Copeptin,adropin and irisin concentrations in breast milk and plasma of healthy women and those with gestational diabetes mellitus

Copeptin, adropin and irisin are polypeptide hormones implicated in energy homostasis and diabetes. The purposes of this study were (1) to compare the copeptin, adropin and irisin concentrations between colostrum, transitional and mature milk and plasma in lactating women with and without GDM and (2) to compare these values with those from non-lactating women. Venous blood samples were obtained before suckling from 15 healthy lactating women aged 26–30 years, 15 lactating women with GDM aged 26–32 years, and 14 age-matched controls aged 25–31 years. Colostrum, transitional milk and mature milk samples were collected just before suckling. The concentration of copeptin was determined by EIA while the concentrations of adropin and irisin were determined by ELISA. The levels of copeptin, adropin and irisin in the colostrum were significantly higher than those in transitional and mature milk samples from healthy women; also, transitional milk had higher copeptin, adropin and irisin concentrations than mature milk. The amounts of copeptin in the colostrum and transitional milk were significantly higher than in mature milk samples from women with GDM, while the amounts of adropin and irisin were significantly lower. The relative concentrations of copeptin, adropin and irisin in the plasma samples from these groups of women were similar to those in the colostrum, transitional and mature milk samples, but the latter concentrations were higher than those in the plasma. These peptides could influence the regulation of metabolic pathways and the postnatal growth and development of different organs in the newborn.     

Nimbolide prevents myocardial damage by regulating cardiac biomarkers,antioxidant level,and apoptosis signaling against doxorubicin‐induced cardiotoxicity in rats

The current work planned to assess the protecting properties of nimbolide against doxorubicin (DOX)‐treated myocardial damage. Myocardial damage was produced with 2.5 mg/kg of DOX given on alternative days (14 days). Thiobarbituric acid reactive substances (TBARS) levels of a lipid peroxidative marker were elevated, whereas reduced body weight, heart weight, blood pressure indices and reduced levels of antioxidants like glutathione‐S‐transferase, superoxide dismutase, catalase, glutathione peroxidase, glutathione, and glutathione reductase were observed in the heart tissue of DOX‐treated animals. DOX‐treated animals showed augmented levels of cardiac markers likes monocyte chemotactic protein‐1, interferon‐gamma, aspartate transferase, creatine kinase, lactate dehydrogenase, creatine kinase‐muscle/brain, heart‐type fatty acid‐binding protein, glycogen phosphorylase isoenzyme BB, transforming growth factor‐β, brain natriuretic peptide, myoglobin, and cTnI in serum. Histopathological assessment confirmed the DOX‐induced cardiotoxicity. Furthermore, DOX‐induced rats showed augmented inflammatory mediators (nuclear factor‐κB [NF‐kB], tumor necrosis factor‐α [TNF‐α], and interleukin‐1β [IL‐1β]) and increased PI3K/Akt signaling proteins (PI3K, p‐Bad/Bad, caspase‐3, and p‐Akt), whereas decreased oxidative markers (HO‐1 and NQO‐1) and p‐PTEN were observed. Nimbolide‐supplemented rats showed reduced activity/levels of cardiac markers and TBARS levels in serum and heart tissue. Levels of enzymatic and nonenzymatic antioxidants were augmented in the heart tissue of nimbolide‐supplemented rats. Nimbolide influence decreased apoptosis, inflammation, and enhanced antioxidant markers through the modulation of p‐Bad/Bad, caspase‐3, PI3K, p‐Akt, TNF‐α, NF‐kB, IL‐1β, HO‐1, NQO‐1, and p‐PTEN markers. The histopathological explanations were observed to be in line with biochemical analysis. Therefore, the finding of current work was that nimbolide has a defensive effect on the myocardium against DOX‐induced cardiac tissue damage.     

Cardiotoxicity of doxorubicin/paclitaxel combination in rats: effect of sequence and timing of administration

The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administered intraperitoneally (i.p.) at a single dose of 5 mg x kg(-1) every other 2 days, 2 doses per week for a total cumulative dose of 20 mg x kg(-1). PTX was administered by an i.p. route at a dose of 20 mg x kg(-1) every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment.     

Resveratrol treatment protects against doxorubicin-induced cardiotoxicity by alleviating oxidative damage

The possible protective effects of resveratrol (RVT) against cardiotoxicity were investigated in Wistar albino rats treated with saline, saline+doxorubicin (DOX; 20 mg/kg) or RVT (10 mg/kg)+DOX. Blood pressure and heart rate were recorded on the 1^st week and on the 7^th week, while cardiomyopathy was assessed using transthoracic echocardiography before the rats were decapitated. DOX-induced cardiotoxicity resulted in decreased blood pressure and heart rate, but lactate dehydrogenase, creatine phosphokinase, total cholesterol, triglyceride, aspartate aminotransferase and 8-OHdG levels were increased in plasma. Moreover, DOX caused a significant decrease in plasma total antioxidant capacity along with a reduction in cardiac superoxide dismutase, catalase and Na⁺,K⁺-ATPase activities and glutathione contents, while malondialdehyde, myelopreoxidase activity and the generation of reactive oxygen species were increased in the cardiac tissue. On the other hand, RVT markedly ameliorated the severity of cardiac dysfunction, while all oxidant responses were prevented; implicating that RVT may be of therapeutic use in preventing oxidative stress due to DOX toxicity.     

Inflammatory response and matrix metalloproteinases in chronic kidney failure: Modulation by adropin and spexin

Chronic kidney disease is a major global public health problem. The peptide hormones adropin and spexin modulate many physiological functions such as energy balance and glucose, lipid and protein metabolism. However, it is unclear whether these peptides may exert effects on renal damage, tissue remodeling, and inflammatory conditions. In view of the limited information, we aimed to investigate the effect of adropin and spexin on matrix metalloproteinase and inflammatory response genes a rat model of adenine-induced chronic kidney failure. Chronic kidney failure was induced in rats by administering adenine hemisulfate. Renal function was determined in an autoanalyzer. Histopathological modifications were assessed by H&E staining. mRNA expression levels of ALOX 15, COX 1, COX 2, IL-1β, IL-10, IL-17A, IL-18 IL-21, IL-33, KIM-1, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, NGAL, TGFβ1, TIMP-1, and TNFα in kidney tissue were measured by qPCR. Our results showed an increase of 24-h urine volume, serum creatinine, BUN, and urine protein levels in group with adenine-induced CKF. Adropin and spexin treatments decreased urine protein and 24-h urine volume. Renal damage, TIMP-1, IL-33, and MMP-2 increased after CKF induction, while COX 1, MMP-9, and MMP-13 levels were significantly reduced. Furthermore, KIM-1, TIMP-1, IL-33, and MMP-2 were downregulated by spexin treatment. Renal damage, NGAL, TIMP-1 IL-17A, IL-33, MMP-2, and MMP-3 decreased after adropin treatment, while MMP-13 levels were upregulated. Treatment with adropin+spexin decreased KIM-1, NGAL, TIMP-1, IL-1β, IL-17A, IL-18, IL-33, ALOX 15, COX 1, COX 2, TGFβ1, TNFα, MMP-2, MMP-3, and MMP-7, but increased MMP-13 levels. Our findings revealed that inflammatory response and MMP genes were modulated by adropin and spexin. These peptides may have protective effects on inflammation and chronic kidney damage progression.     

Cardiac,skeletal muscle and serum irisin responses to with or without water exercise in young and old male rats: Cardiac muscle produces more irisin than skeletal muscle

Irisin converts white adipose tissue (WAT) into brown adipose tissue (BAT), as regulated by energy expenditure. The relationship between irisin concentrations after exercise in rats compared humans after exercise remains controversial. We therefore: (1) measured irisin expression in cardiac and skeletal muscle, liver, kidney, peripheral nerve sheath and skin tissues, as also serum irisin level in 10 week-old rats without exercise, and (2) measured tissue supernatant irisin levels in cardiac and skeletal muscle, and in response to exercise in young and old rats to establishing which tissues produced most irisin. Young (12 months) and old rats (24 months) with or without 10 min exercise (water floating) and healthy 10 week-old Sprague-Dawley rats without exercise were used. Irisin was absent from sections of skeletal muscle of unexercised rats, the only part being stained being the perimysium. In contrast, cardiac muscle tissue, peripheral myelin sheath, liver, kidneys, and skin dermis and hypodermis were strongly immunoreactivity. No irisin was seen in skeletal muscle of unexercised young and old rats, but a slight amount was detected after exercise. Strong immunoreactivity occurred in cardiac muscle of young and old rats with or without exercise, notably in pericardial connective tissue. Serum irisin increased after exercise, being higher in younger than older rats. Irisin in tissue supernatants (cardiac and skeletal muscle) was high with or without exercise. High supernatant irisin could come from connective tissues around skeletal muscle, especially nerve sheaths located within it. Skeletal muscle is probably not a main irisin source.     

Beneficial effects of angiotensin II receptor blocker,olmesartan, in limiting the cardiotoxic effect of daunorubicin in rats

Abstract

The aim was to evaluate the role of the combination of olmesartan, an angiotensin II (Ang II) receptor blocker (ARB), with daunorubicin (DNR) in reducing cardiac toxicity in rats. DNR was administered at a dose of 3 mg/kg/day every other day for 12 days. Olmesartan was administered orally every day for 12 days. Rats treated with DNR alone showed cardiac toxicity as evidenced by worsening cardiac function, elevation of malondialdehyde level in heart tissue and decreased in the level of total glutathione peroxidase activity; treatment with ARB reversed these changes. Furthermore, ARB treatment down-regulated matrix metalloproteinase-2 expression, myocardial expression of Ang II, attenuated the increased protein expressions of p67^phox and Nox4 and reduced oxidative stress-induced DNA damage evaluated by expression of 8-hydroxydeoxyguanosine. In conclusion, the result demonstrated that Ang II and oxidative stress play a key role in anthracycline-induced cardiotoxicity and that treatment with ARB will be beneficial against DNR-induced cardiotoxicity.     

Creatine Kinase-Overexpression Improves Myocardial Energetics,Contractile Dysfunction and Survival in Murine Doxorubicin Cardiotoxicity

Doxorubicin (DOX) is a commonly used life-saving antineoplastic agent that also causes dose-dependent cardiotoxicity. Because ATP is absolutely required to sustain normal cardiac contractile function and because impaired ATP synthesis through creatine kinase (CK), the primary myocardial energy reserve reaction, may contribute to contractile dysfunction in heart failure, we hypothesized that impaired CK energy metabolism contributes to DOX-induced cardiotoxicity. We therefore overexpressed the myofibrillar isoform of CK (CK-M) in the heart and determined the energetic, contractile and survival effects of CK-M following weekly DOX (5mg/kg) administration using in vivo ³¹P MRS and ¹H MRI. In control animals, in vivo cardiac energetics were reduced at 7 weeks of DOX protocol and this was followed by a mild but significant reduction in left ventricular ejection fraction (EF) at 8 weeks of DOX, as compared to baseline. At baseline, CK-M overexpression (CK-M-OE) increased rates of ATP synthesis through cardiac CK (CK flux) but did not affect contractile function. Following DOX however, CK-M-OE hearts had better preservation of creatine phosphate and higher CK flux and higher EF as compared to control DOX hearts. Survival after DOX administration was significantly better in CK-M-OE than in control animals (p<0.02). Thus CK-M-OE attenuates the early decline in myocardial high-energy phosphates and contractile function caused by chronic DOX administration and increases survival. These findings suggest that CK impairment plays an energetic and functional role in this DOX-cardiotoxicity model and suggests that metabolic strategies, particularly those targeting CK, offer an appealing new strategy for limiting DOX-associated cardiotoxicity.     

Antioxidant and antiapoptotic effects of proanthocyanidin and ginkgo biloba extract against doxorubicin‐induced cardiac injury in rats

Grape seed proanthocyanidins (GSPE) and ginkgo biloba extract (EGb761) are considered to have protective effects against several diseases. The cardiotoxicity of doxorubicin (DOX) has been reported to be associated with oxidative damage. This study was conducted to evaluate the cardioprotective effects of GSPE and EGb761 against DOX‐induced heart injury in rats. DOX was administered as a single i.p. dose (20 mg kg^–1) to adult male rats. DOX‐intoxicated rats were orally administered GSPE (200 mg kg^–1 day^–1) or EGb761 (100 mg kg^–1 day^–1) for 15 consecutive days, starting 10 days prior DOX injection. DOX‐induced cardiotoxicity was evidenced by a significant increase in serum aspartate transaminase (AST), creatine phosphokinase isoenzyme (CK‐MB), lactate dehydrogenase (LDH), total cholesterol (TC) and triglyceride (TG) activities and levels. Increased oxidative damage was expressed by the depletion of cardiac reduced glutathione (GSH), elevation of cardiac total antioxidant (TAO) level and accumulation of the lipid peroxidation product, malondialdehyde (MDA). Significant rises in cardiac tumour necrosis factor‐alpha (TNF‐α) and caspase‐3 levels were noticed in DOX‐intoxicated rats. These changes were ameliorated in the GSPE and EGb761‐treated groups. Histopathological analysis confirmed the cardioprotective effects of GSPE and EGb761. In conclusion, GSPE and EGb761 mediate their protective effect against DOX‐induced cardiac injury through antioxidant, anti‐inflammatory and antiapoptotic mechanisms. Copyright © 2012 John Wiley & Sons, Ltd.     

Beneficial role of aminoguanidine on acute cardiomyopathy related to doxorubicin-treatment

Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic that has cardiotoxicity as a major side effect. One mechanism of this toxicity is believed to involve the reactive oxygen radical species (ROS); these agents likely account for the pathophysiology of DOX-induced cardiomyopathy. Aminoguanidine (AG) is an effective antioxidant and free radical scavenger which has long been known to protect against ROS formation. We investigated the effects of AG on DOX-induced changes in thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content. The rats were divided into four groups:1) Control; 2) DOX group; injected intraperitoneally (i.p.) with DOX 20 mg/kg in a single dose 3) AG-treated group; injected i.p. in single dose of 20 mg/kg DOX plus 100 mg/kg AG 1 h before the DOX for 3 days, 4) AG group; injected i.p. with AG 100 mg/kg for 3 days. DOX administration to control rats increased TBARS and decreased GSH levels. AG administration before DOX injection caused significant decrease in TBARS and increase in GSH levels in the heart tissue when compared with DOX only. Morphological changes, including severe myocardial fibrosis and inflammatory cell infiltration were clearly observed in the DOX-treated heart. AG reversed the DOX-induced heart damage. Therefore AG could protect the heart tissue against free radical injury. The application of AG during cancer chemotherapy may attenuate tissue damage and improve the therapeutic index of DOX.     

Cardiac response to doxorubicin and dexrazoxane in intact and ovariectomized young female rats at rest and after swim training

The impact of cancer therapies on adult cardiac function is becoming a concern as more children survive their initial cancer. Cardiovascular disease is now a significant problem to adult survivors of childhood cancer. Specifically, doxorubicin (DOX) may be particularly harmful in young girls. The objective of this study was to characterize DOX damage and determine the ability of dexrazoxane (DEX) to reduce DOX-mediated cardiac damage in sedentary and swim-trained female rats. Female Sprague-Dawley rats were left intact or ovariectomized (OVX) at weaning then injected with DEX (60 mg/kg) before DOX (3 mg/kg), DOX alone, or PBS. Rats were separated into sedentary and swim cohorts. Body weight was reduced in DOX:DEX- but not PBS- or DOX-treated rats. Echocardiographic parameters were similar in sedentary rats. Swim training revealed greater concentric remodeling in DOX-treated rats and reduced fractional shortening in DOX:DEX-treated rats. Calsequestrin 2 was reduced with DOX and increased with DOX:DEX postswim. Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a was reduced and calsequestrin 2 reduced further by swim training only in intact rats. OVX rats were heavier and developed eccentric remodeling post-swim with DOX and eccentric hypertrophy with DOX:DEX. Changes in SERCA2a and calsequestrin 2 expression were not observed. Ovariectomized DOX- and DOX:DEX-treated rats stopped growing during swim training. DEX coinjection did not relieve DOX-mediated cardiotoxicity in intact or hormone-deficient rats. DOX-mediated reductions in growth, cardiac function, and expression of calcium homeostasis proteins were exacerbated by swim. DEX coadministration did not substantially relieve DOX-mediated cardiotoxicity in young female rats. Ovarian hormones reduce DOX-induced cardiotoxicity.     

Effect of aloe vera (Aloe barbadensis Miller) gel on doxorubicin-induced myocardial oxidative stress and calcium overload in albino rats

Administration of a single dose of doxorubicin (DOX) (7.5 mg/kg, i.v.) produces cardiotoxicity, manifested biochemically by significant decrease in blood glutathione (GSH) and tissue GSH along with elevated levels of serum lactate dehydrogenase (LDH) and serum creatine phosphokinase (CPK). In addition, cardiotoxicity was further confirmed by significant increase in lipid peroxides expressed as malondialdehyde (MDA, secondary indicator of lipid peroxidation), tissue catalase and tissue superoxide dismutase (SOD). Administration ofA. vera gel (100 and 200 mg/kg) orally for 10 days produced a significant protection against cardiotoxicity induced by DOX evidenced by significant reductions in serum LDH, serum CPK, cardiac lipid peroxides, tissue catalase and tissue SOD along with increased levels of blood and tissue GSH. The results revealed that A. vera gel produced a dose dependent protection against DOX induced cardiotoxiaty.     

Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction

Both weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.Subject terms: Cell death, Heart stem cells     

Immunohistochemical expressions of adropin and ınducible nitric oxide synthase in renal tissues of rats with streptozotocin-ınduced experimental diabetes

Diabetes is characterized by high blood glucose levels; it occurs in 30–35% of the population. Elevated glucose levels can damage a number of organs, including the kidneys. Several peptide hormones participate in maintaining glucose homeostasis including the recently discovered “adropin,” a 42 amino acid peptide hormone. Adropin also alters inducible nitric oxide synthase (iNOS) expression. Therefore, we studied how adropin and iNOS expression is altered in the renal tissues of streptozotocin (STZ) induced diabetic rats. Seven sham, seven control and seven Wistar albino male rats were fed standard rat pellets and water ad libitum for 10 weeks. The rats in the diabetic group were injected i.p. with a single dose of 60 mg/kg STZ dissolved in 0.1 M phosphate-citrate buffer, pH 4.5. After the 10-week experimental period, the rats in both groups were anesthetized and decapitated. Kidney tissues were excised and placed in 10% formaldehyde solution, taken through routine histological procedures, and embedded in paraffin. Sections 5–6 μm thick were stained immunohistochemically using the avidin-biotin complex (ABC) method. Adropin and iNOS immunoreactivity were co-localized in the glomeruli, peritubular interstitial cells and peritubular capillary endothelium of the cortex; the thin limb of the loop of Henle in the medulla; and medullary peritubular interstitial cells and endothelium of the peritubular capillaries in both the control and diabetic groups. The intensities of adropin and iNOS immunoreactivity increased with the severity of the diabetes. Intense adropin immunoreactivity was detected in both the smooth muscle and human small intestine Paneth cells that were used as positive controls. The elevated levels of adropin and iNOS in the kidney indicates that these substances are involved in the pathophysiology of diabetes; this constitutes a compensatory mechanism against the damage inflicted by the disease.     

Resveratrol attenuates doxorubicin-induced cardiotoxicity in rats by up-regulation of vascular endothelial growth factor B

Doxorubicin (DOX) is a broad spectrum antitumor agent. However, its clinical utility is limited due to the well-known cardiotoxicity. Resveratrol (RSV) has been reported to exert cardioprotective effect in some cardiovascular diseases. In this study, we aimed to determine the effect of RSV on DOX-induced cardiotoxicity, and further explore the underlying mechanism in this process.Male Sprague-Dawley (SD) rats were randomly divided into four groups: CON, DOX, RSV, or DOX+RSV group (10 rats in each group). DOX treatment significantly decreased cardiac function, and increased the release of serum lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) in rat serum. Increased cell death and apoptosis of cardiomyocytes were also observed in DOX group in comparison with CON group. DOX treatment dramatically down-regulated expression of VEGF-B either in vivo or in vitro. In contrast, the combination of RSV and DOX markedly attenuated DOX-induced cardiotoxicity with the up-regulation of VEGF-B. Inhibition of VEGF-B by small interfering RNA (siRNA) abolished the protective effects of RSV on DOX-treated cardiomyocytes.Consequently,our findings indicated that RSV attenuates DOX-induced cardiotoxicity through up-regulation of VEGF-B.     

Thymol and Carvacrol Prevent Doxorubicin‐Induced Cardiotoxicity by Abrogation of Oxidative Stress,Inflammation, and Apoptosis in Rats

The aim of this study was to assess the possible protective effects of thymol and carvacrol (CAR) against doxorubicin (DOX)‐induced cardiotoxicity. A single dose of DOX (10 mg/kg i.v.) injected to male rats revealed significant increases in serum lactate dehydrogenase, creatine kinase, creatine kinase isoenzyme‐MB, aspartate transaminase, tumor necrosis factor‐alpha, and cardiac troponin levels. It also increased heart contents of malondialdehyde and caspase‐3 accompanied by a significant reduction in heart content of reduced glutathione as well as catalase and superoxide dismutase activity as compared with the control group. In contrast, administration of thymol (20 mg/kg p.o.) and/or CAR (25 mg/kg p.o.) for 14 days before DOX administration and for 2 days after DOX injection ameliorated the heart function and oxidative stress parameters. Summarily, thymol was more cardioprotective than CAR. Moreover, a combination of thymol and CAR had a synergistic cardioprotective effect that might be attributed to antioxidant, anti‐inflammatory, and antiapoptotic activities.     

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX’s cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly[ADP]-ribose polymerase 1 [PARP]-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.     

Presence of adropin,nesfatin-1, apelin-12, ghrelins and salusins peptides in the milk,cheese whey and plasma of dairy cows

Biological fluids (milk and serum/plasma) and cheese whey milk-derived fluid contain numerous molecules, especially amino acids and proteins. Therefore, the purpose of this study was to find out whether cheese whey (n:6), cow milk (n:6) and its blood (n = 6) have adropin, nesfatin-1, apelin-12, ghrelins and salusin peptides. Adropin, nesfatin-1, apelin-12 concentrations were measured by ELISA, whereas ghrelin and salusin concentrations were measured by EIA methods. It was found that adropin, nesfatin-1, apelin-12, des-acylated ghrelin and salusins in cheese whey were higher than in the corresponding milk peptides and plasma of dairy cows, with the exception of salusin alpha and acylated ghrelin in milk being the same than that of the corresponding cheese whey concentration and plasma of dairy cows. A correlation was also found between milk peptides and cheese whey, as also with plasma of dairy cows. The data suggest that peptides in cow milk might be an important and nutritious food for (neonatal) calves and human diet due to their biological and physiological properties.