SGLT2 inhibitors and AMPK: The road to cellular housekeeping?

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, known as Gliflozins, are a class of Glucose-lowering drugs in adults with type 2 diabetes (T2D) that induce glucosuria by blocking SGLT2 co-transporters in the proximal tubules. Several lines of evidence suggest that SGLT2 inhibitors regulate multiple mechanisms associated with the regulation of varying cellular pathways. The 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway plays an important role in metabolic homeostasis by influencing cellular processes. Recently, it has been shown that SGLT2 inhibitors can affect the AMPK pathway in differing physiological and pathological ways, resulting in kidney, intestinal, cardiovascular, and liver protective effects. Additionally, they have therapeutic effects on nonalcoholic fatty liver disease and diabetes mellitus-associated complications. In this review, we summarize the results of studies of AMPK-associated therapeutic effects of SGLT2 inhibitors in different organelle functions.

Curcumin and targeting of molecular and metabolic pathways in multiple sclerosis.

Multiple sclerosis (MS) is a life-threading disease that poses a great threat to the human being lifestyle. Having said extensive research in the realm of underlying mechanisms and treatment procedures, no definite remedy has been found. Over the past decades, many medicines have been disclosed to alleviate the symptoms and marking of MS. Meanwhile, the substantial efficacy of herbal medicines including curcumin must be underscored. Accumulated documents demonstrated the fundamental role of curcumin in the induction of the various signaling pathways. According to evidence, curcumin can play a role in mitochondrial dysfunction and apoptosis, autophagy, and mitophagy. Also, by targeting the signaling pathways AMPK, PGC-1α/PPARγ, and PI3K/Akt/mTOR, curcumin interferes with the metabolism of MS. The anti-inflammatory, antioxidant, and immune regulatory effects of this herbal compound are involved in its effectiveness against MS. Thus, the present review indicates the molecular and metabolic pathways associated with curcumin's various pharmacological actions on MS, as well as setting into context the many investigations that have noted curcumin-mediated regulatory effects in MS.

Investigation of Factors Affecting COVID-19 and Sixth Wave Management Using a System Dynamics Approach.

The COVID-19 pandemic has plunged the world into a health and economic crisis never seen before since the Spanish flu pandemic in 1918. The closure of schools and universities, the banning of rallies, and other social distancing in countries have been done to disrupt the transmission of the virus. Governments have planned to reduce restrictions on corona management by implementing vaccination programs. This research aims to better understand the Coronavirus disease's behavior, identify the prevalent factors, and adopt effective policies to control the pandemic. This study examines the different scenarios of releasing the constraints and returning to normal conditions before Corona to analyze the results of different scenarios to prevent the occurrence of subsequent peaks. The system dynamics approach is an effective means of studying COVID-19's behavioral characteristics. The factors that affect Coronavirus disease outbreak and control by expanding the basic SEIR model, interventions, and policies, such as vaccination, were investigated in this research. Based on the obtained results, the most critical factor in reducing the prevalence of the disease is reducing the behavioral risks of people and increasing the vaccination process. Observance of hygienic principles leads to disruption of the transmission chain, and vaccination increases the immunity of individuals against the acute type of infection. In addition, the closure of businesses and educational centers, along with government support for incomes, effectively controls and reduces the pandemic, which requires cooperation between the people and the government. In a situation where a new type of corona has spread, if the implementation of the policy of reducing restrictions and reopening schools and universities is done without planning, it will cause a lot of people to suffer.

Dapagliflozin attenuates high glucose-induced endothelial cell apoptosis and inflammation through AMPK/SIRT1 activation.

Hyperglycaemia is a major cause of pathophysiological processes such as oxidative stress, inflammation, and apoptosis in diabetes. Dapagliflozin (DAPA), a novel hypoglycaemic drug, has been shown to have anti-apoptotic, anti-inflammatory, and antioxidant effects in multiple experimental studies. In this study, we investigated the protective effects of DAPA in the hyperglycaemic condition to identify associated molecular mechanisms. human umbilical vein endothelial cells (HUVEC) endothelial cells were treated with 40 mM glucose for 72 h to establish an in vitro high glucose (HG) condition model, and then additional groups co-treated with or without DAPA before glucose treatment. Then, cell viability, reactive oxygen species (ROS), pro-inflammatory cytokines (IL-6 and TNF-α), apoptosis, and SIRT1 expression were measured. The results showed that DAPA pretreatment resulted in increased cell viability. Additionally, DAPA pretreatment decreased endothelial ROS, IL-6, and TNF-α levels in endothelial cells subjected to HG conditions. Moreover, DAPA pretreatment significantly prevented HG-induced apoptosis and caspase-3 activity in HUVECs. Furthermore, DAPA increased the expression of SIRT1, PGC-1α, and increased the phosphorylation levels of AMPK (p-AMPK) in a set of HG conditions in HUVECs. However, the endothelial protective effects of DAPA were abolished when cells were subjected to the SIRT1 inhibitor (EX-527) and AMPK inhibitor (Compound C). These findings suggest that DAPA can abrogate HG-induced endothelial cell dysfunction by AMPK/SIRT1 pathway up-regulation. Therefore, suggesting that the activation of AMPK/SIRT1 axis by DAPA may be a novel target for the treatment of HG-induced endothelial cell injury.

Dapagliflozin Protects H9c2 Cells Against Injury Induced by Lipopolysaccharide via Suppression of CX3CL1/CX3CR1 Axis and NF-κB Activity.

BACKGROUND: Dapagliflozin, a selective Sodium-glucose cotransporter-2 (SGLT2) inhibitor, has been shown to play a key role in the control and management of metabolic and cardiac diseases. OBJECTIVE: The current study aims to address the effects of dapagliflozin on the expression of fractalkine (FKN), known as CX3CL1, and its receptors CX3CR1, Nuclear factor-kappa B(NF-κB) p65 activity, Reactive oxygen species (ROS), and inflammation in LPS-treated H9c2 cell line. METHODS: H9c2 cells were cultured with lipopolysaccharide (LPS) to establish a model of LPS-induced damage, and then, subsequently were treated with dapagliflozin for 72 h. Our work included measurement of cell viability (MTT), Malondialdehyde (MDA), intracellular ROS, tumor necrosis factor-α (TNF-α), NF-κB activity, and expression of CX3CL1/CX3CR1. RESULTS: The results showed that LPS-induced reduction of cell viability was successfully rescued by dapagliflozin treatment. The cellular levels of MDA, ROS, and TNF-α, as an indication of cellular oxidative stress and inflammation, were significantly elevated in H9c2 cells compared to the control group. Furthermore, dapagliflozin ameliorated inflammation and oxidative stress through the modulation of the levels of MDA, TNF-α, and ROS. Correspondingly, dapagliflozin reduced the expression of CX3CL1/CX3CR1, NF-κB p65 DNA binding activity, and it also attenuated nuclear acetylated NF-κB p65 in LPS-induced injury in H9c2 cells compared to untreated cells. CONCLUSION: These findings shed light on the novel pharmacological potential of dapagliflozin in the alleviation of LPS-induced CX3CL1/CX3CR1-mediated injury in inflammatory conditions such as sepsis-induced cardiomyopathy.

The serum levels of testosterone in coronary artery disease patients; relation to NO, eNOS, endothelin-1, and disease severity.

OBJECTIVES: The changes in testosterone level and its correlation with the endothelial nitric oxide systems balance in patients with coronary artery disease (CAD) remains uncertain. Therefore, in our study, we aimed to evaluate the levels of testosterone, endothelin-1 (ET-1), nitric oxide (NO), and endothelial NOS (eNOS) in CAD patients, and control group to find the relationship between these parameters and disease severity. METHODS: Forty-four patients as CAD group with significant (≥50%) stenosis confirmed by angiography was included in the study, and 40 healthy men were included as the control group. According to the number of vessels obstruction, CAD severity was determined. The serum indicated parameters were assessed to discriminate between patients and controls. RESULTS: It was found that testosterone levels in the CDA group were significantly lower than those of the control group (p<0.05). In addition, the level of ET-1 in the CAD group was higher than that in the control group, but levels of NO and eNOS in observation were significantly lower than those in the control group (p<0.05). The correlation analysis revealed that testosterone was passivity correlated with serum NO levels (r=0.550, p=0.001). CONCLUSIONS: The current study reports that serum levels of testosterone are closely related to endothelial NO levels and might be of relevance to the pathogenesis of endothelial dysfunction and disease severity in CAD patients.

Amnion membrane proteins attenuate LPS-induced inflammation and apoptosis by inhibiting TLR4/NF-κB pathway and repressing MicroRNA-155 in rat H9c2 cells.

OBJECTIVE: Amnion membrane (AM) has been popular for the treatment of inflammatory disorders due to its cell repairing properties. This current study aims to find the underlying mechanisms of amnion membrane proteins (AMPs) against the pro-inflammatory miRNA, miR-155, miR-146, and anti-apoptotic microRNA, miR-21, in LPS-treated H9c2 cells. METHODS: Cell viability and apoptosis were determined by MTT assay and annexin V/PI staining. The production of the cytokines, TNF-α and IL-6 were evaluated by using qPCR and Enzyme-linked immunosorbent assay (ELISA), respectively. In addition, the expression of miRNAs was quantified by qPCR, and also the protein level of TLR4 and NF-kß was determined with western blotting. RESULTS: We found that AMPs ameliorated LPS-induced reduction of cell viability and augment apoptosis in H9c2 cells. AMPs efficiently inhibited cytokine expression (IL-6 and TNF-α) and activity of TLR4/NF-κB pathway in LPS-treated H9c2 cells. Correspondingly, in parallel with the suppression of pro-inflammatory cytokines and apoptosis, AMPs mitigated pro-inflammatory miRNA, miR-155 expression, while, the expression of miR-155 was found to be increased in LPS-treated H9c2 cells. Also, AMPs activated miR-146 expression in H9c2 cells under LPS treatment. Additionally, the elevated expression of miR-21 provoked by LPS was further enhanced by AMPs. CONCLUSIONS: In conclusion, AMPs could alleviate LPS-induced cardiomyocytes cells injury via up-regulation of miR-21, miR-146, and suppression of TLR4/NF-κB pathway, which plays a key role in the down-regulation of LPS-mediated miR-155 and inflammatory cytokine expression.

Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis.

The occurrence of neurodegenerative disease is increasingly raised. From physiopathological aspect, the emergence of auto-reactive antibodies against the nervous system antigens contributes to de-myelination in Multiple sclerosis (MS). These features cause the nervous system dysfunction. The follow-up of molecular alterations could give us a real-state vision about intracellular status during pathological circumstances. In this review, we focus on the autophagic response during MS progression and further understand the relationship between autophagy and MS and its modulatory effect on the MS evolution. The authors reviewed studies published on the autophagy status in neurodegenerative disease and on the autophagy modulation in MS prognosis, diagnosis, and possible therapies. The inevitable role of autophagy was shown in the early-stage progression of MS. Due to critical role of autophagy in different stage of cell activity in nervous system, the distinct role of autophagy should not be neglected in the development, pathogenesis, and treatment of MS.

Human Amnion Membrane Proteins Prevent Doxorubicin-Induced Oxidative Stress Injury and Apoptosis in Rat H9c2 Cardiomyocytes.

Doxorubicin (DOX) is widely used as an effective chemotherapy agent in cancer treatment. Cardiac toxicity in cancer treatment with DOX demand urgent attention and no effective treatment has been established for DOX-induced cardiomyopathy. It has been well documented that human amniotic membrane proteins (AMPs), extracted from amnion membrane (AM), have antioxidant, anti-apoptotic, and cytoprotective properties. Therefore, in this study, we aimed to investigate the protective effects of AMPs against cardiotoxicity induced by DOX in cultured rat cardiomyocyte cells (H9c2). DOX-induced cell injury was evaluated using multi-parametric assay including thiazolyl blue tetrazolium bromide (MTT), the release of lactic dehydrogenase (LDH), intracellular Ca2+ , reactive oxygen species (ROS) levels, cellular antioxidant status, mitochondrial membrane potential (ΔΨm), malondialdehyde (MDA), and NF-κB p65 DNA-binding activity. Moreover, expression profiling of apoptosis-related genes (P53, Bcl-2, and Bax) and Annexin V by flow cytometry were used for cell apoptosis detection. It was shown that AMPs pretreatment inhibited the cell toxicity induced by DOX. AMPs effectively attenuated the increased levels of LDH, Ca2+ , ROS, and MDA and also simultaneously elevated the ΔΨm and antioxidant status such as superoxide dismutase (SOD) and Catalase (CAT) in pretreated H9c2 cardiomyocytes. Besides, the activity of NF-kB p65 was reduced and the p53 and Bax protein levels were inhibited in these myocardial cells subjected to DOX. These findings provide the first evidence that AMPs potently suppressed DOX-induced toxicity in cardiomyocytes through inhibition of oxidative stress and apoptosis. Thus, AMPs can be a potential therapeutic agent against DOX cardiotoxicity.

Curcumin ameliorated myocardial infarction by inhibition of cardiotoxicity in the rat model.

Cardiovascular diseases are the main cause of death globally. Many attempts have been done to ameliorate the pathological changes after the occurrence of myocardial infarction. Curcumin is touted as a polyphenol phytocompound with appropriate cardioprotective properties. In this study, the therapeutic effect of curcumin was investigated on acute myocardial infarction in the model of rats. Rats were classified into four groups; control, isoproterenol hydrochloride (ISO) (100 mg/kbw), curcumin (50 mg/kbw), and curcumin plus ISO treatment groups. After 9-day administration of curcumin, levels of lactate dehydrogenase (LDH), creatine kinase (CK), and cardiac troponin I (cTnI) were determined. Superoxide dismutase (SOD) and malondialdehyde (MDA) contents were measured to investigate the oxidative status in infarct rats received curcumin. By using H & E staining, tissue inflammation was performed. Masson's trichrome staining was conducted to show cardiac remodeling and collagen deposition. The number of apoptotic cells was determined by using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Data showed the serum decrease of LDH, CK, and cTnI in infarct rats after curcumin intake compared to the rats given (ISO) ( P < 0.05). Curcumin was found to reduce oxidative status by reducing SOD and MDA contents ( P < 0.05). Gross and microscopic examinations revealed that the decrease of infarct area, inflammation response and collagen deposition in rats given ISO plus curcumin ( P < 0.05). We noted the superior effect of curcumin to reduce the number of apoptotic cardiomyocytes after 9 days. Data point the cardioprotective effect of curcumin to diminish the complication of infarction by the reduction of cell necrosis and apoptosis in a rat model of experimental infarction.

Nrf2 activation and down-regulation of HMGB1 and MyD88 expression by amnion membrane extracts in response to the hypoxia-induced injury in cardiac H9c2 cells.

BACKGROUND: human Amniotic Membrane (hAM) extracts contain bioactive molecules such as growth factors and cytokines. Studies have confirmed the ability of hAM in reduction of post-operative dysfunction in patients with cardiac surgery. However, the function of Amniotic Membrane Proteins (AMPs), extracted from hAM, against hypoxia-induced H9c2 cells injury have never been investigated. In this study, we aimed to appraise the protective impact of AMPs on H9c2 cells under hypoxia condition. METHODS: Cardiomyocyte cells were pre-incubated with AMPs and subjected to 24 h hypoxia to elucidate its effects on expression of Nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1). Furthermore, the high mobility group box-1 (HMGB1) and Myeloid differentiation primary response 88 (MyD88) expressions were detected by qPCR and western-blotting. The mitochondrial membrane potential (ΔΨm) was estimated by JC-1 using fluorescent microscopy and fluorimetry. Moreover, the cell apoptosis and intracellular calcium levels were measured by flow cytometry. RESULTS: Pre-treatment of AMPs resulted in significant induction in cell viability and decreased the LDH release under hypoxic condition in H9c2 cells. Accordingly, these protective effects of AMPs were associated with a reduction in apoptosis rates and intracellular Ca2+, meanwhile, ΔΨm was increased. Pre-treatment with AMPs resulted in degradation of HMGB1 and MyD88 levels and depicted pro-survival efficacy of AMPs against hypoxia-induced cell damage through induction of HO-1 and Nrf2. CONCLUSION: The data indicated that AMPs mediated HO-1 regulation by Nrf2 activation and plays critical protective effects in hypoxia-induced H9c2 injury in vitro by the inhibition of myocardial HMGB1 and MyD88 inflammatory cascade.

Bovine lactoferrin ameliorates antioxidant esterase activity and 8-isoprostane levels in high-cholesterol-diet fed rats.

The main aim of the present study was to show the effect of bovineLactoferrin (bLF), an 80 kD iron-binding glycoprotein, its application on antioxidant esterase activities and 8-isoprostane changes in high-cholesterol-diet fed (HCD-Fed) rats. The 44 adult Sprague-Dawley male rats were randomly assigned into four experimental groups. They were randomly assigned into four equivalent groups (n = 11). The groups included the control group which was fed with normal diet, bLF group, the third group which were made hypercholesterolemia by being fed with high cholesterol diet, and the last group which consisted of hypercholesterolemia rats treated with bLF (HCD + bLF) for 4 weeks (200 mg.kg-1 per day wt. dissolved in 0.9% normal saline).After 4 weeks, the serum Paraoxonase1 (PON1), Arylesterase (ARE) activity and 8-isoprostane with lipid profile were measured. Upon treatment with the bLF, the decrease in LDL-Cholesterol (LDL-C), Glucoses, Triglyceride (TG) and Total-Cholesterol (TC) levels and an increase in HDL-Cholesterol (HDL-C) level were observed. The co-administration of bLf for 4 weeks had decreased the 8-isoprostane levels significantly (P < 0.001) (86.36 ± 7.1 vs 117.18 ± 8.62) when compared to hypercholesterolemia-induced rats. Also, the Atherogenic Index (AI) in HCD + bLF group showed a significant decrease as compared to the HCD group (P < 0.001) (0.37 ± 0.07 vs 0.57 ± 0.09). The results indicated that bLF was effective against oxidative stress by its ability to increase PON1 activity and reduce the lipid peroxidation in high-cholesterol-fed rats.

Prevalence and risk factors of postoperative delirium in patients undergoing open heart surgery in northwest of iran.

INTRODUCTION: Delirium as a relatively common complication following cardiac surgery remains a contributory factor in postoperative mortality and an obstacle to early discharge of patients. METHODS: In the present study 329 patients who underwent open heart surgery between 1st January 2008 to 1st January 2009 in Shahid Madani Heart Center, Tabriz, Iran were enrolled. RESULTS: Overall 4.9% of patients developed delirium after cardiac surgery. We found atrial fibrillation (P = 0.005), lung diseases (P = 0.04) and hypertension (P = 0.02) to be more common in patients who develop delirium postoperatively. Furthermore, the length of intensive care unit (ICU) stay, cardiopulmonary bypass (CPB) time, and ventilation period were also significantly increased. Also a statistically meaningful relationship between the female gender and development of delirium was also noted (P = 0.02). On the other hand no meaningful relationship was detected between diabetes, history of cerebral vascular diseases, peripheral vascular diseases, myocardial infarction, development of pneumonia following surgery, and laboratory levels of sodium, potassium, glucose, and complete blood cell count (CBC) including white blood cells, red blood cells, platelets in the blood-hemoglobin and hematocrits. Also environmental factors like presence of other patients or companion with the patient, and objects like clock, window and calendar in the patient's room did not affect prevention of delirium. CONCLUSION: Based on this and other investigations, it can be suggested to use MMPI test to recognize pathologic elements to prevented delirium after surgery and complementary treatment for coping with delirium.

Patient's Perception of Stressors Associated with Coronary Artery Bypass Surgery.

INTRODUCTION: Cardiac surgery, due to being associated with stressors, has many physiological, psychological, emotional, growths, and spiritual potential consequences. However, few studies have been conducted about identifying the stressors. Therefore, the objective of the study was to determine patients' perceptions of stressors associated with coronary artery bypass surgery. METHODS: In this descriptive study during the two-month investigation, qualified patients for participation in the study (68 persons) undergoing coronary artery bypass graft surgery on the third to fifth postoperative day were selected and with using of Revised Cardiac Surgery Stressors Scale (RCSSS), interpersonal, intrapersonal, and extra personal stressors were determined. RESULTS: The findings showed that intrapersonal stressors are perceived more than interpersonal and extra personal stressors by patients. In the analysis of data, the highest stressors were "pain and discomfort", "the need to have heart surgery", "death due to illness or surgery", "being away from home and work", "having chest tube". CONCLUSION: In this study the intrapersonal stressors were perceived more than interpersonal and extra personal stressors by patients, which nurses should put emphasis on identification and elimination of intrapersonal stressors based on the needs of patients.

Depression in coronary artery disease.

INTRODUCTION: Depression is one of the Common psychological disorders. From the cognitive point of view, the unhealthy attitudes increase the severity of the depression. The aim of this study was to investigate depression and unhealthy attitudes in coronary patients hospitalized at Tabriz Shahid Madani Heart Center. METHODS: One hundred twenty eight hospitalized patients having myocardial Infarctions were studied regarding unhealthy attitudes, severity of depression and demographic data. RESULTS: The study showed a significant relation between unhealthy attitudes, BDI (Beck Depression Inventory) and severe depression. Moreover, a significant relation existed between gender and depression (P=0.0001). In addition, the level of education increased the intensity of unhealthy attitudes (P=0.0001). Several researches in both outside and inside Iran support the idea. CONCLUSION: Based on present study and more other investigations, it can be suggested to provide the necessary elements and parameters such as antidepressant medication, psychologists, complementary treatment for coping with negative mood and its unwanted consequences.

Seroprevalence of cytomegalovirus in patients with and without coronary artery diseases at Madani Heart Center, Iran.

Inflammation plays a major role in coronary artery disease (CAD). Currently, it is unclear, whether Cytomegalovirus (CMV) infection is associated with the risk of the atherosclerosis. The aim of this study was to determine the prevalence of anti- CMV antibodies in CAD and non CAD patients undergoing artery bypass surgery. Sera from 157 patients who underwent coronary angiography were tested for CMV by enzyme linked immunosorbent assay (ELISA) at Madani Heart Hospital, Tabriz University of Medical Sciences, Iran. Our study population was 58.6% male and 41.4% female, with an age range of 38 to 86 years. The prevalence of CMV positivity tended to be higher in coronary artery diseases patients than in those without non coronary artery diseases (83.2% versus 63.6%) (P= 0.01). This analysis demonstrated that CMV seropositivity may be a risk factor for CAD in the present study population.