bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic and Functional Heterogeneity of Monocyte Subsets in Chronic Heart Failure Patients
Authors: Mongirdienė Aušra , Liobikas Julius
Published: January 2022

Chronic heart failure (CHF) results when the heart cannot consistently supply the body’s tissues with oxygen and required nutrients. CHF can be categorized as heart failure (HF) with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF). There are different causes and mechanisms underlying HF pathogenesis; however, inflammation can be regarded as one of the factors that promotes both HFrEF and HFpEF. Monocytes, a subgroup of leukocytes, are known to be cellular mediators in response to cardiovascular injury and are closely related to inflammatory reactions. These cells are a vital component of the immune system and are the source of macrophages, which participate in cardiac tissue repair after injury. However, these monocytes are not as homogenous as thought and can present different functions under different cardiovascular disease conditions. In addition, there is still an open question regarding whether the functions of monocytes and macrophages should be regarded as causes or consequences in CHF development. Therefore, the aim of this work was to summarize current studies on the functions of various monocyte subsets in CHF with a focus on the role of a certain monocyte subset in HFpEF and HFrEF patients, as well as the subsets’ relationship to inflammatory markers.
SLC26A9 as a Potential Modifier and Therapeutic Target in Cystic Fibrosis Lung Disease
Authors: Gorrieri Giulia , Zara Federico , Scudieri Paolo
Published: January 2022

SLC26A9 belongs to the solute carrier family 26 (SLC26), which comprises membrane proteins involved in ion transport mechanisms. On the basis of different preliminary findings, including the phenotype of SlC26A9-deficient mice and its possible role as a gene modifier of the human phenotype and treatment response, SLC26A9 has emerged as one of the most interesting alternative targets for the treatment of cystic fibrosis (CF). However, despite relevant clues, some open issues and controversies remain. The lack of specific pharmacological modulators, the elusive expression reported in the airways, and its complex relationships with CFTR and the CF phenotype prevent us from conclusively understanding the contribution of SLC26A9 in human lung physiology and its real potential as a therapeutic target in CF. In this review, we summarized the various studies dealing with SLC26A9 expression, molecular structure, and function as an anion channel or transporter; its interaction and functional relationships with CFTR; and its role as a gene modifier and tried to reconcile them in order to highlight the current understanding and the gap in knowledge regarding the contribution of SLC26A9 to human lung physiology and CF disease and treatment.
Interaction of TOR and PKA Signaling in S. cerevisiae
Authors: Plank Michael
Published: January 2022

TOR and PKA signaling are the major growth-regulatory nutrient-sensing pathways in S. cerevisiae. A number of experimental findings demonstrated a close relationship between these pathways: Both are responsive to glucose availability. Both regulate ribosome production on the transcriptional level and repress autophagy and the cellular stress response. Sch9, a major downstream effector of TORC1 presumably shares its kinase consensus motif with PKA, and genetic rescue and synthetic defects between PKA and Sch9 have been known for a long time. Further, studies in the first decade of this century have suggested direct regulation of PKA by TORC1. Nonetheless, the contribution of a potential direct cross-talk vs. potential sharing of targets between the pathways has still not been completely resolved. What is more, other findings have in contrast highlighted an antagonistic relationship between the two pathways. In this review, I explore the association between TOR and PKA signaling, mainly by focusing on proteins that are commonly referred to as shared TOR and PKA targets. Most of these proteins are transcription factors which to a large part explain the major transcriptional responses elicited by TOR and PKA upon nutrient shifts. I examine the evidence that these proteins are indeed direct targets of both pathways and which aspects of their regulation are targeted by TOR and PKA. I further explore if they are phosphorylated on shared sites by PKA and Sch9 or when experimental findings point towards regulation via the PP2ASit4/PP2A branch downstream of TORC1. Finally, I critically review data suggesting direct cross-talk between the pathways and its potential mechanism.
Histone 2B Facilitates Plasminogen-Enhanced Endothelial Migration through Protease-Activated Receptor 1 (PAR1) and Protease-Activated Receptor 2 (PAR2)
Authors: Das Mitali , Ithychanda Sujay Subbayya , Plow Edward F.
Published: January 2022

Plasminogen and its multiple receptors have been implicated in the responses of many different cell types. Among these receptors, histone 2B (H2B) has been shown to play a prominent role in macrophage responses. The contribution of H2B to plasminogen-induced endothelial migration, an event relevant to wound healing and angiogenesis, is unknown. Plasminogen enhanced the migration of endothelial cells, which was inhibited by both Protease-Activated Receptor-1 (PAR1) and 2 (PAR2) antagonists. H2B was detected on viable endothelial cells of venous and arterial origin, and an antibody to H2B that blocks plasminogen binding also inhibited the plasminogen-dependent migration by these cells. The antibody blockade was as effective as PAR1 or PAR2 antagonists in inhibiting endothelial cell migration. In pull-down experiments, H2B formed a complex with both PAR1 and PAR2 but not β3 integrin, another receptor implicated in endothelial migration in the presence of plasminogen. H2B was found to be associated with clathrin adapator protein, AP2µ (clathrin AP2µ) and β-arrestin2, which are central to the internationalization/signaling machinery of the PARs. These associations with PAR1-clathrin adaptor AP2µ- and PAR2-β-arrestin2-dependent internalization/signaling pathways provide a mechanism to link plasminogen to responses such as wound healing and angiogenesis.
microRNA-Mediated Encoding and Decoding of Time-Dependent Signals in Tumorigenesis
Authors: Tealdi Simone , Ferro Elsi , Campa Carlo Cosimo , Bosia Carla
Published: January 2022

microRNAs, pivotal post-transcriptional regulators of gene expression, in the past decades have caught the attention of researchers for their involvement in different biological processes, ranging from cell development to cancer. Although lots of effort has been devoted to elucidate the topological features and the equilibrium properties of microRNA-mediated motifs, little is known about how the information encoded in frequency, amplitude, duration, and other features of their regulatory signals can affect the resulting gene expression patterns. Here, we review the current knowledge about microRNA-mediated gene regulatory networks characterized by time-dependent input signals, such as pulses, transient inputs, and oscillations. First, we identify the general characteristic of the main motifs underlying temporal patterns. Then, we analyze their impact on two commonly studied oncogenic networks, showing how their dysfunction can lead to tumorigenesis.
Transcribed Ultraconserved Regions Are Associated with Clinicopathological Features in Breast Cancer
Authors: Zambalde Erika Pereira , Adamoski Douglas , Gradia Daniela Fiori , Rabinovich Iris , Rodrigues Ana Carolina , Ivan Cristina , Ribeiro Enilze M. S. F. , Calin George Adrian , Carvalho de Oliveira Jaqueline
Published: January 2022

Ultraconserved regions (UCRs) are 481 genome segments, with length longer than 200 bp, that are 100% conserved among humans, mice, and rats. The majority of UCRs are transcriptionally active (T-UCRs) as many of them produce non-coding RNAs. In a previous study, we evaluated the expression level of T-UCRs in breast cancer (BC) patients and found that 63% of transcripts correlated with some clinical and/or molecular parameter of BC. In this study, we delved into the expression levels of 12 T-UCRs and correlated them with clinicopathological parameters, immunohistochemical markers, and overall survival in two breast cancer cohorts: TCGA and Brazilian patients. We found that uc.268 is more expressed in TCGA patients under 40 years of age, associated with progesterone receptor (PR) and estrogen receptor (ER), and its high expression is found in luminal A. Lower uc.84 and uc.376 were respectively observed in metastatic and stage IV tumors associated with good prognostic in luminal B. Moreover, uc.84 was only related to the HER2+, while uc.376 was related to ER+ and PR+, and HER2+. A panel composed of uc.147, uc.271, and uc.427 distinguished luminal A from triple negative patients with an AUC of 0.9531 (sensitivity 92.19% and specificity 86.76%). These results highlight the potential role of T-UCRs in BC and provide insights into the potential application of T-UCRs as biomarkers.
The Expanded Endocannabinoid System Contributes to Metabolic and Body Mass Shifts in First-Episode Schizophrenia: A 5-Year Follow-Up Study
Authors: Parksepp Madis , Haring Liina , Kilk Kalle , Koch Kadri , Uppin Kärt , Kangro Raul , Zilmer Mihkel , Vasar Eero
Published: January 2022

Alterations in the expanded endocannabinoid system (eECS) and cell membrane composition have been implicated in the pathophysiology of schizophrenia spectrum disorders. We enrolled 54 antipsychotic (AP)-naïve first-episode psychosis (FEP) patients and 58 controls and applied a targeted metabolomics approach followed by multivariate data analysis to investigate the profile changes in the serum levels of endocannabinoids: 2-arachidonoylglycerol (2-AG) and anandamide, endocannabinoids-like N-acylethanolamines (NAEs: linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide), and their dominating lipid precursor’s phosphatidylcholines. Biomolecule profiles were measured at the onset of first-episode psychosis (FEP) and 0.6 years and 5.1 years after the initiation of AP treatment. The results indicated that FEP might be characterized by elevated concentrations of NAEs and by decreased 2-AG levels. At this stage of the disease, the NAE-mediated upregulation of peroxisome proliferator-activated receptors (PPARs) manifested themselves in energy expenditure. A 5-year disease progression and AP treatment adverse effects led to a robust increase in 2-AG levels, which contributed to strengthened cannabinoid (CB1) receptor-mediated effects, which manifested in obesity. Dynamic 2-AG, NAEs, and their precursors in terms of phosphatidylcholines are relevant to the description of the metabolic shifts resulting from the altered eECS function during and after FEP.
Acetylcholine Reduces IKr and Prolongs Action Potentials in Human Ventricular Cardiomyocytes
Authors: Koncz István , Verkerk Arie O. , Nicastro Michele , Wilders Ronald , Árpádffy-Lovas Tamás , Magyar Tibor , Tóth Noémi , Nagy Norbert , Madrid Micah , Lin Zexu , Efimov Igor R.
Published: January 2022

Vagal nerve stimulation (VNS) has a meaningful basis as a potentially effective treatment for heart failure with reduced ejection fraction. There is an ongoing VNS randomized study, and four studies are completed. However, relatively little is known about the effect of acetylcholine (ACh) on repolarization in human ventricular cardiomyocytes, as well as the effect of ACh on the rapid component of the delayed rectifier K+ current (IKr). Here, we investigated the effect of ACh on the action potential parameters in human ventricular preparations and on IKr in human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs). Using standard microelectrode technique, we demonstrated that ACh (5 µM) significantly increased the action potential duration in human left ventricular myocardial slices. ACh (5 µM) also prolonged repolarization in a human Purkinje fiber and a papillary muscle. Optical mapping revealed that ACh increased the action potential duration in human left ventricular myocardial slices and that the effect was dose-dependent. Perforated patch clamp experiments demonstrated action potential prolongation and a significant decrease in IKr by ACh (5 µM) in hiPSC-CMs. Computer simulations of the electrical activity of a human ventricular cardiomyocyte showed an increase in action potential duration upon implementation of the experimentally observed ACh-induced changes in the fully activated conductance and steady-state activation of IKr. Our findings support the hypothesis that ACh can influence the repolarization in human ventricular cardiomyocytes by at least changes in IKr.
Bladder Ultrastructure and Urinary Cytokine Abnormality in Patients with Recurrent Urinary Tract Infection and the Changes after Intravesical Platelet-Rich Plasma Injections
Authors: Jhang Jia-Fong , Ho Han-Chen , Hsu Yuan-Hsiang , Jiang Yuan-Hong , Kuo Hann-Chorng
Published: January 2022

This study investigates the bladder from patients with recurrent urinary tract infection (rUTI) at baseline and after intravesical platelet-rich plasma (PRP) injections. Patients with rUTI who underwent repeated intravesical PRP injections provided bladder and urine specimens at baseline and after treatment. Bladder specimens were investigated with electron microscopy and Western blotting. The urine sample was analyzed with commercially available Milliplex immunoassays. A total of 29 patients were enrolled. At baseline, the rUTI bladders exhibited defects of integrity in umbrella cells, a widened tight junction, and lysed organelles. Intracellular bacterial community incubations in the epithelial cells were also noted. Improvement in bladder defects after PRP injection was noted in 25–42% of patients. Bladder UPK3 expression was significantly lower in the patients with rUTI than in controls. Baseline levels of urinary inflammatory cytokine interleukin (IL)-6, IL-8, and brain-derived neurotrophic factor were higher in the patients with rUTI than in the controls, but there were lower levels of vascular endothelial growth factor and nerve growth factor. In the patients with rUTI who recovered from acute infection, the bladders still had immature urothelium, various ultrastructural defects, and elevated urinary inflammatory cytokines. PRP injection has the potential to promote bladder recovery in some of these patients.
Mitoquinone Helps Combat the Neurological, Cognitive, and Molecular Consequences of Open Head Traumatic Brain Injury at Chronic Time Point
Authors: Haidar Muhammad Ali , Shakkour Zaynab , Barsa Chloe , Tabet Maha , Mekhjian Sarin , Darwish Hala , Goli Mona , Shear Deborah , Pandya Jignesh D. , Mechref Yehia , El Khoury Riyad , Wang Kevin , Kobeissy Firas
Published: January 2022

Traumatic brain injury (TBI) is a heterogeneous disease in its origin, neuropathology, and prognosis, with no FDA-approved treatments. The pathology of TBI is complicated and not sufficiently understood, which is the reason why more than 30 clinical trials in the past three decades turned out unsuccessful in phase III. The multifaceted pathophysiology of TBI involves a cascade of metabolic and molecular events including inflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction. In this study, an open head TBI mouse model, induced by controlled cortical impact (CCI), was used to investigate the chronic protective effects of mitoquinone (MitoQ) administration 30 days post-injury. Neurological functions were assessed with the Garcia neuroscore, pole climbing, grip strength, and adhesive removal tests, whereas cognitive and behavioral functions were assessed using the object recognition, Morris water maze, and forced swim tests. As for molecular effects, immunofluorescence staining was conducted to investigate microgliosis, astrocytosis, neuronal cell count, and axonal integrity. The results show that MitoQ enhanced neurological and cognitive functions 30 days post-injury. MitoQ also decreased the activation of astrocytes and microglia, which was accompanied by improved axonal integrity and neuronal cell count in the cortex. Therefore, we conclude that MitoQ has neuroprotective effects in a moderate open head CCI mouse model by decreasing oxidative stress, neuroinflammation, and axonal injury.
Role of NLRP7 in Normal and Malignant Trophoblast Cells
Authors: Abi Nahed Roland , Elkhoury Mikhael Maya , Reynaud Deborah , Collet Constance , Lemaitre Nicolas , Michy Thierry , Hoffmann Pascale , Sergent Frederic , Marquette Christel , Murthi Padma , Raia-Barjat Tiphaine , Alfaidy Nadia , Benharouga Mohamed
Published: January 2022

Gestational choriocarcinoma (CC) is an aggressive cancer that develops upon the occurrence of abnormal pregnancies such as Hydatidiform moles (HMs) or upon non-molar pregnancies. CC cells often metastasize in multiple organs and can cause maternal death. Recent studies have established an association between recurrent HMs and mutations in the Nlrp7 gene. NLRP7 is a member of a new family of proteins that contributes to innate immune processes. Depending on its level of expression, NLRP7 can function in an inflammasome-dependent or independent pathway. To date, the role of NLRP7 in normal and in malignant human placentation remains to be elucidated. We have recently demonstrated that NLRP7 is overexpressed in CC trophoblast cells and may contribute to their acquisition of immune tolerance via the regulation of key immune tolerance-associated factors, namely HLA family, βCG and PD-L1. We have also demonstrated that NLRP7 increases trophoblast proliferation and decreases their differentiation, both in normal and tumor conditions. Actual findings suggest that NLRP7 expression may ensure a strong tolerance of the trophoblast by the maternal immune system during normal pregnancy and may directly affect the behavior and aggressiveness of malignant trophoblast cells. The proposed review summarizes recent advances in the understanding of the significance of NLRP7 overexpression in CC and discusses its multifaceted roles, including its function in an inflammasome-dependent or independent pathways.
Irisin—A Pancreatic Islet Hormone
Authors: Norman Daniel , Drott Carl Johan , Carlsson Per-Ola , Espes Daniel
Published: January 2022

Irisin is a myokine involved in glucose homeostasis. It is primarily expressed in skeletal muscle, but also in the pancreas. This study aimed to elucidate its presence and role in the islets of Langerhans—i.e., its effect on insulin and glucagon secretion as well as on blood flow in the pancreas. The precursor of irisin, fibronectin type III domain-containing protein 5 (FNDC5), was identified in rat and human islets by both qPCR and immunohistochemistry. Both α- and β-cells stained positive for FNDC5. In human islets, we found that irisin was secreted in a glucose-dependent manner. Neither irisin nor an irisin-neutralizing antibody affected insulin or glucagon secretion from human or rat islets in vitro. The insulin and glucagon content in islets was not altered by irisin. The intravenous infusion of irisin in Sprague Dawley rats resulted in nearly 50% reduction in islet blood flow compared to the control. We conclude that irisin is an islet hormone that has a novel role in pancreatic islet physiology, exerting local vascular effects by diminishing islet blood flow without affecting insulin secretion per se.
Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease
Authors: Lazarenko Victor , Churilin Mikhail , Azarova Iuliia , Klyosova Elena , Bykanova Marina , Ob'edkova Natalia , Churnosov Mikhail , Bushueva Olga , Mal Galina , Povetkin Sergey , Kononov Stanislav , Luneva Yulia , Zhabin Sergey , Polonikova Anna , Gavrilenko Alina , Saraev Igor , Solodilova Maria , Polonikov Alexey
Published: January 2022

The study was designed to evaluate putative mechanisms by which lipid-associated loci identified by genome-wide association studies (GWAS) are involved in the molecular pathogenesis of coronary artery disease (CAD) using a comprehensive statistical and bioinformatics analysis. A total of 1700 unrelated individuals of Slavic origin from the Central Russia, including 991 CAD patients and 709 healthy controls were examined. Sixteen lipid-associated GWAS loci were selected from European studies and genotyped using the MassArray-4 system. The polymorphisms were associated with plasma lipids such as total cholesterol (rs12328675, rs4846914, rs55730499, and rs838880), LDL-cholesterol (rs3764261, rs55730499, rs1689800, and rs838880), HDL-cholesterol (rs3764261) as well as carotid intima-media thickness/CIMT (rs12328675, rs11220463, and rs1689800). Polymorphisms such as rs4420638 of APOC1 (p = 0.009), rs55730499 of LPA (p = 0.0007), rs3136441 of F2 (p < 0.0001), and rs6065906 of PLTP (p = 0.002) showed significant associations with the risk of CAD, regardless of sex, age, and body mass index. A majority of the observed associations were successfully replicated in large independent cohorts. Bioinformatics analysis allowed establishing (1) phenotype-specific and shared epistatic gene–gene and gene–smoking interactions contributing to all studied cardiovascular phenotypes; (2) lipid-associated GWAS loci might be allele-specific binding sites for transcription factors from gene regulatory networks controlling multifaceted molecular mechanisms of atherosclerosis.
Disinhibition-Like Behavior Correlates with Frontal Cortex Damage in an Animal Model of Chronic Alcohol Consumption and Thiamine Deficiency
Authors: Moya Marta , López-Valencia Leticia , García-Bueno Borja , Orio Laura
Published: January 2022

Wernicke–Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated with impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the relative contributions of each factor (alcohol and TD, either isolated or in interaction) to these phenomena are still poorly understood. A rat model was used by forced consumption of 20% (w/v) alcohol for 9 months (CA), TD hit (TD diet + pyrithiamine 0.25 mg/kg, i.p. daily injections the last 12 days of experimentation (TDD)), and both combined treatments (CA+TDD). Motor and cognitive performance and cortical damage were examined. CA caused hyperlocomotion as a possible sensitization of ethanol-induced excitatory effects and recognition memory deficits. In addition, CA+TDD animals showed a disinhibited-like behavior which appeared to be dependent on TDD. Additionally, combined treatment led to more pronounced alterations in nitrosative stress, lipid peroxidation, apoptosis and cell damage markers. Correlations between injury signals and disinhibition suggest that CA+TDD disrupts behaviors dependent on the frontal cortex. Our study sheds light on the potential disease-specific mechanisms, reinforcing the need for neuroprotective therapeutic approaches along with preventive treatments for the nutritional deficiency in WKS.
Aspirin and Infection: A Narrative Review
Authors: Di Bella Stefano , Luzzati Roberto , Principe Luigi , Zerbato Verena , Meroni Elisa , Giuffrè Mauro , Crocè Lory Saveria , Merlo Marco , Perotto Maria , Dolso Elisabetta , Maurel Cristina , Lovecchio Antonio , Dal Bo Eugenia , Lagatolla Cristina , Marini Bruna , Ippodrino Rudy , Sanson Gianfranco
Published: January 2022

Acetylsalicylic acid (ASA) is one of the most commonly used drugs in the world. It derives from the extract of white willow bark, whose therapeutic potential was known in Egypt since 1534 BC. ASA’s pharmacological effects are historically considered secondary to its anti-inflammatory, platelet-inhibiting properties; however, human studies demonstrating a pro-inflammatory effect of ASA exist. It is likely that we are aware of only part of ASA’s mechanisms of action; moreover, the clinical effect is largely dependent on dosages. During the past few decades, evidence of the anti-infective properties of ASA has emerged. We performed a review of such research in order to provide a comprehensive overview of ASA and viral, bacterial, fungal and parasitic infections, as well as ASA’s antibiofilm properties.
Antibody Based Delivery of Toxins and Other Active Molecules for Cancer Therapy
Authors: Polito Letizia
Published: January 2022

The use of radio- and chemotherapeutic agents in cancer therapy have demonstrated evident antitumor effects, but also limitations (remarkable side-effects due to lack of selectivity for tumor cells, development of drug resistance, and occurrence of secondary malignancies) [...]
Metabolically Improved Stem Cell Derived Hepatocyte-Like Cells Support HBV Life Cycle and Are a Promising Tool for HBV Studies and Antiviral Drug Screenings
Authors: Tricot Tine , Thibaut Hendrik Jan , Abbasi Kayvan , Boon Ruben , Helsen Nicky , Kumar Manoj , Neyts Johan , Verfaillie Catherine
Published: January 2022

More than 300 million people worldwide are diagnosed with a chronic hepatitis B virus (HBV) infection. Nucleos(t)ide viral polymerase inhibitors are available on the market and can efficiently treat patients with chronic HBV. However, life-long treatment is needed as covalently closed circular DNA (cccDNA) persists in the hepatocyte nucleus. Hence, there is a high demand for novel therapeutics that can eliminate cccDNA from the hepatocyte nucleus and cure chronically infected HBV patients. The gold standard for in vitro HBV studies is primary human hepatocytes (PHHs). However, alternatives are needed due to donor organ shortage and high batch-to-batch variability. Therefore, human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) are being explored as an in vitro HBV infection model. We recently generated hPSC lines that overexpress three transcription factors (HC3x) and that, upon differentiation in a high amino-acid supplemented maturation medium, generate a more mature hepatocyte progeny (HC3x-AA-HLCs). Here, we demonstrate that HBV can efficiently infect these HC3x-AA-HLCs, as was shown by the presence of HBV core (HBc) and surface antigens. A clear increasing release of HBV surface and e antigens was detected, indicating the formation of functional cccDNA. Moreover, back-titration of culture supernatant of HBV-infected HC3x-AA-HLCs on HepG2-NTCP cells revealed the production of novel infectious HBV particles. Additionally, an increasing number of HBc-positive HC3x-AA-HLCs over time suggests viral spreading is occurring. Finally, the HC3x-AA-HLC model was validated for use in antiviral drug studies using the nucleoside reverse-transcriptase inhibitor, lamivudine, and the HBV entry inhibitor, Myrcludex B.
Different Changes in Adipokines, Lipid Profile, and TNF-Alpha Levels between 10 and 20 Whole Body Cryostimulation Sessions in Individuals with I and II Degrees of Obesity
Authors: Pilch Wanda , Piotrowska Anna , Wyrostek Joanna , Czerwińska-Ledwig Olga , Ziemann Ewa , Antosiewicz Jędrzej , Zasada Mariusz , Kulesa-Mrowiecka Małgorzata , Żychowska Małgorzata
Published: January 2022

Obesity is associated with chronic inflammation. While cold therapy influences the pro/antioxidative status of an individual, by affecting adipokine levels and the lipid profile, the effect of body mass index (BMI) on the response to cold exposure is unclear. We analyzed the link between BMI and the differences in effects of whole-body stimulation, depending on the number of treatments, on specific physiological parameters in men. Twenty-seven non-active men were divided into three groups: N (n = 9, BMI < 24.9), IOb (n = 9, BMI 30.0–34.9), and IIOb (BMI ≥ 35.0). The subjects participated in 20 3-min cryochamber sessions (−120 °C), 1/day, 5 days/week. Body composition was analyzed before and after treatment. Blood adiponectin (ADP), leptin (LEP), and tumor necrosis factor alpha (TNF-alpha) levels, and the lipid profile were analyzed three times: at baseline and up to 2 h after 10 and 20 sessions. The 20 treatments caused significant changes in body composition. Between 10 and 20 whole-body cryostimulation (WBC) sessions, a significant decreased was observed in the LEP and TNF-alpha levels. No significant changes in the lipid profile were noted. However, a positive tendency to regain the metabolic balance in adipose tissue was apparent in the IOb group in the tested period (decreased TG levels, increased HDL levels or the HDL/LDL ratio, and significantly decreased visceral adiposity index levels). Collectively, for people with obesity increasing the number of treatments above the standard 10 should be recommended.
Vitisin A, a Resveratrol Tetramer, Improves Scopolamine-Induced Impaired Learning and Memory Functions in Amnesiac ICR Mice
Authors: Chen Lih-Geeng , Wang Ching-Chiung , Lee Yi-Shan , Sie Yi-Yan , Chang Chi-I , Hou Wen-Chi
Published: January 2022

Resveratrol has been reported to exhibit neuroprotective activities in vitro and in vivo. However, little is known about resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B with the same molecular mass in the improvement of degenerative disorders. In this study, two 95% ethanol extracts (95EE) from stem parts of Vitis thunbergii Sieb. & Zucc. (VT-95EE) and from the root (R) parts of Vitis thunbergii var. taiwaniana (VTT-R-95EE) showed comparable acetylcholinesterase (AChE) inhibitory activities. It was found that VT-95EE and VTT-R-95EE showed different distribution patterns of identified resveratrol and resveratrol tetramers of hopeaphenol, vitisin A, and vitisin B based on the analyses of HPLC chromatographic profiles. The hopeaphenol, vitisin A, and vitisin B, showed AChE and monoamine oxidase-B inhibitions in a dose-dependent manner, among which vitisin B and vitisin A exhibited much better activities than those of resveratrol, and had neuroprotective activities against methylglyoxal-induced SH-SY5Y cell deaths. The scopolamine-induced amnesiac ICR mice treated with VT-95EE and its ethyl acetate-partitioned fraction (VT-95EE-EA) at doses of 200 and 400 mg/kg, or vitisin A at a dose of 40 mg/kg, but not vitisin B (40 mg/kg), were shown significantly to improve the impaired learning behaviors by passive avoidance tests compared to those in the control without drug treatments (p < 0.05). Compared to mice in the control group, the brain extracts in the vitisin A-treated mice or donepezil-treated mice showed significant reductions in AChE activities and malondialdehyde levels (p < 0.05), and elevated the reduced protein expressions of brain-derived neurotrophic factor (BDNF) and BDNF receptor, tropomyosin receptor kinase B (TrkB). These results revealed that vitisin A was the active constituent in the VT-95EE and VTT-95EE, and the VT medicinal plant and that the endemic variety of VTT has potential in developing functional foods for an unmet medical need for neurodegenerative disorders.
Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction
Authors: Befekadu Rahel , Grenegård Magnus , Larsson Anders , Christensen Kjeld , Ramström Sofia
Published: January 2022

Pentraxin-3 (PTX3) and neprilysin have been associated with increased morbidity and mortality in chronic inflammatory disease and heart failure, but these biomarkers have been studied less in patients with ST segment elevation myocardial infarction (STEMI). We investigated the dynamic changes in these biomarkers, as well as the well-known C-reactive protein (CRP), in STEMI patients. PTX3, neprilysin and CRP were measured in samples from 165 STEMI patients, collected at the acute stage, 1–3 days after and 3 months after percutaneous coronary intervention (PCI), and from 40 healthy donors. Patient survival was followed for approximately 8 years after the PCI. As compared with samples from healthy donors, plasma levels of CRP and PTX3 were significantly increased in the acute samples and 1–3 days after PCI, but not at 3 months. CRP levels peaked at 1–3 days, while PTX3 was similarly high in both acute and 1–3 days samples. For neprilysin, no significant differences were observed at the group level. We found no significant differences when comparing patients with patent versus occluded culprit vessels or between patients having a thrombus aspiration or not. However, we found a significant reduction in survival for individuals with PTX3 above the median, both for samples collected at the acute stage and 1–3 days after PCI (p = 0.0001 and p = 0.0008, respectively). For CRP, no significant differences were observed using this approach, but patients above the reference range for healthy donors in the acute samples showed significantly lower survival (p = 0.0476). Conclusions: Survival analysis suggests that PTX3 might be a promising marker to predict mortality in this patient population.
E-Selectin Is Associated with Daytime and 24-Hour Diastolic Blood Pressure Variability in Type 2 Diabetes
Authors: Ciobanu Dana Mihaela , Bala Cornelia , Rusu Adriana , Cismaru Gabriel , Roman Gabriela
Published: January 2022

E-selectin is an endothelial cell adhesion molecule involved in vascular inflammation. Elevated E-selectin has been reported in patients with high blood pressure and diabetes. Given the increasing clinical relevance of parameters derived from ambulatory blood pressure monitoring, further investigation of their relationships with E-selectin is of interest. In this study, we aimed to investigate the association between serum E-selectin, office blood pressure and 24 h ambulatory blood pressure parameters in patients with type 2 diabetes. Blood pressure variability was assessed by computing the standard deviation of mean systolic and diastolic blood pressure separately for daytime and nighttime during 24 h ambulatory blood pressure monitoring in a cohort of patients with type 2 diabetes (n = 132). Additionally, were assessed nighttime systolic dipping and pulse pressure separately for daytime, nighttime, and 24 h. Serum E-selectin was measured using the enzyme-linked immunosorbent assay technique. We found that E-selectin was consistently associated with 24 h diastolic blood pressure variability (r = 0.238; p = 0.019) and daytime diastolic blood pressure variability (r = 0.258; p = 0.012), after adjustment for confounding factors. No association of E-selectin with office blood pressure and other 24 h ambulatory blood pressure parameters was observed. In conclusion, endothelial activation indicated by elevated serum E-selectin is associated with increased ambulatory diastolic blood pressure variability in patients with type 2 diabetes.
Identification and Characterization of Besifovir-Resistant Hepatitis B Virus Isolated from a Chronic Hepatitis B Patient
Authors: Kim Jong Chul , Lee Hye Young , Lee Ah Ram , Dezhbord Mehrangiz , Lee Da Rae , Kim Seong Ho , Won Juhee , Park Soree , Kim Na Yeon , Shin Jae Jin , Kim Sang Gyune , Kim Young Seok , Yoo Jeong-Ju , Kim Kyun-Hwan
Published: January 2022

Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient’s serum were cloned into the replication-competent HBV 1.2 mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.
Lipid-Based Nanocarriers in Renal RNA Therapy
Authors: Su Chi-Ting , See Daniel H. W. , Huang Jenq-Wen
Published: January 2022

Kidney disease is a multifactorial problem, with a growing prevalence and an increasing global burden. With the latest worldwide data suggesting that chronic kidney disease (CKD) is the 12th leading cause of death, it is no surprise that CKD remains a public health problem that requires urgent attention. Multiple factors contribute to kidney disease, each with its own pathophysiology and pathogenesis. Furthermore, microRNAs (miRNAs) have been linked to several types of kidney diseases. As dysregulation of miRNAs is often seen in some diseases, there is potential in the exploitation of this for therapeutic applications. In addition, uptake of interference RNA has been shown to be rapid in kidneys making them a good candidate for RNA therapy. The latest advancements in RNA therapy and lipid-based nanocarriers have enhanced the effectiveness and efficiency of RNA-related drugs, thereby making RNA therapy a viable treatment option for renal disease. This is especially useful for renal diseases, for which a suitable treatment is not yet available. Moreover, the high adaptability of RNA therapy combined with the low risk of lipid-based nanocarriers make for an attractive treatment choice. Currently, there are only a small number of RNA-based drugs related to renal parenchymal disease, most of which are in different stages of clinical trials. We propose the use of miRNAs or short interfering RNAs coupled with a lipid-based nanocarrier as a delivery vehicle for managing renal disease.
CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications
Authors: Arjomandnejad Motahareh , Kopec Acadia L. , Keeler Allison M.
Published: January 2022

Regulatory T cells are critical for maintaining immune tolerance. Recent studies have confirmed their therapeutic suppressive potential to modulate immune responses in organ transplant and autoimmune diseases. However, the unknown and nonspecific antigen recognition of polyclonal Tregs has impaired their therapeutic potency in initial clinical findings. To address this limitation, antigen specificity can be conferred to Tregs by engineering the expression of transgenic T-cell receptor (TCR) or chimeric antigen receptor (CAR). In contrast to TCR Tregs, CAR Tregs are major histocompatibility complex (MHC) independent and less dependent on interleukin-2 (IL-2). Furthermore, CAR Tregs maintain Treg phenotype and function, home to the target tissue and show enhanced suppressive efficacy compared to polyclonal Tregs. Additional development of engineered CAR Tregs is needed to increase Tregs’ suppressive function and stability, prevent CAR Treg exhaustion, and assess their safety profile. Further understanding of Tregs therapeutic potential will be necessary before moving to broader clinical applications. Here, we summarize recent studies utilizing CAR Tregs in modulating immune responses in autoimmune diseases, transplantation, and gene therapy and future clinical applications.
Love Wave Sensor with High Penetration Depth for Potential Application in Cell Monitoring
Authors: Segura Chávez Pedro , Bonhomme Jérémy , Bellaredj Mohamed , Olive Lucile , Beyssen Denis , Oudich Mourad , Charette Paul , Sarry Frédéric
Published: January 2022

Love wave (L-SAW) sensors have been used to probe cell monolayers, but their application to detect changes beyond the focal adhesion points on cell monolayers, as viscosity changes on the cytoskeleton, has not been explored. In this work we present for the first time a Love wave sensor with tuned penetration depth and sensitivity to potentially detect mechanical changes beyond focal adhesion points of cell monolayers. We designed and fabricated a Love wave sensor operating at 30 MHz with sensitivity to detect viscous changes between 0.89 and 3.3 cP. The Love wave sensor was modeled using an acoustic transmission line model, whereas the response of interdigital transducers (IDTs) was modeled with the Campbell’s cross-field circuit model. Our design uses a substrate with a high electromechanical coupling coefficient (LiNbO3 36Y-X), and an 8-µm polymeric guiding layer (SU-8). The design aims to overcome the high insertion losses of viscous liquid environments, and the loss of sensitivity due to the low frequency. The fabricated sensor was tested in a fluidic chamber glued directly to the SU-8 guiding layer. Our experiments with liquids of viscosity similar to those expected in cell monolayers showed a measurable sensor response. In addition, experimentation with SaOs-2 cells within a culture medium showed measurable responses. These results can be of interest for the development of novel cell-based biosensors, and novel characterization tools for cell monolayers.
Electrophoretic µPAD for Purification and Analysis of DNA Samples
Authors: Heinsohn Natascha Katharina , Niedl Robert Raimund , Anielski Alexander , Lisdat Fred , Beta Carsten
Published: January 2022

In this work, the fabrication and characterization of a simple, inexpensive, and effective microfluidic paper analytic device (µPAD) for monitoring DNA samples is reported. The glass microfiber-based chip has been fabricated by a new wax-based transfer-printing technique and an electrode printing process. It is capable of moving DNA effectively in a time-dependent fashion. The nucleic acid sample is not damaged by this process and is accumulated in front of the anode, but not directly on the electrode. Thus, further DNA processing is feasible. The system allows the DNA to be purified by separating it from other components in sample mixtures such as proteins. Furthermore, it is demonstrated that DNA can be moved through several layers of the glass fiber material. This proof of concept will provide the basis for the development of rapid test systems, e.g., for the detection of pathogens in water samples.
Psychopathological Symptoms and Personality Traits as Predictors of Problematic Smartphone Use in Different Age Groups
Authors: Wickord Lea-Christin , Quaiser-Pohl Claudia
Published: January 2022

The study investigates psychopathological symptoms and the Big Five personality traits as predictors of “problematic smartphone use” (PSU) in different generational groups. The generational groups were selected to analyze whether the different life stages and developmental tasks that need to be completed have an impact on PSU. The groups were divided into digital immigrants, digital natives, and Generation Y and Z as subgroups of digital natives. A total of 399 subjects participated (312 women, 86 men, 1 diverse; mean age = 25.9; range 14–67; 44 digital immigrants, 355 digital natives, 35 Generation Y, and 320 Generation Z). They completed the ICD-10 Symptom Rating (ISR), the Big Five Inventory-10 (BFI-10), and the Mobile Phone Problematic Use Scale (MPPUS). The results show differences between digital immigrants and digital natives in the expression of PSU, neuroticism, conscientiousness, depression, anxiety, and compulsivity. Concerning Generations Y and Z, differences were only found in the expression of the PSU. Regression revealed that symptoms for obsessive-compulsive disorders, depression, conscientiousness, and gender were significant predictors of PSU. Moderations have shown that being a digital immigrant/native moderates the impact of eating disorders on PSU. Belonging to Generation Y/Z moderates the influence of conscientiousness and depression on PSU. Thus, it shows that in different generations, different factors seem to play a role in the development and maintenance of PSU.
Has the Sudden Health Emergency Impacted Public Awareness? Survey-Based Evidence from China
Authors: Guo Xiaojia , Li Jingzhong , Su Fang , Chen Xingpeng , Cheng Yeqing , Xue Bing
Published: January 2022

Public environmental cognition is an important basis for optimizing environmental management and reducing tensions between humans and land. Although the level of environmental cognition is a gradual process under normal conditions, it often changes qualitatively because of major public emergencies. During the 2019 new coronavirus epidemic (COVID-19), the most significant public health event in recent years, 24,188 national samples were obtained based on a network survey. The comprehensive evaluation method was used to assess the impact of major public events on public environmental cognition and the characteristics of spatial and temporal distribution. The findings are as follows. (1) During the epidemic period, sudden public health emergencies effectively promoted the national residents’ environmental awareness, whether urban residents or rural; most respondents generally agreed with the concept of “respect nature and cherish life”. (2) The environmental cognition of national residents was higher in the northwest and lower in the northeast of China, which is suitable for economic and social development and humanistic tradition. (3) There was a clear positive correlation between environmental awareness and education level. (4) During the epidemic, nervousness of respondents had a negative effect on environmental cognition. This study provides scientific support and a basis for decision making for the government to carry out environmental management optimization and improve the ecological and environmental cognition of the public, as well as devise effective intervention mechanisms with different time and space dimensions for similar future public health emergencies.
A Systematic Review on the Role of Substance Consumption in Work-Related Road Traffic Crashes Reveals the Importance of Biopsychosocial Factors in Prevention
Authors: Frumento Sergio , Bufano Pasquale , Zaccaro Andrea , Poma Anello Marcello , Persechino Benedetta , Gemignani Angelo , Laurino Marco , Menicucci Danilo
Published: January 2022

Objective: Since many jobs imply driving, a relevant part of all road traffic crashes (RTC) is related to work. Statistics considering all crashes suggest that they are significantly associated with consumption of substances, but the root causes are not yet clear. The objective of the present paper was to systematically review the scientific literature concerning substances consumption and work-related RTC. We queried the PubMed and Scopus electronic databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles were included if they reported all necessary data and survived a quality assessment. We selected a final sample of 30 articles from an initial pool of 7113. As hypothesized, taking any of the considered substances was found to increase the risk of work-related RTC. Descriptive statistics on work-related RTC showed a higher average positivity rate for medicines (14.8%) than for alcohol (3.02%) and drugs (0.84%). Interestingly, the impact of some medications found an unconvincing explanation in the mere occurrence of side effects, and it suggests that psychosocial and/or medical conditions could be better predictors of RTC. We therefore propose an intervention and prevention model that also considers biopsychosocial factors, for which further studies are needed in future research.