SGLT-2 inhibitors in nephrotic-range proteinuria: emerging clinical evidence.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of novel oral anti-hyperglycemic agents which are increasingly used in clinical practice. SGLT-2 inhibitors improve glycemic control and cardiorenal outcomes, promote weight loss, and reduce blood pressure. Randomized controlled trials have demonstrated that SGLT-2 inhibitors reduce proteinuria and delay progression of kidney disease in patients with albuminuria. However, whether SGLT-2 inhibitors have similar benefits in patients with nephrotic-range proteinuria has not been well established. Evidence to date has been limited to case reports, case series and secondary analyses of randomized controlled trials. This is the first comprehensive review on the effectiveness of SGLT-2 inhibitors for the treatment of patients with nephrotic-range albuminuria or proteinuria. Overall findings support a likely beneficial role of SGLT-2 inhibitors in reducing proteinuria and delaying chronic kidney disease progression in patients with nephrotic-range proteinuria.

The cytotoxic concentration of rosmarinic acid increases MG132-induced cytotoxicity, proteasome inhibition, autophagy, cellular stresses, and apoptosis in HepG2 cells.

Rosmarinic acid (RA) is a natural polyphenolic compound derived from many common herbal plants. Although it is known that RA has many important biological activities, its effect on proteasome inhibitor-induced changes in cancer treatment or its effects on any experimental proteasome inhibition model is unknown. The aim of the study was to investigate the effect of RA on MG132-induced cytotoxicity, proteasome inhibition, autophagy, cellular stresses, and apoptosis in HepG2 cells. HepG2 cells were treated with 10, 100, and 1000 µM RA in the presence of MG132 for 24 h; 10 and 100 µM RA did not affect but 1000 µM RA decreased cell viability in HepG2 cells. MG132 caused a significant decrease in cell viability and phosphorylation of mammalian target of rapamycin and a significant increase in levels of polyubiquitinated protein, microtubule-associated proteins 1A/1B light chain 3B-II (LC3B-II), heat shock protein 70 (HSP70), binding immunoglobulin protein (BiP), activating transcription factor 4 (ATF4), protein carbonyl, and cleaved poly(adenosine diphosphate-ribose) polymerase 1 (PARP1); 10 and 100 µM RA did not significantly change these effects of MG132 in HepG2 cells; 1000 µM RA caused a significant decrease in cell viability and a significant increase in polyubiquitinated protein, LC3B-II, HSP70, BiP, ATF4, protein carbonyl, and cleaved PARP1 levels in MG132-treated cells. Our study showed that only 1000 µM RA increased MG132-induced cytotoxicity, proteasome inhibition, autophagy, cellular stresses, and apoptosis in HepG2 cells. According to our results, cytotoxic concentration of RA can potentiate the effects of MG132 in hepatocellular carcinoma treatment.

Effect of Lipoic Acid on Serum Paraoxonase-1 and Paraoxonase-3 Protein Levels and Activities in Diabetic Rats.

The aim of the present study was to investigate the effect of streptozotocin-induced diabetes mellitus and lipoic acid treatment on serum paraoxonase-1 and paraoxonase-3 protein levels and paraoxonase, arylesterase and lactonase activities.36 rats were equally and randomly divided into 4 groups as control, lipoic acid, diabetes and diabetes+lipoic acid. To induce diabetes, a single dose of streptozotocin (40 mg/kg) was injected intraperitoneally to diabetes and diabetes+lipoic acid groups. Lipoic acid (10 mg/kg/day) was injected intraperitoneally for 14 days to lipoic acid and diabetes+lipoic acid groups. Serum PON1 and PON3 protein levels were measured by western blotting. Serum paraoxonase, arylesterase and lactonase activities were determined by the measuring initial rate of substrate (paraoxon, phenylacetate and dihydrocoumarin) hydrolysis.Streptozotocin-induced diabetes mellitus caused a significant decrease whereas lipoic acid treatment caused a significant increase in serum PON1 and PON3 protein levels and paraoxonase, arylesterase and lactonase activities. The increase percent of serum PON3 protein was higher than that of serum PON1 protein and the increase percent of serum lactonase activity was higher than that of serum paraoxonase and arylesterase activities in diabetes+lipoic acid group.We can report that, like PON1 protein, PON3 protein and actually its lactonase activity may also have a role as an antioxidant in diabetes mellitus and lipoic acid treatment may be useful for the prevention of the atherosclerotic complications of diabetes by increasing serum PON1 and PON3 protein levels and serum enzyme activities.

The effect of lipoic acid in the prevention of myocardial infarction in diabetic rats.

OBJECTIVES: We aimed to investigate the effect of lipoic acid in the prevention of myocardial infarction in diabetic rats. METHODS: Rats were divided into five groups as control, ISO, LA+ISO, STZ+ISO and STZ+LA+ISO. To induce diabetes, single dose of streptozotocin was injected to STZ+ISO and STZ+LA+ISO groups. Lipoic acid (10 mg/kg/day) was injected for 14 days to LA+ISO and STZ+LA+ISO groups. To induce myocardial infarction, isoproterenol was injected to ISO, LA+ISO, STZ+ISO and STZ+LA+ISO groups on the days 13 and 14 of lipoic acid treatment. Cardiac necrosis and leucocyte infiltration were investigated histopathologically. Serum malondialdehyde levels, paraoxonase and lactonase activities were measured spectrophotometrically. RESULTS: Isoproterenol caused a significant increase in cardiac necrosis, leucocyte infiltration and serum lipid peroxidation whereas a significant decrease in serum paraoxonase and lactonase activities. In myocardial infarcted non-diabetic rats, while lipoic acid caused a significant decrease in cardiac necrosis, leucocyte infiltration and serum lipid peroxidation and a significant increase in serum paraoxonase and lactonase activities, it did not change these histopathologic or biochemical parameters in myocardial infarcted diabetic rats. CONCLUSION: Lipoic acid, at the dose of 10 mg/kg, is effective to prevent myocardial infarction in non-diabetic rats but it is insufficient in diabetic rats (Tab. 1, Fig. 2, Ref. 35).

Type I cardiorenal syndrome in patients with acutely decompensated heart failure: the importance of new renal biomarkers.

OBJECTIVE: Type 1 cardiorenal syndrome (CRS) is an acute renal failure in patients with acute decompensated heart failure with an incidence of 24% to 45%. The aim of our study was to investigate the significance of new renal biomarkers to predict type 1 CRS. PATIENTS AND METHODS: The study included 111 patients with acute decompensated heart failure diagnosed at the Istanbul Medical Faculty Emergency Department between 2014 and 2016, and 24 healthy volunteers. All urine samples were stored at -80°C after centrifugation. Samples were run according to the instructions of TIMP-2, ILGF-7, KIM-1, and IGFBP-7 ELISA kits. Diuretic treatments were then administered with intravenous administration of at least 80 mg furosemide per day. Follow-up biochemical and spot urine specimens were taken after 72 hours. For statistical analysis, SPSS version 21.0 statistical software was used. Significance was evaluated at p<0.05. RESULTS: The baseline creatinine level was measured as 1.33 ± 0.39 mg/dL in the heart failure group. It was seen that 67% (75) of the patients had increased creatinine levels and developed type 1 CRS. ILGF-7, TIMP-2, and (ILGF-7 * TIMP-2) values were significantly higher in patients with cardiorenal syndrome when we separated the two groups as patients with and without cardiorenal syndrome (0.40 (0.25-0.71), p1: 0.049/2.40 (1.42-3.70), p2: 0.003/1.15 (0.29-2.43), p3: 0.001). CONCLUSIONS: Renal tubular markers reveal promising developments in the pathophysiology of cardiorenal syndrome in light of recently obtained data. Renal tubular biomarkers may have the potential to be a predictor of heart failure and cardiorenal syndrome.

Treatment of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of spinal cord and cortical motoneurons. Despite improved understanding of the mechanisms underlying ALS, in clinical practice the management of ALS remains essentially supportive and focused on symptom relief. However, over the past few years stem cell research has expanded greatly as a tool for developing potential new therapies for treating incurable neurodegenerative diseases. METHODS: Thirteen patients with sporadic amyotrophic lateral sclerosis (SALS) were included in this study, and bone marrow (BM)-derived hematopoietic progenitor stem cells were used. We selected patients with bulbar involvement and severe loss of movement. Our aim was to put the stem cells into the end of the brain stem and at the beginning of the spinal cord because the blood-brain barrier is intact in ALS and this region was the most affected part in our patients. Under general anesthesia, a total laminectomy was performed at the C1-C2 level. Stem cells were injected to the anterior part of the spinal cord. RESULTS: During the follow-up of 1 year after stem cell implantation, nine patients became much better compared with their pre-operative status, confirmed by electro neuro myography (ENMG). One patient was stable without any decline or improvement in his status. Three patients died 1.5, 2 and 9 months, respectively, after stem cell therapy as a result of lung infection and myocardial infarction (MI). DISCUSSION: These results show that stem cell therapy is a safe, effective and promising treatment for ALS patients.

Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up.

BACKGROUND: Transplanted bone marrow (BM) cells have been found to improve neurologic disease in central nervous system (CNS) injury models by generating neural cells or myelin-producing cells. The results in treated patients and animal models suggest that BM cells could potentially be used as a therapy for spinal cord injury (SCI) patients. METHODS: Nine patients with chronic complete SCI with American Spinal Injury Association (ASIA) Impairment Scale (ASIA) grade A were included in this study. They were treated with autologous BM-derived hematopoietic progenitor stem cell transplantation without any serious complications. All patients completed the protocols successfully. RESULTS: Three weeks after the operation all patients' movements and sensations were improved. All patients had ASIA grade B or C after the operation. DISCUSSION: We used autologous hematopoietic progenitor stem cells in order to avoid the problems associated with immunologic rejection and graft-versus-host (GvH) reactions, which are frequently caused by allografts. The advantage of this type of cell therapy is that it is not associated with carcinogenesis, which sometimes occurs with embryogenic stem cell therapy. To evaluate the patients we used neurologic impairment scales (ASIA scores), pre- and post-operative Somato Sensorial Evoked Potential (SSEP) assessments and pre- and post-operative Magnetic Resonance Imaging (MRI). All the data showed that BM-derived autologous stem cell therapy is effective and safe for the treatment of chronic SCI.