Olive Flounder By-Product Prozyme2000P Hydrolysate Ameliorates Age-Related Kidney Decline by Inhibiting Ferroptosis.

This study explores olive flounder by-product Prozyme2000P (OFBP) hydrolysate as a potential treatment for age-related kidney decline. Ferroptosis, a form of cell death linked to iron overload and oxidative stress, is increasingly implicated in aging kidneys. We investigated whether OFBP could inhibit ferroptosis and improve kidney health. Using TCMK-1 cells, we found that OFBP treatment protected cells from ferroptosis induced by sodium iodate (SI). OFBP also preserved the mitochondria health and influenced molecules involved in ferroptosis regulation. In aging mice, oral administration of OFBP significantly improved kidney health markers. Microscopic examination revealed reduced thickening and scarring in the kidney's filtering units, a hallmark of aging. These findings suggest that OFBP hydrolysate may be a promising therapeutic candidate for age-related kidney decline. By inhibiting ferroptosis, OFBP treatment appears to improve both cellular and structural markers of kidney health. Further research is needed to understand how OFBP works fully and test its effectiveness in more complex models.

Disease Modeling of Rare Neurological Disorders in Zebrafish.

Rare diseases are those which affect a small number of people compared to the general population. However, many patients with a rare disease remain undiagnosed, and a large majority of rare diseases still have no form of viable treatment. Approximately 40% of rare diseases include neurologic and neurodevelopmental disorders. In order to understand the characteristics of rare neurological disorders and identify causative genes, various model organisms have been utilized extensively. In this review, the characteristics of model organisms, such as roundworms, fruit flies, and zebrafish, are examined, with an emphasis on zebrafish disease modeling in rare neurological disorders.

Evaluation of a Rapid and Simple Method for Assessing Retinal Vessel Structures in Adult Zebrafish.

The evaluation of retinal vascular structures is important for analyzing various ophthalmic diseases. Conventional trypsin digestion was used for separating retinal vasculatures in mouse, rat, and other animal models; however, the trypsin method alone is technically difficult to perform and has not been reported in zebrafish to date. In this study, we introduced a rapid and convenient method that allows the investigation of fine vessel structures at a cellular level in the relatively intact retinal vasculature of adult zebrafish. Using an anti-ZO-1 antibody, tight junction structures in retinal vessels were examined in detail and several different cell types constituting blood vessels in arterial and capillary areas were identified. In addition, using cell type-specific antibodies, we identified smooth muscle cells, blood cells, and endothelial cells in the retinal vasculature. Finally, using the hyperglycemic model, we observed the dilation of retinal vessels, the downregulation of tight junction proteins, and the reduction in smooth muscle cells. Based on these results, we provide a rapid and convenient method for the study of retinal vasculature disease in the zebrafish animal model.

Dieckol Decreases Caloric Intake and Attenuates Nonalcoholic Fatty Liver Disease and Hepatic Lymphatic Vessel Dysfunction in High-Fat-Diet-Fed Mice.

Increased inflammation is the main pathophysiology of nonalcoholic fatty liver disease (NAFLD). Inflammation affects lymphatic vessel function that contributes to the removal of immune cells or macromolecules. Dysfunctional lymphatic vessels with decreased permeability are present in NAFLD. High-fat diet (HFD) is known to increase body weight, food intake, and inflammation in the liver. Previously, it was reported that Ecklonia cava extracts (ECE) decreased food intake or weight gain, and low-calorie diet and weight loss is known as a treatment for NAFLD. In this study, the effects of ECE and dieckol (DK)-which is one component of ECE that decreases inflammation and increases lymphangiogenesis and lymphatic drainage by controlling lymphatic permeability in high-fat diet (HFD)-fed mice-on weight gain and food intake were investigated. ECE and DK decreased weight gain and food intake in the HFD-fed mice. NAFLD activities such as steatosis, lobular inflammation, and ballooning were increased by HFD and attenuated by ECE and DK. The expression of inflammatory cytokines such as IL-6 and TNF-α and infiltration of M1 macrophages were increased by HFD, and they were decreased by ECE or DK. The signaling pathways of lymphangiogenesis, VEGFR-3, PI3K/pAKT, and pERK were decreased by HFD, and they were restored by either ECE or DK. The expression of VE-cadherin (which represents lymphatic junctional function) was increased by HFD, although it was restored by either ECE or DK. In conclusion, ECE and DK attenuated NAFLD by decreasing weight gain and food intake, decreasing inflammation, and increasing lymphangiogenesis, as well as modulating lymphatic vessel permeability.

Attenuating Effects of Dieckol on High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Decreasing the NLRP3 Inflammasome and Pyroptosis.

Nonalcoholic fatty liver disease (NAFLD), which promotes serious health problems, is related to the increase in the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome and pyroptosis by a high-fat diet (HFD). Whether dieckol (DK), a component of Ecklonia cava extracts (ECE), attenuated NAFLD in an HFD-induced NAFLD animal model was evaluated. The expression of high mobility group box 1/Toll-like receptor 4/nuclear factor-κB, which initiated the NLRP3 inflammasome, was increased in the liver of HFD-fed animals and significantly decreased with ECE or DK administration. The expression of NLRP3/ASC/caspase-1, which are components of the NLRP3 inflammasome, and the number of pyroptotic cells were increased by HFD and decreased with ECE or DK administration. The accumulation of triglycerides and free fatty acids in the liver was increased by HFD and decreased with ECE or DK administration. The histological NAFLD score was increased by HFD and decreased with ECE or DK administration. The expression of lipogenic genes (FASN, SREBP-2, PPARγ, and FABP4) increased and that of lipolytic genes (PPARα, CPT1A, ATGL, and HSL) was decreased by HFD and attenuated with ECE or DK administration. In conclusion, ECE or DK attenuated NAFLD by decreasing the NLRP3 inflammasome and pyroptosis.

Attenuating Effects of Dieckol on Hypertensive Nephropathy in Spontaneously Hypertensive Rats.

Hypertension induces renal fibrosis or tubular interstitial fibrosis, which eventually results in end-stage renal disease. Epithelial-to-mesenchymal transition (EMT) is one of the underlying mechanisms of renal fibrosis. Though previous studies showed that Ecklonia cava extracts (ECE) and dieckol (DK) had inhibitory action on angiotensin (Ang) I-converting enzyme, which converts Ang I to Ang II. It is known that Ang II is involved in renal fibrosis; however, it was not evaluated whether ECE or DK attenuated hypertensive nephropathy by decreasing EMT. In this study, the effect of ECE and DK on decreasing Ang II and its down signal pathway of angiotensin type 1 receptor (AT1R)/TGFß/SMAD, which is related with the EMT and restoring renal function in spontaneously hypertensive rats (SHRs), was investigated. Either ECE or DK significantly decreased the serum level of Ang II in the SHRs. Moreover, the renal expression of AT1R/TGFß/SMAD was decreased by the administration of either ECE or DK. The mesenchymal cell markers in the kidney of SHRs was significantly decreased by ECE or DK. The fibrotic tissue of the kidney of SHRs was also significantly decreased by ECE or DK. The ratio of urine albumin/creatinine of SHRs was significantly decreased by ECE or DK. Overall, the results of this study indicate that ECE and DK decreased the serum levels of Ang II and expression of AT1R/TGFß/SMAD, and then decreased the EMT and renal fibrosis in SHRs. Furthermore, the decrease in EMT and renal fibrosis could lead to the restoration of renal function. It seems that ECE or DK could be beneficial for decreasing hypertensive nephropathy by decreasing EMT and renal fibrosis.

Radiofrequency Irradiation Modulates TRPV1-Related Burning Sensation in Rosacea.

Rosacea is a skin inflammatory condition that is accompanied by not only redness and flushing but also unseen symptoms, such as burning, stinging, and itching. TRPV1 expression in UVB-exposed skin can lead to a painful burning sensation. Upregulated TRPV1 expression helps release neuropeptides, including calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal peptide, which can activate macrophage and inflammatory molecules. In this study, we found that radiofrequency (RF) irradiation reduced TRPV1 activation and neuropeptide expression in a UVB-exposed in vivo model and UVB- or heat-treated in an in vitro model. RF irradiation attenuated neuropeptide-induced macrophage activation and inflammatory molecule expression. Interestingly, the burning sensation in the skin of UVB-exposed mice and patients with rosacea was significantly decreased by RF irradiation. These results can provide experimental and molecular evidence on the effective use of RF irradiation for the burning sensation in patients with rosacea.

Radiofrequency Irradiation Attenuates High-Mobility Group Box 1 and Toll-like Receptor Activation in Ultraviolet B-Induced Skin Inflammation.

Ultraviolet B (UVB) exposure activates various inflammatory molecules of keratinocytes in the epidermis layer. Such UVB-mediated skin inflammation leaves post-inflammatory hyperpigmentation (PIH). Reports show a close relationship between PIH and high-mobility group box 1 (HMGB1) and its receptors. General clinical treatments of PIH, such as oral medication and laser treatment, have reported side effects. Recent studies reported the effects of radiofrequency (RF) irradiation on restoring dermal collagen, modulating the dermal vasculature, and thickening the basement membrane. To validate how RF regulates the inflammatory molecules from UVB-irradiated keratinocytes, we used UVB-radiated keratinocytes and macrophages, as well as animal skin. In addition, we examined two cases of RF-irradiated skin inflammatory diseases. We validated the effects of RF irradiation on keratinocytes by measuring expression levels of HMGB1, Toll-like receptors (TLRs), and other inflammatory factors. The results show that the RF modulates UVB-radiated keratinocytes to secrete fewer inflammatory factors and also modulates the expression of macrophages from HMGB1, TLRs, and inflammatory factors. RF irradiation could alleviate inflammatory skin diseases in patients. RF irradiation can regulate the macrophage indirectly through modulating the keratinocyte and inflammatory molecules of macrophages reduced in vitro and in vivo. Although the study is limited by the low number of cases, it demonstrates that RF irradiation can regulate skin inflammation in patients.

Gamma-aminobutyric acid-salt attenuated high cholesterol/high salt diet induced hypertension in mice.

Excessive salt intake induces hypertension, but several gamma-aminobutyric acid (GABA) supplements have been shown to reduce blood pressure. GABAsalt, a fermented salt by L. brevis BJ20 containing GABA was prepared through the post-fermentation with refined salt and the fermented GABA extract. We evaluated the effect of GABA-salt on hypertension in a high salt, high cholesterol diet induced mouse model. We analyzed type 1 macrophage (M1) polarization, the expression of M1 related cytokines, GABA receptor expression, endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation, and medial thicknesses in mice model. GABA-salt attenuated diet-induced blood pressure increases, M1 polarization, and TNF-α and inducible nitric oxide synthase (NOS) levels in mouse aortas, and in salt treated macrophages in vitro. Furthermore, GABA-salt induced higher GABAB receptor and endothelial NOS (eNOS) and eNOS phosphorylation levels than those observed in salt treated ECs. In addition, GABA-salt attenuated EC dysfunction by decreasing the levels of adhesion molecules (E-selectin, Intercellular Adhesion Molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) and of von Willebrand Factor and reduced EC death. GABA-salt also reduced diet-induced reductions in the levels of eNOS, phosphorylated eNOS, VSMC proliferation and medial thickening in mouse aortic tissues, and attenuated Endothelin-1 levels in salt treated VSMCs. In summary, GABA-salt reduced high salt, high cholesterol diet induced hypertension in our mouse model by reducing M1 polarization, EC dysfunction, and VSMC proliferation.

Radiofrequency irradiation attenuates angiogenesis and inflammation in UVB-induced rosacea in mouse skin.

Rosacea is a skin inflammatory condition accompanied by cutaneous signs such as oedema, flushing, erythema, telangiectasia and pustules. Generally, rosacea is triggered by ultraviolet B (UVB) exposure. When exposed to UVB, skin epidermis thickens and produces elevated levels of pro-inflammatory cytokines, especially keratinocyte-related VEGF, a potent angiogenic factor. The upregulations of VEGF expression and its secretion promote the formation of new blood vessels and exacerbates rosacea. In this study, radiofrequency (RF) irradiation reduced keratinocyte proliferation in the epidermal layer, the expressions of pro-inflammatory cytokines, angiogenesis-related inflammatory factors and VEGF in our UVB-induced model of rosacea in vitro and in vivo. RF irradiation attenuated VEGF-induced angiogenesis-associated processes such as tube formation, cell migration and endothelial cell proliferation. Notably, blood vessel densities in the skins of UVB-treated mice and rosacea patients were significantly decreased by RF irradiation. These results provide experimental and molecular evidence regarding the effectiveness of RF irradiation for the treatment of rosacea.

The Reducing Effects of Pyrogallol-Phloroglucinol-6,6-Bieckol on High-Fat Diet-Induced Pyroptosis in Endothelial and Vascular Smooth Muscle Cells of Mice Aortas.

In hyperlipidemia, pyroptosis in endothelial cells (ECs) induces atherosclerosis via the toll-like receptor 4 (TLR4) pathway. We evaluated the effects of Ecklonia cava extract (ECE) and pyrogallol-phloroglucinol-6,6-bieckol (PPB) on pyroptosis of ECs and vascular smooth muscle cells (VSMCs), which leads to attenuation of these cells and dysfunction of the aorta in high-fat-diet (HFD)-fed mice and in palmitate-treated ECs and VSMCs. The expression of TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which induce formation of NOD-LRR-and pyrin domain-containing protein 3 (NLRP3) inflammasomes, were increased by HFD and were decreased by ECE and PPB. The TLR4/NF-κB pathway was upregulated in palmitate-treated ECs and VSMCs and was decreased by ECE and PPB. The expressions of NLRP3/apoptosis-associated speck like protein containing a caspase recruitment domain, caspase-1, interleukin (IL)-1ß, and IL-18 were increased by HFD and were decreased by ECE and PPB. Pyroptotic cells were increased by HFD and decreased by ECE and PPB. The expressions of the adhesion molecules, intercellular adhesion molecule and vascular cell adhesion molecule, and endothelin-1 were increased by HFD and were decreased by ECE and PPB. ECE and PPB decreased pyroptosis in the ECs and VSMCs, which was induced by HFD in the mouse aorta, and attenuated EC and VSMC dysfunction, an initiation factor of atherosclerosis.

Pyrogallol-Phloroglucinol-6,6-Bieckolon Attenuates Vascular Smooth Muscle Cell Proliferation and Phenotype Switching in Hyperlipidemia through Modulation of Chemokine Receptor 5.

Hyperlipidemia induces vascular smooth muscle cell (VSMC) proliferation and phenotype switching from contractile to synthetic. This process is involved in arterial remodeling via the chemokine ligand 5 (CCL5)/chemokine receptor 5 (CCR5) pathway. Arterial remodeling is related to atherosclerosis or intimal hyperplasia. The purpose of this study was to evaluate whether pyrogallol-phloroglucinol-6,6-bieckol (PPB) from E. cava reduces VSMC proliferation and phenotype switching via the CCL5/CCR5 pathway. The CCL5/CCR5 expression, VSMC proliferation and phenotypic alterations were evaluated using a cell model of VSMC exposed in hyperlipidemia, and an animal model of mice fed a high-fat-diet (HFD). The expression of CCL5/CCR5 increased in both the cell and animal models of hyperlipidemia. Treatment with PPB decreased CCL5/CCR5 expression in both models. The expression of contractile markers of VSMCs, including alpha-smooth muscle actin (α-SMA), smooth muscle myosin heavy chain (SM-MHC), and smooth muscle protein 22 alpha (SM22α), were decreased by hyperlipidemia and restored after treatment with PPB. The silencing of CCR5 attenuated the effects of PPB treatment. VSMC proliferation and the intima-media thickness of the aortas, increased with HFD and decreased after treatment with PPB. The VSMC proliferation ratio and messenger ribonucleic acid (mRNA) expression of cell cycle regulatory factors increased in the in vitro model and were restored after treatment with PPB. PPB treatment reduced VSMC proliferation and phenotype switching induced by hyperlipidemia through inhibition of the CCL5/CCR5 pathway.

Pyrogallol-Phloroglucinol-6,6-Bieckol Alleviates Obesity and Systemic Inflammation in a Mouse Model by Reducing Expression of RAGE and RAGE Ligands.

Ecklonia cava (E. cava) can alleviate diet-induced obesity in animal models, and phlorotannins contained in E. cava help prevent hypertrophy-induced adipocyte differentiation. Receptor for advanced glycation end-products (RAGE) is well known to induce hypertrophy of visceral fat and to trigger inflammation substantially. While the relationship between RAGE and obesity and inflammation has been well-characterized, few studies describe the effects of phlorotannin on RAGE. In this study, we investigated the anti-obesity effects of pyrogallol-phloroglucinol-6,6-bieckol (PPB)-a single compound from the ethanoic extract of E. cava-mediated by a reduction in the inflammation caused by RAGE and RAGE ligands. In visceral fat, PPB (i) significantly inhibited RAGE ligands, (ii) reduced the expression of RAGE, and (iii) reduced the binding ratio between RAGE and RAGE ligands. Under lower expression of RAGE, RAGE ligands and their cognate binding, the differentiation of macrophages found in visceral fat into M1-type-the pro-inflammatory form of this immune cell-was reduced. As the M1-type macrophage decreased, pro-inflammatory cytokines, which cause obesity, decreased in visceral fat. The results of this study highlight the anti-obesity effects of PPB, with the effects mediated by reductions in RAGE, RAGE ligands, and inflammation.

Pyrogallol-Phloroglucinol-6,6-Bieckol from Ecklonia cava Attenuates Tubular Epithelial Cell (TCMK-1) Death in Hypoxia/Reoxygenation Injury.

The hypoxia/reoxygenation (H/R) injury causes serious complications after the blood supply to the kidney is stopped during surgery. The main mechanism of I/R injury is the release of high-mobility group protein B1 (HMGB1) from injured tubular epithelial cells (TEC, TCMK-1 cell), which triggers TLR4 or RAGE signaling, leading to cell death. We evaluated whether the extracts of Ecklonia cava (E. cava) would attenuate TEC death induced by H/R injury. We also evaluated which phlorotannin-dieckol (DK), phlorofucofuroeckol A (PFFA), pyrogallol phloroglucinol-6,6-bieckol (PPB), or 2,7-phloroglucinol-6,6-bieckol (PHB)-would have the most potent effect in the context of H/R injury. We used for pre-hypoxia treatment, in which the phlorotannins from E. cava extracts were added before the onset of hypoxia, and a post- hypoxia treatment, in which the phlorotannins were added before the start of reperfusion. PPB most effectively reduced HMGB1 release and the expression of TLR4 and RAGE induced by H/R injury in both pre- and post-hypoxia treatment. PPB also most effectively inhibited the expression of NF-kB and release of the inflammatory cytokines TNF-α and IL-6 in both models. PPB most effectively inhibited cell death and expression of cell death signaling molecules such as Erk/pErk, JNK/pJNK, and p38/pp38. These results suggest that PPB blocks the HGMB1-TLR4/RAGE signaling pathway and decreases TEC death induced by H/R and that PPB can be a novel target for renal H/R injury therapy.

Effect of Ishophloroglucin A, A Component of Ishige okamurae, on Glucose Homeostasis in the Pancreas and Muscle of High Fat Diet-Fed Mice.

Ishophloroglucin A (IPA), a component of Ishige okamurae (IO), was previously evaluated to standardize the antidiabetic potency of IO. However, the potential of IPA as a functional food for diabetes prevention has not yet been evaluated. Here, we investigated if 1.35 mg/kg IPA, which is the equivalent content of IPA in 75 mg/kg IO, improved glucose homeostasis in high-fat diet (HFD)-induced diabetes after 12 weeks of treatment. IPA significantly ameliorated glucose intolerance, reducing fasting glucose levels as well as 2 h glucose levels in HFD mice. In addition, IPA exerted a protective effect on the pancreatic function in HFD mice via pancreatic ß-cells and C-peptide. The level of glucose transporter 4 (GLUT4) in the muscles of HFD mice was stimulated by IPA intake. Our results suggested that IPA, which is a component of IO, can improve glucose homeostasis via GLUT4 in the muscles of HFD mice. IO may be used as a functional food for the prevention of diabetes.

Pyrogallol-Phloroglucinol-6,6'-Bieckol from Ecklonia cava Improved Blood Circulation in Diet-Induced Obese and Diet-Induced Hypertension Mouse Models.

Blood circulation disorders, such as hyperlipidemia and arteriosclerosis, are not easily cured by dietary supplements, but they can be mitigated. Although Ecklonia cava extract (ECE), as dietary supplements, are associated with improving the conditions, there are not many studies verifying the same. In this study, the beneficial effect of ECE and leaf of Ginkgo biloba extract (GBE), which is a well-known dietary supplement, were first confirmed in a diet induced-obese model. Afterwards, 4 phlorotannins were isolated from ECE, and their inhibitory effects on vascular cell dysfunction were validated. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) was selected to be orally administered in two mice models: the diet induced obese model and diet induced hypertension model. After four weeks of administration, the blood pressure of all mice was measured, after which they were subsequently sacrificed. PPB was found to significantly improve blood circulation, including a reduction of adhesion molecule expression, endothelial cell (EC) death, excessive vascular smooth muscle cell (VSMC) proliferation and migration, blood pressure, and lipoprotein and cholesterol levels. Based on the excellent efficacy in diet-induced mouse models of obese and hypertension, our results demonstrate that PPB is a valuable active compound from among the phlorotannins that were isolated and it has the potential to be used in functional foods for improving the blood circulation.

Phlorotannins from Ecklonia cava Attenuates Palmitate-Induced Endoplasmic Reticulum Stress and Leptin Resistance in Hypothalamic Neurons.

Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava would attenuate the ER stress induced by palmitate and reduce leptin resistance in hypothalamic neurons and microglia. We added palmitate to these cells to mimic the environment induced by high-fat diet in the hypothalamus and evaluated which of the E. cava phlorotannins-dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol-phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol-A (PFFA)-had the most potent effect on attenuating leptin resistance. TLR4 and NF-κB expression induced by palmitate was attenuated most effectively by PPB in both hypothalamic neurons and microglia. ER stress markers were increased by palmitate and were attenuated by PPB in both hypothalamic neurons and microglia. Leptin resistance, which was evaluated as an increase in SOCS3 and a decrease in STAT3 with leptin receptor expression, was increased by palmitate and was decreased by PPB in hypothalamic neurons. The culture medium from palmitate-treated microglia increased leptin resistance in hypothalamic neurons and this resistance was attenuated by PPB. In conclusion, PPB attenuated leptin resistance by decreasing ER stress in both hypothalamic neurons and microglia.

sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer's disease model.

The main causes of Alzheimer's disease (AD) have not determined and effective treatment has not been developed yet, even though extensive researches and several clinical trials have been conducted.. Fortunately, stem cell transplantation is emerging as a potential therapeutic candidate for AD, but the success of stem cell based therapy depends on the survival of transplanted cells. Here, we generated sRAGE secreting mesenchymal stem cells (sRAGE-MSCs) and then injected these MSCs or control MSCs with amyloid beta 1-42 (Aß1-42) into the entorhinal cortices of male Sprague Dawley rats. The survival of transplanted cell, the number of T lymphocytes and microglia, expression of RAGE and its ligands and neuronal cell death were determined, 4 weeks after sRAGE-MSC transplantation. Transplanted sRAGE-MSCs survived longer than control MSCs and sRAGE-MSCs showed reduced level of CD4 and CD3d positive T lymphocyte. Furthermore, the number of M1 microglia in MSCs was more than that of sRAGE-MSCs as well. On the other hand, the number of M2 microglia in sRAGE-MSCs was increased compared with that of MSCs. In addition, sRAGE-MSCs decreased RAGE and RAGE ligand expressions and their interactions more effectively than those of MSCs. Finally, sRAGE-MSC transplantation protected from apoptosis and prevented decreasing numbers of neuron in Aß1-42 treated rat brains. These observations suggest continuous sRAGE secretion from sRAGE-MSCs might appreciably improve the effectiveness of cell therapy in Aß1-42 injected rat brains.

Protective Effect of Pyrogallol-Phloroglucinol-6,6-Bieckol from Ecklonia cava on Monocyte-Associated Vascular Dysfunction.

Ecklonia cava (E. cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.

Protection against RAGE-mediated neuronal cell death by sRAGE-secreting human mesenchymal stem cells in 5xFAD transgenic mouse model.

Alzheimer's disease (AD), which is the most commonly encountered neurodegenerative disease, causes synaptic dysfunction and neuronal loss due to various pathological processes that include tau abnormality and amyloid beta (Aß) accumulation. Aß stimulates the secretion and the synthesis of Receptor for Advanced Glycation End products (RAGE) ligand by activating microglial cells, and has been reported to cause neuronal cell death in Aß1-42 treated rats and in mice with neurotoxin-induced Parkinson's disease. The soluble form of RAGE (sRAGE) is known to reduce inflammation, and to decrease microglial cell activation and Aß deposition, and thus, it protects from neuronal cell death in AD. However, sRAGE protein has too a short half-life for therapeutic purposes. We developed sRAGE-secreting umbilical cord derived mesenchymal stem cells (sRAGE-MSCs) to enhance the inhibitory effects of sRAGE on Aß deposition and to reduce the secretion and synthesis of RAGE ligands in 5xFAD mice. In addition, these cells improved the viability of injected MSCs, and enhanced the protective effects of sRAGE by inhibiting the binding of RAGE and RAGE ligands in 5xFAD mice. These findings suggest sRAGE protein from sRAGE-MSCs has better protection against neuronal cell death than sRAGE protein or single MSC treatment by inhibiting the RAGE cell death cascade and RAGE-induce inflammation.