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Nephrotic syndrome (NS) is a renal disorder that is characterized by massive proteinuria, hypoalbuminemia and edema. One of the main causes of NS is focal segmental glomerulosclerosis (FSGS), which has extremely poor prognosis. Although steroids and immunosuppressants are the first line of treatment, some FSGS cases are refractory, prompting the need to find new therapeutic strategies. We have previously demonstrated that an optimized combination treatment of mild electrical stimulation (MES) and heat shock (HS) has several biological benefits including the amelioration of the pathologies of the genetic renal disorder Alport syndrome. Here, we investigated the effect of MES + HS on adriamycin (ADR)-induced NS mouse model. MES + HS suppressed proteinuria and glomerulosclerosis induced by ADR. The expressions of pro-inflammatory cytokines and pro-fibrotic genes were also significantly downregulated by MES + HS. MES + HS decreased the expression level of cleaved caspase-3 and the number of TUNEL-positive cells, indicating that MES + HS exerted anti-apoptotic effect. Moreover, MES + HS activated the Akt signaling and induced the phosphorylation and inhibition of the apoptotic molecule BAD. In in vitro experiment, the Akt inhibitor abolished the MES + HS-induced Akt-BAD signaling and anti-apoptotic effect in ADR-treated cells. Collectively, our study suggested that MES + HS modulates ADR-induced pathologies and has renoprotective effect against ADR-induced NS via regulation of Akt-BAD axis.

Background: Because of the increasing number of diabetic patients, it is important to generate pancreatic and duodenal homeobox gene 1 (Pdx1)-expressing cells, which are capable of differentiating into pancreatic endocrine β cells. Mild electrical stimulation was reported to modulate the differentiation of ES cells into ectoderm-derived neuronal cells or mesoderm-derived cardiac cells., Results: In this study, we report that mild electrical stimulation with heat shock (MET) potentiates the differentiation of ES cells into definitive endoderm-derived Pdx1-expressing cells. MET has no effect when applied to early definitive endoderm on differentiation day 5. A 1.87-fold increase in the proportion of Pdx1-expressing cells was observed when stimulation was applied to the late definitive endoderm one day prior to the immergence of Pdx1/GFP-expressing cells on differentiation day 7. Pdx1 mRNA was also up-regulated by MET. The potentiating effect of MET synergized with activin and basic fibroblast growth factor into Pdx1-expressing cells. Moreover, MET stimulation on late definitive endoderm up-regulated heat shock protein 72 and activated various kinases including Akt, extracellular signal-regulated kinase, p38, and c-jun NH 2 -terminal kinase in ES cells., Conclusions: Our findings indicate that MET induces the differentiation of Pdx1-expressing cells within the definitive endoderm in a time-dependent manner, and suggest useful application for regenerative medicine.

Electrical current at physiological strength has been applied as a therapeutic approach for various diseases. Several of our works showed that mild electrical stimulation (MES) at 0.1-ms pulse width has positive impact on organisms. But despite the growing evidence of the beneficial effects of MES, its effects on individual animals and the molecular underpinnings are poorly understood and rarely studied. Here, we examined the effects of MES on individual animal and its mechanisms by mainly using Caenorhabditis elegans, a powerful genetic model organism. Interestingly, MES increased stress resistance and suppressed excess fat accumulation in wild-type N2 worms but not in AMPK/AAK-2 and LKB1/PAR-4 mutant worms. MES promoted the nuclear localization of transcription factors DAF-16 and SKN-1 and consequently increased the expression of anti-stress genes, whereas MES inhibited the nuclear localization of SBP-1 and suppressed the expression of lipogenic genes. Moreover, we found that MES induced the activation of LKB1/PAR4-AMPK/AAK2 pathway in C. elegans and in several mammalian cell lines. The mitochondrial membrane potential and cellular ATP level were slightly and transiently decreased by MES leading to the activation of LKB1-AMPK signaling pathway. Together, we firstly and genetically demonstrated that MES exerts beneficial effects such as stress resistance and suppression of excess fat accumulation, via activation of LKB1-AMPK signaling pathway.

Insulin resistance is due to the reduced cellular response to insulin in peripheral tissues. The interaction of insulin with its receptor is the first step in insulin action and thus the identified target of insulin resistance. It has been well established that defects or mutations in the insulin receptor (IR) cause insulin resistance. Therefore, an IR activator might be a novel therapeutic approach for insulin resistance. Our previous report showed that mild electrical stress (MES) enhanced the insulin-induced signaling pathway. However, the molecular mechanism of the effect of MES remains unclear. We assessed the effect of MES, which is characterized by low-intensity direct current, on insulin signaling in vitro and in vivo. Here, we showed that MES activated the insulin signaling in an insulin-independent manner and improved insulin resistance in peripheral tissues of high fat-fed mice. Moreover, we found that MES increased the localization of IR in lipid rafts and enhanced the level of phosphorylated Akt in insulin-resistant hepatic cells. Ablation of lipid rafts disrupted the effect of MES on Akt activation. Our findings indicate that MES has potential as an activator of IR in an insulin-independent manner, and might be beneficial for insulin resistance in type 2 diabetes., (Copyright © 2012 Wiley Periodicals, Inc.)

Activation of Akt by insulin is transmitted via phosphatidylinositol-3-OH kinase (PI-3K) and enhances glucose uptake. The PI-3K/Akt signaling is diminished in insulin resistance. Thus, approaches that activate PI-3K/Akt signaling leading to improved glucose uptake may ameliorate hyperglycemia. Here we showed that low-intensity electrical current or mild electrical stimulation (MES) activated the PI-3K/Akt signaling and increased the glucose uptake in rat skeletal muscle (L6) cells. The glucose uptake enhanced by MES in muscle cells, the major cells involved in glucose disposal, suggests MES may have a possible beneficial effect on hyperglycemia.

Background: Hepatic ischemia/reperfusion (I/R) injury is a pathologic process caused by hepatic surgery and transplantation, and still remains a severe clinical problem. It was shown that preconditioning by hyperthermia might protect tissues against I/R injury. But hyperthermia could be laborious and time-consuming. Alternatively, the application of mild electrical stimulation (MES) has been reported to have positive effects in clinical settings on several medical ailments. Thus, we modified the preconditioning approach by combining short-term mild heat shock (HS) and MES, and evaluated the effect of HS+MES pretreatment on hepatic injury induced by I/R., Materials and Methods: C57BL/6J mice were sham treated or treated three times with HS (42 degrees C) and/or MES (12V) for 20min, carried out every other d within 1 wk. After the last treatment, mice were subjected to hepatic ischemia for 30 or 60min and reperfusion for 6h. Liver injury was assessed by evaluating the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The expressions of pro-inflammatory cytokines and heat shock protein (Hsp) 72 in liver tissues were also assessed by real-time PCR and Western blotting analyses, respectively., Results: HS+MES pretreatment suppressed the hepatic I/R-induced release of serum AST and ALT and the mRNA levels of some pro-inflammatory cytokines. In addition, HS+MES up-regulated the expression of Hsp72 in mice liver., Conclusions: HS+MES preconditioning ameliorated hepatic I/R injury possibly through Hsp72 induction, and suppressed pro-inflammatory cytokine expression in mice liver., (Copyright 2010 Elsevier Inc. All rights reserved.)

Different modes of exogenous electrical stimulation at physiological strength has been applied to various diseases. Previously, we extensively demonstrated the usability of mild electrical stimulation (MES) with low frequency pulse current at 55 pulses per second (MES55) for several disease conditions. Here we found that MES with high frequency pulse-current (5500 pulse per second; MES5500) suppressed the overproduction of pro-inflammatory cytokines induced by phorbol myristate acetate/ionomycin in Jurkat T cells and primary splenocytes. MES5500 also suppressed the overproduction of inflammatory cytokines, improved liver damage and reduced mouse spleen enlargement in concanavalin-A-treated BALB/c mice. The molecular mechanism underlying these effects included the ability of MES5500 to induce modest amount of hydrogen peroxide and control multiple signaling pathways important for immune regulation, such as NF-κB, NFAT and NRF2. In the treatment of various inflammatory and immune-related diseases, suppression of excessive inflammatory cytokines is key, but because immunosuppressive drugs used in the clinical setting have serious side effects, development of safer methods of inhibiting cytokines is required. Our finding provides evidence that physical medicine in the form of MES5500 may be considered as a novel therapeutic tool or as adjunctive therapy for inflammatory and immune-related diseases. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic skin disease caused by immune disorder. The chronic skin inflammation involves inflammatory molecules that are released from T lymphocytes and keratinocytes. Therefore, developing an anti‐inflammatory therapy that is suitable for long‐term treatment is needed. Electrical stimulation induces biological responses by modulating intracellular signaling pathways. Our previous studies showed that the optimized combination treatment of mild electrical stimulation (MES, 0.1‐millisecond; ms, 55‐pulses per second; pps) and heat shock (HS, 42°C) modulates inflammatory symptoms of metabolic disorders and chronic kidney disease in mice models and clinical trials. Here, we investigated the effect of MES+HS treatment on imiquimod‐induced psoriasis mouse model. Topical application of imiquimod cream (15 mg) to mice ear induced keratinocyte hyperproliferation and psoriasis‐like inflammation. In MES+HS‐treated mice, imiquimod‐induced skin hyperplasia was significantly decreased. MES+HS treatment reduced the protein expression of IL‐17A and the infiltration of CD3‐positive cells in lesioned skin. In addition, MES+HS‐treated mice had decreased mRNA expression level of antimicrobial molecules (S100A8 and Reg3γ) which aggravate psoriasis. In IL‐17A‐stimulated HaCaT cells, MES+HS treatment significantly lowered the mRNA expression of aggravation markers (S100A8, S100A9 and β‐defensin2). Taken together, our study suggested that MES+HS treatment improves the pathology of psoriasis via decreasing the expression of inflammatory molecules. [ABSTRACT FROM AUTHOR]

The objective of this study is to investigate the effects of mild electrical stimulation (MES) and heat stress (HS) on heat shock protein 70 (HSP70), that protects chondrocytes and enhances cartilage matrix metabolism, in chondrocyte and articular cartilage. Rabbit articular chondrocytes were treated with MES and/or HS. The safeness was assessed by LDH assay and morphology. HSP70 protein, ubiquitinated proteins and HSP70 mRNA were examined by Western blotting and real-time PCR. Rat knee joints were treated with MES and/or HS. HSP70 protein, ubiquitinated proteins, HSP70 mRNA and proteoglycan core protein (PG) mRNA in articular cartilage were investigated. In vitro, HS increased HSP70 mRNA and HSP70 protein. MES augmented ubiquitinated protein and HSP70 protein, but not HSP70 mRNA. MES + HS raised HSP70 mRNA and ubiquitinated protein, and significantly increased HSP70 protein. In vivo, HS and MES + HS treatment augmented HSP70 mRNA. HS modestly augmented HSP70 protein. MES + HS significantly increased HSP70 protein and ubiquitinated proteins. PG mRNA was markedly raised by MES + HS. This study demonstrated that MES, in combination with HS, increases HSP70 protein in chondrocytes and articular cartilage, and promotes cartilage matrix metabolism in articular cartilage. MES in combination with HS can be a novel physical therapy for osteoarthritis by inducing HSP70 in articular cartilage. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 894-900, 2013 [ABSTRACT FROM AUTHOR]

This review discusses the basic concepts, effects and applications of hyperthermia and mild electrical stimulation (MES) using low-intensity direct current. It also proposes a novel combinatorial use of MES and hyperthermia, and briefly outlines the rationale and the effects of MES and hyperthermia combination treatment on certain diseases (diabetes, hepatic ischaemia/reperfusion injury and gastric ulcer). The integrated modalities of MES and hyperthermia might find therapeutic applications to stress-induced diseases and intractable diseases of dysregulated signalling pathways. [ABSTRACT FROM AUTHOR]

Summary: Objective: Obesity induces chronic inflammation, which contributes to the development and progression of insulin resistance, diabetes and atherosclerosis. We have recently shown that induction of heat shock protein 72 by mild electric current and thermo (MET) treatment in mouse model of type 2 diabetes ameliorated glucose homeostasis and insulin resistance accompanied by reduced adiposity. For clinical application of MET, we confirmed its safety in healthy subjects. Methods: MET was applied for 10 healthy Japanese male (12V, 55pulses/s, 30min at 42°C) twice a week for 8 weeks. Fat volume was measured by CT scan and several parameters were investigated. Results: MET did not induce any adverse effects nor muscle contraction/pain. There were no significant alterations in glucose homeostasis or insulin resistance. Visceral and subcutaneous fat volume showed a trend of decrease without significant difference (−3.9% and −4.3%, respectively), which were restored 8 weeks after withdrawal of MET. Interestingly, serum tumor necrosis factor-α (TNF-α: 0.91±0.05pg/mL vs. 0.67±0.06pg/mL; p =0.006) and high sensitivity C-reactive protein (hs-CRP: 521.9±73.9ng/mL vs. 270.8±43.7ng/mL; p =0.023) levels, both of which are associated with chronic inflammation, were significantly decreased. Conclusion: MET may be beneficial for the reduction of an inflammatory response observed in diabetes and metabolic syndrome. [Copyright &y& Elsevier]