Light–dark condition regulates sirtuin mRNA levels in the retina

AbstractSirtuins (Sirt1–7) are nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases/ADP-ribosyltransferases that modulate many metabolic responses affecting aging. Sirtuins expressed in tissues and organs involved in systemic metabolism have been extensively studied. However, the characteristics of sirtuins in the retina, where local energy expenditure changes dynamically in response to light stimuli, are largely unknown. Here we analyzed sirtuin mRNA levels by real-time PCR, and found that all seven sirtuins are highly expressed in the retina compared with other tissues, such as liver. We then analyzed the sirtuin mRNA profiles in the retina over time, under a 12-h light/12-h dark cycle (LD condition) and in constant darkness (DD condition). All seven sirtuins showed significant daily variation under the LD condition, with all except Sirt6 being increased in the dark phase. The expression patterns were different under the DD condition, suggesting that sirtuin mRNA levels except Sirt6 are affected by light–dark condition. These findings were not obtained in the brain and liver. In addition, the mRNA expression patterns of Nicotinamide phosphoribosyltransferase (Nampt), peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and transcription factor A, mitochondrial (Tfam) in the retina, were similar to those of the sirtuins except Sirt6. Our observations provide new insights into the metabolic mechanisms of the retina and the sirtuins' regulatory systems

Donor mesenchymal stem cells trigger chronic graft-versus-host disease following minor antigen-mismatched bone marrow transplantation

Chronic graft-versus-host disease (cGVHD) is a complication after minor antigen mismatched bone marrow transplantation (BMT) characterized by an autoimmune-type reaction in various organs. Aberration in T cell regulation is involved, with donor mesenchymal stem cells (MSCs) playing a possible role in immunomodulation. In a minor-antigen mismatched mouse BMT model, transplantation of mismatched, but not syngeneic MSCs triggered the onset of cGVHD, and was associated with fibrosis, increased IL-6 secretion, decreased Foxp3+ regulatory T cells and increased Th17 in the peripheral blood. Mismatched MSCs alone were sufficient to induce cGVHD, while removal of donor MSCs rescued mice from cGVHD. RAG2 knockout recipient mice did not suffer cGVHD, indicating that host T cells were involved. Residual host-derived T cells were significantly higher in cGVHD patients compared to non-cGVHD patients. In conclusion, donor MSCs react with residual host T cells to trigger the progression of cGVHD

Transcatheter retrieval of an Amplatzer Vascular Plug

Introduction: An Amplatzer Vascular Plug (AVP), which was designed as a permanent occluding device derived from the Amplatzer Septal Occluder and Amplatzer Duct Occluder, is a useful embolic device that can be precisely deployed in medium to large vessels with high resistance to migration. However, migration of these Amplatzer devices has been reported as a relatively rare but major complication. Case report: A 59-year-old woman was referred for the treatment of advanced pancreatic body cancer; after systemic chemotherapy, distal pancreatectomy with en bloc celiac axis resection (DP-CAR) was planned as curative treatment. Therefore, preoperative embolisation of the common hepatic artery (CHA) for arterial redistribution was performed. Although a 6-mm AVP II was deployed at the mid-portion of the CHA, the AVP migrated to the proper hepatic artery. Although migrated AVP retrieval using a goose neck snare was attempted, it was impossible to retrieve it into the 5-F guiding sheath. Therefore, the AVP was delivered to the splenic artery, which was planned to be resected in DP-CAR. Finally, a 10-mm AVP II was redeployed at the proximal portion of the CHA, and complete occlusion was achieved. Conclusions: When AVP retrieval is not possible, delivery to the other arteries having lesser influence might be an alternate technique

Radically Different Thioredoxin Domain Arrangement of ERp46, an Efficient Disulfide Bond Introducer of the Mammalian PDI Family

SummaryThe mammalian endoplasmic reticulum (ER) contains a diverse oxidative protein folding network in which ERp46, a member of the protein disulfide isomerase (PDI) family, serves as an efficient disulfide bond introducer together with Peroxiredoxin-4 (Prx4). We revealed a radically different molecular architecture of ERp46, in which the N-terminal two thioredoxin (Trx) domains with positively charged patches near their peptide-binding site and the C-terminal Trx are linked by unusually long loops and arranged extendedly, forming an opened V-shape. Whereas PDI catalyzes native disulfide bond formation by the cooperative action of two mutually facing redox-active sites on folding intermediates bound to the central cleft, ERp46 Trx domains are separated, act independently, and engage in rapid but promiscuous disulfide bond formation during early oxidative protein folding. Thus, multiple PDI family members likely contribute to different stages of oxidative folding and work cooperatively to ensure the efficient production of multi-disulfide proteins in the ER

Walking and Sports Participation and Mortality From Coronary Heart Disease and Stroke

ObjectivesWe aimed to examine the impact of exercise on mortality from cardiovascular disease (CVD) in Asian populations.BackgroundFew data have been available in Asian countries, where job-related physical activity is higher than that in Western countries.MethodsBetween 1988 and 1990, 31,023 men and 42,242 women in Japan, ages 40 to 79 years with no history of stroke, coronary heart disease (CHD), or cancer, completed a self-administered questionnaire. Systematic mortality surveillance was performed through 1999, and 1,946 cardiovascular deaths were identified. We chose the second lowest categories of walking and sports participation as the reference to reduce a potential effect of ill health.ResultsMen and women who reported having physical activity in the highest category (i.e., walking ≥1 h/day or doing sports ≥5 h/week) had a 20% to 60% lower age-adjusted risk of mortality from CVD, compared with those in the second lowest physical activity category (i.e., walking 0.5 h/day, or sports participation for 1 to 2 h/week). Adjustment for known risk factors, exclusion of individuals who died within two years of baseline inquiry, or gender-specific analysis did not substantially alter these associations. The multivariate-adjusted hazard ratios (95% confidence interval) for the highest versus the second lowest categories of walking or sports participation were 0.71 (0.54 to 0.94) and 0.80 (0.48 to 1.31), respectively, for ischemic stroke (IS); 0.84 (0.64 to 1.09) and 0.51 (0.32 to 0.82), respectively, for CHD; and 0.84 (0.75 to 0.95) and 0.73 (0.60 to 0.90), respectively, for CVD.ConclusionsPhysical activity through walking and sports participation might reduce the risk of mortality from IS and CHD

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors

IntroductionImmune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear.MethodsWe examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules.Results and DiscussionTwelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM

Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics

Cysteine hydropersulfide (CysSSH) occurs in abundant quantities in various organisms, yet little is known about its biosynthesis and physiological functions. Extensive persulfide formation is apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is believed to result from post-translational processes involving hydrogen sulfide-related chemistry. Here we demonstrate effective CysSSH synthesis from the substrate l-cysteine, a reaction catalyzed by prokaryotic and mammalian cysteinyl-tRNA synthetases (CARSs). Targeted disruption of the genes encoding mitochondrial CARSs in mice and human cells shows that CARSs have a crucial role in endogenous CysSSH production and suggests that these enzymes serve as the principal cysteine persulfide synthases in vivo. CARSs also catalyze co-translational cysteine polysulfidation and are involved in the regulation of mitochondrial biogenesis and bioenergetics. Investigating CARS-dependent persulfide production may thus clarify aberrant redox signaling in physiological and pathophysiological conditions, and suggest therapeutic targets based on oxidative stress and mitochondrial dysfunction

Dietary Lactoferrin Alleviates Age-Related Lacrimal Gland Dysfunction in Mice

BACKGROUND: Decrease in lacrimal gland secretory function is related to age-induced dry eye disease. Lactoferrin, the main glycoprotein component of tears, has multiple functions, including anti-inflammatory effects and the promotion of cell growth. We investigated how oral administration of lactoferrin affects age-related lacrimal dysfunction. METHODS AND FINDINGS: Twelve-month-old male C57BL/6Cr Slc mice were randomly divided into a control fed group and an oral lactoferrin treatment group. Tear function was measured at a 6-month time-point. After euthanasia, the lacrimal glands were subjected to histological examination with 8-hydroxy-2'-deoxyguanosine (8-OHdG) antibodies, and serum concentrations of 8-OHdG and hexanoyl-lysine adduct (HEL) were evaluated. Additionally, monocyte chemotactic protein-1(MCP-1) and tumor necrosis factor-α (TNF-α) gene expression levels were determined by real-time PCR. The volume of tear secretion was significantly larger in the treated group than in the control. Lactoferrin administration reduced inflammatory cell infiltration and the MCP-1 and TNF-α expression levels. Serum concentrations of 8-OHdG and HEL in the lactoferrin group were lower than those in the control group and were associated with attenuated 8-OHdG immunostaining of the lacrimal glands. CONCLUSION: Oral lactoferrin administration preserves lacrimal gland function in aged mice by attenuating oxidative damage and suppressing subsequent gland inflammation