ß-lapachone protects against doxorubicin-induced hepatotoxicity through modulation of NAD+ /SIRT-1/FXR/p-AMPK/NF-kB and Nrf2 signaling axis.

Doxorubicin (DOX) is a widely used antineoplastic drug, but its clinical use is limited by significant toxicities, such as hepatotoxicity. In this study, we evaluated the effects of ß-lapachone (ß-LAP), a natural quinone-containing compound, in a mouse model of DOX-induced hepatotoxicity. ß-LAP was orally administered at 1.25, 2.5, and 5 mg/kg for 4 days, and a single dose of DOX (20 mg/kg) was injected intraperitoneally on the second day. Histopathological changes, liver function markers, antioxidant and inflammatory markers were assessed. ß-LAP ameliorated liver injury and liver function markers evoked by DOX. ß-LAP also downregulated the mRNA expression of nuclear factor-kB-corresponding genes including interleukin-6, interleukin-1ß, and tumor necrosis factor-α. Moreover, ß-LAP increased the nuclear factor erythroid 2-related factor 2 target genes heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1, along with antioxidant enzymes including reduced glutathione, catalase, and superoxide dismutase with simultaneous reduction in the lipid peroxidation product malondialdehyde. Meanwhile, it recovered NAD+ /NADH ratios and subsequently elevated the protein levels of sirtuin-1 (SIRT-1), farnesoid X receptor (FXR), and phosphorylated AMP-activated protein kinase (p-AMPK). Collectively, these findings suggest a protective role of ß-LAP against DOX-induced hepatotoxicity by partly regulating the NAD+ /SIRT-1/FXR/p-AMPK axis.

ß-LAPachone is renoprotective in streptozotocin-induced diabetic mice via regulating the PI3K/Akt/mTOR signaling pathway.

OBJECTIVES: ß-LAPachone (B-LAP) is a natural product with established anti-inflammatory properties. In this study, we investigated the protective potential of B-LAP against diabetic nephropathy in streptozotocin (STZ) induced diabetic mice. MATERIALS AND METHODS: Diabetes induction in mice was carried out by a single intraperitoneal injection of STZ. 2.5 mg/kg/day and 5 mg/kg/day doses of B-LAP were administered orally for twelve weeks and renal histoarchitecture, caspase-3, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), glutathione peroxidase (GPX), as well as urinary nephrin and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated. Additionally, kidney levels of PI3K, phosphorylated (p)-Akt, p-mTOR, p-CREB, and SIRT1 were assessed in the present investigation. RESULTS: 5 mg/kg B-LAP significantly decreased urinary excretions of nephrin and NGAL. It also mitigated renal TNF-α and MDA levels and simultaneously improved GPX activities. 5 mg/kg B-LAP improved renal function in diabetic mice as indicated by elevated values of creatinine clearance. While B-LAP elevated renal levels of SIRT1, it alleviated PI3K, p-Akt, p-mTOR, and p-CREB levels in the kidneys of diabetic mice. CONCLUSION: Collectively, these findings suggest B-LAP as a potential renoprotective agent in STZ-induced diabetic mice probably via modulating the PI3K/Akt/mTOR pathway.

Expression Profiles of MicroRNAs in Stem Cells Differentiation.

Stem cells are undifferentiated cells and have a great potential in multilineage differentiation. These cells are classified into adult stem cells like Mesenchymal Stem Cells (MSCs) and Embryonic Stem Cells (ESCs). Stem cells also have potential therapeutic utility due to their pluripotency, self-renewal, and differentiation ability. These properties make them a suitable choice for regenerative medicine. Stem cells differentiation toward functional cells is governed by different signaling pathways and transcription factors. Recent studies have demonstrated the key role of microRNAs in the pathogenesis of various diseases, cell cycle regulation, apoptosis, aging, cell fate decisions. Several types of stem cells have different and unique miRNA expression profiles. Our review summarizes novel regulatory roles of miRNAs in the process of stem cell differentiation especially adult stem cells into a variety of functional cells through signaling pathways and transcription factors modulation. Understanding the mechanistic roles of miRNAs might be helpful in elaborating clinical therapies using stem cells and developing novel biomarkers for the early and effective diagnosis of pathologic conditions.

Current Status of Used Protocols for Mesenchymal Stem Cell Differentiation: A Focus on Insulin Producing, Osteoblast-Like and Neural Cells.

Mesenchymal stem cells (MSCs) have attracted a great deal of interest in the field of regenerative medicine because of their ability to differentiate into mesodermal derivatives and even other germ layers. The main requirement for better differentiation of MSCs into desired cell lineage is relied on pure population of these cells. During the past years, significant progresses have been developed for the identification of MSCs by introducing new markers or different combination of markers. Currently, direct in vitro differentiation protocols using standard media supplemented with specific growth factors generating osteoblast, insulin producing and neuron cells from MSCs show some key characteristic in in vivo counterparts. However, these efforts should be continued to achieve high amount of fully differentiated cells which have high capacity to be used in cell based therapies and drug screening. This review focuses on common culture based differentiation strategies used for osteoblast, insulin producing cells and neural cells generation from MSCs highlighting important findings and trends in this exciting area.

Interplay between microRNAs and Wnt, transforming growth factor-ß, and bone morphogenic protein signaling pathways promote osteoblastic differentiation of mesenchymal stem cells.

Osteoblasts are terminally differentiated cells with mesenchymal origins, known to possess pivotal roles in sustaining bone microstructure and homeostasis. These cells are implicated in the pathophysiology of various bone disorders, especially osteoporosis. Over the last few decades, strategies to impede bone resorption, principally by bisphosphonates, have been mainstay of treatment of osteoporosis; however, in recent years more attention has been drawn on bone-forming approaches for managing osteoporosis. MicroRNAs (miRNAs) are a broad category of noncoding short sequence RNA fragments that posttranscriptionally regulate the expression of diverse functional and structural genes in a negative manner. An accumulating body of evidence signifies that miRNAs direct mesenchymal stem cells toward osteoblast differentiation and bone formation through bone morphogenic protein, transforming growth factor-ß, and Wnt signaling pathways. MiRNAs are regarded as excellent future therapeutic candidates because of their small size and ease of delivery into the cells. Considering their novel therapeutic significance, this review discusses the main miRNAs contributing to the anabolic aspects of bone formation and illustrates their interactions with corresponding signaling pathways involved in osteoblastic differentiation.

Reduction of renal tubular injury with a RAGE inhibitor FPS-ZM1, valsartan and their combination in streptozotocin-induced diabetes in the rat.

Receptor for advanced glycation end-products (RAGE) is involved in the pathogenesis of diabetic nephropathy. FPS-ZM1, a selective RAGE inhibitor, in combination with valsartan were investigated for their protective potentials on the renal markers of tubular injury in streptozotocin-induced diabetic rats. Rats were assigned into groups of receiving FPS-ZM1 (1 mg/kg/day), valsartan (100 mg/kg/day), and FPS-ZM1 plus valsartan (1 mg/kg/day and 100 mg/kg/day, respectively) for one month. Kidney histology, renal inflammation and oxidative stress, and renal and urinary markers of tubular injury were investigated. FPS-ZM1 and valsartan in combination more significantly attenuated renal expressions of tumor necrosis factor-alpha and interleukin-6 genes and reduced urinary levels of interleukin-6. Moreover, the combination elevated renal NAD+/NADH ratios and Sirt1 activities, and mitigated nuclear acetylated NF-κB p65 levels. In addition to alleviating indices of oxidative stress i.e. malondialdehyde, superoxide dismutase and glutathione peroxidase, the combination of FPS-ZM1 and valsartan more effectively upregulated the renal levels of master antioxidant proteins Nrf2, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase-1. Additionally, this dual therapy ameliorated more efficiently the indices of renal tubular injuries as indicated by decreased renal kidney injury molecule-1 levels as well as reduced urinary levels of cystatin C, retinol binding protein, and beta-2-microglobulin. While FPS-ZM1 alone had no appreciable effects on the renal fibrosis, the combination treatment ameliorated fibrosis better than valsartan in the kidneys. Collectively, these findings underline the extra benefits of FPS-ZM1 and valsartan dual administrations in obviating the renal tubular cell injury in streptozotocin-induced diabetic rats partly by suppressing renal inflammation and oxidative stress.

FPS-ZM1 and valsartan combination protects better against glomerular filtration barrier damage in streptozotocin-induced diabetic rats.

Despite the effectiveness of renin-angiotensin blockade in retarding diabetic nephropathy progression, a considerable number of patients still develop end-stage renal disease. The present investigation aims to evaluate the protective potential of FPS-ZM1, a selective inhibitor of receptor for advanced glycation end products (RAGE), alone and in combination with valsartan, an angiotensin receptor blocker, against glomerular injury parameters in streptozotocin-induced diabetic rats. FPS-ZM1 at 1 mg/kg (i.p.), valsartan at 100 mg/kg (p.o.), and their combination were administered for 4 weeks, starting 2 months after diabetes induction in rats. Tests for kidney function, glomerular filtration barrier, and podocyte slit diaphragm integrities were performed. Combined FPS-ZM1/valsartan attenuated diabetes-induced elevations in renal levels of RAGE and phosphorylated NF-κB p65 subunit. It ameliorated glomerular injury due to diabetes by increasing glomerular nephrin and synaptopodin expressions, mitigating renal integrin-linked kinase (ILK) levels, and lowering urinary albumin, collagen type IV, and podocin excretions. FPS-ZM1 also improved renal function as demonstrated by decreasing levels of serum cystatin C. Additionally, the combination also alleviated indices of renal inflammation as revealed by decreased renal monocyte chemoattractant protein 1 (MCP-1) and chemokine (C-X-C motif) ligand 12 (CXCL12) expressions, F4/80-positive macrophages, glomerular TUNEL-positive cells, and urinary alpha-1-acid glycoprotein (AGP) levels. These findings underline the benefits of FPS-ZM1 added to valsartan in alleviating renal glomerular injury evoked by diabetes in streptozotocin rats and suggest FPS-ZM1 as a new potential adjunct to the conventional renin-angiotensin blockade.