Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder, and the deposition of specific protein aggregates of α-synuclein, termed Lewy bodies, is evident in ...multiple brain regions of PD patients. Although there are several available medications to treat PD symptoms, these medications do not prevent the progression of the disease. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with the pathogenesis of PD. Here we found that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity in the mouse striatum was attenuated by subsequent repeated administration of TPPU, a potent sEH inhibitor. Furthermore, deletion of the sEH gene protected against MPTP-induced neurotoxicity, while overexpression of sEH in the striatum significantly enhanced MPTP-induced neurotoxicity. Moreover, the expression of the sEH protein in the striatum from MPTP-treated mice or postmortem brain samples from patients with dementia of Lewy bodies (DLB) was significantly higher compared with control groups. Interestingly, there was a positive correlation between sEH expression and phosphorylation of α-synuclein in the striatum. Oxylipin analysis showed decreased levels of 8,9-epoxy-5Z,11Z,14Z-eicosatrienoic acid in the striatum of MPTP-treated mice, suggesting increased activity of sEH in this region. Interestingly, the expression of sEH mRNA in human PARK2 iPSC-derived neurons was higher than that of healthy control. Treatment with TPPU protected against apoptosis in human PARK2 iPSC-derived dopaminergic neurons. These findings suggest that increased activity of sEH in the striatum plays a key role in the pathogenesis of neurodegenerative disorders such as PD and DLB. Therefore, sEH may represent a promising therapeutic target for α-synuclein–related neurodegenerative disorders.
The effects of dietary polyphenols on human health have mainly been discussed in the context of preventing degenerative diseases, particularly cardiovascular diseases and cancer. The antioxidant ...properties of polyphenols have been widely studied, but it has become clear that the mechanism of action of polyphenols extends beyond the modulation of oxidative stress, as they are poorly absorbed from the digestive tract. The purpose of this study was to clarify the effects of polyphenols on the colonic environment, intestinal barrier function, and gut microbiota. We demonstrated that dietary polyphenols derived from aronia, haskap, and bilberry, markedly elevated the amount of fecal mucin and immunoglobulin A (IgA) as an intestinal barrier function and ameliorated the disturbance in gut microbiota caused by a high fat diet in rats. These results suggest that dietary polyphenols play a significant role in the prevention of degenerative diseases through improvement of the colonic environment without any absorption from the digestive tract.
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. ...Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper 17 (T
17) cell responses in the liver and increased susceptibility to hepatobiliary injuries. Bacterial culture of mesenteric lymph nodes in these mice isolated K. pneumoniae, Proteus mirabilis and Enterococcus gallinarum, which were prevalently detected in patients with PSC. A bacterial-organoid co-culture system visualized the epithelial-damaging effect of PSC-derived K. pneumoniae that was associated with bacterial translocation and susceptibility to T
17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the T
17 immune response induced by PSC-derived microbiota. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC.
Aims/hypothesis
Accumulation of adipose tissue macrophages is considered pivotal in the development of obesity-associated inflammation and insulin resistance. In addition, recent studies suggest an ...involvement of the intestine as the primary organ in inducing hyperglycaemia and insulin resistance. We have reported that the C-C motif chemokine receptor (CCR) CCR9 is associated with intestinal immunity and has a pathogenic role in various liver diseases. However, its contribution to type 2 diabetes is unknown. In the current study, we aimed to clarify the involvement of CCR9 in the pathology of type 2 diabetes and the potential underlying mechanisms.
Methods
To elucidate how CCR9 affects the development of metabolic phenotypes, we examined the impact of CCR9 deficiency on the pathogenesis of type 2 diabetes using male C57BL/6J (wild-type WT) and CCR9-deficient (CCR9 knockout KO) mice fed a 60% high-fat diet (HFD) for 12 weeks.
Results
WT and
Ccr9
KO mice fed an HFD exhibited a comparable weight gain; however, glucose tolerance and insulin resistance were significantly improved in
Ccr9
KO mice. Moreover, visceral adipose tissue (VAT) and the liver of
Ccr9
KO mice presented with less inflammation and increased expression of glucose metabolism-related genes than WT mice.
Ccr9
and
Ccl25
expression were specifically higher in the small intestine but was not altered by HFD feeding and type 2 diabetes development. Accumulation of IFN-γ-producing CD4
+
T lymphocytes and increased intestinal permeability in the small intestine was observed in WT mice following HFD feeding, but these changes were suppressed in HFD-fed
Ccr9
KO mice. Adoptive transfer of gut-tropic CCR9-expressing T lymphocytes partially reversed the favourable glucose tolerance found in
Ccr9
KO mice via exacerbated inflammation in the small intestine and VAT.
Conclusions/interpretation
CCR9 plays a central role in the pathogenesis of type 2 diabetes by inducing an inflammatory shift in the small intestine. Our findings support CCR9 as a new therapeutic target for type 2 diabetes via the gut–VAT–liver axis.
Graphical abstract
As online resources such as social media are increasingly used in disaster situations, confusion caused by the spread of false information, misinformation, and hoaxes has become an issue. Although a ...large amount of research has been conducted on how to suppress disinformation, i.e., the widespread dissemination of such false information, most of the research from a revenue perspective has been based on prisoner’s dilemma experiments, and there has been no analysis of measures to deal with the actual occurrence of disinformation on disaster SNSs. In this paper, we focus on the fact that one of the characteristics of disaster SNS information is that it allows citizens to confirm the reality of a disaster. Hereafter, we refer to this as collective debunking , and we propose a profit-agent model for it and conduct an analysis using an evolutionary game. As a result, we experimentally found that deception in the confirmation of disaster information uploaded to SNS is likely to lead to the occurrence of disinformation. We also found that if this deception can be detected and punished, for example by patrols, it tends to suppress the occurrence of disinformation.
Chemical intervention of autophagy has been investigated in clinical trials for various age-related conditions such as sarcopenia and neurodegeneration. However, at present, no autophagy inducer has ...been established as a disease-modifying agent against neurodegenerative diseases.
We screened a library consisting of 796 medicines clinically approved (in Japan) for autophagy enhancers as potential neurodegeneration therapeutics using HeLa cells stably expressing green fluorescent protein-microtubule-associated protein light chain 3 (GFP-LC3) followed by an analysis of the molecular mechanisms using various neuronal models.
The primary screening identified 152 hits in a static cellular state. A widely available Alzheimer's disease drug, memantine, which antagonizes N-Methyl-d-aspartate receptor (NMDAR), was one of the hits. Memantine increased the levels of LC3-II in a dose-dependent and time-dependent manner, and upregulated autophagic flux. In addition, the pharmacological effects of memantine on autophagy were independent of mTORC1 activity and NMDAR activation. Furthermore, a VPS34 inhibitor suppressed the memantine-induced LC3-II upregulation, suggesting that memantine may affect VPS34 complex activity. Notably, intracellular Huntington's disease-specific aggregates of elongated huntingtin, a well-established autophagy substrate, were significantly decreased by memantine. In addition, memantine enhanced elimination of degraded mitochondrial in neurons derived from induced pluripotent stem cells of PARK2 or PARK6 patients, who exhibited defective PINK1/parkin-mediated mitophagy, suggests that memantine accelerated the clearance of damaged mitochondria.
These findings indicate that memantine may be beneficial for the treatment of neurodegeneration characterized by the abnormal accumulation of autophagy or mitophagy substrates.
•From a screen of 796 chemicals, memantine was identified as a novel autophagy inducer.•Memantine, clinically used for dementia, induced neuroprotective macroautophagy.•Memantine enhanced elimination of degraded mitochondrial in neurons derived from PD-iPS cells.
In this study, we added voting behavior in which voting proportionately reflects the value of a view (option, opinion, and so on) to the BRT agent. BRT agent is a consensus-building model of the ...decision-making process among a group of human, and is a framework that allows the expression of the collective behavior while maintaining dispersiveness, although it has been noted that it is unable to reach consensus by making use of experience. To resolve this issue, we propose the incorporation of a mechanism of voting at frequencies proportional to the value estimated using reinforcement learning. We conducted a series of computer-based experiments using the box-pushing problem and verified that the proposed method reached a consensus to arrive at solutions based on experience.
Abstract
Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces ...endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with
alcohol dehydrogenase-1B
(
ADH1B
, rs1229984) and
aldehyde dehydrogenase-2
(
ALDH2
, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and
ALDH2*2
transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14
+
monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with
ALDH2/ADH1B
gene polymorphisms, and patients with a combination of
ALDH2*1/*2
and
ADH1B*2
genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered
ALDH2*2
transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms.
The value of pancreatoduodenectomy (PD) with extended lymphadenectomy for pancreatic cancer has been evaluated by many retrospective studies and 3 randomized controlled trials (RCT). However, the ...protocols used and the results found in the 3 RCTs were diverse. Therefore, a multicenter RCT was proposed in 1998 to evaluate the primary end point of long-term survival and the secondary end points of morbidity, mortality and quality of life of patients undergoing standard versus extended lymphadenectomy in radical PD for pancreatic cancer.
From March 2000 to May 2003, 112 patients with potentially curable pancreatic head cancer were enrolled and intraoperatively randomized to a standard or extended lymphadenectomy group. No resected patients received any adjuvant treatments.
A hundred and one eligible patients were analyzed. Demographic and histopathological characteristics of the two groups were similar. The mean operating time, intraoperative blood loss and number of retrieved lymph nodes were greater in the extended group, but the other operative results were comparable.
Although this multicenter RCT was conducted in a strict setting, extended lymphadenectomy in radical PD did not benefit long-term survival in patients with resectable pancreatic head cancer and led to levels of morbidity, mortality and quality of life comparable to those found after standard lymphadenectomy.
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