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Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at [G.sub.2]/M. We explored the relative importance of the PT DNA damage response (DDR) in kidney fibrosis by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor and upstream initiator of the DDR. In human chronic kidney disease, ATR expression inversely correlates with DNA damage. ATR was upregulated in approximately 70% of Lotus tetragonolobus lectin-positive ([LTL.sup.+]) PT cells in cisplatin-exposed human kidney organoids. Inhibition of ATR resulted in greater PT cell injury in organoids and cultured PT cells. PT-specific Atr- knockout ([ATR.sup.RPTC-/-]) mice exhibited greater kidney function impairment, DNA damage, and fibrosis than did WT mice in response to kidney injury induced by either cisplatin, bilateral ischemia-reperfusion, or unilateral ureteral obstruction. [ATR.sup.RPTC-/-] mice had more cells in the [G.sub.2]/M phase after injury than did WT mice after similar treatments. In conclusion, PT ATR activation is a key component of the DDR, which confers a protective effect mitigating the maladaptive repair and consequent fibrosis that follow kidney injury., Introduction Acute kidney injury (AKI) occurs in approximately 13% of hospitalized patients and is associated with high mortality, especially in critically ill patients (1). AKI also predisposes patients to chronic [...]

Background Inhibiting enteropeptidase, a gut serine protease regulating protein digestion, suppresses food intake and ameliorates obesity and diabetes in mice. However, the effects of enteropeptidase inhibition on kidney parameters are largely unknown. Here, we evaluated the chronic effects of an enteropeptidase inhibitor, SCO-792, on kidney function, albuminuria and kidney pathology in spontaneously hypercholesterolaemic (SHC) rats, a rat chronic kidney disease (CKD) model. Methods SCO-792, an orally available enteropeptidase inhibitor, was administered [0.03% and 0.06% (w/w) in the diet] to 20-week-old SHC rats showing albuminuria and progressive decline in glomerular filtration rate (GFR) for five weeks. The effects of SCO-792 and the contribution of amino acids to these effects were evaluated. Results SCO-792 increased the faecal protein content, indicating that SCO-792 inhibited enteropeptidase in SHC rats. Chronic treatment with SCO-792 prevented GFR decline and suppressed albuminuria. Moreover, SCO-792 improved glomerulosclerosis and kidney fibrosis. Pair feeding with SCO-792 (0.06%) was less effective in preventing GFR decline, albuminuria and renal histological damage than SCO-792 treatment, indicating the enteropeptidase-inhibition-dependent therapeutic effects of SCO-792. SCO-792 did not affect the renal plasma flow, suggesting that its effect on GFR was mediated by an improvement in filtration fraction. Moreover, SCO-792 increased hydrogen sulphide production capacity, which has a role in tissue protection. Finally, methionine and cysteine supplementation to the diet abrogated SCO-792-induced therapeutic effects on albuminuria. Conclusions SCO-792-mediated inhibition of enteropeptidase potently prevented GFR decline, albuminuria and kidney fibrosis; hence, it may have therapeutic potential against CKD. [ABSTRACT FROM AUTHOR]

Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19 KO) had higher parasitemia and died earlier than wild-type ( WT) controls. Interestingly, p19 KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17 KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19 KO and 17 KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. [ABSTRACT FROM AUTHOR]

After a brain insult, ATP is released from injured cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor necrosis factor (TNF). The release of TNF appears to be dependent on the P2X[sub7] receptor. The inhibitors 1,4-diamino-2, 3-dicyano-1, 4-bis[2-amino-phenylthio] butadiene (U0126), anthra[1,9-cd] pyrazol-6(2H)-one (SP600125), and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) IH-imidazole (SB203580), which target MEK (mitogen- activated protein kinase kinase), INK (c-Jun N-terminal kinase), and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA is strongly inhibited by U0126 and SP600125. SB203580 did not affect the increased levels of TNF mRNA but did prevent TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38 [but not extracellular signal-regulated kinase (ERK)] could be inhibited by brilliant blue G, a P2X[sub7] receptor blocker, and by genistein and 4-amino-5-br(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-D]pyrimidine, which are general and src-family-specific tyrosine ki- nase inhibitors, respectively. Most important, we found that treatment of the microglia in neuron-microglia cocultures with the P2X[sub7] agonist 2'-3'-O(benzoyl-benzoyl) ATP led to significant reductions in glutamate-induced neuronal cell death, and that either TNF-α converting enzyme inhibitor or anti-TNF readily suppressed the protective effect implied by this result. Together, these findings indicate that both FRK and JNK are involved in the regulation of TNF mRNA expression, that p38 is involved in the nucleocytoplasmic transport of TNF mRNA, and that a PTK (protein tyrosine kinase), possibly a member of the src family, acts downstream of the P2X[sub7] receptor to activate INK and p38. Finally, our data suggest that P2X[sub7] receptor-activated microglia protect neurons... [ABSTRACT FROM AUTHOR]

Objective: The primary objective of this study was to investigate the parenting attitudes towards children with autism spectrum disorders in early childhood in Japan., Design: This study was a cohort study. The participants were enrolled from January 2011 to March 2014. We obtained the prevalence of autism spectrum disorders at 3 years of age, parenting attitudes and other factors from questionnaires. We divided the participants into two groups, an autism spectrum disorders group and a non-autism spectrum disorders group, and compared the parenting attitudes., Setting: This study used data from a Japanese birth cohort study: the Japan Environment and Children's Study, conducted across 15 regional centres in Japan., Participants: The full dataset of the Japan Environment and Children's Study comprised 104 059 records. We excluded 17 889 records because the answer for the autism spectrum disorders in the questionnaire was blank. As a result, we analysed the remaining 82 411 mother-child pairs., Main Outcome Measures: The primary outcome variable was parenting attitudes at 3.5 years of age, which was assessed using a questionnaire. We asked respondents 16 questions related to parenting attitudes, and they answered based on their behaviours. The independent variable was the prevalence of autism spectrum disorders at 3 years of age., Results: Of the 82 411 participants, the children with autism spectrum disorders at 3 years of age were 372 (0.45%). In most questions about parenting attitudes, the autism spectrum disorders group had unfavourable responses. The difference was particularly noticeable when the parents taught their children social discipline. Unfavourable parenting attitudes were 16.6% in the autism spectrum disorders group and 0.8% in the non-autism spectrum disorders group in the question item with the largest difference between the two groups, a significant difference., Conclusions: Parents of children with autism spectrum disorders tended to have unfavourable attitudes, suggesting the importance of parental training., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)