Effect of Anthocyanin-Rich Extract of Sour Cherry for Hyperglycemia-Induced Inflammatory Response and Impaired Endothelium-Dependent Vasodilation

Diabetes mellitus (DM)-related morbidity and mortality are steadily rising worldwide, affecting about half a billion people worldwide. A significant proportion of diabetic cases are in the elderly, which is concerning given the increasing aging population. Proper nutrition is an important component in the effective management of diabetes in the elderly. A plethora of active substances of plant origin exhibit potency to target the pathogenesis of diabetes mellitus. The nutraceutical and pharmaceutical effects of anthocyanins have been extensively studied. In this study, the effect of Hungarian sour cherry, which is rich in anthocyanins, on hyperglycemia-induced endothelial dysfunction was tested using human umbilical cord vein endothelial cells (HUVECs). HUVECs were maintained under both normoglycemic (5 mM) and hyperglycemic (30 mM) conditions with or without two concentrations (1.50 ng/µL) of anthocyanin-rich sour cherry extract. Hyperglycemia-induced oxidative stress and inflammatory response and damaged vasorelaxation processes were investigated by evaluating the level of reactive oxygen species (ROS) and gene expression of four proinflammatory cytokines, namely, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1α (IL-1α), as well as the gene expression of nitric oxide synthase (NOS) endothelin-1 (ET-1) and endothelin-converting enzyme-1 (ECE-1). It was found that hyperglycemia-induced oxidative stress was significantly suppressed by anthocyanin-rich sour cherry extract in a concentration-dependent manner. The gene expression of the tested proinflammatory cytokines increased under hyperglycemic conditions but was significantly reduced by both 1 and 50 ng/µL anthocyanin-rich sour cherry extract. Further, although increased ET-1 and ECE-1 expression due to hyperglycemia was reduced by anthocyanin-rich sour cherry extract, NOS expression was increased by the extract. Collectively, these data suggest that anthocyanin-rich sour cherry extract could alleviate hyperglycemia-induced endothelial dysfunction due to its antioxidant, anti-inflammatory, and vasorelaxant effects.

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GTP Cyclohydrolase I Gene Polymorphisms Are Associated with Endothelial Dysfunction and Oxidative Stress in Patients with Type 2 Diabetes Mellitus

PLoS ONE ◽

10.1371/journal.pone.0108587 ◽

2014 ◽

Vol 9 (11) ◽

pp. e108587 ◽

Cited By ~ 8

Author(s):

Pawel P. Wolkow ◽

Wladyslaw Kosiniak-Kamysz ◽

Grzegorz Osmenda ◽

Grzegorz Wilk ◽

Beata Bujak-Gizycka ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Gene Polymorphisms ◽

Gtp Cyclohydrolase I ◽

And Oxidative Stress ◽

I Gene

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Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

Experimental Diabetes Research ◽

10.1155/2012/481840 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 56

Author(s):

Basma Basha ◽

Samson Mathews Samuel ◽

Chris R. Triggle ◽

Hong Ding

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Clinical Trials ◽

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Cardiovascular Complications ◽

Therapeutic Agents ◽

Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

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Oxidative stress increases megalin expression in the renal proximal tubules during the normoalbuminuric stage of diabetes mellitus

AJP Renal Physiology ◽

10.1152/ajprenal.00108.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. F462-F470 ◽

Cited By ~ 5

Author(s):

Yoshifumi Kurosaki ◽

Akemi Imoto ◽

Fumitaka Kawakami ◽

Masanori Yokoba ◽

Tsuneo Takenaka ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Hydrogen Peroxide ◽

High Glucose ◽

Renal Cortex ◽

Dependent Manner ◽

Phosphatidylinositol 3 Kinase ◽

Phosphorylated Akt ◽

Stress Dependent ◽

Phosphatidylinositol 3

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

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Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease

Biomolecules ◽

10.3390/biom11070994 ◽

2021 ◽

Vol 11 (7) ◽

pp. 994

Author(s):

Natasha Ting Lee ◽

Lin Kooi Ong ◽

Prajwal Gyawali ◽

Che Mohd Nasril Che Mohd Nassir ◽

Muzaimi Mustapha ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Inflammatory Response ◽

Small Vessel Disease ◽

Ischemia Reperfusion ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Purinergic Signalling ◽

Vessel Disease ◽

The Brain

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood–brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.

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Oxidative stress, endothelial dysfunction and inflammatory response in rat heart to NO2 inhalation exposure

Chemosphere ◽

10.1016/j.chemosphere.2010.11.055 ◽

2011 ◽

Vol 82 (11) ◽

pp. 1589-1596 ◽

Cited By ~ 24

Author(s):

Hongyan Li ◽

Ming Han ◽

Lin Guo ◽

Guangke Li ◽

Nan Sang

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Inflammatory Response ◽

Rat Heart ◽

Inhalation Exposure

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Biomarkers of oxidative stress and endothelial dysfunction in glucose intolerance and diabetes mellitus

Clinical Biochemistry ◽

10.1016/j.clinbiochem.2008.08.074 ◽

2008 ◽

Vol 41 (18) ◽

pp. 1454-1460 ◽

Cited By ~ 39

Author(s):

Edimar Cristiano Pereira ◽

Simone Ferderbar ◽

Marcelo Chiara Bertolami ◽

André Arpad Faludi ◽

Osmar Monte ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Endothelial Dysfunction ◽

Glucose Intolerance ◽

Biomarkers Of Oxidative Stress

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Oxidative stress and macrophage function: a failure to resolve the inflammatory response

Biochemical Society Transactions ◽

10.1042/bst0350284 ◽

2007 ◽

Vol 35 (2) ◽

pp. 284-287 ◽

Cited By ~ 54

Author(s):

P. Kirkham

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Inflammatory Response ◽

Carbonyl Stress ◽

Apoptotic Cells ◽

Inflammatory Gene Expression ◽

Macrophage Function ◽

Inflammatory Gene ◽

Ecm Proteins ◽

Inflammatory State

The suppression of pro-inflammatory gene expression along with the clearance of apoptotic cells by phagocytosis can play an important role in resolving the inflammatory response. Any impairment of these processes can therefore lead to a chronic inflammatory state. Oxidative stress can have both direct and indirect effects on macrophage function. This mini-review highlights a mechanism through which oxidative stress via the production of reactive carbonyls alters the ECM (extracellular matrix) environment of macrophages, thereby altering their behaviour. Carbonyl modification of ECM proteins causes increased macrophage adhesion and activation through receptors that are also involved in phagocytosis. Moreover, interaction of macrophages with these carbonyl-modified ECM proteins leads to decreased phagocytic activity towards apoptotic cells. At a more direct level, both oxidative and carbonyl stress inhibits activity of the transcriptional co-repressor HDAC-2 (histone deacetylase 2), which under normoxic conditions helps to suppress pro-inflammatory gene expression. Consequently, macrophages activated under conditions of oxidative or carbonyl stress can lead to a more enhanced inflammatory response. Coupled with an impairment of the phagocytic response, this can lead to ineffective clearance of apoptotic cells and secondary necrosis, with the result being failure to resolve the inflammatory response and the establishment of a chronic inflammatory state.

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Cytokine and chemokine levels in the heart tissue of aged rats following severe acute pancreatitis

European Journal of Inflammation ◽

10.1177/1721727x17712398 ◽

2017 ◽

Vol 15 (2) ◽

pp. 102-106 ◽

Cited By ~ 4

Author(s):

Rízia Callou Amaral ◽

Denise Frediani Barbeiro ◽

Marcia Kiyomi Koike ◽

Charles Mady ◽

Marcel Cerqueira César Machado ◽

...

Keyword(s):

Gene Expression ◽

Acute Pancreatitis ◽

Growth Factors ◽

Inflammatory Response ◽

Severe Acute Pancreatitis ◽

Systemic Inflammation ◽

The Elderly ◽

Study Groups ◽

Interleukin 10 ◽

The Body

Severe acute pancreatitis (AP) is a disease associated with high mortality and characterized by overwhelming systemic inflammation. Older people have a prolonged hospital stay and worst prognosis, when affected by this disease. Our group hypothesized, thus, that the systemic inflammatory response in the elderly would promote more organ damage when compared to the young. We sought to investigate the effect of systemic inflammation on the gene expression of cytokines, chemokines, and growth factors in the hearts of older and younger rats in an animal model of AP. AP was induced in all rats by injection of 0.5 mL of 2.5% taurocholate. There were two healthy age-matched control groups. An array of 79 cytokines, chemokines, and growth factors was measured in samples of cardiac tissue taken from the AP rats after 10 h, and from control rats. Older healthy rats had significantly higher levels of interleukin-10 (IL-10) and CCL1 gene expression than younger ones ( P < 0.05), but all other measurements were similar among the study groups. This study indicates the systemic inflammation may show unique features for different organs in the body, but older animals with systemic inflammation are similar to the young regarding the cardiac inflammatory response.

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ANTI-DIABETIC EFFECT OF ETHANOL EXTRACT OF Copaifera salikounda (HECKEL) AGAINST ALLOXAN-INDUCED DIABETES IN RATS

Slovenian Veterinary Research ◽

10.26873/svr-1072-2020 ◽

2021 ◽

Vol 58 (2) ◽

Author(s):

Chinyere Aloke ◽

Emmanuel Igwe ◽

Nwogo Obasi ◽

Pascal Amu ◽

Egwu Ogbonnia

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Body Weight ◽

Blood Glucose ◽

Medicinal Plants ◽

Fasting Blood Glucose ◽

Ethanol Extract ◽

The Body ◽

Albino Rats ◽

Dependent Manner

Accumulating evidences have reinforced the use of medicinal plants in the treatment of various ailments as a result of negative side effects associated with conventional drugs. Plant components such as phenols and flavonoids with antioxidant potential have confirmed protective roles against oxidative stress-induced degenerative diseases like diabetes mellitus (DM). The current study was carried out to investigate the effect of seed pod ethanol extract from Copaifera salikounda (SPEECS) in alloxan-induced diabetic rats. SPEECS was obtained by maceration of seed pod powder in absolute ethanol for 72 h, filtered, concentrated and dried in-vacuo. Gas chromatography-mass spectrometry (GC–MS) technique was used to quantitatively elucidate the chemical constituents of SPEECS. Twenty-four male albino rats were randomly allocated into four groups (n=6): normal control, DM control, DM + 200 mg/kg SPEECS and DM + 400 mg/kg SPEECS groups. DM was induced in the Wistar albino rats through intraperitoneal injection of 200 mg/kg body weight of alloxan. After 14 days of treatment, the body weight changes and the fasting blood glucose level were determined in the different groups. Also, serum biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) were estimated. The GC-MS results confirm nine bioactive compounds with 9-octadecenoic acid (55.75%) being most abundant. SPEECS (200 and 400 mg/kg) administration significantly (P 0.05) caused gain in weight, decreased fasting blood glucose and reversed the elevated liver function enzymes (ALT, AST, ALP) while total TP and ALB were markedly elevated relative to DM control group. Furthermore, SPEECS attenuated the activities of SOD and CAT while the level of MDA was significantly (P 0.05) decreased in dose dependent manner in comparison to the DM control. This study indicated that SPEECS can alleviate hyperglyceamia of DM. Key words: Copaifera salikounda; oxidative stress; medicinal plants; diabetes mellitus; phytochemicals; orthodox ANTIDIABETIČNI UČINEK EKSTRAKTA ETANOLA Copaifera salikounda (HECKEL) NA SLADKORNO BOLEZEN, SPROŽENO Z ALLOXAN-om, PRI PODGANAHIzvleček: Obstaja vedno več dokazov, ki poudarjajo uporabnost zdravilnih rastlin pri zdravljenju različnih bolezni, tudi zaradi različnih negativnih stranskih učinkov, povezanih s konvencionalnimi zdravili. Rastlinske sestavine kot so fenoli in flavonoidi z antioksidativnim potencialom, imajo po nekaterih raziskavah zaščitno vlogo pred degenerativnimi boleznimi, ki jih povzroča oksidativni stres, kot je sladkorna bolezen diabetes mellitus (DM). Študija je bila izvedena z namenom raziskovanja učinka etanolnega semenskega ekstrakta iz rastline Copaifera salikounda (SPEECS) pri podganah s sladkorno boleznijo, ki jo je povzročil alloxan. SPEECS je bil pridobljen z maceracijo praška semen v prahu v absolutnem etanolu 72 ur ter nadaljnjo filtracijo, koncentracijo in sušenjem v vakuumu. Za kvantitativno ugotavljanje kemijskih sestavin SPEECS je bila uporabljena tehnika plinske kromatografije in masne spektrometrije (GC-MS). Štiriindvajset samcev podgan Wistar je bilo naključno razporejenih v štiri skupine (n=6): normalna kontrola, kontrola DM, DM + 200 mg/kg SPEECS in DM + 400 mg/kg SPEECS. DM je bil pri podganah sprožen z intraperitonealno injekcijo 200 mg/kg telesne mase alloxana. Po 14 dneh zdravljenja so bile pri različnih skupinah določene spremembe telesne teže in nivo glukoze v krvi (na tešče). Poleg tega so avtorji raziskave izmerili še nekatere serumske biokemične parametre kot so ravni alaninske aminotransferaze (ALT), aspartatne aminotransferaze (AST), alkalne fosfataze (ALP), albumina (ALB), skupnih proteinov (TP), malondialdehida (MDA), superoksiddismutaze (SOD) in katalaze (CAT). Rezultati GC-MS so v izvlečku SPEECS pokazali devet bioaktivnih spojin, v katerih je največ 9-oktadecenojske kisline (55,75%). SPEECS (200 in 400 mg/kg) je povzročil znatno (P 0,05) povečanje telesne mase, znižanje glukoze v krvi na tešče in znižal raven encimov pokazateljev jetrne funkcije (ALT, AST, ALP), medtem ko je bila raven TP in ALB pri podganah, ki so prejemale SPEECS izrazito povišana v primerjavi z DM kontrolno skupino. Zdravljenje s SPEECS je tudi oslabilo aktivnosti SOD in CAT, medtem ko se je raven MDA znatno zmanjšala (P 0,05) v primerjavi s kontrolno skupino DM. Ta študija je pokazala, da lahko SPEECS ublaži hiperglikemijo pri sladkorni bolezni pri podganah.Ključne besede: Copaifera salikounda; oksidativni stres; zdravilne rastline; sladkorna bolezen; fitokemikalije; ortodoksni

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Giardia duodenalis Induces Proinflammatory Cytokine Production in Mouse Macrophages via TLR9-Mediated p38 and ERK Signaling Pathways

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.694675 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xudong Pu ◽

Xin Li ◽

Lili Cao ◽

Kaiming Yue ◽

Panpan Zhao ◽

...

Keyword(s):

Inflammatory Response ◽

Signaling Pathways ◽

Proinflammatory Cytokines ◽

Giardia Duodenalis ◽

Erk Signaling ◽

Enzyme Linked Immunosorbent Assay ◽

Dependent Manner ◽

Mouse Macrophages ◽

Host Inflammatory Response

Giardia duodenalis, also known as Giardia lamblia or Giardia intestinalis, is an important opportunistic, pathogenic, zoonotic, protozoan parasite that infects the small intestines of humans and animals, causing giardiasis. Several studies have demonstrated that innate immunity-associated Toll-like receptors (TLRs) are critical for the elimination of G. duodenalis; however, whether TLR9 has a role in innate immune responses against Giardia infection remains unknown. In the present study, various methods, including reverse transcriptase–quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, immunofluorescence, inhibitor assays, and small-interfering RNA interference, were utilized to probe the role of TLR9 in mouse macrophage-mediated defenses against G. lamblia virus (GLV)–free or GLV-containing Giardia trophozoites. The results revealed that in G. duodenalis–stimulated mouse macrophages, the secretion of proinflammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and IL-12 p40, was enhanced, concomitant with the significant activation of TLR9, whereas silencing TLR9 attenuated the host inflammatory response. Notably, the presence of GLV exacerbated the secretion of host proinflammatory cytokines. Moreover, G. duodenalis stimulation activated multiple signaling pathways, including the nuclear factor κB p65 (NF-κB p65), p38, ERK, and AKT pathways, the latter three in a TLR9-dependent manner. Additionally, inhibiting the p38 or ERK pathway downregulated the G. duodenalis–induced inflammatory response, whereas AKT inhibition aggravated this process. Taken together, these results indicated that G. duodenalis may induce the secretion of proinflammatory cytokines by activating the p38 and ERK signaling pathways in a TLR9-dependent manner in mouse macrophages. Our in vitro findings on the mechanism underlying the TLR9-mediated host inflammatory response may help establish the foundation for an in-depth investigation of the role of TLR9 in the pathogenicity of G. duodenalis.

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