Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic ...immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (
Ldlr
−/−
) mice on a high-fat, high-cholesterol diet independently of low-density lipoprotein (LDL) cholesterol metabolism. Therefore, we allowed compassionate use of olamkicept (600 mg intravenously biweekly for 10 weeks) in a patient with very-high-risk ASCVD. Despite optimal LDL cholesterol under maximum tolerated lipid-lowering treatment, the patient had a remaining very high risk for future cardiovascular events related to significant arterial wall inflammation with lipoprotein (a) Lp(a)-cholesterol as the main contributor.
18
Fluorodeoxyglucose positron emission tomography/computed tomography (
18
FDG PET/CT) measurements were performed before and after the treatment period. Olamkicept reduced arterial wall inflammation in this patient without interfering with lipoprotein metabolism. No clinical or laboratory side effects were observed during or after treatment with olamkicept. Our findings in this patient matched the results from our mechanistic study in
Ldlr
−/−
mice, which were extended by additional analyses on vascular inflammation. Olamkicept may be a promising option for treating ASCVD independently of LDL cholesterol metabolism. A Phase II trial of olamkicept in ASCVD is currently being prepared.
The Food Chain Plus (FoCus) cohort was launched in 2011 for population-based research related to metabolic inflammation. To characterize this novel pathology in a comprehensive manner, data ...collection included multiple omics layers such as phenomics, microbiomics, metabolomics, genomics, and metagenomics as well as nutrition profiling, taste perception phenotyping and social network analysis. The cohort was set-up to represent a Northern German population of the Kiel region. Two-step recruitment included the randomised enrolment of participants via residents’ registration offices and via the Obesity Outpatient Centre of the University Medical Center Schleswig–Holstein (UKSH). Hence, both a population- and metabolic inflammation- based cohort was created. In total, 1795 individuals were analysed at baseline. Baseline data collection took place between 2011 and 2014, including 63% females and 37% males with an age range of 18–83 years. The median age of all participants was 52.0 years IQR: 42.5; 63.0 years and the median baseline BMI in the study population was 27.7 kg/m
2
IQR: 23.7; 35.9 kg/m
2
. In the baseline cohort, 14.1% of participants had type 2 diabetes mellitus, which was more prevalent in the subjects of the metabolic inflammation group (MIG; 31.8%). Follow-up for the assessment of disease progression, as well as the onset of new diseases with changes in subject’s phenotype, diet or lifestyle factors is planned every 5 years. The first follow-up period was finished in 2020 and included 820 subjects.
The present study explored the effects of ascorbic-acid (AA)/retinol and timed inflammation on the stemness, the regenerative potential, and the transcriptomics profile of gingival mesenchymal ...stem/progenitor cells' (G-MSCs). STRO-1 (mesenchymal stem cell marker) immuno-magnetically sorted G-MSCs were cultured in basic medium (control group), in basic medium with IL-1β (1 ng/mL), TNF-α (10 ng/mL) and IFN-γ (100 ng/mL, inflammatory-medium), in basic medium with AA (250 µmol/L) and retinol (20 µmol/L) (AA/retinol group) or in inflammatory medium with AA/retinol (inflammatory/AA/retinol group;
= 5/group). The intracellular levels of phosphorylated and total β-Catenin at 1 h, the expression of stemness genes over 7 days, the number of colony-forming units (CFUs) as well as the cellular proliferation aptitude over 14 days, and the G-MSCs' multilineage differentiation potential were assessed. Next-generation sequencing was undertaken to elaborate on up-/downregulated genes and altered intracellular pathways. G-MSCs demonstrated all mesenchymal stem/progenitor cells characteristics. Controlled inflammation with AA/retinol significantly elevated
(
< 0.05). The AA/retinol-mediated reduction in intracellular phosphorylated β-Catenin was restored through the effect of controlled inflammation (
< 0.05). Cellular proliferation was highest in the AA/retinol group (
< 0.05). AA/retinol counteracted the inflammation-mediated reduction in G-MSCs' clonogenic ability and CFUs. Amplified chondrogenic differentiation was observed in the inflammatory/AA/retinol group. At 1 and 3 days, the differentially expressed genes were associated with development, proliferation, and migration (
,
,
,
,
,
,
), survival (
,
,
), differentiation and mineral absorption (
,
,
,
,
,
), inflammation and MHC-II antigen processing (
,
,
) and intracellular pathway activation (
,
). Less as well as more genes were activated the longer the G-MSCs remained in the inflammatory medium or AA/retinol, respectively. Combined, current results point at possibly interesting interactions between controlled inflammation or AA/retinol affecting stemness, proliferation, and differentiation attributes of G-MSCs.
•lincRNAs are transcripts from non-coding DNA.•We found that IL-6 and TNF-α regulate different types of lincRNAs in vivo.•Our data suggest a role for lincRNA in the pathophysiology of RA.•Our data ...indicate lincRNAs to be specifically regulated by pharmaceutical agents.
lincRNAs recently have been discovered as evolutionary conserved transcripts of non-coding DNA sequences and have been implicated in the regulation of cellular differentiation. In humans, molecular studies have suggested a functional role for lincRNAs in cancer development. The aim of the present study was to examine whether these novel molecules are specifically regulated by different cytokines in cells of the innate immune system in humans in vivo and whether lincRNAs thereby might be involved in the pathophysiology of rheumatoid arthritis (RA). Therefore, CD14+ monocytes were isolated from RA patients before and after anti-IL-6R (tocilizumab) or anti-TNF-α (adalimumab) therapy and lincRNA transcription was analysed by a microarray based experiment. As expected, we found lincRNAs to be present in CD14+ monocytes of RA patients. However, of the total number of 7.419 lincRNAs examined in this study only a very small number was significantly regulated by either IL-6 or TNF-α (85 lincRNAs, corresponding to 1.1%). The numbers of lincRNAs regulated was higher due to TNF-α compared to IL-6. Interestingly, none of the identified lincRNAs was influenced by both, IL-6 and TNF-α, suggesting the regulation of lincRNA transcription to be highly specific for distinct cytokines. Taken together, our results suggest (1) that lincRNAs are novel intracellular molecular effectors of specific cytokines in cells of the innate immune system in humans in vivo and (2) that lincRNAs might be involved in the molecular pathophysiology of RA.
Abstract Atherosclerosis is a lipid-driven inflammatory disease, for which nanomedicinal interventions are under evaluation. Previously, we showed that liposomal nanoparticles loaded with ...prednisolone (LN-PLP) accumulated in plaque macrophages, however, induced proatherogenic effects in patients. Here, we confirmed in low-density lipoprotein receptor knockout ( LDLr−/− ) mice that LN-PLP accumulates in plaque macrophages. Next, we found that LN-PLP infusions at 10 mg/kg for 2 weeks enhanced monocyte recruitment to plaques. In follow up, after 6 weeks of LN-PLP exposure we observed (i) increased macrophage content, (ii) more advanced plaque stages, and (iii) larger necrotic core sizes. Finally, in vitro studies showed that macrophages become lipotoxic after LN-PLP exposure, exemplified by enhanced lipid loading, ER stress and apoptosis. These findings indicate that liposomal prednisolone may paradoxically accelerate atherosclerosis by promoting macrophage lipotoxicity. Hence, future (nanomedicinal) drug development studies are challenged by the multifactorial nature of atherosclerotic inflammation.
Aim
Recombinant secreted frizzled‐related protein 5 (sFRP5) improved periodontal status in mice. Thus, this study aimed to investigate this finding in human periodontitis using an epidemiological ...approach.
Materials and Methods
sFRP5 and wnt5a concentrations were determined in human serum from the Food Chain Plus cohort using ELISAs. A total of 128 patients with periodontitis and tooth loss and 245 patients with periodontitis without tooth loss were compared to 373 sex‐, smoker‐, age‐ and BMI‐matched individuals in a nested case–control design.
Results
Systemic sFRP5 serum levels were significantly lower in patients with periodontitis and tooth loss (2.5 0.0–10.4 ng/ml, median IQR) compared to patients with periodontitis without tooth loss (6.0 2.5–15.8 ng/ml, median IQR, p = 0.04 and matched controls (7.0 2.5–18.3 ng/ml, median IQR, p = 0.02). No significant differences in sFRP5 serum levels were found among patients with periodontitis without tooth loss (6.0 2.5–15.8 ng/ml, median IQR) and controls (3.1 0.0–10.6 ng/ml, median IQR, p = 0.06).
Conclusions
sFRP5 might serve as a novel biomarker for periodontitis severity. Modulating the inflammatory background of severe forms of periodontitis, in the time of precision medicine, needs to be revealed in further studies.
Inflammation and metabolism have been shown to be evolutionary linked and increasing evidence exists that pro-inflammatory factors are involved in the pathogenesis of obesity and type 2 diabetes. ...Until now, most data suggest that within adipose tissue these factors are secreted by cells of the innate immune system, e. g. macrophages. In the present study we demonstrate that B lymphocyte stimulator (BLyS) is increased in human obesity. In contrast to several pro-inflammatory factors, we found the source of BLyS in human adipose tissue to be the adipocytes rather than immune cells. In grade 3 obese human subjects, expression of BLyS in vivo in adipose tissue is significantly increased (p<0.001). Furthermore, BLyS serum levels are elevated in grade 3 human obesity (862.5+222.0 pg/ml vs. 543.7+60.7 pg/ml in lean controls, p<0.001) and are positively correlated to the BMI (r = 0.43, p<0.0002). In the present study, bariatric surgery significantly altered serum BLyS concentrations. In contrast, weight loss due to a very-low-calorie-formula-diet (800 kcal/d) had no such effect. To examine metabolic activity of BLyS, in a translational research approach, insulin sensitivity was measured in human subjects in vivo before and after treatment with the human recombinant anti-BLyS antibody belimumab. Since BLyS is known to promote B-cell proliferation and immunoglobulin secretion, the present data suggest that adipocytes of grade 3 obese human subjects are able to activate the adaptive immune system, suggesting that in metabolic inflammation in humans both, innate and adaptive immunity, are of pathophysiological relevance.
Animal and human studies suggest that a malleable protein matrix (MPM) from whey decreases plasma lipid concentrations and may positively influence other components of the metabolic syndrome such as ...glucose metabolism and blood pressure (BP). The primary objective of this double-blind, multi-centre trial was to investigate the effects of a low-fat yoghurt supplemented with whey MPM on fasting TAG concentrations in patients with the metabolic syndrome. A total of 197 patients were randomised to receive MPM or a matching placebo yoghurt identical in protein content (15 g/d). Patients were treated during 3 months with two daily servings of 150 g yoghurt each to compare changes from baseline in efficacy variables. MPM treatment resulted in a significantly larger reduction of TAG concentrations in comparison to placebo (relative change − 16 %, P = 0·004). The difference was even more pronounced in subjects with elevated fasting TAG ( ≥ 200 mg/dl) at baseline ( − 18 %, P = 0·005). The relative treatment difference in fasting plasma glucose was − 7·1 mg/dl (P = 0·089). This effect was also more pronounced in subjects with impaired fasting glucose at baseline ( − 11 mg/dl, P = 0·03). In patients with hypertension, the relative treatment difference in systolic BP reached − 5·9 mmHg (P = 0·054). The relative treatment difference in body weight was − 1·7 kg (P = 0·015). The most common adverse events were gastrointestinal in nature. Conclusions from the present study are that consumption of a low-fat yoghurt supplemented with whey MPM twice a day over 3 months significantly reduces fasting TAG concentrations in patients with the metabolic syndrome and improves multiple other cardiovascular risk factors.
Abstract Background Macrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we ...documented nanomedicinal delivery of the anti -inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages. Methods and results. We evaluated the effect of several candidate drugs on macrophage activity, rating overall performance with respect to changes in cytokine release, oxidative stress, lipid handling, endoplasmic reticulum (ER) stress, and proliferation of macrophages. Using this in vitro approach, we observed that the anti -inflammatory effect of prednisolone was counterbalanced by multiple adverse effects on other key pathways. Conversely, pterostilbene, T0901317 and simvastatin had an overall anti -atherogenic effect on multiple pathways, suggesting their potential for liposomal delivery. Conclusion This dedicated assay setup provides a framework for high-throughput assessment. Further in vivo studies are warranted to determine the predictive value of this macrophage-based screening approach and its potential value in nanomedicinal drug development for cardiovascular patients.
Despite advances in immunosuppression and liver transplant in the past, mortality and morbidity caused by infections remain major problems. We present a 71-year-old man who was admitted to our ...internal intensive care unit with septicemia. Upon admission, he had poorly localized epigastric pain and fever of 2 days ' duration. Twenty years earlier, he had undergone an orthotopic liver transplant. Testing revealed a high C-reactive protein level, elevated liver enzymes, and an acute kidney injury. A computer tomography scan showed 2 circular, non--rim-enhancing, totally emphysematous intrahepatic lesions. Additionally, gas could be seen in the portal veins mainly, as well as in the biliary system, in the right auricle, and the splenic veins. To the best of our knowledge, he showed no malignant lesion or predisposing trauma. Empirically, treatment with broad-spectrum antibiotics was begun, and the patient was transferred to the operating suite. When surgery began, blood cultures revealed the presence of gram-positive bacilli, which were identified as Clostridium perfringens. Seven hours after the surgery, the patient developed asystole and died. In septic patients presenting with severe hemolysis, Clostridium perfringens infection must be considered in the absence of a malignant lesion or a predisposing trauma; a previous episode of gastroenteritis might be a predisposing trauma by impairing the barrier of the intestinal flora, leading to Clostridium perfringens infection.
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