Pericytes are a vital component of the blood-brain barrier, and their involvement in acute inflammation was recently suggested. However, it remains unclear whether pericytes contribute to ...hypothalamic chronic inflammation and energy metabolism in obesity. The present study investigated the impact of pericytes on the pathophysiology of obesity by focusing on platelet-derived growth factor (PDGF) signaling, which regulates pericyte functions.
Tamoxifen-inducible systemic conditional PDGF receptor β knockout mice (Pdgfrb
-KO) and Calcium/calmodulin-dependent protein kinase type IIa (CaMKIIa)-positive neuron-specific PDGF receptor β knockout mice (Pdgfrb
-KO) were fed a high-fat diet, and metabolic phenotypes before and 3 to 4 weeks after dietary loading were examined. Intracellular energy metabolism and relevant signal transduction in lipopolysaccharide- and/or platelet-derived growth factor-BB (PDGF-BB)-stimulated human brain pericytes (HBPCs) were assessed by the Seahorse XFe24 Analyzer and Western blotting. The pericyte secretome in conditioned medium from HBPCs was studied using cytokine array kit, and its impact on polarization was examined in bone marrow-derived macrophages (BMDMs), which are microglia-like cells.
Energy consumption increased and body weight gain decreased after high-fat diet loading in Pdgfrb
-KO mice. Cellular oncogene fos (cFos) expression increased in proopiomelanocortin (POMC) neurons, whereas microglial numbers and inflammatory gene expression decreased in the hypothalamus of Pdgfrb
-KO mice. No significant changes were observed in Pdgfrb
-KO mice. In HBPCs, a co-stimulation with lipopolysaccharide and PDGF-BB shifted intracellular metabolism towards glycolysis, activated mitogen-activated protein kinase (MAPK), and modulated the secretome to the inflammatory phenotype. Consequently, the secretome showed an increase in various proinflammatory chemokines and growth factors including Epithelial-derived neutrophil-activating peptide 78 (C-X-C motif chemokine ligand (CXCL)5), Thymus and activation-regulated chemokine (C-C motif chemokine (CCL)17), Monocyte chemoattractant protein 1 (CCL2), and Growth-regulated oncogene α (CXCL1). Furthermore, conditioned medium from HBPCs stimulated the inflammatory priming of BMDMs, and this change was abolished by the C-X-C motif chemokine receptor (CXCR) inhibitor. Consistently, mRNA expression of CXCL5 was elevated by lipopolysaccharide and PDGF-BB treatment in HBPCs, and the expression was significantly lower in the hypothalamus of Pdgfrb
-KO mice than in control Pdgfrb
mice (FL) following 4 weeks of HFD feeding.
PDGF receptor β signaling in hypothalamic pericytes promotes polarization of macrophages by changing their secretome and contributes to the progression of obesity.
Aims/hypothesis
The imbalance between maternal insulin resistance and a relative lack of insulin secretion underlies the pathogenesis of gestational diabetes mellitus (GDM). Alterations in T cell ...subtypes and increased levels of circulating proinflammatory cytokines have been proposed as potential mechanisms underlying the pathophysiology of insulin resistance in GDM. Since oestrogen modulates T cell immunity, we hypothesised that oestrogen plays a homeostatic role in visceral adipose tissue by coordinating T cell immunity through oestrogen receptor α (ERα) in T cells to prevent GDM.
Methods
Female CD4-cre ERα
fl/fl
(KO) mice on a C57BL/6 background with ERα ablation specifically in T cells, and ERα
fl/fl
(ERα-floxed FL) mice were fed 60 kJ% high-fat diet (HFD) for 4 weeks. Female mice mated with male BALB/c mice to achieve allogenic pregnancy and were maintained on an HFD to generate the GDM model. Mice were divided into four experimental groups: non-pregnant FL, non-pregnant KO, pregnant FL (FL-GDM) and pregnant KO (KO-GDM). GTTs and ITTs were performed on day 12.5 or 13.5 and 16.5 after breeding, respectively. On day 18.5 after breeding, mice were killed and T cell subsets in the gonadal white adipose tissue (gWAT) and spleen were analysed using flow cytometry. Histological examination was also conducted and proinflammatory gene expression in gWAT and the liver was evaluated.
Results
KO mice that mated with BALB/c mice showed normal fertility rates and fetal weights as compared with FL mice. Body and tissue weights were similar between FL and KO mice. When compared with FL-GDM mice, KO-GDM mice showed decreased insulin secretion (serum insulin concentration 15 min after glucose loading: 137.3 ± 18.3 pmol/l and 40.1 ± 36.5 pmol/l, respectively;
p
< 0.05), impaired glucose tolerance (glucose AUC in GTT: 2308.3 ± 54.0 mmol/l × min and 2620.9 ± 122.1 mmol/l × min, respectively;
p
< 0.05) and increased numbers of T helper (Th)17 cells in gWAT (0.4 ± 0.0% vs 0.8 ± 0.1%;
p
< 0.05). However, the contents of Th1 and regulatory T cells (Tregs) in gWAT remained similar between FL-GDM and KO-GDM. Glucose-stimulated insulin secretion was similar between isolated islets derived from FL and KO mice, but was reduced by IL-17A treatment. Moreover, the levels of proinflammatory gene expression, including expression of
Emr1
and
Tnfa
in gWAT, were significantly higher in KO-GDM mice than in FL-GDM mice (5.1-fold and 2.7-fold, respectively;
p
< 0.01 for both). Furthermore, KO-GDM mice showed increased expression of genes encoding hepatokines,
Ahsg
and
Fgf21
(both were 2.4-fold higher vs FL-GDM mice;
p
< 0.05 and
p
= 0.09, respectively), with no changes in inflammatory gene expression (e.g.,
Tnfa
and
Ifng
) in the liver compared with FL-GDM mice.
Conclusions/interpretation
Deletion of ERα in T cells caused impaired maternal adaptation of insulin secretion, changes in hepatokine profiles, and enhanced chronic inflammation in gWAT alongside an abnormal increase in Th17 cells. These results suggest that the ERα-mediated oestrogen signalling effects in T cells regulate T cell immunity and contribute to glucose homeostasis in pregnancy.
Graphical abstract
MC903 is a synthetic derivative of vitamin D3 that has been designed to diminish its impact on calcium metabolism and is clinically used as a transdermal reagent for psoriasis. Animal studies showed ...that an oral or intraperitoneal vitamin D3 treatment prevented the development of obesity. In contrast, the bioavailability of orally administered vitamin D3 is reported to be low in obese patients. In the current study, we aimed to investigate the impact of a transdermal treatment with MC903 in established obese mice. We further studied the underlying mechanisms of MC903-mediated metabolic improvement.
Male C57BL/6 J mice were fed standard chow or a 60% high-fat diet (HFD) for 7 weeks, and a transdermal treatment with MC903 on the ear auricle was initiated thereafter. The metabolic profiles of mice were analyzed during 4 weeks of treatment, and mice were dissected for histological and gene expression analyses. The direct impacts of MC903 and vitamin D3 were investigated using 3T3-L1 adipocytes and C2C12 myotubes in vitro.
HFD-fed mice showed significant increases in body and epididymal white adipose tissue (eWAT) weights with enlarged adipocytes. They exhibited glucose intolerance, decreased oxygen consumption, and chronic inflammation in eWAT. The transdermal treatment with MC903 significantly ameliorated these metabolic abnormalities in HFD-fed mice without affecting food consumption. In accordance with enhanced energy metabolism, myofiber diameters and the expression of uncoupling protein 3 (UCP3) in the gastrocnemius and soleus muscle were significantly increased in MC903-treated HFD mice. In addition, vitamin D3 and MC903 both suppressed adipogenic differentiation and enhanced lipolysis in 3T3-L1 adipocytes, and increased UCP3 expression in cultured C2C12 myotubes. Furthermore, MC903 increased oxygen consumption and UCP3 knockdown significantly decreased them in C2C12 myotubes.
A transdermal treatment with MC903 increased myofiber diameter and energy metabolism and decreased visceral fat accumulation, thereby improving obesity and glucose intolerance in mice.
AIM To evaluate the lower-limb muscle oxygenation in hemodialysis（HD） patients and identify the factors associating with muscle oxygenation.METHODS Sixty-seven HD patients（53 men and 14 women; mean ...age, 67.1 ± 1.2 years; mean HD duration, 5.6 ± 0.9 years） were recruited. In addition, 15 healthy individuals（nine men and six women; mean age, 38.2 ± 4.6 years） were recruited as the control group. Lower-limb muscle regional saturation of oxygen（rS O2） was monitored on the lateral side of the gastrocnemius muscle before HD using an INVOS 5100C（Covidien Japan, Tokyo, Japan）, which utilizes near-infrared spectroscopy. Here, we evaluated the association between lower-limb muscle rS O2 and clinical parameters.RESULTS The r SO2 values were significantly lower in patients undergoing HD than in healthy individuals（50.0%± 1.7% vs 76.8% ± 2.5%, P < 0.001）. Lower-limb muscle r SO2 showed significant positive correlations with diastolic blood pressure, blood urea nitrogen concentration, serum creatinine concentration, serum potassium concentration, serum inorganic phosphate concentration, and serum albumin concentration as well as negative correlation with HD duration. We conducted a multiple linear regression analysis using parameters that were significantly correlated with the lower-limb muscle r SO2 in a simple linear regression analysis. Multiple regression analysis demonstrated that lowerlimb muscle r SO2 was independently associated with serum inorganic phosphate（standardized coefficient: 0.27） and serum albumin concentrations（standardized coefficient: 0.24）. In addition, there were no differences in lower-limb muscle r SO2 between diabetic and nondiabetic HD patients. This study has several limitations. Firstly, its sample size was relatively small. Secondly, we could not evaluate the association between lowerlimb muscle r SO2 and calculated nutritional markers, including normalized protein catabolic rate and body mass index, anthropometric measurements representing nutritional status, and the severity of protein-energy wasting. Finally, we did not routinely examine the arterial vascular status of HD patients without symptoms of peripheral artery disease. As such, it is possible that some HD patients with subclinical peripheral artery disease may have been included in this study.CONCLUSION In HD patients, the oxygenation of lower-limb muscle tissue was associated with serum inorganic phosphate and albumin concentrations, both of which represent nutritional status.
The interconversion between formic acid and H2/CO2 using half‐sandwich rhodium and ruthenium catalysts with 4,4’‐dihydroxy‐2,2’‐bipyridine (DHBP) was investigated. The influence of substituents of ...the bipyridine ligand was studied. Chemical shifts of protons in bipyridine linearly correlated with Hammett substituent constants. In the hydrogenation of CO2/bicarbonate to formate under basic conditions, significant activations of the catalysts were caused by the electronic effect of oxyanions generated by deprotonation of the hydroxyl group. Initial turnover frequencies of the ruthenium‐ and rhodium‐DHBP complexes increased 65‐ and 8‐fold, respectively, compared to the corresponding unsubstituted bipyridine complexes. In the decomposition of formic acid under acidic conditions, activity enhancement by the electronic effect of the hydroxyl group was observed for the ruthenium catalyst. The rhodium‐DHBP catalyst showed high activity without CO contamination in a relatively wide pH range. Pressurized H2 can be obtained using an autoclave reactor. The highest turnover frequency and number were obtained at 80 °C. The catalytic system provides valuable insight into the use of CO2 as a H2 storage material by combining CO2 hydrogenation with formic acid decomposition.
RuRhgebiet: The interconversion between formic acid and H2/CO2 using rhodium and ruthenium catalysts is demonstrated. In the hydrogenation of CO2/bicarbonate under basic conditions, catalytic activation is caused by an electronic substituent effect of oxyanions. In the decomposition of formic acid under acidic conditions, the rhodium catalyst induces highly efficient CO‐free H2 evolution.
Kaposi's sarcoma–associated herpesvirus (KSHV) is responsible for the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. The expression of ...immunosuppressive genes, such as IL‐10 and CD274/PD‐L1 is observed during KSHV‐associated pathogenesis, and the modulation of the host immune system by KSHV contributes to establishing viral persistence in the host. Understanding the mechanism that allows the virus to evade host cell immunity would be helpful in order to develop therapeutic strategies for KSHV malignancy. In this study, we show that KSHV replication and transcriptional activator (K‐RTA), an essential activator of the viral lytic cycle, transactivates the CD274/PD‐L1 gene promoter. Mechanistically, we demonstrate that the binding of K‐RTA to the cellular specificity protein 1 (SP1) is critical for K‐RTA–mediated CD274/PD‐L1 promoter activation. These findings suggest that K‐RTA cooperates with intracellular SP1 to activate the expression of CD274/PD‐L1, which helps the virus regulate immune checkpoints to escape and survive.
Various viruses including Kaposi's sarcoma–associated herpesvirus (KSHV) abuse the negative regulators of the host immune checkpoint system. KSHV K‐RTA cooperates with SP1 to activate CD274/PD‐L1 expression. The binding of viral K‐RTA to cellular SP1 is critical for K‐RTA–mediated CD274/PD‐L1 promoter activation.
ReveromycinA (RMA) was developed and is a unique agent for inhibiting osteoclast activity. In a previous study, we experimentally induced periodontal disease in a high-turnover osteoporosis ...osteoprotegerin-knockout mice (OPG KO) model and found that intraperitoneal administration of RMA inhibited alveolar bone resorption. We prepared a novel RMA-containing ointment for topical non-invasive administration in the oral cavity, in preparation for possible future clinical application. And we investigated whether this ointment can inhibit alveolar bone resorption in an experimental mouse model of periodontal disease. We examined wild-type (WT) and OPG KO mice ligated with wire around contact points on the left first and second molars to cause food impaction and induce experimental periodontal disease. RMA was administered three times a day. Using micro-computed tomography, we measured the volume of alveolar bone loss and also performed histological analysis. Our findings showed that localized administration of RMA containing ointment resulted in suppressed alveolar bone resorption, reduced osteoclast count, and lower immunostaining scores of inflammation sites compared with controls in both OPG KO and WT mice. Localized application of the specific osteoclast suppressor RMA in ointment form in the oral cavity could be a novel treatment for periodontitis that inhibits alveolar bone resorption locally.
The hepato-splanchnic circulation directly influences oxygenation of the abdominal organs and plays an important role in compensating for the blood volume reduction that occurs in the central ...circulation during hemodialysis (HD) with ultrafiltration. However, the hepato-splanchnic circulation and oxygenation cannot be easily evaluated in the clinical setting of HD therapy. We included 185 HD patients and 15 healthy volunteers as the control group in this study. Before HD, hepatic regional oxygen saturation (rSO.sub.2 ), a marker of hepatic oxygenation reflecting the hepato-splanchnic circulation and oxygenation, was monitored using an INVOS 5100c oxygen saturation monitor. Hepatic rSO.sub.2 was significantly lower in patients undergoing HD than in healthy controls (56.4 ± 14.9% vs. 76.2 ± 9.6%, p < 0.001). Multivariable regression analysis showed that hepatic rSO.sub.2 was independently associated with body mass index (BMI; standardized coefficient: 0.294), hemoglobin (Hb) level (standardized coefficient: 0.294), a history of cardiovascular disease (standardized coefficient: -0.157), mean blood pressure (BP; standardized coefficient: 0.154), and serum albumin concentration (standardized coefficient: 0.150) in Model 1 via a simple linear regression analysis. In Model 2 using the colloid osmotic pressure (COP) in place of serum albumin concentration, the COP (standardized coefficient: 0.134) was also identified as affecting hepatic rSO.sub.2 . Basal hepatic oxygenation before HD might be affected by BMI, Hb levels, a history of cardiovascular disease, mean BP, serum albumin concentration, and the COP. Further prospective studies are needed to clarify whether changes in these parameters, including during HD, affect the hepato-splanchnic circulation and oxygenation in HD patients.
A decline in estimated glomerular filtration rate (eGFR) is reportedly associated with increased prevalence rates of cognitive impairment. However, data concerning the association between the ...cerebral saturation of oxygen (rSO2) and cognitive function of patients with chronic kidney disease (CKD) is limited. This study aimed to (i) elucidate the clinical factors associating with cerebral rSO2 and (ii) investigate the association between cerebral rSO2 and cognitive assessment in CKD patients.
A total of 40 CKD patients not requiring dialysis (26 men and 14 women; mean age, 61.0 ± 2.7 years) were recruited. The numbers of patients at each CKD stage were as follows: G1, 5; G2, 8; G3a, 6; G3b, 5; G4, 11; and G5, 5. Cerebral rSO2 was monitored at the forehead using the oxygen saturation monitor INVOS 5100C. The cognitive function of each patient was confirmed using the Mini-Mental State Examination (MMSE).
Cerebral rSO2 levels were significantly higher in CKD patients than in hemodialysis patients (63.8 ± 1.5% vs. 44.9 ± 2.2%, p < 0.001). Multiple regression analysis showed that cerebral rSO2 was independently associated with eGFR (standardized coefficient: 0.530), serum albumin concentration (standardized coefficient: 0.365), and serum sodium concentration (standardized coefficient: 0.224). Furthermore, MMSE showed a significantly positive correlation with cerebral rSO2 (r = 0.624, p < 0.001).
Cerebral rSO2 was affected by eGFR and serum albumin and sodium concentrations in CKD patients. Furthermore, cerebral rSO2 monitoring, which reflected MMSE scores, might be a useful method for assessing cognitive function in CKD patients.
The hepato-splanchnic circulation directly influences oxygenation of the abdominal organs and plays an important role in compensating for the blood volume reduction that occurs in the central ...circulation during hemodialysis (HD) with ultrafiltration. However, the hepato-splanchnic circulation and oxygenation cannot be easily evaluated in the clinical setting of HD therapy. We included 185 HD patients and 15 healthy volunteers as the control group in this study. Before HD, hepatic regional oxygen saturation (rSO2), a marker of hepatic oxygenation reflecting the hepato-splanchnic circulation and oxygenation, was monitored using an INVOS 5100c oxygen saturation monitor. Hepatic rSO2 was significantly lower in patients undergoing HD than in healthy controls (56.4 ± 14.9% vs. 76.2 ± 9.6%, p < 0.001). Multivariable regression analysis showed that hepatic rSO2 was independently associated with body mass index (BMI; standardized coefficient: 0.294), hemoglobin (Hb) level (standardized coefficient: 0.294), a history of cardiovascular disease (standardized coefficient: -0.157), mean blood pressure (BP; standardized coefficient: 0.154), and serum albumin concentration (standardized coefficient: 0.150) in Model 1 via a simple linear regression analysis. In Model 2 using the colloid osmotic pressure (COP) in place of serum albumin concentration, the COP (standardized coefficient: 0.134) was also identified as affecting hepatic rSO2. Basal hepatic oxygenation before HD might be affected by BMI, Hb levels, a history of cardiovascular disease, mean BP, serum albumin concentration, and the COP. Further prospective studies are needed to clarify whether changes in these parameters, including during HD, affect the hepato-splanchnic circulation and oxygenation in HD patients.
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