Psoriasis is a chronic inflammatory skin disease. Recently, lysophosphatidic acid (LPA)/LPAR5 signaling has been reported to be involved in both NLRP3 inflammasome activation in macrophages and ...keratinocyte activation to produce inflammatory cytokines, contributing to psoriasis pathogenesis. However, the effect and molecular mechanisms of LPA/LPAR signaling in keratinocyte proliferation in psoriasis remain unclear. In this study, we investigated the effects of LPAR1/3 inhibition on imiquimod (IMQ)-induced psoriasis-like mice. Treatment with the LPAR1/3 antagonist, ki16425, alleviated skin symptoms in IMQ-induced psoriasis-like mouse models and decreased keratinocyte proliferation in the lesion. It also decreased LPA-induced cell proliferation and cell cycle progression via increased cyclin A2, cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 expression and decreased p27Kip1 expression in HaCaT cells. LPAR1 knockdown in HaCaT cells reduced LPA-induced proliferation, suppressed cyclin A2 and CDK2 expression, and restored p27Kip1 expression. LPA increased Rho-associated protein kinase 2 (ROCK2) expression and PI3K/AKT activation; moreover, the pharmacological inhibition of ROCK2 and PI3K/AKT signaling suppressed LPA-induced cell cycle progression. In conclusion, we demonstrated that LPAR1/3 antagonist alleviates IMQ-induced psoriasis-like symptoms in mice, and in particular, LPAR1 signaling is involved in cell cycle progression via ROCK2/PI3K/AKT pathways in keratinocytes.
Recent evidence of gut microbiota dysbiosis in the context of psoriasis and the increased cooccurrence of inflammatory bowel disease and psoriasis suggest a close relationship between skin and gut ...immune responses. Using a mouse model of psoriasis induced by the Toll-like receptor (TLR) 7 ligand imiquimod, we found that psoriatic dermatitis was accompanied by inflammatory changes in the small intestine associated with eosinophil degranulation, which impaired intestinal barrier integrity. Inflammatory responses in the skin and small intestine were increased in mice prone to eosinophil degranulation. Caco-2 human intestinal epithelial cells were treated with media containing eosinophil granule proteins and exhibited signs of inflammation and damage. Imiquimod-induced skin and intestinal changes were attenuated in eosinophil-deficient mice, and this attenuation was counteracted by the transfer of eosinophils. Imiquimod levels and the distribution of eosinophils were positively correlated in the intestine. TLR7-deficient mice did not exhibit intestinal eosinophil degranulation but did exhibit attenuated inflammation in the skin and small intestine following imiquimod administration. These results suggest that TLR7-dependent bidirectional skin-to-gut communication occurs in psoriatic inflammation and that inflammatory changes in the intestine can accelerate psoriasis.
Accumulating data have indicated a fundamental role of eosinophils in regulating adipose tissue homeostasis. Here, we performed whole-genome RNA sequencing of the small intestinal tract, which ...suggested the presence of impaired lipid metabolism in eosinophil-deficient ΔdblGATA mice. ΔdblGATA mice fed a high-fat diet (HFD) showed reduced body fat mass, impaired enlargement of adipocytes, decreased expression of adipogenic genes, and developed glucose intolerance. HFD induced accumulation of eosinophils in the perigonadal white adipose tissue. Concordantly, adipocyte-differentiated 3T3-L1 cells promoted the migration of eosinophils through the expression of CCL11 (eotaxin-1) and likely promoted their survival through the expression of interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor. HFD-fed ΔdblGATA mice showed increased infiltration of macrophages, CD4
T-cells, and B-cells, increased expression of interferon-γ, and decreased expression of IL-4 and IL-13 in white adipose tissue. Interferon-γ treatment significantly decreased lipid deposition in adipocyte-differentiated 3T3-L1 cells, while IL-4 treatment promoted lipid accumulation. Notably, HFD-fed ΔdblGATA mice showed increased lipid storage in the liver as compared with wild-type mice. We propose that obesity promotes the infiltration of eosinophils into adipose tissue that subsequently contribute to the metabolic homeostasis by promoting adipocyte maturation.
The oligosaccharyl transferase (OST) protein complex mediates the N-linked glycosylation of substrate proteins in the endoplasmic reticulum (ER), which regulates stability, activity, and localization ...of its substrates. Although many OST substrate proteins have been identified, the physiological role of the OST complex remains incompletely understood. Here we show that the OST complex in C. elegans is crucial for ER protein homeostasis and defense against infection with pathogenic bacteria Pseudomonas aeruginosa (PA14), via immune-regulatory PMK-1/p38 MAP kinase. We found that genetic inhibition of the OST complex impaired protein processing in the ER, which in turn up-regulated ER unfolded protein response (UPRER). We identified vitellogenin VIT-6 as an OST-dependent glycosylated protein, critical for maintaining survival on PA14. We also showed that the OST complex was required for up-regulation of PMK-1 signaling upon infection with PA14. Our study demonstrates that an evolutionarily conserved OST complex, crucial for ER homeostasis, regulates host defense mechanisms against pathogenic bacteria.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Underweight imposes significant burden on cardiovascular outcomes in patients with diabetes mellitus. However, less is known about the impact of serial change in body weight status measured as body ...mass index (BMI) on the risk of sudden cardiac arrest (SCA). This study investigated the association between SCA and temporal change in BMI among patients with diabetes mellitus.
Based on Korean National Health Insurance Service database, participants with diabetes mellitus who underwent health examination between 2009 and 2012 and had prior health examination data (four years ago, 2005-2008) were retrospectively analyzed. BMI was measured at baseline (2005-2008) and 4-year follow-up health examination (2009-2012). Patients were classified in four groups according to the body weight status and its temporal change: sustained non-underweight, sustained underweight, previous underweight, and newly developed underweight. Primary outcome was defined as occurrence of SCA.
A total of 1,355,746 patients with diabetes mellitus were included for analysis, and SCA occurred in 12,554 cases. SCA was most common in newly developed underweight (incidence rate = 4.45 per 1,000 person-years), followed by sustained underweight (incidence rate = 3.90), previous underweight (incidence rate = 3.03), and sustained non-underweight (incidence rate = 1.34). Adjustment of covariates resulted highest risk of SCA in sustained underweight (adjusted hazard ratio = 2.60, 95% confidence interval 2.25-3.00, sustained non-underweight as a reference), followed by newly developed underweight (2.42, 2.15-2.74), and previous underweight (2.12, 1.77-2.53).
In diabetes mellitus, sustained underweight as well as decrease in body weight during 4-year follow-up imposes substantial risk on SCA. Recovery from underweight over time had relatively lower, but yet increased risk of SCA. Both underweight and dynamic decrease in BMI can be associated with increased risk of SCA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dyslipidemia measured as low-density lipoprotein (LDL)-cholesterol is an established risk factor of cardiovascular disease, which is more pronounced in diabetes population. Less is known about the ...association of LDL-cholesterol level and sudden cardiac arrest (SCA) risk in diabetes mellitus patients. This study investigated the association of LDL-cholesterol level and SCA risk in diabetes population.
This study was based on Korean National Health Insurance Service database. Patients who received general examination from 2009 to 2012 and diagnosed as type 2 diabetes mellitus were analyzed. Primary outcome was defined as SCA event identified with International Classification of Disease code.
A total of 2,602,577 patients were included, with total follow-up duration of 17,851,797 person * year. Mean follow-up duration was 6.86 years, and 26,341 SCA cases were identified. Overall incidence of SCA was highest in the lowest LDL-cholesterol group (< 70 mg/dL) and decreased in a linear manner as LDL-cholesterol rises, till 160 mg/dL. Adjustment of covariates resulted in U-shape association, with highest risk of SCA in the highest LDL-cholesterol group (≥ 160 mg/dL) followed by lowest LDL-cholesterol group (< 70 mg/dL). In subgroup analysis, U-shape association between SCA risk and LDL-cholesterol was more pronounced in male, non-obese people, and those who did not use statins.
In people with diabetes, the association between SCA and LDL-cholesterol level was U-shaped with highest and lowest LDL-cholesterol group having higher risk of SCA than others. Low LDL-cholesterol level can be a surrogate marker for increased risk of SCA in people with diabetes mellitus and this paradoxical association should be recognized and extended to clinical preventive measures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Variations in formulations used to prepare platelet-rich plasmas (PRPs) result in differences in the cellular composition and biomolecular characteristics.
Purpose:
To evaluate the ...cellular composition and the cytokine-release kinetics of PRP according to differences in the preparation protocols.
Study Design:
Controlled laboratory study.
Methods:
Five preparation procedures were performed for 14 healthy subjects, including 2 manual procedures (single-spin SS at 900g for 5 minutes; double-spin DS at 900g for 5 minutes and then 1500g for 15 minutes) and 3 methods with commercial kits (Arthrex ACP, Biomet GPS, and Prodizen Prosys). After evaluation of cellular composition, each preparation was divided into 4 aliquots and incubated for 1 hour, 24 hours, 72 hours, and 7 days for the assessment of cytokine release over time. The cytokine-release kinetics were evaluated by assessing platelet-derived growth factor (PDGF), transforming growth factor (TGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), interleukin-1 (IL-1), and matrix metalloproteinase–9 (MMP-9) concentrations of each aliquot with bead-based sandwich immunoassay.
Results:
The DS PRP had a higher concentration of platelets and leukocytes than did the SS PRP. Every PRP preparation exhibited an increase in PDGF, TGF, VEGF, and FGF release when compared with whole blood samples. The FGF and TGF release occurred quickly and decreased over time, while the PDGF and VEGF release was constant and sustained over 7 days. The PDGF and VEGF concentrations were higher in the DS PRP than in the SS PRP, whereas the TGF and FGF concentrations were higher in the SS PRP than in the DS PRP. Biomet GPS had the highest VEGF and MMP-9 concentrations but the lowest TGF concentration. Arthrex ACP had the highest FGF concentration but the lowest PDGF concentration. Prodizen Prosys had the highest IL-1 concentration and higher PDGF concentration than Arthrex ACP.
Conclusion:
The DS method generally led to a higher concentration of platelet relative to the SS method. However, the cytokine content was not necessarily proportional to the cellular composition of the PRPs, as the greater content could be different between the SS or DS method depending on the type of cytokine.
Clinical Relevance:
Physicians should select proper PRP preparations after considering their biomolecular characteristics and patient indications.
Atopic dermatitis is a chronic skin inflammatory disease mediated by Th2-type immune responses. Although intestinal immune responses have been shown to play a critical role in the development or ...prevention of atopic dermatitis, the precise influence of intestinal immunity on atopic dermatitis is incompletely understood. We show here that orally tolerized mice are protected from experimental atopic dermatitis induced by sensitization and epicutaneous (EC) challenge to ovalbumin. Although the expression of Th2-type cytokines in the small intestine of orally tolerized and EC-challenged mice did not change significantly, these mice showed decreased inflammatory responses in the small intestine with restoration of microbial change elicited by the EC challenge. Interestingly, an increase in small intestinal eosinophils was observed with the EC challenge, which was also inhibited by oral tolerance. The role of small intestinal eosinophils and microbiota in the pathogenesis of experimental atopic dermatitis was further substantiated by decreased inflammatory mediators in the small intestine and attenuated Th2-type inflammation in the skin of eosinophil-deficient and microbiota-ablated mice with EC challenges. Based on these data, we propose that the bidirectional interaction between the skin and the intestine has a role in the pathogenesis of atopic dermatitis and that modulation of the intestinal microenvironments could be a therapeutic approach to atopic dermatitis.
Hypertension is a known risk factor for sudden cardiac arrest (SCA). However, the role of temporal changes in blood pressure on the risk of SCA is not fully understood. This study was conducted to ...determine whether a temporal increase or decrease in blood pressure is associated with the risk of SCA. This study was based on nationwide healthcare insurance data. Individuals who underwent nationwide health check-ups in 2009 and 2011 were analyzed. A total of 2,801,153 individuals were evaluated for 8100 SCA events during the 17, 740, 420 person-years of follow-up. In a multivariate analysis, there were linear association between the degree of temporal elevation of systolic blood pressure (SBP) and the risk of SCA: (i) adjusted-hazard ratio (HR) 1.11 (p = 0.001) in 10 ≤ ΔSBP < 20 (mmHg) group; (ii) adjusted-HR 1.40 (p < 0.001) in 20 ≤ ΔSBP < 40 group; and (iii) adjusted-HR 1.88 (p < 0.001) in 40 ≤ ΔSBP group as compared with the reference group (- 10 ≤ ΔSBP < 10). Temporal increase in diastolic blood pressure (DBP) also a showed significant association with SCA risk with the highest risk observed in ∆DBP ≥ 25 group (adjusted-HR 1.61; p < 0.001) as compared with the reference group (- 5 ≤ ΔDBP < 5). The association between SBP and SCA was not affected by age, sex, presence of diabetes mellitus, or baseline SBP. In conclusion, a temporal increase in blood pressure was significantly associated with the occurrence of SCA, and this association was consistent across all subgroups. However, a temporary decrease in blood pressure does not reduce the risk of SCA. Prevention of elevated blood pressure may play an important role in preventing SCA.
The risk of having atrial fibrillation (AF) is associated with alcohol intake. However, it is not clear whether sudden cardiac arrest (SCA) and ventricular arrhythmia (VA) including ventricular ...tachycardia, flutter, or fibrillation have similar associations with alcohol. We aimed to evaluate the association of alcohol intake with all-cause death, new-onset AF, VA, and SCA using single cohort with a sufficient sample size. A total of 3,990,373 people without a prior history of AF, VAs, or SCA was enrolled in this study based on nationwide health check-up in 2009. We classified the participants into four groups according to weekly alcohol consumption, and evaluated the association of alcohol consumption with each outcome. We observed a significant association between mild (hazard ratio HR = 0.826; 95% confidence interval CI = 0.815-0.838) to moderate (HR = 0.930; 95% CI = 0.912-0.947) drinking with decreased risk of all-cause mortality. However heavy drinking (HR = 1.108; 95% CI = 1.087-1.129) was associated with increased all-cause death. The risk of new-onset AF was significantly associated with moderate (HR = 1.129; 95% CI = 1.097-1.161) and heavy (HR = 1.298; 95% CI = 1.261-1.337) drinking. However, the risk of SCA showed negative association with all degrees of alcohol intake: 20% (HR = 0.803; 95% CI = 0.769-0.839), 15% (HR = 0.853; 95% CI = 0.806-0.902), and 8% (HR = 0.918; 95% CI = 0.866-0.974) lower risk for mild, moderate, and heavy drinkers, respectively. Mild drinking was associated with reduced risk of VA with moderate and heavy drinking having no associations. In conclusion, the association between alcohol and various outcomes in this study were heterogeneous. Alcohol might have different influences on various cardiac disorders.
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