Exosomes isolated from melatonin-stimulated mesenchymal stem cells improve kidney function by regulating inflammation and fibrosis in a chronic kidney disease mouse model.

Chronic kidney disease (CKD) is defined as structural and functional abnormalities of the kidney due to inflammation and fibrosis. We investigated the therapeutic effects of exosomes secreted by melatonin-stimulated mesenchymal stem cells (Exocue) on the functional recovery of the kidney in a CKD mouse model. Exocue upregulated gene expression of micro RNAs (miRNAs) associated with anti-inflammatory and anti-fibrotic effects.

Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis.

Dysregulation in mitophagy, in addition to contributing to imbalance in the mitochondrial dynamic, has been implicated in the development of renal fibrosis and progression of chronic kidney disease (CKD). However, the current understanding of the precise mechanisms behind the pathogenic loss of mitophagy remains unclear for developing cures for CKD. We found that miR-4516 is downregulated and its target SIAH3, an E3 ubiquitin protein ligase that reduces PINK1 accumulation to damaged mitochondria, is upregulated in the renal cortex of CKD mice.

Melatonin Protects Chronic Kidney Disease Mesenchymal Stem/Stromal Cells against Accumulation of Methylglyoxal via Modulation of Hexokinase-2 Expression.

Treatment options for patients with chronic kidney disease (CKD) are currently limited; therefore, there has been significant interest in applying mesenchymal stem/stromal cell (MSC)-based therapy to treat CKD. However, MSCs harvested from CKD patients tend to show diminished viability and proliferation due to sustained exposure to uremic toxins in the CKD environment, which limits their utility for cell therapy. The application of melatonin has been demonstrated to improve the therapeutic efficacy of MSCs derived from and engrafted to tissues in patients suffering from CKD, although the underlying biological mechanism has not been elucidated.

PrP Aptamer Conjugated-Gold Nanoparticles for Targeted Delivery of Doxorubicin to Colorectal Cancer Cells.

Anticancer drugs, such as fluorouracil (5-FU), oxaliplatin, and doxorubicin (Dox) are commonly used to treat colorectal cancer (CRC); however, owing to their low response rate and adverse effects, the development of efficient drug delivery systems (DDSs) is required. The cellular prion protein PrP, which is a cell surface glycoprotein, has been demonstrated to be overexpressed in CRC, however, there has been no research on the development of PrP-targeting DDSs for targeted drug delivery to CRC. In this study, PrP aptamer (Apt)-conjugated gold nanoparticles (AuNPs) were synthesized for targeted delivery of Dox to CRC.

Knockdown of CK2α reduces -cresol-induced fibrosis in human renal proximal tubule epithelial cells via the downregulation of profilin-1.

Renal fibrosis is one of the main causes of chronic kidney disease. Many studies have focused on fibroblasts and myofibroblasts involved in renal fibrogenesis. Recently, several studies have reported that renal proximal tubule epithelial cells are possible initiators of renal fibrosis.

Role of PrP in Cancer Stem Cell Characteristics and Drug Resistance in Colon Cancer Cells.

Background/aim: Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrP on cancer stem cell characteristics, migration, invasion, and drug resistance of 5FU-resistant CRC cells.

Materials And Methods: PrP negative and PrP positive cells were isolated from 5FU-resistant CRC cells using magnetic activated cell sorting.

Melatonin Suppresses Renal Cortical Fibrosis by Inhibiting Cytoskeleton Reorganization and Mitochondrial Dysfunction through Regulation of miR-4516.

Renal fibrosis, a major risk factor for kidney failure, can lead to chronic kidney disease (CKD) and is caused by cytoskeleton reorganization and mitochondrial dysfunction. In this study, we investigated the potential of melatonin treatment to reduce renal fibrosis by recovering the cytoskeleton reorganization and mitochondrial dysfunction. We found that miR-4516 expression was downregulated in the renal cortex of CKD mice and -cresol-treated TH1 cells.

Melatonin Protects Human Renal Proximal Tubule Epithelial Cells Against High Glucose-Mediated Fibrosis via the Cellular Prion Protein-TGF-β-Smad Signaling Axis.

Diabetes-mediated hyperglycemia is a major risk factor for renal fibrosis, resulting in the development of chronic kidney diseases. To address this issue, the effect of melatonin, which has an antioxidative potential, on renal fibrosis in human renal proximal tubule epithelial cells under high glucose conditions was investigated. Under high glucose conditions, the generation of reactive oxygen species was drastically increased in human renal proximal tubule epithelial cells, which lead to the inhibition of cell proliferation, enlargement of cell size, reduction of cell survival, and suppression of antioxidant enzyme activities.

Melatonin-stimulated exosomes enhance the regenerative potential of chronic kidney disease-derived mesenchymal stem/stromal cells via cellular prion proteins.

Chronic kidney disease (CKD) is caused by dysfunctional kidneys, which result in complications like cardiovascular diseases. Chronic kidney disease-induced pathophysiological conditions decrease efficacy of autologous mesenchymal stem/stromal cell (MSC)-based therapy by reducing MSC functionality. To enhance therapeutic potential in patients with CKD, we isolated exosomes derived from melatonin-treated healthy MSCs (MT exosomes) and assessed the biological functions of MT exosome-treated MSCs isolated from patients with CKD (CKD-MSCs).

Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L-mitophagy pathway.

Mesenchymal stem cells (MSCs) are a popular cell source for stem cell-based therapy. However, continuous ex vivo expansion to acquire large amounts of MSCs for clinical study induces replicative senescence, causing decreased therapeutic efficacy in MSCs. To address this issue, we investigated the effect of melatonin on replicative senescence in MSCs.

Protective Role of Fucoidan on Cisplatin-mediated ER Stress in Renal Proximal Tubule Epithelial Cells.

Background/aim: Administration of cisplatin in cancer patients is limited by the kidney-related adverse effects; however, a protective strategy is absent. We hypothesized that fucoidan protects the proximal tubule epithelial (TH-1) cells against the effects of cisplatin.

Materials And Methods: To assess the effect of fucoidan, its effect on reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress response, DNA damage response (DDR), apoptosis, and cell-cycle arrest in TH-1 cells was investigated.

Melatonin Enhances Mitophagy by Upregulating Expression of Heat Shock 70 kDa Protein 1L in Human Mesenchymal Stem Cells under Oxidative Stress.

Human mesenchymal stem cells (hMSCs) are a potent source of cell-based regenerative therapeutics used to treat patients with ischemic disease. However, disease-induced oxidative stress disrupts mitochondrial homeostasis in transplanted hMSCs, resulting in hMSC apoptosis and reducing their efficacy post-transplantation. To address this issue, we evaluated the effects of melatonin on cellular defense mechanisms and mitophagy in hMSCs subjected to oxidative stress.

Pioglitazone Improves the Function of Human Mesenchymal Stem Cells in Chronic Kidney Disease Patients.

Mesenchymal stem cells (MSCs) are optimal sources of autologous stem cells for cell-based therapy in chronic kidney disease (CKD). However, CKD-associated pathophysiological conditions, such as endoplasmic reticulum (ER) stress and oxidative stress, decrease MSC function. In this work, we study the protective effect of pioglitazone on MSCs isolated from CKD patients (CKD-MSCs) against CKD-induced ER stress.

TUDCA-treated chronic kidney disease-derived hMSCs improve therapeutic efficacy in ischemic disease via PrP.

Although autologous human mesenchymal stem cells (hMSCs) are a promising source for regenerative stem cell therapy in chronic kidney disease (CKD), the barriers associated with pathophysiological conditions limit therapeutic applicability to patients. We confirmed that level of cellular prion protein (PrP) in serum was decreased and mitochondria function of CKD-derived hMSCs (CKD-hMSCs) was impaired in patients with CKD. We proved that treatment of CKD-hMSCs with tauroursodeoxycholic acid (TUDCA), a bile acid, enhanced the mitochondrial function of these cells through regulation of PINK1-PrP-dependent pathway.

TUDCA-Treated Mesenchymal Stem Cells Protect against ER Stress in the Hippocampus of a Murine Chronic Kidney Disease Model.

Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD; however severe pathophysiological conditions can decrease their therapeutic potential.

Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression.

Object: The purpose of this study was to explore whether melatonin could protect mesenchymal stem cells (MSCs) against ischaemic injury, by inhibiting endoplasmic reticulum (ER) stress and autophagy both in vivo and in vitro.

Materials And Methods: To confirm the protective effect of melatonin against ER stress in MSCs, markers of cell viability, apoptosis and autophagy were analysed. To further investigate the regenerative effect of melatonin-treated MSCs in ischaemic tissues, a murine hindlimb ischaemic model was established.

Pioglitazone Protects Mesenchymal Stem Cells against -Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1.

Mesenchymal stem cells (MSC) could be a candidate for cell-based therapy in chronic kidney disease (CKD); however, the uremic toxin in patients with CKD restricts the therapeutic efficacy of MSCs. To address this problem, we explored the effect of pioglitazone as a measure against exposure to the uremic toxin -cresol (PC) in MSCs. Under PC exposure conditions, apoptosis of MSCs was induced, as well as PC-induced dysfunction of mitochondria by augmentation of mitofusion, reduction of mitophagy, and inactivation of mitochondrial complexes I and IV.

Melatonin Promotes Apoptosis of Oxaliplatin-resistant Colorectal Cancer Cells Through Inhibition of Cellular Prion Protein.

Background/aim: Drug resistance restricts the efficacy of chemotherapy in colorectal cancer. However, the detailed molecular mechanism of drug resistance in colorectal cancer cells remains unclear.

Materials And Methods: The level of cellular prion protein (PrP) in oxaliplatin-resistant colorectal cancer (SNU-C5/Oxal-R) cells was assessed.

Role of hypoxia‑mediated cellular prion protein functional change in stem cells and potential application in angiogenesis (Review).

Cellular prion protein (PrPC) can replace other pivotal molecules due to its interaction with several partners in performing a variety of important biological functions that may differ between embryonic and mature stem cells. Recent studies have revealed major advances in elucidating the putative role of PrPC in the regulation of stem cells and its application in stem cell therapy. What is special about PrPC is that its expression may be regulated by hypoxia‑inducible factor (HIF)‑1α, which is the transcriptional factor of cellular response to hypoxia.

GRP78 Regulates Apoptosis, Cell Survival and Proliferation in 5-Fluorouracil-resistant SNUC5 Colon Cancer Cells.

5-Fluorouracil (5-FU) is an effective anticancer drug. However, the development of drug resistance has limited its chemotherapeutic efficacy. To address this problem, we investigated the expression of glucose-regulated protein (GRP78, 78 kDa) in 5-FU-resistant colorectal cancer (CRC) cells (SNUC5/5FUR).

Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis.

Mesenchymal stem cells (MSC) are ideal materials for stem cell-based therapy. As MSCs reside in hypoxic microenvironments (low oxygen tension of 1% to 7%), several studies have focused on the beneficial effects of hypoxic preconditioning on MSC survival; however, the mechanisms underlying such effects remain unclear. This study aimed to uncover the potential mechanism involving 78-kDa glucose-regulated protein (GRP78) to explain the enhanced MSC bioactivity and survival in hindlimb ischemia.

Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein.

Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2α, ATF4, IRE1α, JNK, p38, and CHOP.

Hypoxia-induced expression of cellular prion protein improves the therapeutic potential of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are 'adult' multipotent cells that promote regeneration of injured tissues in vivo. However, differences in oxygenation levels between normoxic culture conditions (21% oxygen) and both the MSC niche (2-8% oxygen) and ischemic injury-induced oxidative stress conditions in vivo have resulted in low efficacy of MSC therapies in both pre-clinical and clinical studies. To address this issue, we examined the effectiveness of hypoxia preconditioning (2% oxygen) for enhancing the bioactivity and tissue-regenerative potential of adipose-derived MSCs.

Pivotal Roles of Ginsenoside Rg3 in Tumor Apoptosis Through Regulation of Reactive Oxygen Species.

Background: Elevated production of reactive oxygen species (ROS) is observed in various cancer types and pathophysiological conditions. In cancer cells, ROS induce cell proliferation, genetic instability, and a malignant phenotype. Ginsenoside Rg3 is the main pharmacologically active component in ginseng and has been reported to have an antioxidant effect.