scholarly journals ACE2/ANG-(1-7)/Mas Receptor Axis Activation Prevents Inflammation, Glial Activation And Cognitive Decline In a Rat Model of STZ Induced Impairment of Learning and Memory

2021 ◽  
Author(s):  
Virendra Tiwari ◽  
Jitendra Singh ◽  
Priya Tiwari ◽  
Swati Chaturvedi ◽  
Shivangi Gupta ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Rat Model ◽  
Protective Effects ◽  
Ang Ii ◽  
Diminazene Aceturate ◽  
Experimental Conditions ◽  
Mas Receptor ◽  
Amyloid Pathology

Abstract Activation of the renin-angiotensin system (RAS), mediated by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid pathology, induces neurodegeneration and cognitive impairment leading to Alzheimer's disease (AD). On the contrary, Angiotensin converting enzyme2 (ACE2) produces Ang -(1-7) which binds with the Mas receptor and counters ACE/Ang II/AT1 axis. To date, the involvement of ACE2/Ang-(1–7)/MasR axis in etiology and progression of AD largely remains to be elucidated. Hence, the present study is aimed to determine the role of ACE2/Ang-(1–7)/MasR axis in STZ induced model of neurodegeneration using Diminazene aceturate (DIZE), an ACE2 activator in both in vitro/in vivo experimental conditions. Interestingly, ROS content and oxidative stress burden in N2A cells were found to be attenuated along with a decrease in enzymatic activity of AChE following DIZE treatment. In contrast, activation of this axis led to altered mitochondrial membrane potential (MMP) in addition to ablated intracellular Ca2+ influx. ACE2/Ang-(1–7)/MasR axis activation further resulted in reduction of astrogliosis as indicated by decreased intensity of NFκB and dwindled expression of its downstream NLRP3 cascade signaling molecules. These results were confirmed by using a selective inhibitor of ACE-2, MLN-4760, which reversed the protective effects of ACE2 activation by DIZE. Subsequently, treatment with DIZE in STZ induced rat model of AD prevented cognitive impairment and progression of amyloid pathology. Therefore, the involvement of ACE2/Ang-(1–7)/Mas axis suggests that it could be further explored as a potential pathway in AD, owing to its inhibitory effect on inflammation/astrogliosis and restoring cognitive functions.

scholarly journals Amyloid Beta: Multiple Mechanisms of Toxicity and Only Some Protective Effects?

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Paul Carrillo-Mora ◽  
Rogelio Luna ◽  
Laura Colín-Barenque
Keyword(s):  
Amyloid Beta ◽  
Protective Effects ◽  
Protective Mechanisms ◽  
Experimental Conditions ◽  
Mechanisms Of Toxicity ◽  
Mitochondrial Alterations ◽  
Physiological Properties ◽  
Wide Range

Amyloid beta (Aβ) is a peptide of 39–43 amino acids found in large amounts and forming deposits in the brain tissue of patients with Alzheimer’s disease (AD). For this reason, it has been implicated in the pathophysiology of damage observed in this type of dementia. However, the role of Aβin the pathophysiology of AD is not yet precisely understood. Aβhas been experimentally shown to have a wide range of toxic mechanismsin vivoandin vitro, such as excitotoxicity, mitochondrial alterations, synaptic dysfunction, altered calcium homeostasis, oxidative stress, and so forth. In contrast, Aβhas also shown some interesting neuroprotective and physiological properties under certain experimental conditions, suggesting that both physiological and pathological roles of Aβmay depend on several factors. In this paper, we reviewed both toxic and protective mechanisms of Aβto further explore what their potential roles could be in the pathophysiology of AD. The complete understanding of such apparently opposed effects will also be an important guide for the therapeutic efforts coming in the future.

scholarly journals Cardioprotective Effects of 20(S)-Ginsenoside Rh2 against Doxorubicin-Induced CardiotoxicityIn VitroandIn Vivo

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Hongbo Wang ◽  
Pengfei Yu ◽  
Haitao Gou ◽  
Jianqiao Zhang ◽  
Mei Zhu ◽  
...  
Keyword(s):  
Rat Model ◽  
A549 Cells ◽  
H9c2 Cell ◽  
Protective Agent ◽  
Protective Effects ◽  
Ginsenoside Rh2 ◽  
Cardioprotective Effects ◽  
Heart Injury

Doxorubicin (DOX) is considered as one of the best antineoplastic agents. However, its clinical use is restricted by its associated cardiotoxicity, which is mediated by the production of reactive oxygen species. In this study, 20(S)-ginsenoside Rh2 (Rh2) was explored whether it had protective effects against DOX-induced cardiotoxicity.In vitrostudy on H9C2 cell line, as well asin vivoinvestigation in one mouse and one rat model of DOX-induced cardiomyopathy, was carried out. The results showed that pretreatment with Rh2 significantly increased the viability of DOX-injured H9C2 cells. In the mouse model, Rh2 could suppress the DOX-induced release of the cardiac enzymes into serum and improved the occurred pathological changes through ameliorating the decreased antioxidant biomolecules and the cumulated lipid peroxidation malondialdehyde in heart tissues. In the rat model, Rh2 could attenuate the change of ECG resulting from DOX administration. Furthermore, Rh2 enhanced the antitumor activity of DOX in A549 cells. Our findings thus demonstrated that Rh2 pretreatment could effectively alleviate heart injury induced by DOX, and Rh2 might act as a novel protective agent in the clinical usefulness of DOX.

scholarly journals DL-3-n-Butylphthalide Attenuates Myocardial Hypertrophy by Targeting Gasdermin D and Inhibiting Gasdermin D Mediated Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Bingjiang Han ◽  
Jiajun Xu ◽  
Xiaowen Shi ◽  
Zhanxiong Zheng ◽  
Fengjie Shi ◽  
...  
Keyword(s):  
Myocardial Hypertrophy ◽  
Pressure Overload ◽  
Pathophysiological Mechanism ◽  
Protective Effects ◽  
Ang Ii ◽  
N Protein ◽  
Cardioprotective Effects ◽  
Induced Changes

Pressure overload leads to a hypertrophic milieu that produces deleterious cardiac dysfunction. Inflammation is a key pathophysiological mechanism underpinning myocardial hypertrophy. DL-3-n-butylphthalide (NBP), a neuroprotective agent, also has potent cardioprotective effects. In this study, the potential of NBP to antagonize myocardial hypertrophy was evaluated in C57BL/6 mice in vivo and in rat primary cardiomyocytes in vitro. In mice, NBP treatment reduced cardiac hypertrophy and dysfunction in a transverse aortic constriction (TAC)-induced pressure overload model. In angiotensin (Ang) II-challenged cardiomyocytes, NBP prevents cell size increases and inhibits gasdermin D (GSDMD)-mediated inflammation. Furthermore, overexpression of GSDMD-N reduced the protective effects of NBP against Ang II-induced changes. Using molecular docking and MD simulation, we found that the GSDMD-N protein may be a target of NBP. Our study shows that NBP attenuates myocardial hypertrophy by targeting GSDMD and inhibiting GSDMD-mediated inflammation.

scholarly journals Intra-Articular Route for the System of Molecules 14G1862 from Centella asiatica: Pain Relieving and Protective Effects in a Rat Model of Osteoarthritis

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1618
Author(s):  
Laura Micheli ◽  
Lorenzo Di Cesare Mannelli ◽  
Luisa Mattoli ◽  
Sara Tamimi ◽  
Enrico Flamini ◽  
...  
Keyword(s):  
Rat Model ◽  
Centella Asiatica ◽  
Inos Expression ◽  
Histological Evaluation ◽  
Spontaneous Pain ◽  
No Production ◽  
Protective Effects ◽  
Reference Drug

Current pharmacological therapies for the management of chronic articular diseases are far from being satisfactory, so new strategies need to be investigated. We tested the intra-articular pain relieving properties of a system of molecules from a characterized Centella asiatica extract (14G1862) in a rat model of osteoarthritis induced by monoiodoacetate (MIA). 14G1862 (0.2–2 mg mL−1) was intra-articularly (i.a.) injected 7 days after MIA, behavioural and histological evaluations were performed 14, 30 and 60 days after treatments. Moreover, the effect of 14G1862 on nitrate production and iNOS expression in RAW 264.7 macrophages stimulated with LPS was assessed. In vitro, 14G1862 treatment attenuated LPS-induced NO production and iNOS expression in a comparable manner to celecoxib. In vivo, 14G1862 significantly reduced mechanical allodynia and hyperalgesia, spontaneous pain and motor alterations starting on day 14 up to day 60. The efficacy was higher or comparable to that evoked by triamcinolone acetonide (100 μg i.a.) used as reference drug. Histological evaluation highlighted the improvement of several morphological parameters in MIA + 14G1862-treated animals with particularly benefic effects on joint space and fibrin deposition. In conclusion, i.a. treatment with Centella asiatica is a candidate to be a novel effective approach for osteoarthritis therapy.

Differential regulation of angiotensin II and losartan binding sites in glomeruli and mesangial cells

1994 ◽  
Vol 266 (3) ◽  
pp. F384-F393 ◽  
Author(s):  
D. Chansel ◽  
T. Bizet ◽  
S. Vandermeersch ◽  
P. Pham ◽  
B. Levy ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Binding Sites ◽  
Mesangial Cells ◽  
Present Report ◽  
Mrna Levels ◽  
Ang Ii ◽  
Experimental Conditions ◽  
Human Mesangial Cells

The aim of the present report was to examine the effect of several agents on angiotensin II (ANG II) and losartan receptors using 125I-[Sar1,Ala8]ANG II and [3H]losartan as radiolabeled ligand, respectively. ANG II receptors were downregulated in glomeruli from rats infused with ANG II during 3 wk or rats receiving losartan orally during 1 wk. The number of sites (Bmax) was reduced, but the dissociation constant (Kd) value was unchanged. Losartan receptors were downregulated in glomeruli from rats receiving losartan, but remained unchanged in glomeruli from rats infused with ANG II. Since in vivo administration of losartan results in increase of plasma ANG II and formation of metabolites, in vitro studies using human mesangial cells were performed to better analyze the present findings. Treatment of mesangial cells during 4 days by ANG II, losartan, or its metabolite, EXP-3174, also produced downregulation of 125I-[Sar1,Ala8]ANG II binding sites with a decreased Bmax and unchanged Kd value. Only treatment of mesangial cells by ANG II or EXP-3174 produced downregulation of [3H]losartan binding sites. In contrast, exposure of these cells to losartan resulted in upregulation of [3H]losartan binding sites. Under all conditions, only Bmax was modified. Whereas internalization of [3H]losartan in mesangial cells was negligible under all experimental conditions, there was an increase of the percentage of internalized 125I-[Sar1,Ala8]ANG II after exposure of the cells to ANG II or AT1 antagonists. No change was observed in mesangial cell AT1 receptor mRNA levels. This study demonstrates that 1) AT1 mRNA is expressed in human mesangial cells; 2) the characteristics of 125I-[Sar1,Ala8]ANG II and [3H]losartan binding sites in rat glomeruli and human mesangial cells are different, with Kd and Bmax values greater in both preparations when [3H]losartan was utilized; 3) both types of binding sites obey different regulations, and the effects of losartan in vivo are due in part to the associated increase in plasma ANG II levels and the transformation of the drug into its metabolite, EXP-3174; 4) downregulation of AT1 receptors does not depend on changes in mRNA expression but is associated with increased relative internalization.

scholarly journals The Role of EGCG in Breast Cancer Prevention and Therapy

2020 ◽  
Vol 20 ◽  
Author(s):  
Adriana Romano ◽  
Fátima Martelb
Keyword(s):  
Breast Cancer ◽  
Cancer Prevention ◽  
Molecular Mechanisms ◽  
Experimental Models ◽  
Breast Cancer Prevention ◽  
Protective Effects ◽  
Experimental Conditions ◽  
Prevention And Therapy

Background: Breast cancer is the most frequent cancer in women. Green tea has been studied for breast cancer chemopreventive and possibly chemotherapeutic effects due to its high content in polyphenolic compounds, including epigallocatechin-3-gallate (EGCG). Method: This review is based on a literature research that included papers registered on the Medline database. The research was conducted through PubMed, with the application of the following query: “EGCG”AND "breast cancer”. The result was a total of 88 articles in which this review stands on. Results: In vitro, EGCG shows antioxidant or pro-oxidant properties, depending on the concentration and exposure time. EGCG blocks cell cycle progression and modulates signaling pathways that affects cell proliferation and differentiation. EGCG also induces apoptosis, negatively modulates different steps involved in metastasis and targets angiogenesis by inhibiting VEGF transcription. In vivo, investigations have shown that oral administration of EGCG results in reduction of tumor growth and in antimetastatic and antiangiogenic effects in animal xenograft and allograft models. Discussion: Much remains unknown about the molecular mechanisms involved in the protective effects of EGCG on mammary carcinogenesis. In addition, more studies in vivo are necessary to determine the potential toxicity of EGCG at higher doses and to elucidate its interactions with other drugs. Conclusion: A protective effect of EGCG has been shown in different experimental models and under different experimental conditions, suggesting clinical implications of EGCG for breast cancer prevention and therapy. The data presented in this review support the importance of further investigations.

Superoxide, Xanthine Oxidase and Platelet Reactions: Further Studies on Mechanisms by which Oxidants Influence Platelets

1981 ◽  
Vol 45 (03) ◽  
pp. 290-293 ◽  
Author(s):  
Peter H Levine ◽  
Danielle G Sladdin ◽  
Norman I Krinsky
Keyword(s):  
Superoxide Dismutase ◽  
Cytochrome C ◽  
Xanthine Oxidase ◽  
Direct Effect ◽  
Platelet Function ◽  
Experimental Conditions ◽  
Release Reaction

SummaryIn the course of studying the effects on platelets of the oxidant species superoxide (O- 2), Of was generated by the interaction of xanthine oxidase plus xanthine. Surprisingly, gel-filtered platelets, when exposed to xanthine oxidase in the absence of xanthine substrate, were found to generate superoxide (O- 2), as determined by the reduction of added cytochrome c and by the inhibition of this reduction in the presence of superoxide dismutase.In addition to generating Of, the xanthine oxidase-treated platelets display both aggregation and evidence of the release reaction. This xanthine oxidase induced aggreagtion is not inhibited by the addition of either superoxide dismutase or cytochrome c, suggesting that it is due to either a further metabolite of O- 2, or that O- 2 itself exerts no important direct effect on platelet function under these experimental conditions. The ability of Of to modulate platelet reactions in vivo or in vitro remains in doubt, and xanthine oxidase is an unsuitable source of O- 2 in platelet studies because of its own effects on platelets.

Desmopressin (DDAVP) Enhances Platelet Adhesion to the Extracellular Matrix of Cultured Human Endothelial Cells through Increased Expression of Tissue Factor

1997 ◽  
Vol 77 (05) ◽  
pp. 0975-0980 ◽  
Author(s):  
Angel Gálvez ◽  
Goretti Gómez-Ortiz ◽  
Maribel Díaz-Ricart ◽  
Ginés Escolar ◽  
Rogelio González-Sarmiento ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Tissue Factor ◽  
Platelet Adhesion ◽  
Umbilical Vein ◽  
Procoagulant Activity ◽  
Experimental Conditions ◽  
Chromogenic Assay

SummaryThe effect of desmopressin (DDAVP) on thrombogenicity, expression of tissue factor and procoagulant activity (PCA) of extracellular matrix (ECM) generated by human umbilical vein endothelial cells cultures (HUVEC), was studied under different experimental conditions. HUVEC were incubated with DDAVP (1, 5 and 30 ng/ml) and then detached from their ECM. The reactivity towards platelets of this ECM was tested in a perfusion system. Coverslips covered with DD A VP-treated ECMs were inserted in a parallel-plate chamber and exposed to normal blood anticoagulated with low molecular weight heparin (Fragmin®, 20 U/ml). Perfusions were run for 5 min at a shear rate of 800 s1. Deposition of platelets on ECMs was significantly increased with respect to control ECMs when DDAVP was used at 5 and 30 ng/ml (p <0.05 and p <0.01 respectively). The increase in platelet deposition was prevented by incubation of ECMs with an antibody against human tissue factor prior to perfusion. Immunofluorescence studies positively detected tissue factor antigen on DDAVP derived ECMs. A chromogenic assay performed under standardized conditions revealed a statistically significant increase in the procoagulant activity of the ECMs produced by ECs incubated with 30 ng/ml DDAVP (p <0.01 vs. control samples). Northern blot analysis revealed increased levels of tissue factor mRNA in extracts from ECs exposed to DDAVP. Our data indicate that DDAVP in vitro enhances platelet adhesion to the ECMs through increased expression of tissue factor. A similar increase in the expression of tissue factor might contribute to the in vivo hemostatic effect of DDAVP.

Antioxidant Activity, Phenolic Content and Hematoprotective Effects of Cleome arabica Polyphenolic Leaf Extract

2019 ◽  
Author(s):  
C. Tigrine ◽  
A. Kameli
Keyword(s):  
Antioxidant Activity ◽  
Biological Effects ◽  
Reducing Power ◽  
Hematological Toxicity ◽  
Protective Effects ◽  
Ferrous Ions ◽  
Polyphenolic Extract ◽  
Cleome Arabica

In this study a polyphenolic extract from Cleome arabica leaves (CALE) was investigated for its antioxidant activity in vitro using DPPH•, metal chelating and reducing power methods and for its protective effects against AraC-induced hematological toxicity in vivo using Balb C mice. Results indicated that CALE exhibited a strong and dose-dependent scavenging activity against the DPPH• free radical (IC50 = 4.88 μg/ml) and a high reducing power activity (EC50 = 4.85 μg/ml). Furthermore, it showed a good chelating effects against ferrous ions (IC50 = 377.75 μg/ml). The analysis of blood showed that subcutaneous injection of AraC (50 mg/kg) to mice during three consecutive days caused a significant myelosupression (P < 0.05). The combination of CALE and AraC protected blood cells from a veritable toxicity. Where, the number of the red cells, the amount of hemoglobin and the percentage of the hematocrite were significantly high. On the other hand, AraC cause an elevation of body temperature (39 °C) in mice. However, the temperature of the group treated with CALE and AraC remained normal and did not exceed 37.5 °C. The observed biological effects of CALE, in vitro as well as in vivo, could be due to the high polyphenol and flavonoid contents. In addition, the antioxidant activity of CALE suggested to be responsible for its hematoprotective effect.

Applicability of Instability Index for In vitro Protein Stability Prediction

2019 ◽  
Vol 26 (5) ◽  
pp. 339-347 ◽  
Author(s):  
Dilani G. Gamage ◽  
Ajith Gunaratne ◽  
Gopal R. Periyannan ◽  
Timothy G. Russell
Keyword(s):  
Protein Stability ◽  
Caulobacter Crescentus ◽  
Effect Of Temperature ◽  
Instability Index ◽  
Dipeptide Composition ◽  
Experimental Conditions ◽  
The Stability ◽  
Vitro Protein

Background: The dipeptide composition-based Instability Index (II) is one of the protein primary structure-dependent methods available for in vivo protein stability predictions. As per this method, proteins with II value below 40 are stable proteins. Intracellular protein stability principles guided the original development of the II method. However, the use of the II method for in vitro protein stability predictions raises questions about the validity of applying the II method under experimental conditions that are different from the in vivo setting. Objective: The aim of this study is to experimentally test the validity of the use of II as an in vitro protein stability predictor. Methods: A representative protein CCM (CCM - Caulobacter crescentus metalloprotein) that rapidly degrades under in vitro conditions was used to probe the dipeptide sequence-dependent degradation properties of CCM by generating CCM mutants to represent stable and unstable II values. A comparative degradation analysis was carried out under in vitro conditions using wildtype CCM, CCM mutants and two other candidate proteins: metallo-β-lactamase L1 and α -S1- casein representing stable, borderline stable/unstable, and unstable proteins as per the II predictions. The effect of temperature and a protein stabilizing agent on CCM degradation was also tested. Results: Data support the dipeptide composition-dependent protein stability/instability in wt-CCM and mutants as predicted by the II method under in vitro conditions. However, the II failed to accurately represent the stability of other tested proteins. Data indicate the influence of protein environmental factors on the autoproteolysis of proteins. Conclusion: Broader application of the II method for the prediction of protein stability under in vitro conditions is questionable as the stability of the protein may be dependent not only on the intrinsic nature of the protein but also on the conditions of the protein milieu.

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