The role of the rice aquaporin Lsi1 in arsenite efflux from roots

When supplied with arsenate (As(V)), plant roots extrude a substantial amount of arsenite (As(III)) to the external medium through as yet unidentified pathways. The rice (Oryza sativa) silicon transporter Lsi1 (OsNIP2;1, an aquaporin channel) is the major entry route of arsenite into rice roots. Whether Lsi1 also mediates arsenite efflux was investigated. Expression of Lsi1 in Xenopus laevis oocytes enhanced arsenite efflux, indicating that Lsi1 facilitates arsenite transport bidirectionally. Arsenite was the predominant arsenic species in arsenate-exposed rice plants. During 24-h exposure to 5 mu M arsenate, rice roots extruded arsenite to the external medium rapidly, accounting for 60-90% of the arsenate uptake. A rice mutant defective in Lsi1 (lsi1) extruded significantly less arsenite than the wild-type rice and, as a result, accumulated more arsenite in the roots. By contrast, Lsi2 mutation had little effect on arsenite efflux to the external medium. We conclude that Lsi1 plays a role in arsenite efflux in rice roots exposed to arsenate. However, this pathway accounts for only 15-20% of the total efflux, suggesting the existence of other efflux transporters

Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy

There is a hot debate concerning actual amount of albumin filtered through glomeruli and reabsorbed at proximal tubules in normal kidneys and diabetic conditions. To overcome current technical problems, we generated a drug-inducible megalin knockout mouse line, megalin(lox/lox);Ndrg1-CreER[T2] (or iMegKO), whose protein reabsorption can be shut off anytime by tamoxifen (Tam). After Tam administration, renal megalin protein expression was reduced by 92% compared to wild-type C57BL/6J mice, and renal reabsorption of intravenously-injected retinol binding protein was almost completely abrogated. Urinary albumin excretion increased to 175 μg/day (0.460 mg/mg-creatinine), suggesting that this was the amount of total nephron albumin filtration. Glomerular sieving coefficient of albumin was 1.7 x 10[-5]. By comparing streptozotocin-induced, Tam-treated, diabetic STZ;iMegKO mice with non-STZ;iMegKO mice, we estimated that daily albumin filtration was increased by 1.9-fold, reabsorption was increased by 1.8-fold, and reabsorption efficiency was reduced to 86% by development of diabetes (versus 96% in control). Such abnormalities were well normalized after insulin treatment. Another type 1 diabetic model of Akita;iMegKO mice showed equivalent results. This study reveals actual values and changes of albumin filtration and reabsorption in early diabetic nephropathy, bringing new insights into our understanding of renal albumin dynamics in hyperfiltration status of diabetic nephropath

Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition

Guanylyl cyclase-A (GC-A) signaling, a natriuretic peptide receptor, exerts renoprotective effects by stimulating natriuresis and reducing blood pressure. Previously we demonstrated massive albuminuria with hypertension in uninephrectomized, aldosterone-infused, and high salt-fed (ALDO) systemic GC-A KO mice with enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in podocytes. In the present study, we examined the interaction between p38 MAPK and GC-A signaling. The administration of FR167653, p38 MAPK inhibitor, reduced systolic blood pressure (SBP), urinary albumin excretion, segmental sclerosis, podocyte injury, and apoptosis. To further investigate the local action of natriuretic peptide and p38 MAPK in podocytes, we generated podocyte-specific (pod) GC-A conditional KO (cKO) mice. ALDO pod GC-A cKO mice demonstrated increased urinary albumin excretion with marked mesangial expansion, podocyte injury and apoptosis, but without blood pressure elevation. FR167653 also suppressed urinary albumin excretion without reducing SBP. Finally, we revealed that atrial natriuretic peptide increased phosphorylation of MAPK phosphatase-1 (MKP-1) concomitant with inhibited phosphorylation of p38 MAPK in response to MAPK kinase 3 activation, thereby resulting in decreased mRNA expression of the apoptosis-related gene, Bax, and Bax/Bcl2 ratio in cultured podocytes. These results indicate that natriuretic peptide exerts a renoprotective effect via inhibiting phosphorylation of p38 MAPK in podocytes.</p

A circulating subset of iNKT cells mediates antitumor and antiviral immunity

新規の循環型iNKT細胞を発見 --抗腫瘍・抗ウイルス感染効果の高い免疫細胞療法の開発への貢献に期待--. 京都大学プレスリリース. 2022-10-24.Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244⁻CXCR6⁻), C1 (CD244⁻CXCR6⁺), or C2 (CD244⁺CXCR6⁺) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell–like features, whereas C1 iNKT cells showed more T cell–like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244⁺CXCR6⁺ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell–like properties distinct from conventional tissue-resident iNKT cells

N- and C-terminal Upf1 phosphorylations create binding platforms for SMG-6 and SMG-5:SMG-7 during NMD

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades mRNAs containing premature termination codons (PTCs). SMG-1-mediated Upf1 phosphorylation takes place in the decay inducing complex (DECID), which contains a ribosome, release factors, Upf1, SMG-1, an exon junction complex (EJC) and a PTC-mRNA. However, the significance and the consequence of Upf1 phosphorylation remain to be clarified. Here, we demonstrate that SMG-6 binds to a newly identified phosphorylation site in Upf1 at N-terminal threonine 28, whereas the SMG-5:SMG-7 complex binds to phosphorylated serine 1096 of Upf1. In addition, the binding of the SMG-5:SMG-7 complex to Upf1 resulted in the dissociation of the ribosome and release factors from the DECID complex. Importantly, the simultaneous binding of both the SMG-5:SMG-7 complex and SMG-6 to phospho-Upf1 are required for both NMD and Upf1 dissociation from mRNA. Thus, the SMG-1-mediated phosphorylation of Upf1 creates a binding platforms for the SMG-5:SMG-7 complex and for SMG-6, and triggers sequential remodeling of the mRNA surveillance complex for NMD induction and recycling of the ribosome, release factors and NMD factors

Hydrogen in Drinking Water Reduces Dopaminergic Neuronal Loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model of Parkinson's Disease

It has been shown that molecular hydrogen (H2) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H2-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration-dependency of H2 showed that H2 as low as 0.08 ppm had almost the same effect as saturated H2 water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H2-containing water, whereas production of superoxide (O2•−) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H2 in drinking water can reduce oxidative stress in the brain. Thus, drinking H2-containing water may be useful in daily life to prevent or minimize the risk of life style-related oxidative stress and neurodegeneration

Percutaneous coronary intervention using new-generation drug-eluting stents versus coronary arterial bypass grafting in stable patients with multi-vessel coronary artery disease: From the CREDO-Kyoto PCI/CABG registry Cohort-3

AIMS: There is a scarcity of studies comparing percutaneous coronary intervention (PCI) using new-generation drug-eluting stents (DES) with coronary artery bypass grafting (CABG) in patients with multi-vessel coronary artery disease. METHODS AND RESULTS: The CREDO-Kyoto PCI/CABG registry Cohort-3 enrolled 14927 consecutive patients who underwent first coronary revascularization with PCI or isolated CABG between January 2011 and December 2013. The current study population consisted of 2464 patients who underwent multi-vessel coronary revascularization including revascularization of left anterior descending coronary artery (LAD) either with PCI using new-generation DES (N = 1565), or with CABG (N = 899). Patients in the PCI group were older and more often had severe frailty, but had less complex coronary anatomy, and less complete revascularization than those in the CABG group. Cumulative 5-year incidence of a composite of all-cause death, myocardial infarction or stroke was not significantly different between the 2 groups (25.0% versus 21.5%, P = 0.15). However, after adjusting confounders, the excess risk of PCI relative to CABG turned to be significant for the composite endpoint (HR 1.27, 95%CI 1.04-1.55, P = 0.02). PCI as compared with CABG was associated with comparable adjusted risk for all-cause death (HR 1.22, 95%CI 0.96-1.55, P = 0.11), and stroke (HR 1.17, 95%CI 0.79-1.73, P = 0.44), but with excess adjusted risk for myocardial infarction (HR 1.58, 95%CI 1.05-2.39, P = 0.03), and any coronary revascularization (HR 2.66, 95%CI 2.06-3.43, P<0.0001). CONCLUSIONS: In this observational study, PCI with new-generation DES as compared with CABG was associated with excess long-term risk for major cardiovascular events in patients who underwent multi-vessel coronary revascularization including LAD

精神的ストレスによるアレルギー性気道炎症の増悪

Stress and other psychological factors have long been hypothesized to be associated with asthma symptoms. One of the fundamental features of bronchial asthma is chronic airway inflammation, characteristic of the infiltration and activation of inflammatory cells, such as eosinophils and T lymphocytes. Psychological stress can modulate the inflammatory response through activation of hypothalamus-pituitary-adrenal axis and the sympathetic nervous system increasing the secretion of cortisol and catecholamines. However, the mechanisms linking stress and asthma are not well defined. Therefore, we investigated the effects of psychological stress on asthmatic airway inflammation using a murine model of allergic asthma. Female BALB/c mice and C57BL/6J mice were exposed to restraint stress (RS) during the antigen inhalation, which procedure was repeated 3 times for every seven days. Seven days after the last procedure, the mice were challenged with ovalbumin (OVA), and the airway inflammation was evaluated by the numbers of inflammatory cells in bronchoalveolar lavage fluids. RS significantly increased the numbers of total cells and lymphocytes in BALB/c mice. In C57BL/6J mice, in contrast, the numbers of inflammatory cells were not significantly different between mice exposed and not exposed to RS. Our findings suggest that psychological stress can enhance antigen-induced airway inflammation and, furthermore, that genetic background is involved in the pathogenesis of stress-induced asthma. This model using female BALB/c mice may be useful to elucidate the mechanisms by which psychological stress exacerbates asthma symptoms

Crystal structure of 4,4′-dimethoxy-2,2′-bipyridine

In the title compound, C12H12N2O2, the dihedral angle between the planes of the two pyridine rings is 5.8 (1)°. Neighbouring molecules are linked via C(Me)—H...N interactions, generating a two-dimensional sheet structure; C—H...π interactions further link the molecules into a three-dimensional network. An overlapped arrangement of parallel pyridine rings in neighbouring molecules [centroid-to-centroid distance = 3.6655 (15) Å] is observed in the crystal structure