax, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Rita C Tostes
- Pharmacology Department, Ribeirao Preto Medical School, University of São Paulo, Brazil
| | - Francesc Jiménez-Altayó
- Department of Pharmacology, Therapeutics and Toxicology, Neuroscience Institute, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
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Razavi F, Farhad A, Razavi S, Saatchi M, Manshaei M. Histological assessment of the local effect of different concentrations of aminoguanidine hydrochloride on bone healing in rats. Dent Res J (Isfahan) 2021. [DOI: 10.4103/1735-3327.324022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Kakabadze K, Megreladze I, Khvichia N, Mitagvaria N, Kipiani N, Dumbadze M, Sanikidze T. Some Aspects of Role of Nitric Oxide in the Mechanisms of Hypertension (Experimental Study). Cardiol Res 2020; 12:16-24. [PMID: 33447321 PMCID: PMC7781263 DOI: 10.14740/cr1172] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/18/2020] [Indexed: 12/03/2022] Open
Abstract
Background Modulation of endothelial function is a therapeutic option to reduce some of the significant complications of hypertension. However, the relationship between endothelial dysfunction reduced nitric oxide (NO) production, and the development of hypertension is not fully understood. To establish a potential pathogenetic link between impaired NO synthesis and hypertension, we investigated the results of competitive interaction of the substrate of NO synthase, L-arginine, and its analog, an non-selective inhibitor of NO synthase, N-nitro-methyl ether-L-arginine (L-NAME), in experimental rats. Methods Arterial hypertension was induced in male Wistar rats by intraperitoneal administration of L-NAME (Sigma-Aldrich) for 4 - 7 weeks. During the last 3 weeks, to a separate group of animals simultaneously with L-NAME, L-arginine (Sigma-Aldrich) was administered. In animals monitored for systolic and diastolic pressure, the level of NO in blood samples was determined spectrophotometrically using a Griess reagent. Results Administration of L-NAME for 4 - 7 weeks induced an irreversible decrease of NO content in blood, a reversible increase of systolic pressure (SP) and diastolic pressure (DP), and an irreversible increase in pulse pressure (PP). In rats against the background of 7 weeks of intraperitoneal administration of L-NAME, during the last 3 weeks, they were injected with L-arginine, the SP and DP indices returned to their initial values, PP decreased and the NO content in arterial blood increased. Conclusions The results of the study indicate the presence of residual endothelial dysfunction (characterized by insufficient NO) after the correction of hypertension. Therefore, in developing the new therapeutic approaches for the treatment of hypertension, it is necessary to include drugs that, in addition to correcting blood pressure, will support normalization, and potentiation of endothelial function and endogenous NO synthesis.
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Affiliation(s)
- Katevan Kakabadze
- Department of Physics, Biophysics, Biomechanics and Informational Technologies, Tbilisi State Medical University, Tbilisi, Georgia
| | | | - Nino Khvichia
- Department of Pathology, Faculty of Medicine, I. Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Nodar Mitagvaria
- I. Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
| | - Nina Kipiani
- Department of Physics, Biophysics, Biomechanics and Informational Technologies, Tbilisi State Medical University, Tbilisi, Georgia
| | | | - Tamar Sanikidze
- Department of Physics, Biophysics, Biomechanics and Informational Technologies, Tbilisi State Medical University, Tbilisi, Georgia.,I. Beritashvili Center of Experimental Biomedicine, Tbilisi, Georgia
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48
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Khan FH, Dervan E, Bhattacharyya DD, McAuliffe JD, Miranda KM, Glynn SA. The Role of Nitric Oxide in Cancer: Master Regulator or NOt? Int J Mol Sci 2020; 21:ijms21249393. [PMID: 33321789 PMCID: PMC7763974 DOI: 10.3390/ijms21249393] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Nitric oxide (NO) is a key player in both the development and suppression of tumourigenesis depending on the source and concentration of NO. In this review, we discuss the mechanisms by which NO induces DNA damage, influences the DNA damage repair response, and subsequently modulates cell cycle arrest. In some circumstances, NO induces cell cycle arrest and apoptosis protecting against tumourigenesis. NO in other scenarios can cause a delay in cell cycle progression, allowing for aberrant DNA repair that promotes the accumulation of mutations and tumour heterogeneity. Within the tumour microenvironment, low to moderate levels of NO derived from tumour and endothelial cells can activate angiogenesis and epithelial-to-mesenchymal transition, promoting an aggressive phenotype. In contrast, high levels of NO derived from inducible nitric oxide synthase (iNOS) expressing M1 and Th1 polarised macrophages and lymphocytes may exert an anti-tumour effect protecting against cancer. It is important to note that the existing evidence on immunomodulation is mainly based on murine iNOS studies which produce higher fluxes of NO than human iNOS. Finally, we discuss different strategies to target NO related pathways therapeutically. Collectively, we present a picture of NO as a master regulator of cancer development and progression.
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Affiliation(s)
- Faizan H. Khan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Eoin Dervan
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Dibyangana D. Bhattacharyya
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Jake D. McAuliffe
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
| | - Katrina M. Miranda
- Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA;
| | - Sharon A. Glynn
- Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, National University of Ireland Galway (NUIG), H91 YR71 Galway, Ireland; (F.H.K.); (E.D.); (D.D.B.); (J.D.M.)
- Correspondence:
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Abu Dayyih W, Abu Rayyan W, Al-Matubsi HY. Impact of sildenafil-containing ointment on wound healing in healthy and experimental diabetic rats. Acta Diabetol 2020; 57:1351-1358. [PMID: 32601730 DOI: 10.1007/s00592-020-01562-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/17/2020] [Indexed: 01/02/2023]
Abstract
AIM The study evaluated the effect of different concentrations of sildenafil-containing ointment on wound healing in healthy and streptozotocin (STZ)-induced diabetic rats. METHODS A total of 108 Sprague Dawley male rats aged 5 months were randomly divided into two groups: healthy and diabetes-inducing rats. Following induction of diabetes by intraperitoneal STZ injection (55 mg/kg), diabetic and healthy rats were subdivided into six groups (9 rats each). Linear incisions of the dorsal backs of rats were made. Then, rats were treated twice daily with either 2%, 2% + Fucidin, 5% sildenafil-containing ointments, oral sildenafil (13.0 mg/kg), moist exposed burn ointment or vehicle. During treatment, the percent reduction of the wound area and tensile strength were measured on days 3, 7 and 10. Furthermore, histopathology was performed on the wounded skin on similar days for the assessment of collagen synthesis and proliferation of new capillary vessels. RESULTS In healthy and STZ-induced diabetic rats, the percent reduction in wound area on day 3 was significantly higher in sildenafil-containing ointment-treated groups than all other groups, whereas on day 7 only the 5% sildenafil-containing ointment-treated group showed better response in healthy rats. Although the sildenafil-containing ointment significantly showed better tensile strength than all other groups, the 5% sildenafil-treated group significantly enhanced the tensile better than the 2% and 2% + Fucidin dose. Furthermore, the histological evaluation revealed that sildenafil-containing ointment promoted collagen synthesis and proliferation of new capillary vessels. CONCLUSION Our results suggest that sildenafil-containing ointment can provide an advantage in wound healing by promoting wound contractions and resistance to wound breakage in healthy and diabetic conditions. Therefore, 5% sildenafil-containing ointment can be used as a support factor for wound healing in healthy and diabetic conditions; however, clinical trials are required to confirm the benefits of sildenafil in wound healing.
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Affiliation(s)
- Wael Abu Dayyih
- Department of Pharmaceutical Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Walid Abu Rayyan
- Department of Pharmacology and Medical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Hisham Y Al-Matubsi
- Department of Pharmacology and Medical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.
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Aerobic exercise increases sprouting angiogenesis in the male rat motor cortex. Brain Struct Funct 2020; 225:2301-2314. [PMID: 32918614 DOI: 10.1007/s00429-020-02100-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022]
Abstract
Exercise is beneficial to brain health, and historically, the advantageous effects of exercise on the brain have been attributed to neuronal plasticity. However, it has also become clear that the brain vascular system also exhibits plasticity in response to exercise. This plasticity occurs in areas involved in movement, such as the motor cortex. This experiment aimed to further characterize the effects of exercise on structural vascular plasticity in the male rat motor cortex, by specifically identifying whether features of angiogenesis, the growth of new capillaries, or changes in vessel diameter were present. Male rats in the exercise group engaged in a 5-week bout of voluntary wheel running, while a second group of rats remained sedentary. After the exercise regimen, vascular corrosion casts, resin replicas of the brain vasculature, were made for all animals and imaged using a scanning electron microscope. Results indicate sprouting angiogenesis was the primary form of structural vascular plasticity detected in the motor cortex under these aerobic exercise parameters. Additionally, exercised rats displayed a slight increase in capillary diameter and expanded endothelial cell nuclei diameters in this region.
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