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In the brain, neurons, glial cells, vascular endothelial cells (ECs), and mural cells form a functional structure referred to as the neurovascular unit (NVU). The functions of the NVU become impaired with aging. To gain insight into the mechanism underlying the aging-related changes in the NVU, we characterized in the present study the gliovascular interface in transgenic mice expressing a dominant-negative form of the telomeric repeat-binding factor 2 (TERF2) specifically in ECs using the Tie2 promoter. In these transgenic mice, senescence occurred in the cerebral ECs and was accompanied by upregulation of the mRNAs of proinflammatory cell adhesion molecules and cytokines. It is noteworthy that in the deep layers of the cerebral cortex, astrocytes exhibited an increase in the signals for S100β as well as a decrease in the polarization of the water channel aquaporin-4 (AQP4) to the perivascular endfeet of the astrocytes. Mechanistically, the perivascular localization of dystroglycan and its ligand, laminin α2, was decreased, and their localization correlated well with the perivascular localization of AQP4, which supports the notion that their interaction regulates the perivascular localization of AQP4. The diminished perivascular localization of laminin α2 may be attributed to its proteolytic degradation by the matrix metalloproteinase-2 released by senescent ECs. Pericyte coverage was increased and negatively correlated with the decrease in the perivascular localization of AQP4. We propose that aging-related changes in ECs induce a mild morphological alteration of astrocytes and affect the localization of AQP4 at the gliovascular interface.

Objective: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N -acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2 −/− /LDLr −/− (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2 +/+ /LDLr −/− littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36—an important macrophage membrane scavenger receptor—was differentially regulated. Conclusions: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.

Background: Chronic inflammation caused by pathogenic immune response is crucial in the pathogenesis of kidney disease. In particular, T-cell-mediated adaptive immune responses evoke pathogenic immunoinflammatory responses and contribute to kidney injury (KI). Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a potent negative regulator of T-cell immune responses, protects against immunoinflammatory diseases of the arteries such as atherosclerosis and abdominal aortic aneurysm. However, the role of this molecule in kidney disease remains undetermined. Methods and Results: To examine the effects of CTLA-4 overexpression on angiotensin II (AngII)-induced KI, we induced KI in CTLA-4 transgenic/apolipoprotein E-deficient (CTLA-4-Tg/Apoe -/-) mice or Apoe -/- mice fed a high-cholesterol diet by continuously infusing AngII. Overexpression of CTLA-4 ameliorated the development of AngII-induced KI and fibrosis. Moreover, CTLA-4-Tg/Apoe -/- mice had decreased expression of pro-inflammatory molecules in the kidney. Conclusions: CTLA-4 overexpression has a protective effect on AngII-induced KI, and increasing CTLA-4 may be a novel therapeutic strategy to prevent the progression of kidney disease.

Seismic buckling of vessels is one of main concerns for the design of fast reactor plants in Japan. Rational design is important because of two conflicting requirements; thicker walls are preferable to prevent seismic buckling of vessels, while excessively thick walls introduce large thermal stress causing unacceptable creep–fatigue interaction damage. In previous studies, we discussed evaluation methods of seismic buckling probability of vessels by taking account of seismic hazards in order to rationalize seismic buckling evaluation, and proposed a rule for seismic buckling of vessels based on the load and resistant factor design method. The proposed rule is expected to widen design window regarding seismic buckling and contribute to more reasonable design of vessels of fast reactors. However, there is still a room for more rational design. The proposed method deals with only seismic load, but in actuality, dead weight and internal pressure also exist. The existence of these loads contributes to reducing the buckling probability because axial compressive load decreases. In this study, the rule was expanded so that dead weight and internal pressure can be taken into account. Furthermore, the influences of dead weight and internal pressure to seismic buckling evaluation were discussed. As result, it was shown that approximately 10 to 20% of further rationalization of allowable seismic load could be achieved by considering dead weight and internal pressure in the evaluation. In addition, it was found that the previously proposed design rule, not considering dead weight and internal pressure, includes approximately 2 to 10 times margins in terms of seismic buckling probability.

Compelling evidence suggests a crucial role for Foxp3

The efficacy of cisplatin (CDDP) has been demonstrated in the treatment of various cancers as monotherapy and combination therapy with immunotherapy. However, acquired CDDP resistance is a major obstacle to successful treatment. In the present study, the mechanisms underlying acquired CDDP resistance were examined using ACR20 cells, which are CDDP‑resistant cells derived from A549 lung cancer cells. CDDP induces cytotoxicity by binding nuclear DNA and generating reactive oxygen species (ROS). Contrary to our expectation, ROS levels were elevated in ACR20 cells not treated with CDDP. Pretreatment with an ROS inhibitor enhanced the sensitivity of ACR20 cells to CDDP and prevented the activation of nuclear factor (NF)‑кB signaling and upregulation of inhibitor of apoptosis proteins (IAPs). Notably, evaluation of the mitochondrial oxygen consumption rate and mitochondrial superoxide levels revealed a deterioration of mitochondrial function in ACR20 cells. Mitochondrial DNA PCR‑RFLP analysis revealed four mutations with varying percentage levels in ACR20 cells. In addition, in cytoplasmic hybrids with mitochondria from ACR20 cells, intrinsic ROS levels were elevated, expression of IAPs was increased, and complex I activity and sensitivity to CDDP were decreased. Analysis of three‑dimensional structure data indicated that a mutation (ND2 F40L) may impact the proton translocation pathway, thereby affecting mitochondrial complex I activity. Together, these findings suggest that intrinsic ROS levels were elevated by mitochondrial DNA mutations, which decreased the sensitivity to CDDP via activation of NF‑κB signaling and induction of IAP expression in ACR20 cells. These findings indicate that newly identified mutations in mitochondrial DNA may lead to acquired cisplatin resistance in cancer.

Here, we developed a novel in vitro co-culture model, in which process-bearing astrocytes and isolated cerebral microvessels from mice were co-cultured. Astrocytes formed contacts with microvessels from both adult and neonatal mice. However, concentrated localization of the immunofluorescence signal for aquaporin-4 (AQP4) at contact sites between perivascular endfoot processes and blood vessels was only detected with neonatal mouse microvessels. Contact between astrocytic processes and microvessels was retained, whereas concentrated localization of AQP4 signal at contact sites was lost, by knockdown of dystroglycan or α-syntrophin, reflecting polarized localization of AQP4 at perivascular regions in the brain. Further, using our in vitro co-culture model, we found that astrocytes predominantly extend processes to pericytes located at the abluminal surface of microvessels, providing additional evidence that this model is representative of the in vivo situation. Altogether, we have developed a novel in vitro co-culture model that can reproduce aspects of the in vivo situation and is useful for assessing contact formation between astrocytes and blood vessels.

Background Gut microbiome composition or circulating microbiome-related metabolites in patients with heart failure (HF) have not been investigated at different time points (i.e., in the decompensated (Decomp) and compensated (Comp) phases). Methods and Results: We prospectively enrolled 22 patients admitted for HF and 11 age-, sex-, and comorbidity-matched hospitalized control subjects without a history of HF. Gut flora and plasma microbiome-related metabolites were evaluated by amplicon sequencing of the bacterial 16S ribosomal RNA gene and capillary electrophoresis time-of-flight mass spectrometry, respectively. HF patients were evaluated in both the Decomp and Comp phases during hospitalization. The phylum Actinobacteria was enriched in HF patients compared with control subjects. At the genus level, Bifiodobacterium was abundant while Megamonas was depleted in HF patients. Meanwhile, plasma concentration of trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, was increased in HF patients (Decomp HF vs. control, P=0.003; Comp HF vs. control, P=0.004). A correlation analysis revealed positive correlations between the abundance of the genus Escherichia/Shigella and levels of TMAO and indoxyl sulfate (IS, a microbe-dependent uremic toxin) in Comp HF (TMAO: r=0.62, P=0.002; IS: r=0.63, P=0.002). Escherichia/Shigella was more abundant in Decomp than in Comp HF (P=0.030). Conclusions Our results suggest that gut microbiome composition and microbiome-related metabolites are altered in HF patients.

Cisplatin (CDDP) is widely used as an anti-cancer platinum agent but its therapeutic efficacy is limited by acquired drug resistance. To develop a new therapeutic strategy that could overcome this resistance, it is important to characterize CDDP-resistant cancer cells. Here we established human lung cancer A549 cell-derived low- and high-grade CDDP-resistant sublines, termed ACR4 and ACR20 cells, by stepwise increasing CDDP concentrations up to 4 and 20 μM, respectively. ACR4 and ACR20 cells showed 6- and 16-fold higher resistance to CDDP than A549 cells, respectively. Cell migration, invasion, and sphere formation were significantly decreased, whereas expression of the stem cell marker CD44v was increased in order of A549, ACR4, and ACR20 cells. The expression of the cystine-glutamate transporter xCT, which is encoded by SLC7A11, was upregulated because of the increased cell surface expression of CD44v in ACR20 cells. Treatment with the xCT inhibitor salazosulfapyridine and knockdown of SLC7A11 mRNA by a specific siRNA significantly improved sensitivity to CDDP in A549, ACR4, and ACR20 cells. Thus, our results suggest that CD44v overexpression is not involved in cancer stem cell properties but increases xCT expression, which leads to the acquisition of CDDP-resistance. This mechanism may contribute to the development of a new therapeutic strategy that can overcome resistance.

Background: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. Methods: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. Results: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei . Conclusions: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. Clinical Trial Registration: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.

Bronsted and Lewis base catalysis of hexametalate clusters of group 5 metals [M(V)6O19]8– (M(V) = Ta, Nb) and group 6 metals [M(VI)6O19]2– (M(VI) = Mo, W) was studied using Knoevenagel condensation...

Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfateChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.

Background Regulatory T cells (Tregs) are demonstrated to play a protective role in the development of atherosclerosis. However, their sites of action in atherosclerosis remain unclear. Although C-C chemokine receptor 4 (CCR4) has been shown to contribute to the accumulation of Tregs in inflamed tissues and prevention of experimental autoimmune diseases, the role of CCR4 in Treg migration to atherosclerotic lesions and suppression of plaque formation remains unknown. Methods and results We intraperitoneally injected 8-week-old apolipoprotein E–deficient mice fed a normal diet with vehicle (n=9) or a 4-μg dose of a CCR4 antagonist (n=10) 3 times weekly for 8 weeks and evaluated atherosclerotic lesions at 16 weeks old. Administration of the CCR4 antagonist significantly aggravated atherosclerotic plaque formation (aortic sinus plaque area: 2.91±0.87×104 μm2 versus 5.41±0.98×104 μm2 in control vehicle-treated and CCR4 antagonist-treated mice, respectively; P Conclusions Our findings indicate an important role for CCR4 in promotion of Treg recruitment into atherosclerotic lesions and subsequent prevention of early atherosclerosis and suggest CCR4 as a novel therapeutic target for atherosclerosis. Funding Acknowledgement Type of funding source: None

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Data presented in this article are supplementary material to our research article entitled “Impact of CD14++CD16+ monocytes on coronary plaque vulnerability assessed by optical coherence tomography in coronary artery disease patients” [1]. This article contains the data of study population, diagnostic ability of CD14++CD16+ monocytes to identify thin-cap fibroatheromas, and association between laboratory variables and plaque properties.

Background and aims This study examined the impact of CD14++CD16+ monocytes on coronary plaque vulnerability, as assessed by optical coherence tomography (OCT), and investigated their association with daily glucose fluctuation. Although increased CD14++CD16+ monocyte levels have been reported to increase cardiovascular events, their impact on coronary plaque vulnerability in coronary artery disease (CAD) patients with or without diabetes mellitus (DM) remains unclear. Methods This prospective observational study included 50 consecutive patients with CAD, receiving lipid-lowering therapy and undergoing coronary angiography and OCT. Patients were divided into 3 tertiles according to the CD14++CD16+ monocyte percentages assessed by flow cytometry. Standard OCT parameters were assessed for 97 angiographically intermediate lesions (diameter stenosis: 30–70%). Daily glucose fluctuation was analyzed by measuring the mean amplitude of glycemic excursion (MAGE). Results CD14++CD16+ monocytes negatively correlated with fibrous cap thickness (r = −0.508, p Conclusions CD14++CD16+ monocytes were associated with coronary plaque vulnerability in CAD patients with well-regulated lipid levels both in DM and non-DM patients. Cross-talk between glucose fluctuation and CD14++CD16+ monocytes may enhance plaque vulnerability, particularly in non-DM patients. CD14++CD16+ monocytes could be a possible therapeutic target for coronary plaque stabilization.

Atherosclerotic diseases, including ischemic heart disease and stroke, are a main cause of mortality worldwide. Chronic vascular inflammation via immune dysregulation is critically involved in the pathogenesis of atherosclerosis. Accumulating evidence suggests that regulatory T cells (Tregs), responsible for maintaining immunological tolerance and suppressing excessive immune responses, play an important role in preventing the development and progression of atherosclerosis through the regulation of pathogenic immunoinflammatory responses. Several strategies to prevent and treat atherosclerosis through the promotion of regulatory immune responses have been developed, and could be clinically applied for the treatment of atherosclerotic cardiovascular disease. In this review, we summarize recent advances in our understanding of the protective role of Tregs in atherosclerosis and discuss attractive approaches to treat atherosclerotic disease by augmenting regulatory immune responses.

N-glycosylation of proteins is important for protein folding and function. We have recently reported that FAM5C/BRINP3 contributes to the tumor necrosis factor-α-induced expression of leukocyte adhesion molecules in vascular endothelial cells (ECs). However, regulatory mechanism of the FAM5C biosynthesis is poorly understood. Co-immunoprecipitation assay revealed the interaction of FAM5C with UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), a glycoprotein folding-sensor enzyme. FAM5C ectopically expressed in HEK293 cells was localized to the endoplasmic reticulum and co-localized with endogenously expressed UGGT1. Molecular size of FAM5C was reduced by treatment with N-glycosidase F and in FAM5C-expressing cells cultured in the presence of the N-glycosylation inhibitor tunicamycin. FAM5C was secreted by the cells and the secretion of FAM5C was blocked by tunicamycin. Among six potential N-glycosylation sites, the potential site at Asn168 was not N-glycosylated, and Asn337, Asn456, Asn562, Asn609, and Asn641 mutants were poorly secreted by the cells. These results demonstrated that FAM5C is an N-glycosylated protein and N-glycosylation is necessary for the secretion of FAM5C.

Optical time-stretch microscopy has recently attracted intensive attention for its capability of acquiring images at an ultrahigh frame rate. Unfortunately, its achievable frame rate is limited by the requirement of having no overlap between consecutive frames, which leads to a tradeoff between the frame rate (pulse repetition rate) and the amount of the temporal dispersion used for optical image serialization. In this paper, we demonstrate compressive sensing on the platform of optical time-stretch microscopy to overcome the tradeoff between frame rate and temporal dispersion (time stretch) and achieve 50 times higher frame rate than conventional optical time-stretch microscopy. Specifically, we computationally perform compressed optical time-stretch microscopy with an experimental dataset acquired by conventional optical time-stretch microscopy and demonstrate its effects in terms of spatial resolution and cell classification accuracy. Our results indicate that the spatial resolution and cell classification accuracy reach 780 nm and 95% at a line scan rate of 675 MHz and 6.75 GHz, respectively, which correspond to five times and 50 times higher frame rates than what conventional optical time-stretch microscopy can achieve with the same dispersion amount and digitizer sampling rate.

Seismic buckling of vessels is one of the main concerns for the design of nuclear power plants in Japan. Rational design is important, especially for fast reactor plants. Although thicker walls are preferable in terms of prevention of seismic buckling, excessively thick walls cause unacceptable creep-fatigue interaction damage. In a previous study, we proposed an evaluation method for the seismic buckling probability of a reactor vessel considering seismic hazards and showed that among the random variables considered in the evaluation, seismic load had the most significant impact on buckling probability. This suggests that more rational vessel designs can be realized by taking appropriate account of seismic load variations. The load and resistance factor design (LRFD) method enables us to determine design factors corresponding to target reliability by considering the variations of random variables. Therefore, in this study, we used the LRFD method to develop a new design rule for the prevention of seismic buckling of vessels. The equation in the proposed rule is almost the same as that in the Japan Society of Mechanical Engineers fast reactor codes, but every random variable, seismic load and yield stress, has its own design factor. In addition, mean or median values are used in the evaluation instead of design values including conservativeness. The effectiveness of the new design rule was illustrated in comparison with the current provision.

Objective— UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. Approach and Results— Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4 + forkhead box P3 + regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell–depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4 + forkhead box P3 + regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. Conclusions— Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis.

Aims Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. In the present study, we determined the effects of CTLA-4 overexpression on experimental AAA. Methods and results We continuously infused 12-week-old CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E–deficient (Apoe−/−) mice (n=35) or control Apoe−/− mice (n=40) fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter (18%) of AAA (incidence: P=0.0104; mortality: P=0.031; diameter: P=0.011). These protective effects were associated with a decreased number of effector CD4+ T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c+ dendritic cells in lymphoid tissues. In addition, by performing in situ zymography of the abdominal aortic aneurysm lesions, we observed a trend toward a decrease in MMP activity in the aneurysmal lesion following overexpression of CTLA-4. Finally, CTLA-4-Tg/Apoe−/− mice had reduced macrophage and CD4+ T cell accumulation and MMP activity in the aneurysmal lesion, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Conclusion Our findings suggest that CTLA-4 protects against AAA by suppressing immunoinflammatory responses and could be an attractive therapeutic target for AAA.

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease., Vascular senescence is closely associated with individual ageing, while its causative role remains unclear. Here Barinda et al. generate endothelial cell-specific progeroind mice, and reveal that endothelial cell senescence directly induces metabolic disorders through senescence-messaging secretomes.

Nonalcoholic steatohepatitis (NASH) progresses from nonalcoholic fatty liver disease (NAFLD), however, efficacious drugs for NASH treatment are lacking. Sodium alginate (SA), a soluble dietary fiber extracted from brown algae, could protect the small intestine from enterobacterial invasion. NASH pathogenesis has been suggested to be associated with enterobacterial invasion, so we examined the effect of SA on methionine- and choline-deficient (MCD) diet-induced steatohepatitis in mice (the most widely-used model of NASH). The mice (n = 31) were divided into three groups (mice fed with regular chow, MCD diet, and MCD diet premixed with 5% SA) for 4 and 8 weeks. The MCD diet increased lipid accumulation and inflammation in the liver, the NAFLD Activity Score and hepatic mRNA expression of tumor necrosis factor- and collagen 11, and induced macrophage infiltration. Villus shortening, disruption of zonula occludens-1 localization and depletion of mucus production were observed in the small intestine of the MCD-group mice. SA administration improved lipid accumulation and inflammation in the liver, and impaired barrier function in the small intestine. Collectively, these results suggest that SA is useful for NASH treatment because it can prevent hepatic inflammation and fatty degeneration by maintaining intestinal barrier function.

The association between atherosclerosis and gut microbiota has been attracting increased attention. We previously demonstrated a possible link between gut microbiota and coronary artery disease. Our aim of this study was to clarify the gut microbiota profiles in coronary artery disease patients using data mining analysis of terminal restriction fragment length polymorphism (T-RFLP). This study included 39 coronary artery disease (CAD) patients and 30 age- and sex- matched no-CAD controls (Ctrls) with coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by T-RFLP and data mining analysis using the classification and regression algorithm. Five additional CAD patients were newly recruited to confirm the reliability of this analysis. Data mining analysis could divide the composition of gut microbiota into 2 characteristic nodes. The CAD group was classified into 4 CAD pattern nodes (35/39 = 90 %), while the Ctrl group was classified into 3 Ctrl pattern nodes (28/30 = 93 %). Five additional CAD samples were applied to the same dividing model, which could validate the accuracy to predict the risk of CAD by data mining analysis. We could demonstrate that operational taxonomic unit 853 (OTU853), OTU657, and OTU990 were determined important both by the data mining method and by the usual statistical comparison. We classified the gut microbiota profiles in coronary artery disease patients using data mining analysis of T-RFLP data and demonstrated the possibility that gut microbiota is a diagnostic marker of suffering from CAD.

The aim of this study was to clarify the impact of acquired and innate immunity on spinal cord ischemia and reperfusion injury using a mouse model of spinal cord ischemia.To define the ischemic duration that caused paraplegia, wild-type and severe combined immunodeficiency (SCID) mice were subjected to cross-clamping of the aorta for 7, 9, 9.5, or 10.5 min with ischemic preconditioning for intestinal protection. In wild-type and SCID mice with paraplegia, histological analyses were performed to investigate viable neurons, inflammatory cells, and reactive astrocytes at 12, 24, 48, and 72 h as well as 7 days after reperfusion.In both wild-type and SCID mice, immediate paraplegia was induced by occlusion for 10.5 min. In both wild-type and SCID mice, no infiltration of T or B lymphocytes was observed at any point after reperfusion, but reactive astrocytes were clearly visible at 7 days after reperfusion, and the number of activated microglia peaked at 12 and 48 h after reperfusion. Although there was no significant difference, wild-type mice had a tendency to have more activated microglia than SCID mice at 12 h after reperfusion, and to have less viable neurons than SCID mice at 12, 24, 48, and 72 h after reperfusion. There was a tendency that the frequency of immediate paraplegia in wild-type mice was more than SCID mice though no statistical difference was observed.Innate immunity, rather than acquired immunity, may be involved in the developing immediate paraplegia in our mouse model.

AIM: Recent studies have suggested that metabolic disorders such as obesity and type 2 diabetes are associated with gut microbiota. The association between atherosclerosis and gut microbiota has also been attracting increased attention. Our aim was to specify a characteristic trend of gut microbiota in coronary artery disease (CAD). METHODS: This study included 39 CAD patients, 30 age- and sex-matched no-CAD controls (Ctrls) with coronary risk factors and 50 healthy volunteers (HVs) without coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by terminal restriction fragment length polymorphism. RESULTS: A characteristic change of gut microbiota was observed in CAD patients, where the order Lactobacillales was increased (CAD, Ctrl vs. HV; 13.6% ± 12.0%, 6.2% ± 7.7% vs. 4.1% ± 5.9%; p < 0.001) and the phylum Bacteroidetes (Bacteroides + Prevotella) was decreased (CAD, Ctrl vs. HV; 35.5% ± 11.6%, 43.9% ± 11.2% vs. 47.4% ± 11.5%; p < 0.001). The CAD group was over-represented in enterotype “others” (III), compared with the Ctrl or HV group (p < 0.001, chi-squared test), although we could not deny the possibility that some drugs affect the gut flora types. CONCLUSIONS: Although this study had some limitations, we demonstrated that the incidence of CAD was linked with an alteration of gut microbiota. A prospective study is desired to clarify a causal relationship between CAD and gut microbiota.

Gut microbiota have been attracting increased attention in many fields of medicine recently. We can perform a comprehensive analysis of gut microbiota using next-generation sequencing techniques together with bioinformatics technology, which expands our knowledge of a large ecosystem consisting of a host and gut microbiota. We summarize some reports about the correlations between gut microbiota and metabolic disorders, particularly atherosclerosis, and discuss future directions for the diagnostic or therapeutic potential of gut microbiota. To take simple examples, we demonstrated that the order Lactobacillales was significantly increased; while the phylum Bacteroidetes was significantly decreased in coronary artery disease (CAD) patients compared with controls or healthy volunteers. The characteristics of gut microbiota in type 2 diabetes and dyslipidemia have been reported. However, these studies have limitations, and the biological significance of gut microbiota and the causal relationships are still controversial. We hope the reports listed in this review article might lead to the development of a novel therapy to prevent CAD via modulating gut microbiota or their metabolites.