Apple polyphenol phloretin complexed with ruthenium is capable of reprogramming the breast cancer microenvironment through modulation of PI3K/Akt/mTOR/VEGF pathways.

Our recent investigation directed to synthesize a novel ruthenium-phloretin complex accompanied by the study of antioxidant in addition to DNA binding capabilities, to determine the chemotherapeutic activity against breast carcinoma in vitro and in vivo. Ruthenium-phloretin complex was synthesized and characterized by different spectroscopic methods. The complex was further investigated to determine its efficacy in both MCF-7 and MDA-MB-231 human carcinoma cell lines and finally in an in vivo model of mammary carcinogenesis induced by DMBA in rats. Our studies confirm that the chelation of the metal and ligand was materialize by the 3-OH and 9-OH functional groups of the ligand and the complex is found crystalline and was capable of intercalating with CT-DNA. The complex was capable of reducing cellular propagation and initiate apoptotic events in MCF-7 and MDA-MB-231 breast carcinoma cell lines. Ruthenium-phloretin complex could modulate p53 intervene apoptosis in the breast carcinoma, initiated by the trail of intrinsic apoptosis facilitated through Bcl2 and Bax and at the same time down regulating the PI3K/Akt/mTOR pathway coupled with MMP9 regulated tumor invasive pathways. Ruthenium-phloretin chemotherapy could interrupt, revoke or suspend the succession of breast carcinoma by altering intrinsic apoptosis along with the anti-angiogenic pathway.

The ERK5 pathway in BRAFV600E melanoma cells plays a role in development of acquired resistance to dabrafenib but not vemurafenib.

Malignant melanoma, an aggressive skin cancer with a poor prognosis, frequently features BRAFV600E mutation resulting in activation of the MAPK pathway and melanocyte proliferation and survival. BRAFV600E inhibitors like vemurafenib and dabrafenib have enhanced patient survival, yet drug resistance remains a significant challenge. We investigated the role of the ERK5 pathway in BRAFV600E melanoma cells and cells with acquired resistance to PLX4720 (vemurafenib) and dabrafenib. In BRAFV600E melanoma, ERK5 inhibition minimally affected viability compared to ERK1/2 inhibition. In vemurafenib-resistant cells, ERK5 inhibition alone didn't impact viability or restore drug sensitivity to vemurafenib. However, in dabrafenib-resistant cells, ERK5 inhibition reduced viability and enhanced the anti-proliferative effect of MEK1/2 inhibition. Targeting the ERK5 pathway may represent a therapeutic opportunity in dabrafenib-resistant melanoma.

VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells.

Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within the activation loop. ERK5 then undergoes a conformational change, facilitating phosphorylation on residues in the C-terminal domain and translocation to the nucleus where it regulates MEF2 transcriptional activity. Our previous research into the importance of ERK5 in endothelial cells highlighted its role in VEGF-mediated tubular morphogenesis and cell survival, suggesting that ERK5 played a unique role in endothelial cells. Our current data show that in contrast to EGF-stimulated HeLa cells, VEGF-mediated ERK5 activation in human dermal microvascular endothelial cells (HDMECs) does not result in C-terminal phosphorylation of ERK5 and translocation to the nucleus, but instead to a more plasma membrane/cytoplasmic localisation. Furthermore, the use of small-molecule inhibitors to MEK5 and ERK5 shows that instead of regulating MEF2 activity, VEGF-mediated ERK5 is important for regulating AKT activity. Our data define a novel pathway for ERK5 activation in endothelial cells leading to cell survival.

Downregulation of apoptosis and modulation of TGF-ß1 by sodium selenate prevents streptozotocin-induced diabetic rat renal impairment.

To investigate whether sodium selenate treatment would impact on the onset of diabetic nephropathy, we examined blood glucose, serum biochemical components, and interrelationship between oxidative stress, TGF-ß1, and apoptosis in streptozotocin (STZ) induced diabetic rats. Sixty male Wistar rats were divided into six groups. Group I (n = 10), normal control; Group II (n = 10), diabetic control; Group III (n = 10), sodium selenate (16 µmoles/kg) + diabetic; Group IV (n = 10), sodium selenate (32 µmoles/kg) + diabetic; Group V (n = 10), sodium selenate (16 µmoles/kg) control; and Group VI (n = 10), sodium selenate (32 µmoles/kg) control. Sodium selenate was administered via orogastric route for 10 weeks. In the diabetic group, diabetes was induced by single intraperitoneal injection of STZ (50 mg/kg). The levels of blood glucose were estimated and total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, creatinine, urea, and albumin were detected in serum. Antioxidant status was examined by measuring the superoxide dismutase (SOD), catalase, glutathione, and lipid peroxidation in kidney tissues. Histopathological studies were performed in the kidney tissue sections. The expression of TGF-ß1 was estimated by the immunohistochemical analysis in kidneys. Apoptotic study in kidney was performed using the TdT-mediated dUTP nick end labeling technique. It was observed that blood glucose, serum, total cholesterol, HDL cholesterol, triglycerides, creatinine, urea, and albumin were significantly higher in diabetic control groups. Diabetic + sodium selenate (16 and 32 µmoles/kg) significantly reduced blood glucose, serum, total cholesterol, HDL cholesterol, triglycerides, creatinine, urea, and albumin levels. Selenium-treated groups significantly increased antioxidant enzyme activities (SOD, catalase, and glutathione) in kidneys of diabetic rats. All enzyme activities of selenium control groups did not differ compared with the normal control. Sodium selenate reduces significantly lipid peroxidation in diabetic rats. Cellular architecture of the diabetic rats was altered whereas sodium selenate administration rectifies the degenerative changes of the kidney. Profound immunopositivity of TGF-ß1 was observed in the glomerular and tubulointerstitial cells of diabetic rat kidney. Immunopositivity of TGF-ß1 was significantly reduced in both low and high dose of sodium-selenate-treated rats (P < 0.05, P < 0.01). High numbers of apoptotic cells were observed in diabetic rats whereas sodium selenate in both doses significantly reduces the incidence of apoptosis (P < 0.05, P < 0.01). We conclude herein that sodium selenate has the potential to play a significant role in limiting the renal impairment by altering the apoptosis and TGF-ß1 in experimental diabetic rats.

Methoxy VO-salen stimulates pancreatic ß cell survival by upregulation of eNOS and downregulation of apoptosis in STZ-induced diabetic rats.

The present study was designed to investigate the effect of MetVO-salen in ameliorating diabetes and oxidative stress in the pancreas of diabetic rats. Streptozotocin (STZ)-induced diabetic rats were treated with MetVO-salen complex intraperitonially (0.3 and 0.6 mg/kg) thrice a week and continued for 8 weeks. Total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides in serum, and blood glucose were estimated. Furthermore, oxidative stress in rats was also investigated in terms of superoxide dismutase (SOD), catalase, lipid peroxidation, and glutathione (GSH). In addition, the anti-diabetic activity of MetVO-salen was also investigated by assessing histopathological, immunohistochemical in terms of endothelial nitric oxide synthase expression, and apoptotic events in pancreas. Treatment with MetVO-salen complex reduced the blood glucose level and significantly altered the serum biochemical parameters of diabetic rats. Treatment with above complex decreased the lipid peroxidation and the antioxidant enzymes such as SOD, CAT, and GSH to near-control levels. Histopathological, immunohistochemical, and apoptotic studies also revealed that MetVO-salen-induced amelioration of the diabetic state appears to be significant to the preservation of a functional portion of the pancreatic ß cells which initially prevent STZ toxicity. This study provides new direction for the management of diabetes but needs further clinical evaluation.