Hydrogen-rich water protects against liver injury in nonalcoholic steatohepatitis through HO-1 enhancement via IL-10 and Sirt 1 signaling.

Nonalcoholic steatohepatitis (NASH) could progress to hepatic fibrosis in the absence of effective control. The purpose of our experiment was to investigate the protective effect of drinking water with a high concentration of hydrogen, namely, hydrogen-rich water (HRW), on mice with nonalcoholic fatty liver disease to elucidate the mechanism underlying the therapeutic action of molecular hydrogen. The choline-supplemented, l-amino acid-defined (CSAA) or the choline-deficient, l-amino acid-defined (CDAA) diet for 20 wk was used to induce NASH and fibrosis in the mice model and simultaneously treated with the high-concentration 7-ppm HRW for different periods (4 wk, 8 wk, and 20 wk). Primary hepatocytes were stimulated by palmitate to mimic liver lipid metabolism during fatty liver formation. Primary hepatocytes were cultured in a closed vessel filled with 21% O2 + 5% CO2 + 3.8% H2 and N2 as the base gas to verify the response of primary hepatocytes in a high concentration of hydrogen gas in vitro. Mice in the CSAA + HRW group had lower serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and milder histological damage. The inflammatory cytokines were expressed at lower levels in the HRW group than in the CSAA group. Importantly, HRW reversed hepatocyte fatty acid oxidation and lipogenesis as well as hepatic inflammation and fibrosis in preexisting hepatic fibrosis specimens. Molecular hydrogen inhibits the lipopolysaccharide-induced production of inflammation cytokines through increasing heme oxygenase-1 (HO-1) expression. Furthermore, HRW improved hepatic steatosis in the CSAA + HRW group. Sirtuin 1 (Sirt1) induction by molecular hydrogen via the HO-1/adenosine monophosphate activated protein kinase (AMPK)/peroxisome proliferator-activated receptor α (PPARα)/peroxisome proliferator-activated receptor γ (PPAR-γ) pathway suppresses palmitate-mediated abnormal fat metabolism. Orally administered HRW suppressed steatosis induced by CSAA and attenuated fibrosis induced by CDAA, possibly by reducing oxidative stress and the inflammation response.NEW & NOTEWORTHY The mRNA expression of inflammatory cytokines in the HRW group was lower than in the CSAA group. HRW reversed hepatocyte apoptosis as well as hepatic inflammation and fibrosis in NASH specimens. Molecular hydrogen inhibits LPS-induced inflammation via an HO-1/interleukin 10 (IL-10)-independent pathway. HRW improved hepatic steatosis in the CSAA + HRW group. Sirt1 induction by molecular hydrogen via the HO-1/AMPK/PPARα/PPARγ pathway suppresses palmitate-mediated abnormal fat metabolism.

Oral administration of 5-aminolevulinic acid induces heme oxygenase-1 expression in peripheral blood mononuclear cells of healthy human subjects in combination with ferrous iron.

Heme oxygenase-1 (HO-1) is a major anti-inflammatory enzyme and a key regulator that induces immune tolerance through affecting the differentiation of dendritic cells. The aim of this study is to determine whether the combination of 5-aminolevulinic acid (ALA) and iron induces HO-1 expression in healthy human peripheral blood mononuclear cells (PBMC). The study was an open labeled, non-randomized, non-placebo-controlled trial using healthy male adults and consisted of three parts. Study A aimed to find the peak HO-1 expression at 0, 1, 2, 3, 4, 6, 8, 12, 16, and 24 h after administration. Study B aimed to examine HO-1 dose dependency at 150, 300, and 600 mg of ALA and the need for iron supplementation. Study C aimed to investigate HO-1 changes during a three-day, repetitive administration of ALA and iron. The combination of ALA 600 mg and sodium ferrous citrate (SFC) 942 mg upregulated HO-1 in PBMC at 8 h after administration while sole administration of ALA or SFC was unable to induce HO-1. HO-1 in blood myeloid and plasmacytoid dendritic cells was also upregulated with ALA+SFC. Clear dose dependency of ALA+SFC was not detected, and a slight tendency towards a cumulative effect of HO-1 after three-day, repetitive administration was observed. ALA, which is already approved for use in several countries as a diagnosis agent for cancer, has the potential to become a novel therapeutic drug for diseases stemming from unwanted immune response such as autoimmune diseases and the rejection response following organ transplantation.

Preservation of rat limbs by hyperbaric carbon monoxide and oxygen.

Cold ischemia times ranging from <6 h to as long as 24 h are generally quoted as the limits for attempting the replantation of amputated extremities. In this study, we aimed to assess the effect of hyperbaric carbon monoxide (CO) and oxygen (O2) on rat limb preservation. Donor rat limbs were preserved in a chamber filled with hyperbaric CO and O2 for 3 days (CO + O2 3 days) or 7 days (CO + O2 7 days). Positive and negative control groups were created by using non-preserved limbs (NP) and limbs wrapped in saline-moistened gauze for 3 days (SMG 3 days), respectively. The survival rate of transplanted limbs at postoperative day 90 was 88% in the NP and 86% in the CO + O2 3 days. The corresponding survival rate was 50% in the CO + O2 7 days at postoperative day 90 but was 0% in the SMG 3 days at postoperative day 3. Muscle mass decreased in the CO + O2 3 days and CO + O2 7 days compared with the NP, but sciatic-tibial nerve conduction velocities did not differ. These results indicate that amputated extremities preservation with hyperbaric CO and O2 could extend the time limits of preservation, maintaining their viability for replantation.

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury.

Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe(2+)), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe(2+) 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe(2+) increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe(2+) treatments significantly decreased the tubular damage and number of apoptotic cells. IRI-induced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe(2+) group. Furthermore, mRNA expression of HO-1, TNF-α, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-α and interferon-γ were decreased in the 5-ALA/Fe(2+)-pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/Fe(2+) can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.

Curcumin has bright prospects for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). It is associated with a variety of pathophysiological features, including breakdown of the blood-brain barrier (BBB), autoimmune attack, injury of axons and myelin sheaths. Th17 cells are considered as a key immunological player for the pathophysiological process of MS. Neuroprotective approaches work best prior to the initiation of damage, suggesting that some safe and effective prophylaxis would be highly desirable. Curcumin, a dietary spice from turmeric, has outstanding anti-inflammation and neuroprotective effects. Herein, we review key features of curcumin involved biology, pharmacology, and medicinal chemistry and discuss its potential relevance to pathophysiological progress of MS.

Chinese herbal medicines as adjuvant treatment during chemo- or radio-therapy for cancer.

Numerous studies have indicated that in cancer treatment Chinese herbal medicines in combination with chemo- or radio-therapy can be used to enhance the efficacy of and diminish the side effects and complications caused by chemo- and radio-therapy. Therefore, an understanding of Chinese herbal medicines is needed by physicians and other health care providers. This review provides evidence for use of Chinese herbal medicines as adjuvant cancer treatment during chemo- or radio-therapy. First, Chinese herbal medicines (e.g. Astragalus, Turmeric, Ginseng, TJ-41, PHY906, Huachansu injection, and Kanglaite injection) that are commonly used by cancer patients for treating the cancer and/or reducing the toxicity induced by chemo- or radio-therapy are discussed. Preclinical and clinical studies have shown that these Chinese herbal medicines possess great advantages in terms of suppressing tumor progression, increasing the sensitivity of chemo- and radio-therapeutics, improving an organism's immune system function, and lessening the damage caused by chemo- and radio-therapeutics. Second, clinical trials of Chinese herbal medicines as adjuvant cancer treatment are reviewed. By reducing side effects and complications during chemo- and radio-therapy, these Chinese herbal medicines have a significant effect on reducing cancer-related fatigue and pain, improving respiratory tract infections and gastrointestinal side effects including diarrhea, nausea, and vomiting, protecting liver function, and even ameliorating the symptoms of cachexia. This review should contribute to an understanding of Chinese herbal medicines as adjuvant treatment for cancer and provide useful information for the development of more effective anti-cancer drugs.

Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production.

Experimental autoimmune encephalomylitis (EAE), an animal mode of multiple sclerosis (MS), was previously considered that be mediated by Th1 cells. However, a number of recent studies provided strong evidence that T helper cells that produce IL-17 play a dominant role in the pathogenesis of EAE. Curcumin (1,7-Bis 94-hydroxy-3-methoxyphenyl)-1,6 heptadiene-3, 5-di-one) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has been strongly implicated as an anti-inflammatory agent, but the precise mechanisms of its action are largely unknown. In the present study, we have investigated the efficacy and mechanism of curcumin against EAE. The treatment of Lewis rats with curcumin significantly reduced the clinical severity of EAE, and had a dramatic reduction in the number of inflammatory cells infiltration in the spinal cord. The proliferation of the MBP-reaction lymphocyte also was reduced in a curcumin dose-dependent manner. Furthermore, the mRNA expression of the cytokine profiles was assessed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), revealing the dramatic decrease of IL-17, TGF-beta, IL-6, IL-21, STAT3, and RORgammat expression in curcumin-treated groups and STAT3-phosphorylation also was inhibited. These findings indicated that curcumin amelioration EAE was, to a large extent, due to inhibit differentiation and development of Th17 cells depends on down-regulating expression of IL-6, IL-21, RORgammat signaling and inhibition STAT3-phosphorylation, suggests it is useful in the treatment of MS and other Th17 cell-mediated inflammatory diseases.

Lysophosphatidylcholine upregulates LOX-1, chemokine receptors, and activation-related transcription factors in human T-cell line Jurkat.

In arteriosclerosis, activated T cells infiltrating the atherosclerotic lesions are directly involved in the pathogenesis of these vascular disorders. Infiltration and accumulation of T cells into the vascular wall occur at the earliest stage of atherosclerosis. The atherosclerotic lesion also sees the accumulation of modified lipids such as lysophosphatidylcholine (lysoPC), the main phospholipid component of oxidized low-density lipoprotein. However, it remains less clear how lysoPC affects CD4 T cells. Therefore, we assessed the effect of lysoPC on various mRNA expressions in human T cells using real-time quantitative Reverse Transcription-PCR. Exposure of Jurkat cells (a human CD4 T-cell line) to lysoPC resulted in upregulation of CXCR4 and CCR5 chemokine receptors, receptor for oxidized low-density lipoprotein (LOX-1), the transcription factors, nuclear factor-kappa beta (NF-kB) and Yin Yang 1, and target molecules of NF-kB, A1/Bfl1/BCL2A1 and c-IAP1/BIRC2, in a dose-dependent manner. These data indicate that lysoPC is a positive regulator of the inflammatory response in human CD4 T cells. Further, it suggested that lysoPC and CD4 T cells accumulating in atherosclerotic lesions contribute to the development of arteriosclerosis.

Green-tea polyphenol (-)-epigallocatechin-3-gallate provides resistance to apoptosis in isolated islets.

BACKGROUND/PURPOSE: Apoptosis resulting from disruption of the normal cell-matrix relationship (anoikis) during islet isolation, and the reactive oxygen and nitrogen species generated following hypoxia/reoxygenation (H/R) can lead to a loss of islet tissue in culture and the reduced survival of transplanted pancreatic islets. The aim of this study was to investigate the effect of (-)-epigallocatechin-3-gallate (EGCG), a well-known antiapoptotic agent, on inhibiting anoikis and H/R injury in an in vitro islet culture system. METHODS: Islets were isolated from F344 rats and cultured under normal or H/R condition with/without EGCG. RESULTS: EGCG inhibited apoptosis and lactate-dehydrogenase leakage from anoikis and H/R in a dose-dependent manner. Further, EGCG prevent increases in 8-hydroxy-2'-deoxyguanosine content and inhibited the decline of insulin secretory function induced by H/R. CONCLUSIONS: These results suggest that the addition of EGCG to an islet culture system may improve the survival rate of isolated islets and reduce the loss of functional islet mass that compromises the stable reversal of diabetes after islet transplantation.