A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats

Background

Metabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect.

Methods

A 28-week high-carbohydrate diet-induced MetS-rats received DAPA (5 mg/kg), INSU (0.15 mg/kg) or vehicle for 2 weeks. To validate MetS-induction, we monitored all animals weekly by measuring body weight, blood glucose and HOMO-IR index, electrocardiograms, heart rate, systolic and diastolic pressures.

Results

DAPA-treatment of MetS-rats significantly augmented the increased blood pressure, prolonged Q–R interval, and low heart rate with depressed left ventricular function and relaxation of the aorta. Prolonged-action potentials were preserved with DAPA-treatment, more prominently than INSU-treatment, at most, through the augmentation in depressed voltage-gated K⁺-channel currents. DAPA, more prominently than INSU-treatment, preserved the depolarized mitochondrial membrane potential, and altered mitochondrial protein levels such as Mfn-1, Mfn-2, and Fis-1 as well as provided significant augmentation in cytosolic Ca²⁺-homeostasis. Furthermore, DAPA also induced significant augmentation in voltage-gated Na⁺-currents and intracellular pH, and the cellular levels of increased oxidative stress, protein-thiol oxidation and ADP/ATP ratio in cardiomyocytes from MetS rats. Moreover, DAPA-treatment normalized the increases in the mRNA level of SGLT2 in MetS-rat heart.

Conclusions

Overall, our data provided a new insight into DAPA-associated cardioprotection in MetS rats, including suppression of prolonged ventricular-repolarization through augmentation of mitochondrial function and oxidative stress followed by improvement of fusion–fission proteins, out of its glucose-lowering effect.

     

Investigation of Heavy Metal Level and Mineral Nutrient Status in Widely Used Medicinal Plants’ Leaves in Turkey: Insights into Health Implications

The use of plants in treatments has been as old as humanity and it has preserved its popularity for centuries til now because of their availability, affordability and safeness. However, despite their widespread use, safety and quality issues have been major concerns in the world due to industrial- and anthropogenic-based heavy metal contamination risks. Thus, this study was attempted to analyze the heavy metal levels and mineral nutrient status of widely used medicinal plants in Turkey to have insights about their health implications on humans. The plant concentrations of B, Ca, Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb and Zn were analyzed by ICP-OES in the leaves of 44 medical plants purchased from herbal markets of three different districts of Istanbul/Turkey. The measured lowest to highest concentrations were 0.065–79.749 mg kg⁻¹ B, 921.802–12,854.410 mg kg⁻¹ Ca, 0.020–0.558 mg kg⁻¹ Cd, 0.015–4.978 mg kg⁻¹ Cr, 0.042–8.489 mg kg⁻¹ Cu, 34.356–858.446 mg kg⁻¹ Fe, 791.323–15,569.349 mg kg⁻¹ K, 102.236–2837.836 mg kg⁻¹ Mg, 4.915–91.519 mg kg⁻¹ Mn, 10.224–3213.703 mg kg⁻¹ Na, 0.001–5.589 mg kg⁻¹ Ni, 0.003–3.636 mg kg⁻¹ Pb and 2.601–36.102 mg kg⁻¹ Zn. Those levels in plants were in acceptable limits though some elements in some plants have high limits which were not harmful. Variations (above acceptable limits) in element concentrations also indicated that these plants could be contaminated with other metals and that genetic variations may influence accumulation of these elements at different contents. Overall, analyzed medicinal plants are expected not to pose any serious threat to human health.

     

Improving the Extent of Malignant Glioma Resection by Dual Intraoperative Visualization Approach

Despite continuing debates around cytoreductive surgery in malignant gliomas, there is broad consensus that increased extent of tumor reduction improves overall survival. However, maximization of the extent of tumor resection is hampered by difficulty in intraoperative discrimination between normal and pathological tissue. In this context, two established methods for tumor visualization, fluorescence guided surgery with 5-ALA and intraoperative MRI (iMRI) with integrated functional neuronavigation were investigated as a dual intraoperative visualization (DIV) approach. Thirty seven patients presumably suffering from malignant gliomas (WHO grade III or IV) according to radiological appearance were included. Twenty-one experimental sequences showing complete resection according to the 5-ALA technique were confirmed by iMRI. Fourteen sequences showing complete resection according to the 5-ALA technique could not be confirmed by iMRI, which detected residual tumor. Further analysis revealed that these sequences could be classified as functional grade II tumors (adjacent to eloquent brain areas). The combination of fluorescence guided resection and intraoperative evaluation by high field MRI significantly increased the extent of tumor resection in this subgroup of malignant gliomas located adjacent to eloquent areas from 61.7% to 100%; 5-ALA alone proved to be insufficient in attaining gross total resection without the danger of incurring postoperative neurological deterioration. Furthermore, in the case of functional grade III gliomas, iMRI in combination with functional neuronavigation was significantly superior to the 5-ALA resection technique. The extent of resection could be increased from 57.1% to 71.2% without incurring postoperative neurological deficits.     

The relation between the effect of a subhypnotic dose of thiopental on claw pain threshold in rats and adrenalin,noradrenalin and dopamine levels

Thiopental sodium (TPS) needs to be applied together with adrenalin in order to establish its analgesic effect in general anesthesia. We aimed to investigate the effect of TPS on the claw pain threshold in rats and evaluated its relationship with endogenous adrenalin (ADR), noradrenalin (NDR), and dopamine (DOP) levels. Intact and adrenalectomized rats were used in the experiment. Intact animals were divided into the following groups: 15 mg/kg TPS (TS), 0.3 mg/kg ADR+15 mg/kg TPS (ATS) and 0.3 mg/kg ADR alone (ADR). Adrenalectomized animals were divided into the following groups: 15 mg/kg TPS (A-TS), 0.3 mg/kg ADR+15 mg/kg TPS (A-ATS) and 0.3 mg/kg ADR alone (A-ADR). Claw pain threshold and blood ADR, NDR, and DOP levels were measured. The TS group’s claw pain threshold was found low. However, the claw pain thresholds of the ATS and ADR groups increased significantly. In the A-TS group, the pain threshold decreased compared with normal, and in the A-ATS and A-ADR groups, the pain threshold increased. TPS reduced the blood ADR levels in intact rats; however, no significant changes were observed in the NDR and DOP levels. #TPS provides hyperalgesia by reducing the production of ADR in rats. The present study shows that to achieve analgesic activity, TPS needs to be applied together with ADR.     

Surgical outcomes of the brachial plexus lesions caused by gunshot wounds in adults

Background

The management of brachial plexus injuries due to gunshot wounds is a surgical challenge. Better surgical strategies based on clinical and electrophysiological patterns are needed. The aim of this study is to clarify the factors which may influence the surgical technique and outcome of the brachial plexus lesions caused by gunshot injuries.

Methods

Two hundred and sixty five patients who had brachial plexus lesions caused by gunshot injuries were included in this study. All of them were male with a mean age of 22 years. Twenty-three patients were improved with conservative treatment while the others underwent surgical treatment. The patients were classified and managed according to the locations, clinical and electrophysiological findings, and coexisting lesions.

Results

The wounding agent was shrapnel in 106 patients and bullet in 159 patients. Surgical procedures were performed from 6 weeks to 10 months after the injury. The majority of the lesions were repaired within 4 months were improved successfully. Good results were obtained in upper trunk and lateral cord lesions. The outcome was satisfactory if the nerve was intact and only compressed by fibrosis or the nerve was in-contunuity with neuroma or fibrosis.

Conclusion

Appropriate surgical techniques help the recovery from the lesions, especially in patients with complete functional loss. Intraoperative nerve status and the type of surgery significantly affect the final clinical outcome of the patients.     

The Modified Sequential Treatment Regimen Containing Levofloxacin for Helicobacter pylori Eradication in Turkey

Background:  Eradication rates of Helicobacter pylori have declined to unacceptable levels in recent years. New and effective treatment options are warranted both as a first and second line treatment.
Aim:  To test an effectiveness of modified sequential therapy with levofloxacin for H. pylori eradication in Turkey.
Material and Methods:  Helicobacter pylori infected dyspeptic patients were included to the study. Subjects were treated with modified sequential therapy consisting of rabeprazole 20 mg b.i.d. and amoxicillin 1 g b.i.d., for 7 days followed by rabeprazole 20 mg b.i.d, levofloxacin 500 mg q.d. and metronidazole 500 mg b.i.d for the remaining 7 days.
Results:  Sixty-three treatment naive patients and 37 previous treatment failures were enrolled to the study (59 F, 41 M, age: 21–80 years). There was five drop out. Helicobacter pylori eradication was achieved in 80 patients, intention-to-treat (ITT): 80% (95% CI: 71–87%) and per-protocol (PP): 84.2% (95% CI: 75–91%), totally. In treatment naive patients ITT and PP eradication rates were 82.5% (95% CI: 71–91%), and 86.7% (95% CI: 75–94%), respectively. As a second line treatment eradication was successful in ITT 75.7%.(95% CI: 59–88%), and PP 80% (95% CI: 63–92%).Mild side effects were reported by 8 patients (8.4%).
Conclusions:  Sequential therapy using "rabeprazole and amoxicillin 7 days followed by rabeprazole, metronidazole and levofloxacin for 7 days" is a new regimen with acceptable eradication rates in naïve patients in Turkey. Further modifications in the dose or duration of this new sequential therapy might increase its effectiveness as both first and second line treatment.     

Effects of garlic extract consumption on plasma and erythrocyte antioxidant parameters in atherosclerotic patients

Effects of ingesting garlic extract on plasma and erythrocyte antioxidant parameters of atherosclerotic patients were investigated in this study. Eleven patients with atherosclerosis participated in the study. They ingested a dose of 1 ml/kg body weight of garlic extract daily for 6 months (study period). Before and after this period, fasting blood samples were obtained, and oxidant (malondialdehyde, MDA and xanthine oxidase, XO) and antioxidant (superoxide dismutase, SOD and glutathione peroxidase, GSH-Px) parameters were studied in plasma and erythrocytes obtained from the patients. Blood samples obtained from 11 healthy subjects served as the controls. Plasma XO activity and MDA levels were higher, but plasma and erythrocyte GSH-Px activities were lower, in patients with atherosclerosis relative to those of the control group. Our results showed that ingestion of garlic extract leads to significantly lowered plasma and erythrocyte MDA levels in the patients even in the absence of changes in antioxidant enzyme activities. Our results also demonstrated the presence of oxidant stress in blood samples from patients with atherosclerosis, but ingesting garlic extract prevented oxidation reactions by eliminating this oxidant stress. Thus, it is possible that reduced peroxidation processes may play a part in some of the beneficial effects of garlic in atherosclerotic diseases.     

Antioxidant potential of cancerous human kidney tissues

Antioxidant potentials (AOP) of cancerous and noncancerous adjacent human kidney tissues from 12 patients were measured. AOP of the cancerous tissues was found to be significantly lower than that of noncancerous ones. However, tissue malondialdehyde (MDA) levels were significantly higher in the cancerous tissues compared with noncancerous ones. In the intra-correlation analysis, carried out between AOP and MDA levels, significant correlation was found in the cancerous tissues (r = 0.9) but no correlation observed in the noncancerous ones. In the inter-correlation analysis, negative correlation was found between AOP's of cancerous and noncancerous tissues (r = -0.49) and positive correlation between MDA levels (r = 0.51). Results suggest that antioxidant potential of cancerous kidney tissues is significantly reduced compared with noncancerous ones. Therefore, they expose to high oxidant stress and free radical-induced peroxidative attacks, the results of which are cellular deformations.