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Background and objectives: Dyslipidemia is one of the most important modifiable risk factors in the pathogenesis of cardiovascular disease in the general population, but its importance in the hemodialysis (HD) population is uncertain. Materials and Methods: This retrospective cohort study includes HD patients hospitalized due to acute coronary syndrome (ACS) in the period 2015–2020 with lipid profile data during ACS. A control group with preserved kidney function was matched. Risk factors for 30-day and 1-year mortality were assessed. Results: Among 349 patients included in the analysis, 246 were HD-dependent (“HD group”). HD group patients had higher prevalence of diabetes, hypertension, and heart disease than the control group. At ACS hospitalization, lipid profile and chronic statin treatment were comparable between groups. Odds ratios for 30-day mortality in HD vs. control group was 5.2 (95% CI 1.8–15; p = 0.002) and for 1-year, 3.4 (95% CI 1.9–6.1; p p = 0.995, 0.823, respectively). However, survival after ACS in HD patients correlated positively with nutritional parameters such as serum albumin (r = 0.368, p < 0.001) and total cholesterol (r = 0.185, p < 0.001), and inversely with the inflammatory markers C-reactive protein (CRP; r = −0.348, p < 0.001) and neutrophils-to-lymphocytes ratio (NLR; r = −0.181, p = 0.019). Multivariate analysis demonstrated that heart failure was the only significant predictor of 1-year mortality (OR 2.8, p = 0.002). LDL < 70 mg/dL at ACS hospitalization did not predict 1-year mortality in the HD group. Conclusions: Despite comparable lipid profiles and statin treatment before and after ACS hospitalization, mortality rates were significantly higher among HD group. While malnutrition–inflammation markers were associated with survival of dialysis patients after ACS, LDL cholesterol was not. Thus, our study results emphasize that better nutritional status and less inflammation are associated with improved survival among HD patients.

Background: Endothelial dysfunction, vascular inflammation and accelerated atherosclerosis have been investigated extensively in patients with chronic kidney disease (CKD). These conditions, as well as protein–energy malnutrition and oxidative stress, impair kidney function and contribute to increased morbidity and mortality among patients with end-stage kidney disease undergoing hemodialysis (HD). TXNIP, a key regulator of oxidative stress, has been linked to inflammation and suppresses eNOS activity. STAT3 activation adds to endothelial cell dysfunction, macrophage polarization, immunity and inflammation. Therefore, it is critically involved in atherosclerosis. This study evaluated the effect of sera from HD patients on the TXNIP-eNOS-STAT3 pathway using an in vitro model of human umbilical vein endothelial cells (HUVECs). Methods: Thirty HD patients with end-stage kidney disease and ten healthy volunteers were recruited. Serum samples were taken at dialysis initiation. HUVECs were treated with HD or healthy serum (10% v/v) for 24 h. Then, cells were collected for mRNA and protein analysis. Results: TXNIP mRNA and protein expression were significantly increased in HUVECs treated with HD serum compared to healthy controls (fold changes: 2.41 ± 1.84 vs. 1.41 ± 0.5 and 2.04 ± 1.16 vs. 0.92 ± 0.29, respectively), as were IL-8 mRNA (fold changes: 2.22 ± 1.09 vs. 0.98 ± 0.64) and STAT3 protein expression (fold changes: 1.31 ± 0.75 vs. 0.57 ± 0.43). The expression of eNOS mRNA and protein (fold changes: 0.64 ± 0.11 vs. 0.95 ± 0.24; 0.56 ± 0.28 vs. 4.35 ± 1.77, respectively) and that of SOCS3 and SIRT1 proteins were decreased. Patients’ nutritional status, reflected by their malnutrition–inflammation scores, did not affect these inflammatory markers. Conclusions: This study showed that sera from HD patients stimulated a novel inflammatory pathway, regardless of their nutritional status.

Background and Aims: Idiopathic pulmonary fibrosis (IPF) is a common and severe form of pulmonary fibrosis. Nintedanib, a triple angiokinase inhibitor, is approved for treating IPF. Galectin 3 (Gal-3) activates a variety of profibrotic processes. Currently, the Gal-3 inhibitor TD139 is being tested in phase II clinical trials. Since this treatment is given ‘on top’ of nintedanib, it is important to estimate its effect on Gal-3 levels. Therefore, we evaluated the impact of nintedanib on Gal-3 expression using both in vitro and in vivo models, in addition to serum samples from patients with IPF. Methods: Gal-3 levels were evaluated in IPF and control tissue samples, primary human lung fibroblasts (HLFs) following nintedanib treatment (10–100 nM, quantitative polymerase chain reaction), and in a silica-induced fibrosis mouse model with/without nintedanib (0.021–0.21 mg/kg) by immunohistochemistry. In addition, Gal-3 levels were analyzed in serum samples from 41 patients with interstitial lung disease patients with/without nintedanib treatment by ELISA. Results: Nintedanib addition to HLFs resulted in significant elevations in Gal-3, phospho-signal transducer and activator of transcription 3 (pSTAT3), as well as IL-8 mRNA levels ( p

Mast cells (MCs) function as a component of the tumor microenvironment (TME) and have both pro- and anti-tumorigenic roles depending on the tumor type and its developmental stage. Several reports indicate the involvement of MCs in angiogenesis in the TME by releasing angiogenic mediators. Tumor cells and other cells in the TME may interact by releasing extracellular vesicles (EVs) that affect the cells in the region. We have previously shown that tumor-derived microvesicles (TMVs) from non-small-cell lung cancer (NSCLC) cells interact with human MCs and activate them to release several cytokines and chemokines. In the present study, we characterized the MC expression of other mediators after exposure to TMVs derived from NSCLC. Whole-genome expression profiling disclosed the production of several chemokines, including CC chemokine ligand 18 (CCL18). This chemokine is expressed in various types of cancer, and was found to be associated with extensive angiogenesis, both in vitro and in vivo. We now show that CCL18 secreted from MCs activated by NSCLC-TMVs increased the migration of human umbilical cord endothelial cells (HUVECs), tube formation and endothelial- to-mesenchymal transition (EndMT), thus promoting angiogenesis. Our findings support the conclusion that TMVs have the potential to influence MC activity and may affect angiogenesis in the TME.

Aims: Class A2 gestational diabetes mellitus (GDMA2) has short- and long-term effects on the mother and child. These may include abnormalities of placentation, damage to endothelial cells and cardiovascular disease. This research investigated the function and composition of high-density lipoproteins (HDL) among women with GDMA2 and their fetuses. Methods: Thirty pregnant women were recruited during admission for delivery. The function and expression of HDL, paraoxonase1 (PON1) and apolipoprotein A1 (APOA1) in the blood samples and the placental tissue were evaluated. The effect of HDL on migration of endothelial cells was measured in vitro. Results: Compared to normal pregnancy (NP), APOA1 in the maternal plasma of women with GDMA2 was decreased. More APOA1 and PON1 were released from HDL of women with GDMA2, compared to NP. Placental APOA1 and PON1 were decreased in GDMA2. For endothelial cells stimulated with TNFα, HDL cell migration was decreased when cells were evaluated with NP-HDL, as compared to GDMA2-HDL. Conclusions: GDMA2 affects the composition and function of HDL in plasma. Changes in HDL commonly seen in GDMA2 were observed in maternal and placental samples, but not in cord samples. These results might indicate a placental role in protecting the fetus by preserving the components and functions of HDL and require further investigation.

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype–phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care. [ABSTRACT FROM AUTHOR]

The document titled "Reviewers acknowledgement" is a list of individuals who have reviewed articles submitted for publication in Volume 13 of FEBS Open Bio. The editors express their gratitude to these reviewers for their time and expertise in carefully scrutinizing the experimental design and results of the papers. The list includes a diverse range of names from various cultural backgrounds, reflecting the global nature of the research community. [Extracted from the article]

Introduction: Patients with end stage kidney disease undergoing maintenance hemodialysis (MHD) are prone to malnutrition and infections. Objective: The objective of this study was to evaluate the effect of polymorphonuclear (PMN) cell dysfunction on clinical outcomes of MHD patients, in association with nutritional status. Methods: This prospective study investigated 39 MHD patients by evaluating the oxidative activity of their PMN cells using Phorbol 12‐Myristate‐13‐Acetate (PMA) stimulation. Blood samples were taken from each participant at dialysis initiation. Demographics, laboratory data, and clinical outcomes during a 24‐month follow‐up period were obtained from electronic medical records. Results: Phagocytic activity was described in percentiles of mean fluorescence intensity (MFI) of PMA levels. There were no differences in comorbidities between patients with low or high MFI‐PMA percentiles. Patients in the lowest (25th) MFI‐PMA percentile (N = 10) had poorer nutritional status and more frequent severe infections compared to the other 29 patients (4.3 ± 3.4 events versus 2 ± 2.2 events, p = 0.017). Furthermore, they had more frequent hospitalizations (>3) due to infections (70% versus 41%, p = 0.073) and their mortality rate was higher (80% versus 31%, p = 0.007). The odds ratio for all‐cause mortality was 8.85. In multivariate analysis, the MFI‐PMA percentile and ischemic heart disease were the strongest predictors of all‐cause mortality (p = 0.02 and p = 0.005, respectively). Conclusions: Low MFI‐PMA levels were associated with poor nutritional status and adverse clinical outcomes and might serve as a prognostic biomarker, predicting severe infections and mortality among malnourished MHD patients. [ABSTRACT FROM AUTHOR]

Background and objectives: Dyslipidemia is one of the most important modifiable risk factors in the pathogenesis of cardiovascular disease in the general population, but its importance in the hemodialysis (HD) population is uncertain. Materials and Methods: This retrospective cohort study includes HD patients hospitalized due to acute coronary syndrome (ACS) in the period 2015–2020 with lipid profile data during ACS. A control group with preserved kidney function was matched. Risk factors for 30-day and 1-year mortality were assessed. Results: Among 349 patients included in the analysis, 246 were HD-dependent ("HD group"). HD group patients had higher prevalence of diabetes, hypertension, and heart disease than the control group. At ACS hospitalization, lipid profile and chronic statin treatment were comparable between groups. Odds ratios for 30-day mortality in HD vs. control group was 5.2 (95% CI 1.8–15; p = 0.002) and for 1-year, 3.4 (95% CI 1.9–6.1; p <0.001). LDL and LDL < 70 did not change 30-day and 1-year mortality rates in the HD group (p = 0.995, 0.823, respectively). However, survival after ACS in HD patients correlated positively with nutritional parameters such as serum albumin (r = 0.368, p < 0.001) and total cholesterol (r = 0.185, p < 0.001), and inversely with the inflammatory markers C-reactive protein (CRP; r = −0.348, p < 0.001) and neutrophils-to-lymphocytes ratio (NLR; r = −0.181, p = 0.019). Multivariate analysis demonstrated that heart failure was the only significant predictor of 1-year mortality (OR 2.8, p = 0.002). LDL < 70 mg/dL at ACS hospitalization did not predict 1-year mortality in the HD group. Conclusions: Despite comparable lipid profiles and statin treatment before and after ACS hospitalization, mortality rates were significantly higher among HD group. While malnutrition–inflammation markers were associated with survival of dialysis patients after ACS, LDL cholesterol was not. Thus, our study results emphasize that better nutritional status and less inflammation are associated with improved survival among HD patients. [ABSTRACT FROM AUTHOR]

Background: Endothelial dysfunction, vascular inflammation and accelerated atherosclerosis have been investigated extensively in patients with chronic kidney disease (CKD). These conditions, as well as protein–energy malnutrition and oxidative stress, impair kidney function and contribute to increased morbidity and mortality among patients with end-stage kidney disease undergoing hemodialysis (HD). TXNIP, a key regulator of oxidative stress, has been linked to inflammation and suppresses eNOS activity. STAT3 activation adds to endothelial cell dysfunction, macrophage polarization, immunity and inflammation. Therefore, it is critically involved in atherosclerosis. This study evaluated the effect of sera from HD patients on the TXNIP-eNOS-STAT3 pathway using an in vitro model of human umbilical vein endothelial cells (HUVECs). Methods: Thirty HD patients with end-stage kidney disease and ten healthy volunteers were recruited. Serum samples were taken at dialysis initiation. HUVECs were treated with HD or healthy serum (10% v/v) for 24 h. Then, cells were collected for mRNA and protein analysis. Results: TXNIP mRNA and protein expression were significantly increased in HUVECs treated with HD serum compared to healthy controls (fold changes: 2.41 ± 1.84 vs. 1.41 ± 0.5 and 2.04 ± 1.16 vs. 0.92 ± 0.29, respectively), as were IL-8 mRNA (fold changes: 2.22 ± 1.09 vs. 0.98 ± 0.64) and STAT3 protein expression (fold changes: 1.31 ± 0.75 vs. 0.57 ± 0.43). The expression of eNOS mRNA and protein (fold changes: 0.64 ± 0.11 vs. 0.95 ± 0.24; 0.56 ± 0.28 vs. 4.35 ± 1.77, respectively) and that of SOCS3 and SIRT1 proteins were decreased. Patients' nutritional status, reflected by their malnutrition–inflammation scores, did not affect these inflammatory markers. Conclusions: This study showed that sera from HD patients stimulated a novel inflammatory pathway, regardless of their nutritional status. [ABSTRACT FROM AUTHOR]

Preterm delivery complicates 5–12% of pregnancies and is the primary cause of neonatal morbidity and mortality. The pathophysiology of preterm labor and parturition is not fully known, although it is probably related to inflammation and placental senescence. Telomere shortening is related to senescence and galectin-3 (Gal-3) protein is involved in cell growth, differentiation, inflammation, and fibrosis. This study examined changes in Gal-3 expression and telomere homeostasis (which represent inflammatory and stress markers) in maternal blood and placental tissue of spontaneous preterm births (SPTB) and uncomplicated, spontaneous term pregnancies (NTP) during labor. Participants included 19 women with NTP and 11 with SPTB who were enrolled during admission for delivery. Maternal blood samples were obtained along with placental tissue for Gal-3 analysis and telomere length evaluation. Gal-3 protein expression in placental tissue was increased in SPTB compared to NTP (fold change: 1.89 ± 0.36, P < 0.05). Gal-3 immunohistochemistry demonstrated strong staining in placental extravillous trophoblast tissue from SPTB. Maternal blood levels of Gal-3 protein were elevated in SPTB compared to NTP (19.3 ± 1.3 ng/ml vs. 13.6 ± 1.07 ng/ml, P = 0.001). Placental samples from SPTB had a higher percentage of trophoblasts with short telomeres (47.6%) compared to NTP (15.6%, P < 0.0001). Aggregate formation was enhanced in SPTB (7.8%) compared to NTP (1.98%, P < 0.0001). Maternal blood and placental samples from SPTB had shorter telomeres and increased Gal-3 expression compared to NTP. These findings suggest that increased senescence and inflammation might be factors in the abnormal physiology of spontaneous preterm labor. [ABSTRACT FROM AUTHOR]

Although I FEBS Open Bio i does not seek to judge the importance of submissions, our reviewers carefully scrutinize the experimental design and results of all papers and challenge authors about their conclusions. The editors of I FEBS Open Bio i would like to thank all those who have given their time and expertise to review articles submitted for publication in Volume 12. [Extracted from the article]

Problem: Preeclampsia (PE) and intrauterine growth restriction (IUGR) are leading causes of perinatal complications, affecting 8%–10% of all pregnancies. Inflammasomes are suspected to be one of the mechanisms that lead to the process of term and preterm labors. This study evaluated the inflammasome‐dependent inflammation processes in placental tissue of women with PE and IUGR. Methods of Study: In this prospective cohort study, 14 women with PE, 15 with placental‐related IUGR and 19 with normal pregnancy (NP) were recruited during admission for delivery. Maternal blood was obtained prior to delivery and neonatal cord blood and placental tissue were obtained after delivery. Results: NLRP7 and PYCARD protein expression were higher in placental PE and IUGR samples versus NP samples. Immunostaining revealed that NLRP7 and PYCARD were upregulated in PE and IUGR placental syncytiotrophoblast, stroma and endothelial cells. PYCARD serum levels were significantly higher in women with PE and IUGR. No significant changes were observed in neonatal cord blood. Conclusions: NLRP7 and PYCARD are key inflammatory proteins that are significantly elevated in PE and IUGR. Better understanding their significance may enable them to become markers of prediction or progression of PE and IUGR. [ABSTRACT FROM AUTHOR]

Introduction: Arterial calcification is an integral component of active atherosclerosis and is an independent risk factor for cardiovascular disease. Atherosclerosis is a systemic, life‐threating disease that may occur at different sites and in various clinical presentations. Intracranial and valvular calcifications are common among dialysis patients and have been associated with poor cardiovascular outcomes. The aim of this study was to assess the clinical impact of valvular and intracranial arterial calcifications on mortality among chronic hemodialysis patients. Methods: A blinded neuroradiologist graded intracranial calcifications (ICC) of all hemodialysis patients who underwent brain computerized tomography (CT) from 2015 to 2017 in our institution. Valvular calcifications were assessed by echocardiography. Only hemodialysis patients with available echocardiography and brain CT were included. Findings: This study included 119 patients (mean age 70.6 ± 12.6 years, 57.1% men, and mean dialysis vintage 25.8 ± 42.6 months). Among the cohort, 19 (16%) had no cardiac or brain calcifications and 65 (54.6%) had both valvular and intracranial calcifications. Considering the patients with no calcification as the reference group yielded adjusted odds ratios for all‐cause mortality of 3.68 (95%CI 1.55–8.75) among patients with any brain calcifications, p = 0.002. While valvular calcifications alone did not increase the 1‐year mortality rate, ICC was the most important predictor of all‐cause 1‐year mortality in the study cohort. Discussion: We found an independent association between ICC and the risk of death among hemodialysis patients. Assessing ICC may contribute to the risk stratification of hemodialysis patients. These calcifications are no less important than valvular calcifications. [ABSTRACT FROM AUTHOR]

Brain atrophy (BA) is often found in neuroimaging of hemodialysis patients, representing parenchymal cerebral damage. Likely contributing factors to BA are age, chronic hypertension, diabetes mellitus and other cardiovascular risk factors of atherosclerosis that are also common among hemodialysis patients. BA may also occur due to focal ischemia and hypoperfusion during hemodialysis. However, data on optimal blood pressure (BP) in these patients are limited. The goal of this study was to determine whether the prevalence and severity of BA would be higher among hemodialysis patients with lower BP. A blinded neuroradiologist graded BA of all hemodialysis patients who underwent brain non‐contrast computerized tomography (CT) from 2015 to 2017 in our institution. Age‐ and sex‐matched patients with normal kidney function who underwent brain CT during the same period and technique served as the control group. A total of 280 patients were included in this retrospective study, with average BP of 140/70 mmHg among hemodialysis patients and 142/75 mmHg in the control group. BA was more common in dialysis patients and its severity increased with age and traditional cardiovascular risk factors. We observed a significant negative correlation between diastolic BP (DBP) at dialysis initiation and BA. Average DBP decreased with increasing severity of BA. These findings were observed in both hemodialysis and non‐CKD patients. BA was associated with lower DBP, which may induce cerebral hypoperfusion and ischemia. This finding should discourage over‐treatment of hypertension among hemodialysis patients. [ABSTRACT FROM AUTHOR]

The publication of invaluable papers in the I Journal of Diabetes Investigation i depends on the prompt, careful review of submitted manuscripts. We would like to thank the Editorial Board members, the International Editorial Board members, the Assistant Editorial Board members and the following experts for reviewing manuscripts from September 1, 2021 to August 31, 2022. [Extracted from the article]

Peritoneal dialysis (PD) causes structural and functional changes in the peritoneal membrane, which are attributed to local inflammatory process. This study assessed the presence of galectin‐3 (Gal‐3), a known inflammatory modulator, in dialysate effluent and correlated its levels with markers of inflammatory process. Gal‐3 levels in serum and dialysate effluent were measured in prevalent PD patients on morning visits (n = 27) or during peritoneal equilibration tests (PET, n = 16), it association with clinical and laboratory parameters, including dialysate/plasma creatinine (D/P creatinine) and interleukin‐6 (IL‐6) levels was analysed. Gal‐3 levels in dialysate effluent correlated with D/P creatinine (0.663, p = 0.005) and dialysate effluent IL‐6 levels (0.674, p = 0.002), but not with serum Gal‐3 levels or dialysis vintage. Patients who were high transporters had higher Gal‐3 levels in dialysate effluent, as compared to lower transporters. In multivariate regression analysis, dialysate IL‐6 level was the strongest predictor of dialysate Gal‐3 levels. This study found Gal‐3 in dialysate effluent correlated with D/P creatinine and dialysate IL‐6 levels. These findings may imply that Gal‐3 has a role in the intraperitoneal inflammatory process. However, this needs to be investigated further. SUMMARY AT A GLANCE: Galectin‐3 (Gal‐3) is an important inflammatory modulator. This study showed that dialysate Gal‐3 levels correlated with peritoneal transport parameters, suggesting that Gal‐3 may play a role in the regulation of peritoneal transport. [ABSTRACT FROM AUTHOR]

Background: Predicting the mortality risk of patients un-dergoing hemodialysis (HD) is challenging. Cell-free DNA (cfDNA) is released into circulation from dying cells, and its elevation is predictive of unfavorable outcome. In a pilot study, we found post-HD cfDNA level to be a predictor of all-cause mortality. Thus, the aim of this study was to confirm the prognostic power of cfDNA in a larger prospective cohort study conducted at 2 medical centers. Methods: CfDNA levels were measured by a rapid fluorometric assay on sera obtained before and after 1 HD session. One hundred fifty-three patients were followed up to 46 months for mortality during which time 47 patients died. We compared the predictive value of cfDNA to age, comorbidities, and standard blood tests. Results: Examining standard blood tests, only post-HD cfDNA levels were elevated in the non-survivor group compared to survivors (959 vs. 803 ng/mL, p = 0.04). Pre- and post-HD cfDNA levels correlated with age and diabetes. Patients with elevated cfDNA (>850 ng/mL) showed lower survival than those with normal levels. A Cox proportional hazard regression model demonstrated a significant hazard ratio of 1.92 for post-HD cfDNA levels. Logistic regression models showed that post-HD cfDNA was a significant predictor of mortality at 1–3 years with odd ratios of 4.61, 4.36, and 6.22, respectively. Conclusions: Post-HD cfDNA level was superior to standard blood tests and could serve as a biomarker to assist in decision-making for HD-treated patients. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. Fibrotic diseases, such as IPF, are characterized by uncontrolled activation of fibroblasts. Since the microenvironment is known to affect cell behavior, activated fibroblasts can in turn activate healthy neighboring cells. Thus, we investigated IPF paracrine signaling in human lung fibroblasts (HLFs) derived from patients with IPF.Methods: Primary human fibroblast cultures from IPF (IPF-HLF) and control donor (N-HLF) lung tissues were established and their supernatants were collected. These supernatants were then added to N-HLFs for further culture. Protein and RNA were extracted from IPF/ N-HLFs at baseline. Interleukin-6 (IL-6) and TGF-β-related signaling factors (e.g. STAT3, Smad3) were evaluated by western blot and qPCR. IL-6 levels were measured by ELISA. IL-6 signaling was blocked by Tocilizumab (TCZ) (10 ng/ml).Results: IPF-HLFs were found to significantly overexpress IL-6 receptor (IL-6R), suppressor of cytokine signaling 3 (SOCS3), phospho-STAT3-Y705 and phospho-Smad3 in comparison to N-HLFs (p < 0.05). In addition, they were found to proliferate faster, secrete more IL-6 and express higher levels of the soluble IL-6R. IPF-HLF increased proliferation was inhibited by TCZ. Moreover, IPF-HLF derived supernatants induced both direct and indirect STAT3 activation that resulted in Smad3 phosphorylation and elevated Gremlin levels in N-HLFs. These effects were also successfully blocked by TCZ.Conclusions: IPF-HLF paracrine signaling leads to IL-6R overexpression, which in turn, affects N-HLF survival. The IL-6/STAT3/Smad3 axis facilitates cellular responses that could potentially promote fibrotic disease. This interplay was successfully blocked by TCZ. [ABSTRACT FROM AUTHOR]

To evaluate changes in the inflammatory response of thioredoxin (TXN), thioredoxin interacting protein (TXNIP), transducer and activator of transcription 3, NFƙB-p50 and STAT3 at the level of maternal serum, placenta, and umbilical cord blood of women with gestational diabetes mellitus type 2 (GDMA2) compared to normal pregnancies (NP). Thirty pregnant women (20 with GDMA2 and 10 NP) were recruited during admission for delivery. Blood samples were obtained from the parturients and umbilical cords, as well as placental tissue for mRNA and protein extraction. TXNIP mRNA expression was significantly increased in maternal serum of women with GDMA2 compared to NP women. TXNIP mRNA was significantly decreased in GDMA2 placentas and cord blood compared to NP. TXN/TXNIP mRNA ratio showed significantly high absolute values in placental and cord blood (2.39 and 1.66) respectively, compared to maternal ratio (1.084) (P < 0.001). TXN/TXNIP placenta protein ratio showed similar values between GDMA2 and NP (0.98 and 0.86; P = 0.7). STAT3 and its target protein SOCS3, as well as NFƙB-p50 mRNA expression were significantly increased in placentas of GDMA2. NFƙB-p50 mRNA expression was significantly decreased in cord blood compared to both maternal and placental mRNA expression. Pro-inflammatory changes are expressed by low mRNA TXN/TXNIP ratio in maternal blood of GDMA2 patients, but not in placental and umbilical cord blood samples. This, as well as the feedback role of SOCS3 in STAT3 pathway and NFƙB-p50 expression, may indicate that the placenta has a role in protecting the fetus from damage due to inflammatory response, which is common in diabetes. [ABSTRACT FROM AUTHOR]

The Editors of I FEBS Open Bio i would like to thank all those who have given their time and expertise to review articles submitted for publication in Volume 9. Although I FEBS Open Bio i does not seek to judge the importance of submissions, our reviewers carefully scrutinize the experimental design and results of all papers and challenge authors about their conclusions. The names of these reviewers are listed below; we apologize if we have inadvertently omitted anyone. Joseph Nickels Jr. [Extracted from the article]

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Purpose: The incidence of stroke in patients undergoing hemodialysis (HD) is eight-to-ten times greater than that of the general population. However, data on the outcome of stroke in these patients are limited. Methods: In this retrospective observational cohort study, electronic medical records of all patients undergoing HD from 1.1.2014 to 31.12.2017 at Meir Medical Center, Israel, were reviewed. Stroke was defined as a focal neurological deficit of cerebrovascular origin, and confirmed as ischemic or hemorrhagic by computed tomography. Age- and sex-matched HD patients who did not experience a stroke (HD-NS) and hospitalized stroke patients with normal kidney function (NRF-S) served as the two control groups. Baseline demographic, clinical, and laboratory data were collected. Thrombolytic therapy, duration of hospital stay, and mortality were recorded. Functional status at discharge was assessed by the Modified Rankin Scale. Results: In the cohort study group (HD-S), 52 strokes occurred during 248.3 patient years, an incidence rate of 8.13%, and a stroke rate of 0.19% patients/month. Most strokes in HD patients were ischemic, and only four patients were administered tissue plasminogen activator. HD-S had longer hospitalization than did NRF-S (10.6 ± 9.9 vs. 5.96 ± 5.3 days, p = 0.004) and lower functional status at discharge (Rankin score 3.75 ± 1.57 vs. 2.29 ± 1.89, p < 0.001). HD-S patients had a higher mortality than both HD-NS and NRF-S patients. Conclusions: Stroke outcome in these patients is dismal with prolonged hospital stay, poor functional status at discharge, very limited response to rehabilitation, and increased mortality. [ABSTRACT FROM AUTHOR]

Purpose: Evaluate the efficacy of retraining and catheter exit site care in reducing peritonitis rates. Methods: This interventional study included all prevalent PD patients from 1/2009 to 12/2017 from a single center. Peritonitis rates and causative organisms were assessed and compared in three periods: (1) Before intervention (01/2009–12/2014), (2) after educational intervention: assessment of training process by infection control nurse and repeat training every 3 months, after each peritonitis episode and after hospitalizations > 2 weeks (01/2015–02/2016), and (3) in addition to the measures in period 2, an exit site care protocol including postoperative care, topical antibacterial therapy and nasal Staph aureus screening and eradication was implemented (03/2016–12/2017). Results: The study included 201 patients (149 men, 52 women), mean age was 65.1 ± 12.6 years. After both interventions, including educational and exit site care strategies, peritonitis decreased significantly from 1.05 episodes per patient-year (n = 113) to 0.67 (n = 54); P = 0.017 between periods 1 and 3. The percentage of peritonitis-free patients increased from 27.4 to 52.4 and 55.6%, respectively (P = 0.001 between period 1 vs. 2 and period 1 vs. 3.). Coagulase-negative staph was the most common pathogen, causing 7.56 peritonitis episodes per year, followed by pseudomonas at 4.33 episodes annually and staph aureus at 3.44 episodes per year. Conclusions: Enforcement of an educational program and strict adherence to an exit site care protocol was associated with a significant decrease in peritonitis rates. [ABSTRACT FROM AUTHOR]

Infection is one of the leading causes of mortality in dialysis patients, second only to cardiovascular disease. This retrospective study assessed the efficacy and clinical outcomes of influenza vaccination among hemodialysis (HD) patients. In the 2014–2015 season, 104 of 164 (63.6%) HD patients were vaccinated for influenza by the outpatient community health system facilities. Significantly more patients, 159 of 170 (93.8%), were vaccinated in 2015–2016 by the hospital dialysis unit staff during an inpatient HD session (P <0.001). A trend toward fewer complications from influenza infection was observed in vaccinated patients. Among HD patients with diabetes (who comprised 56% of the study population), the incidence of influenza was 17% among nonvaccinated patients vs. 6.3% among those who were vaccinated (P =0.026). The inpatient vaccination policy resulted in a greater rate of vaccination. HD patients with diabetes benefit from influenza vaccination, with a significantly lower incidence of influenza infection. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate (a) the properties of high-density lipoproteins (HDL)/cholesterol, which include apolipoprotein A-1 (ApoA1) and paraoxonase1 (PON1), both are negative predictors of cardiovascular risk and (b) HDL function, among women with preeclampsia (PE). PE is a multi-system disorder, characterized by onset of hypertension and proteinuria or other end-organ dysfunction in the second half of pregnancy. Preeclampsia is associated with increased risk for later cardiovascular disease. The inverse association between HDL, cholesterol levels and the risk of developing atherosclerotic cardiovascular disease is well-established.Methods: Twenty-five pregnant women [19 with PE and 6 with normal pregnancy (NP)] were recruited during admission for delivery. HDL was isolated from blood samples. PON1 activity and HDL were analyzed. An in vitro model of endothelial cells was used to evaluate the effect of HDL on the transcription response of vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase (eNOS) mRNA expression.Results: PON1 activity (units/ml serum) was lower in the PE group compared to normal pregnancy (NP) (6.51 ± 0.73 vs. 9.98 ± 0.54; P = 0.015). Increased ApoA1 was released from PE-HDL as compared to NP-HDL (3.54 ± 0.72 vs. 0.89 ± 0.35; P = 0.01). PE-HDL exhibited increased VCAM-1 mRNA expression and decreased eNOS mRNA expression on TNF-α stimulated endothelial cells as compared to NP-HDL.Conclusions: HDL from women with PE reduced PON1 activity and increased ApoA1 release from HDL particles. This process was associated with increased HDL diameter, suggesting impaired HDL anti-oxidant activity. These changes might contribute to higher long-term cardiovascular risks among women with PE. [ABSTRACT FROM AUTHOR]

Von Willebrand factor (vWF) is a glycoprotein with a crucial role in the formation of platelet thrombi, and ADAMTS13 is the main enzyme responsible for vWF cleavage. Both are important in the relationship between diabetic nephropathy, hypercoagulability, and cardiovascular disease. This study evaluated a potential relationship between vitamin D (vitD) levels, vWF, ADAMTS13 activity, and inflammation in diabetic patients on chronic hemodialysis (HD). Blood samples from 52 diabetic patients on chronic HD were obtained to determine vitD levels, vWF, and ADAMTS13 activity, and inflammatory markers. HD patients were grouped according to 25-hydroxyvitamin D [25(OH) VitD]<25 nmol/L (n=16) or >25 nmol/L (n=36). vWF antigen and vWF activity were elevated in both groups, with an average of 214.3±82.6% and 175.8±72.6%, respectively. Average ADAMTS13 activity was within the normal range in both groups. Blood samples from the vitD <25 nmol/L group showed a positive correlation between c-reactive protein (CRP) and vWF levels (P =0.023; r=0.564; 95% confidence interval=0.095-0.828), with a negative correlation between HbA1c and 25(OH) VitD (P =0.015; r=-0.337; 95% confidence interval=-0.337-0.19). Diabetic patients on chronic HD had elevated vWF levels and activity with no significant change in ADAMTS13 activity. The correlation between CRP and vWF levels in the 25(OH) VitD<25 nmol/L group suggests inflammatory-related endothelial dysfunction in these patients. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that stimulates insulin secretion and may affect the inflammatory pathways involved in diabetes mellitus. Calcitriol, an active form of vitamin D, plays an important role in renal, endothelial and cardiovascular protection. We evaluated the anti-inflammatory and histologic effects of a GLP-1 analogue (liraglutide) and of calcitriol in a db/db mouse diabetes model and in endothelial cells exposed to a diabetes-like environment.Methods: Diabetic db/db mice were treated with liraglutide and calcitriol for 14 weeks, after which the kidneys were perfused and removed for mRNA and protein analysis and histology. Endothelial cells were stimulated with advanced glycation end products (AGEs), glucose, liraglutide and calcitriol. Total RNA and protein were extracted and analysed for the expression of selected inflammatory markers.Results: Typical histological changes, glomerular enlargement and mesangial expansion were seen in db/db mice compared with control mice. Glomerular hypertrophy was ameliorated with liraglutide, compared with db/db controls. Liraglutide up-regulated endothelial nitric oxide synthase protein expression compared with the db/db control group and down-regulated p65 protein expression. Calcitriol did not further improve the beneficial effect observed on protein expression. In endothelial cells, liraglutide treatment exhibited a dose-dependent ability to prevent an inflammatory response in the selected markers: thioredoxin-interacting protein, p65, IL6 and IL8. In most gene and protein expressions, addition of calcitriol did not enhance the effect of liraglutide.Conclusions: The GLP-1 analogue liraglutide prevented the inflammatory response observed in endothelial cells exposed to a diabetes-like environment and in db/db mice at the level of protein expression and significantly ameliorated the glomerular hypertrophy seen in the diabetic control group. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Endothelial cells (EC) and vascular smooth muscle cells (VSMC) are involved in the development of local and diffuse vasculopathies by participating in inflammatory processes that can lead to uncontrolled vascular complications. Our aim was to study the possible interactions of EC and VSMC in an in vitro coculture model exposed to diabetic-like conditions and the effect of vitamin D on cellular pathways that might lead to an inflammatory response. EC and VSMC were isolated from different umbilical cords and stimulated in an in vitro coculture model in a diabetic-like environment and calcitriol for 24 h. Total RNA and protein were extracted from cells and analyzed for the expression of selected inflammatory-related markers. The EC-VSMC coculture in a diabetic-like environment induced the expression of inflammatory markers such as Kruppel-like factors, thioredoxin-interacting protein (TXNIP), IL-6, and IL-8. Addition of vitamin D to the EC-VSMC coculture induced selective changes in the inflammatory response. This model could lead to a better understanding of the interactions between EC and VSMC in the inflammatory processes involved in diabetes and emphasizes the role of vitamin D in the inflammatory response. The use of different donors strengthens the significance of our findings showing that genetic variations do not affect the impact of vitamin D on the expression of inflammatory-related proteins in our model. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) function as a component of the tumor microenvironment (TME) and have both pro- and anti-tumorigenic roles depending on the tumor type and its developmental stage. Several reports indicate the involvement of MCs in angiogenesis in the TME by releasing angiogenic mediators. Tumor cells and other cells in the TME may interact by releasing extracellular vesicles (EVs) that affect the cells in the region. We have previously shown that tumor-derived microvesicles (TMVs) from non-small-cell lung cancer (NSCLC) cells interact with human MCs and activate them to release several cytokines and chemokines. In the present study, we characterized the MC expression of other mediators after exposure to TMVs derived from NSCLC. Whole-genome expression profiling disclosed the production of several chemokines, including CC chemokine ligand 18 (CCL18). This chemokine is expressed in various types of cancer, and was found to be associated with extensive angiogenesis, both in vitro and in vivo. We now show that CCL18 secreted from MCs activated by NSCLC-TMVs increased the migration of human umbilical cord endothelial cells (HUVECs), tube formation and endothelial- to-mesenchymal transition (EndMT), thus promoting angiogenesis. Our findings support the conclusion that TMVs have the potential to influence MC activity and may affect angiogenesis in the TME. [ABSTRACT FROM AUTHOR]

Background. Previous studies have demonstrated that AST-120 (Kremezin®), a well-known oral adsorbent, inhibits the progression of diabetic (DM) and non-DM chronic kidney disease along with a decrease in oxidative stress. This study was undertaken to investigate whether AST-120 could reduce oxidative stress and ameliorate the development of nephropathy in experimental DM rats with normal renal function. [ABSTRACT FROM PUBLISHER]

Background. High blood and tissue concentrations of glucose and advanced glycation end-products (AGEs) are thought to play an important role in the development of vascular diabetic complications. Therefore, the impact of extracellular AGEs and different glucose concentrations was evaluated by studying the gene expressions and the underlying cellular pathways involved in the development of inflammatory pro-atherosclerotic processes observed in cultured endothelial cells. [ABSTRACT FROM PUBLISHER]

Aims: Class A2 gestational diabetes mellitus (GDMA2) has short- and long-term effects on the mother and child. These may include abnormalities of placentation, damage to endothelial cells and cardiovascular disease. This research investigated the function and composition of high-density lipoproteins (HDL) among women with GDMA2 and their fetuses. Methods: Thirty pregnant women were recruited during admission for delivery. The function and expression of HDL, paraoxonase1 (PON1) and apolipoprotein A1 (APOA1) in the blood samples and the placental tissue were evaluated. The effect of HDL on migration of endothelial cells was measured in vitro. Results: Compared to normal pregnancy (NP), APOA1 in the maternal plasma of women with GDMA2 was decreased. More APOA1 and PON1 were released from HDL of women with GDMA2, compared to NP. Placental APOA1 and PON1 were decreased in GDMA2. For endothelial cells stimulated with TNFα, HDL cell migration was decreased when cells were evaluated with NP-HDL, as compared to GDMA2-HDL. Conclusions: GDMA2 affects the composition and function of HDL in plasma. Changes in HDL commonly seen in GDMA2 were observed in maternal and placental samples, but not in cord samples. These results might indicate a placental role in protecting the fetus by preserving the components and functions of HDL and require further investigation. [ABSTRACT FROM AUTHOR]