Chronic stress and Alzheimer's disease.

Stress is a key factor in the development and progress of diseases. In neurodegenerative conditions, stress management can play an important role in maintaining the quality of life and the capacity to improve. Neurodegenerative diseases, including Alzheimer's disease, cause the motor and cognitive malfunctions that are spontaneously stressful and also can disturb the neural circuits that promote stress responses. The interruption of those circuits leads to aggressive and inappropriate behavior. In addition, stress contributes to illness and may exacerbate symptoms. In this review, we present stress-activated neural pathways involved in Alzheimer's disease from a clinical and experimental point of view, as well as supportive drugs and therapies.

Biosensor-based methods for Crimean-Congo hemorrhagic fever virus detection.

Crimean-Congo hemorrhagic fever is a tick-borne disease with high fatality rate that is endemic in some parts of Asia, Africa and Europe. Rapid diagnostics of Crimean-Congo hemorrhagic fever (CCHF) is necessary for appropriate clinical management of this disease and also can be useful in preventing of secondary spread from human-to-human, though, common tests which are used to diagnose Crimean-Congo hemorrhagic fever have some limitations. Here we review 1) common diagnostic tests for CCHF, 2) limitations in laboratories methods of CCHF and 3) biosensor researches for detection of CCHF. It is necessary to design and develop an effective, rapid, and also low-cost tool such as biosensor to detect Crimean-Congo hemorrhagic fever. Based on the key role of rapid detection of CCHF in the control of infection, development of a biosensor as a rapid tool seems very major in the diagnosis of CCHF, though, there are limited studies on this field and more researches are needed in this issue.

Mothers' willingness to accept and pay for vaccines to their children in western Iran: a contingent valuation study.

BACKGROUND: The clients' willingness to accept (WTA) and willingness to pay (WTP) for a given good or service can help elicit the monetary value of that good or service. This study aims to assess the WTA and WTP of mothers attending primary health centers for vaccines to their children during 2019 in Kermanshah city, western Iran. METHODS: We conducted a cross-sectional study on a total of 667 mothers attending primary health centers for vaccines to their children aged two to 18 months. A multistage sampling technique was employed to involve the mothers in the study, and data were collected using a self-administrated open-ended questionnaire. The multivariate linear regression model was used to identify the factors associated with the mothers' WTP and WTA for vaccines to their children. RESULTS: The study indicated that 94.2 and 93.1% of the mothers respectively had WTA and WTP values greater than zero, with their corresponding mean values of US$ 6.8 and US$ 4.4. The mothers in the higher monthly household income category, mothers born in the urban areas, and being a female child showed statistically significant positive associations with the mothers' WTA for the vaccines. While there was a statistically significant positive relationship between monthly household income and the mothers' WTP; a statistically significant negative relationship exists between the mothers' age and their WTP for the vaccine to their children. CONCLUSIONS: The findings indicated the mothers' WTA to WTP ratio of greater than one for the vaccines to their children. The most important factor associated with the mothers' WTA and WTP was the monthly household income. Thus, improving the socio-economic standards of women in the study area might contribute to reinforcing their immunization services seeking behavior to their children.

Elegant pH-Responsive Nanovehicle for Drug Delivery Based on Triazine Dendrimer Modified Magnetic Nanoparticles.

Owing to properties of magnetic nanoparticles and elegant three-dimensional macromolecule architectural features, dendrimeric structures have been investigated as nanoscale drug delivery systems. In this work, a novel magnetic nanocarrier, generation two (G2) triazine dendrimer modified Fe3O4@SiO2 magnetic nanoparticles (MNP-G2), was designed, fabricated, and characterized by Fourier transform infrared (FT-IR), thermal gravimetric analysis (TGA), vibrating sample magnetometer (VSM), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The prepared MNP-G2 nanosystem offers a new formulation that combines the unique properties of MNPs and triazine dendrimer as a biocompatible material for biomedical applications. To demonstrate the potential of MNP-G2, the nanoparticles were loaded with methotrexate (MTX), a proven chemotherapy drug. The MTX-loaded MNP-G2 (MNP-G2/MTX) exhibited a high drug-loading capacity of MTX and the excellent ability for controlled drug release. The cytotoxicity of MNP-G2/MTX using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide based assay and MCF-7, HeLa, and Caov-4 cell lines revealed that MNP-G2/MTX was more active against the tumor cells than the free drug in a mildly acidic environment. The results of hemolysis, hemagglutination, and coagulation assays confirmed the good blood safety of MNP-G2/MTX. Moreover, the cell uptake and intracellular distribution of MNP-G2/MTX were studied by flow cytometry analysis and confocal laser scanning microscopy (CLSM). This research suggests that MNP-G2/MTX with good biocompatibility and degradability can be selected as an ideal and effective drug carrier in targeted biomedicine studies especially anticancer applications.

A surgical modification in the technique of rat pinealectomy.

BACKGROUND: Several experimental intents require pineal gland removal. The main challenge of the pinealectomy surgical procedure is the hemorrhage due to the transverse sinus torn. The study aimed to modify the rat pinealectomy surgical procedure to reduce the risk of bleeding and the mortality rate. METHODS: Adult male rats experienced pinealectomy surgery. A mini-drill was used to remove a small skull area in the junction of the lambda and sagittal sutures. The pineal gland was removed using a curved-head hook. Animals experienced intensive post-surgical care. Locomotion, cerebellar motor function, working memory, and anxiety were evaluated 2 weeks after pinealectomy by the open field, rotarod, Y maze, and the elevated plus maze, respectively. RESULTS: Surgical modification reduced the bleeding risk and animal mortality rate. No significant alteration was found in locomotion and working memory. However, the pinealectomy was anxiogenic and decreased entry to the open arm. The cerebellar motor performance did not change in the rotarod test. Hematoxylin-Eosin staining of removed tissue confirmed the histology of the pineal gland. CONCLUSION: Advantages of this technique were removing a small skull area, modifying the hook insertion point to prevent damaging the brain veins, reducing the bleeding risk and the mortality rate. Surgery modification was associated with a decreased final number of animals used. Regardless of the melatonin shortage, pinealectomy affects different organs, which should be considered in the research study design.

The effect of Allium saralicum R. M. Fritsch nanocapsules in yogurt on type 2 diabetes in male rats: physicochemical characterization and pharmacodynamics assessment.

To treat illness, people are increasingly turning to natural foods rather than pharmaceuticals. Herbal extracts with antioxidant and anti-diabetic properties could be a good alternative for treating diabetes. The purpose of this study was to look into the effects of ethanol extraction on the Morphology of liver cells and hyperglycemia in rats of Allium saralicum RM Fritsch nanocapsules based on chitosan incorporated with yogurt. In this experimental study, 32 adult Wistar rats were randomly selected. The effect of Nano extraction on hypoglycemia was assessed using blood glucose levels three and fifteen days after a streptozotocin intraperitoneal (60 mg/kg) injection, as well as hepatocyte count and liver tissue morphology. The average size of the chitosan nanoparticles was determined to be 86 nm. After comparing the blood sugar levels of the A. saralicum nanocapsules groups to the untreated diabetes group, a significant decrease was constructed to observe hyperglycemia. Because of increased effective absorption in the intestine, nanocapsules incorporated into yogurt were able to reduce hyperglycemia in diabetic rats. As a result, a new yogurt formulation containing A. saralicum nanocapsules extract is recommended for diabetic patients.

Evaluation of hippocampal arylalkylamine N-acetyltransferase activity in amyloid-ß neurotoxicity.

Arylalkylamine N-acetyltransferase (AANAT), a rate-limiting enzyme in melatonin synthesis, is present in extra-pineal tissues such as the hippocampus. The hippocampal AANAT activity in amyloid ß (Aß) neurotoxicity has not been exactly defined. Adult male rats received bilateral intra-CA1 Aß administration. The hippocampus tissue sampling was performed 2, 12, and 24 h after Aß injection in the morning and night. The inflammation was monitored using tumor necrosis factor-alpha (TNF-α) immunohistochemistry. The AANAT enzyme activity and melatonin levels were measured using western blotting and high-performance liquid chromatography. The sampling in the morning vs night showed no significant differences in the AANAT activity. The Aß increased the area of TNF-α positive staining 24 h after injection, which indicated the induction of an inflammatory context. It was accompanied by a significant reduction in AANAT activity and hippocampal melatonin. A reverse correlation was also detected between TNF-α and AANAT activity in the 24-h group. The TNF-α positive area was significantly increased in the 24-h group as compared to the 12-h group. Data showed that inflammatory processes began 12 h after the Aß injection and augmented 24 h later. In the second experiment, the impact of Aß injection on hippocampus AANAT activity was examined in the pinealectomized (PIN×) animals. The PIN× per se did not affect the hippocampal AANAT and melatonin levels. However, there was a significant decrease in hippocampal melatonin in the PIN×+Aß group. The findings suggest the accompanying hippocampal inflammatory context and AANAT enzyme activity reduction in early stages after Aß administration. Understanding the underlying mechanism of the decreased AANAT activity may suggest new treatment strategies.

Expression, characterization, and activity optimization of a novel cellulase from the thermophilic bacteria Cohnella sp. A01.

Cellulases are hydrolytic enzymes with wide scientific and industrial applications. We described a novel cellulase, CelC307, from the thermophilic indigenous Cohnella sp. A01. The 3-D structure of the CelC307 was predicted by comparative modeling. Docking of CelC307 with specific inhibitors and molecular dynamic (MD) simulation revealed that these ligands bound in a non-competitive manner. The CelC307 protein was purified and characterized after recombinant expression in Escherichia coli (E. coli) BL21. Using CMC 1% as the substrate, the thermodynamic values were determined as Km 0.46 mM, kcat 104.30 × 10-3 (S-1), and kcat/Km 226.73 (M-1 S-1). The CelC307 was optimally active at 40 °C and pH 7.0. The culture condition was optimized for improved CelC307 expression using Plackett-Burman and Box-Behnken design as follows: temperature 20 °C, pH 7.5, and inoculation concentration with an OD600 = 1. The endoglucanase activity was positively modulated in the presence of Na+, Li+, Ca2+, 2-mercaptoethanol (2-ME), and glycerol. The thermodynamic parameters calculated for CelC307 confirmed its inherent thermostability. The characterized CelC307 may be a suitable candidate for various biotechnological applications.

AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation.

Diabetes mellitus (DM) is considered as a main challenge in both developing and developed countries, as lifestyle has changed and its management seems to be vital. Type I and type II diabetes are the main kinds and they result in hyperglycemia in patients and related complications. The gene expression alteration can lead to development of DM and related complications. The AMP-activated protein kinase (AMPK) is an energy sensor with aberrant expression in various diseases including cancer, cardiovascular diseases and DM. The present review focuses on understanding AMPK role in DM. Inducing AMPK signaling promotes glucose in DM that is of importance for ameliorating hyperglycemia. Further investigation reveals the role of AMPK signaling in enhancing insulin sensitivity for treatment of diabetic patients. Furthermore, AMPK upregulation inhibits stress and cell death in ß cells that is of importance for preventing type I diabetes development. The clinical studies on diabetic patients have shown the role of AMPK signaling in improving diabetic complications such as brain disorders. Furthermore, AMPK can improve neuropathy, nephropathy, liver diseases and reproductive alterations occurring during DM. For exerting such protective impacts, AMPK signaling interacts with other molecular pathways such as PGC-1α, PI3K/Akt, NOX4 and NF-κB among others. Therefore, providing therapeutics based on AMPK targeting can be beneficial for amelioration of DM.

Comparative physicochemical stability and clinical anti-wrinkle efficacy of transdermal emulgel preparations of 5% sodium ascorbyl phosphate and or ascorbic acid on human volunteers.

OBJECTIVES: Antioxidant containing cosmeceuticals are commonly prescribed products in treating wrinkles and revitalizing the skin. The aim of this study was the comparative evaluation of physicochemical stability and clinical anti-wrinkle efficacy of transdermal emulgel preparations of sodium ascorbyl phosphate (SAP) and ascorbic acid (AA) on human volunteers. METHODS: Emulgel preparations containing 5% of (SAP) and or (AA) were prepared. HPLC analysis was performed for stability evaluations. Clinical anti-wrinkle efficacy of the formulations was examined on human healthy volunteers in crow's feet area. Elasticity and digital images were recorded before and after treatment. RESULTS: Formulations with added antioxidants and kept in the refrigerator exhibited better stability characteristics. Two-sided blind study and placebo-controlled study showed that both actives were effective in wrinkles depth reduction and also elasticity enhancement but statistically significant difference in the efficacy of the products was not observed. CONCLUSION: Formulations containing (AA) and or (SAP) both improved elasticity and wrinkles of the skin almost by the same extent, and it is necessary to add antioxidant stabilizing agents to both preparations to reach a desired stability.

Synthesis of a green bigel using cottonseed oil/cannabis oil/alginate/ferula gum for quercetin release: Synergistic effects for treating infertility in rats.

Although therapeutic effect of quercetin (Quer) was reported on non-alcoholic fatty liver disease (NAFLD), destructive effects have been shown on male fertility due to its pro-oxidative properties. On the other hand, NAFLD impairs germ cells to produce sperm and leads to male infertility. Herein, a biocompatible and green bigel was designed for Quer delivery to prevent infertility induced by NAFLD as the increasing complications. Bigels were prepared using cottonseed oil/cannabis oil/alginate/ferula gum and optimized by the mixture design method. NAFLD was induced by 58% of dietary calorie as lard and 42 g/l fructose for 16 weeks in Sprague-Dawley rats. So on animals received 2 mg/kg Quer loaded on bigels, free bigels, or free Quer for 45 days as daily gavage. Semen was analyzed, followed by the assessment of DNA integrity. Count, motility, and normal morphology reached the healthy control group at the bigel-Quer-treated one. Moreover, all of these parameters were significantly higher in the bigel-Quer group than the Quer and bigel, alone. The percent of sperms with head and tail abnormality decreased considerably in the bigel-Quer group compared with the Quer, free bigel, and NAFLD groups. Serum testosterone levels significantly increased and reached the healthy control group in the bigel-Quer group. DNA fragmentation of sperm significantly decreased in the bigel-Quer group (p < 0.05). The bigel showed synergistic effects with Quer for treating infertility in rats with NAFLD.

Functionalized graphene oxide/Fe3O4 nanocomposite: A biocompatible and robust nanocarrier for targeted delivery and release of anticancer agents.

The development of efficient drug nanocarriers has remained an important challenge in advanced drug delivery in human body. Combination of graphene-based nanomaterials and cyanuric chloride (CC), as a linker, may improve the success of drug delivery. Herein, a simple approach was used for the synthesis of superparamagnetic graphene oxide (SPMGO) nanocomposite through a chemical precipitation method. The nanocomposite was readily functionalized with cyanuric chloride as a linker for loading the drug. The FTIR spectroscopy confirmed the efficient synthesis of nanocarriers. So did the transmission electron microscopy, atomic force microscopy, and thermo-gravimetric analysis, X-ray diffraction and X-ray photoelectron spectroscopy. Subsequently, the synthesized nanocarriers were studied in terms of their potential for biomedical applications. Immobilization of methotrexate (MTX), as a drug for treatment of cancer was taken into action on the SPMGO and SPMGO/CC. The in vitro assays indicated that the drug nanocarrier systems, SPMGO/MTX and SPMGO/CC/MTX, are hemo-compatible and increase the efficiency of MTX against Caov-4, HeLa and MCF-7 cell lines. The MTX nanocarriers represented a considerably high drug loading and controlled drug release. The overall results indicated the great potential of SPMGO/CC/MTX nanocarrier for targeted drug delivery, particularly in MTX chemotherapy.

STAT3 Pathway in Gastric Cancer: Signaling, Therapeutic Targeting and Future Prospects.

Molecular signaling pathways play a significant role in the regulation of biological mechanisms, and their abnormal expression can provide the conditions for cancer development. The signal transducer and activator of transcription 3 (STAT3) is a key member of the STAT proteins and its oncogene role in cancer has been shown. STAT3 is able to promote the proliferation and invasion of cancer cells and induces chemoresistance. Different downstream targets of STAT3 have been identified in cancer and it has also been shown that microRNA (miR), long non-coding RNA (lncRNA) and other molecular pathways are able to function as upstream mediators of STAT3 in cancer. In the present review, we focus on the role and regulation of STAT3 in gastric cancer (GC). miRs and lncRNAs are considered as potential upstream mediators of STAT3 and they are able to affect STAT3 expression in exerting their oncogene or onco-suppressor role in GC cells. Anti-tumor compounds suppress the STAT3 signaling pathway to restrict the proliferation and malignant behavior of GC cells. Other molecular pathways, such as sirtuin, stathmin and so on, can act as upstream mediators of STAT3 in GC. Notably, the components of the tumor microenvironment that are capable of targeting STAT3 in GC, such as fibroblasts and macrophages, are discussed in this review. Finally, we demonstrate that STAT3 can target oncogene factors to enhance the proliferation and metastasis of GC cells.

MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy.

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

The Effect of Curcumin on TNF-α, IL-6 and CRP Expression in a Model of Polycystic Ovary Syndrome as an Inflammation State.

BACKGROUND: Having low-grade chronic inflammation such as elevated C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) plays a crucial role in polycystic ovary syndrome (PCOS). This study aimed at investigating the therapeutic effects of curcumin on IL-6, CRP and TNF-α and symptoms of polycystic ovary syndrome. METHODS: In this research, 72 female adult Wistar rats were divided into control (n=12), PCOS (n=12) and curcumin-treated PCOS groups (n=48). PCOS was induced by injection of estradiol valerate (2 mg/kg-one-step). PCOS rats were divided into control and experimental groups which received daily intraperitoneal injection of curcumin. After 60 days of syndrome induction, ovaries were collected for histological and immunohistochemical evaluations. Serum IL-6 and CRP was detected by the ELISA kit. Data were analyzed using In-Stat 3 via one-way analysis of variance (ANOVA) and p<0.05 was considered statistically significant. RESULTS: Histological studies showed a significant reduction in thickness of theca layer and increase in the number of corpus luteum (CL) diameter in the curcumin-treated group compared with the PCOS group; also inflammatory markers such as IL-6 and CRP significantly decreased in groups treated with curcumin compared with PCOS groups. Regarding immunohistochemical analysis, the expression of TNF-α in granulosa layer and follicular fluid of follicles and ovarian cysts in PCOS group was more than the control group's expression. However, expression of this factor in the ovaries treated with curcumin was decreased. CONCLUSION: This study showed that the anti-inflammatory and antioxidant effects of curcumin on PCOS may be due to its inhibitory effect on expression and levels of TNF-α, serum IL-6 and CRP.

Anti-Inflammatory Effects of Curcumin on Insulin Resistance Index, Levels of Interleukin-6, C-Reactive Protein, and Liver Histology in Polycystic Ovary Syndrome-Induced Rats.

OBJECTIVES: Curcumin protects the liver against injury and fibrosis through suppressing hepatic inflammation, attenuating hepatic oxidative stress (OS), and inhibiting hepatic stellate cells (HSCs) activation. Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are considered as common metabolic disorders. Low-grade chronic inflammation with different markers, such as elevated C-reactive protein (CRP) and interleukin-6 (IL-6) levels, play a crucial role in PCOS. This study aimed to evaluate the therapeutic effects of curcumin on IL-6 and CRP levels as well as insulin resistance (IR) index on liver function in PCOS rats. MATERIALS AND METHODS: In this experimental study, 90 adult Wistar rats were divided into control (n=18), sham (n=18), PCOS (n=18) and curcumin-treated PCOS groups (n=36). PCOS group was injected subcutaneously with 2 mg estradio-valerate (E2V). After 60 days, PCOS group was treated with curcumin [100 and 300 mg/kg body weight (BW)] for 14 days and anesthetized by chloroform. Blood and liver samples were collected for histological and serological analyses. Data were analyzed using In-Stat 3 via one-way analysis of variance (ANOVA). RESULTS: Histological and serological analyses showed a reduction in number of necrotic cells, IR index, as well as IL-6 and CRP levels in PCOS rats that were treated with various concentrations of curcumin. CONCLUSIONS: In this study, curcumin decreased liver inflammation by induction of insulin sensitivity and reduction of hepatic necrosis. Therefore, curcumin may be considered as protective factor against inflammatory state of PCOS.

Synthesis, Biological Evaluation, and Molecular Docking Studies on the DNA Binding Interactions of Platinum(II) Rollover Complexes Containing Phosphorus Donor Ligands.

Cyclometalated rollover complexes of the type [PtMe(κ2 N,C-bipyO-H)(L)] [bipyO-H=cyclometalated 2,2'-bipyridine N-oxide; L=tricyclohexylphosphine (PCy3 , 2 a), 2-(diphenylphosphino)pyridine (PPh2 py, 2 b), P(OPh)3 (2 c)] were synthesized by treating [PtMe(κ2 N,C-bipyO-H)(SMe2 )] (1) with various monodentate phosphine and phosphite ligands. These complexes were characterized by NMR spectroscopy, and the structure of 2 a was confirmed by single-crystal X-ray diffraction. Complex 1 was treated with bis(diphenylphosphino)methane (dppm) at a 1:1 ratio to give the corresponding [PtMe(κ2 N,C-bipyO-H)(κ1 P-dppm)] (3 b) complex, in which the dppm ligand acts as a monodentate pendant ligand. The biological activities of these complexes were evaluated against a panel of four standard cancer cell lines: lung carcinoma (A549), ovarian carcinoma (OV-90 and SKOV3), and breast carcinoma (MCF-7). Complexes 2 c and especially 3 b indicated effective potent cytotoxic activity regarding the cell lines. Electrophoresis mobility shift assays and molecular-modeling investigations were performed to determine the specific binding mode and the binding orientation of these alkylating agents to DNA. Detection of cellular reactive oxygen species was also determined.

Testosterone and Voluntary Exercise, Alone or Together Increase Cardiac Activation of AKT and ERK1/2 in Diabetic Rats.

BACKGROUND: Impaired angiogenesis in cardiac tissue is a major complication of diabetes. Protein kinase B (AKT) and extracellular signal regulated kinase (ERK) signaling pathways play important role during capillary-like network formation in angiogenesis process. OBJECTIVES: To determine the effects of testosterone and voluntary exercise on levels of vascularity, phosphorylated Akt (P- AKT) and phosphorylated ERK (P-ERK) in heart tissue of diabetic and castrated diabetic rats. METHODS: Type I diabetes was induced by i.p injection of 50 mg/kg of streptozotocin in animals. After 42 days of treatment with testosterone (2mg/kg/day) or voluntary exercise alone or in combination, heart tissue samples were collected and used for histological evaluation and determination of P-AKT and P-ERK levels by ELISA method. RESULTS: Our results showed that either testosterone or exercise increased capillarity, P-AKT, and P-ERK levels in the heart of diabetic rats. Treatment of diabetic rats with testosterone and exercise had a synergistic effect on capillarity, P-AKT, and P-ERK levels in heart. Furthermore, in the castrated diabetes group, capillarity, P-AKT, and P-ERK levels significantly decreased in the heart, whereas either testosterone treatment or exercise training reversed these effects. Also, simultaneous treatment of castrated diabetic rats with testosterone and exercise had an additive effect on P-AKT and P-ERK levels. CONCLUSION: Our findings suggest that testosterone and exercise alone or together can increase angiogenesis in the heart of diabetic and castrated diabetic rats. The proangiogenesis effects of testosterone and exercise are associated with the enhanced activation of AKT and ERK1/2 in heart tissue.

Involvement of Glycogen Synthase Kinase-3ß and Oxidation Status in the Loss of Cardioprotection by Postconditioning in Chronic Diabetic Male Rats.

PURPOSE: Diabetes mellitus as a main risk-factor of ischemic heart disease may interfere with postconditioning'scardioprotective effects. This study aimed to investigate the involvement of glycogen synthase kinase-3ß (GSK-3ß) and oxidation status in chronic diabetes-induced loss of cardioprotective effect of ischemic-postconditioning (IPostC) in Wistar rats. METHODS: After 8 weeks of induction of diabetes by streptozotocin (50mg/kg), hearts of control and diabetic rats were isolated and mounted on a constant-pressure Langendorff system. All hearts were subjected to 30min regional ischemia followed by 60min reperfusion (by occluding and re-opening of left anterior descending coronary artery, respectively). IPostC was applied immediately at the onset of reperfusion. At the end of reperfusion, the infarct size of myocardium was measured via computerized planimetry. Myocardial contents of malondealdehyde and glutathione as indices of oxidative status were assayed spectrophotometrically and the total and phosphorylated forms of myocardial GSK-3ß were quantified through western blotting. RESULTS: IPostC reduced the infarct size of control hearts from 41±2.9% to 28±1.9% (P<0.05), whereas it could not induce significant changes in infarct size of diabetic animals (35±1.8% vs. 39±3.1%). IPostC-induced reduction in malondealdehyde and elevation in glutathione contents were significant only in control not in diabetic hearts. The total forms of GSK-3ß were similar in all groups; however, the phosphorylation of GSK-3ß (at Ser9) by IPostC was greater in control hearts than diabetics (P<0.01). CONCLUSION: The failure of cardioprotection by IPostC in diabetic hearts may be attributed to the loss of phosphorylation of GSK-3ß and thereby increase in oxidative stress in diabetic states.