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Sökning: L773:2227 9059 > (2022)

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1.
  • Amoli, MS, et al. (författare)
  • Materials for Dentoalveolar Bioprinting: Current State of the Art
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Although current treatments can successfully address a wide range of complications in the dentoalveolar region, they often still suffer from drawbacks and limitations, resulting in sub-optimal treatments for specific problems. In recent decades, significant progress has been made in the field of tissue engineering, aiming at restoring damaged tissues via a regenerative approach. Yet, the translation into a clinical product is still challenging. Novel technologies such as bioprinting have been developed to solve some of the shortcomings faced in traditional tissue engineering approaches. Using automated bioprinting techniques allows for precise placement of cells and biological molecules and for geometrical patient-specific design of produced biological scaffolds. Recently, bioprinting has also been introduced into the field of dentoalveolar tissue engineering. However, the choice of a suitable material to encapsulate cells in the development of so-called bioinks for bioprinting dentoalveolar tissues is still a challenge, considering the heterogeneity of these tissues and the range of properties they possess. This review, therefore, aims to provide an overview of the current state of the art by discussing the progress of the research on materials used for dentoalveolar bioprinting, highlighting the advantages and shortcomings of current approaches and considering opportunities for further research.
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2.
  • Befekadu, Rahel, 1968-, et al. (författare)
  • Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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3.
  • Bodahl, Sara, et al. (författare)
  • LL-37 and Double-Stranded RNA Synergistically Upregulate Bronchial Epithelial TLR3 Involving Enhanced Import of Double-Stranded RNA and Downstream TLR3 Signaling
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The human host defense peptide LL-37 influences double-stranded RNA signaling, but this process is not well understood. Here, we investigate synergistic actions of LL-37 and synthetic double-stranded RNA (poly I:C) on toll-like receptor 3 (TLR3) expression and signaling, and examine underlying mechanisms. In bronchial epithelial BEAS-2B cells, LL-37 potentiated poly I:C-induced TLR3 mRNA and protein expression demonstrated by qPCR and Western blot, respectively. Interestingly, these effects were associated with increased uptake of rhodamine-tagged poly I:C visualized by immunocytochemistry. The LL-37/poly I:C-induced upregulation of TLR3 mRNA expression was prevented by the endosomal acidification inhibitor chloroquine, indicating involvement of downstream TLR3 signaling. The glucocorticoid dexamethasone reduced LL-37/poly I:C-induced TLR3 expression on both mRNA and protein levels, and this effect was associated with increased IκBα protein expression, suggesting that dexamethasone acts via attenuation of NF-κB activity. We conclude that LL-37 potentiates poly I:C-induced upregulation of TLR3 through a mechanism that may involve enhanced import of poly I:C and that LL-37/poly I:C-induced TLR3 expression is associated with downstream TLR3 signaling and sensitive to inhibition of NF-κB activity.
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4.
  • Burgos-Moron, Estefania, et al. (författare)
  • In Vitro Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • We recently screened a series of new aziridines beta-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-beta-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore the possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (comet assay). Cells deficient in the nucleotide excision repair (NER) pathway were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. Combinations of AzGalp with oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also showed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.
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5.
  • Cantero-Garcia, N, et al. (författare)
  • The Combination of Galanin (1-15) and Escitalopram in Rats Suggests a New Strategy for Alcohol Use Disorder Comorbidity with Depression
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Alcohol use disorder (AUD) is highly prevalent, and over 50% of AUD patients also suffer major depressive disorders. Selective 5-HT reuptake inhibitors (SSRIs) can reduce rodent ethanol drinking but exert modest clinical efficacy in alcoholic individuals. Finding new pharmacological strategies that could modulate alcohol consumption and depression is necessary. We have analyzed the effect of Galanin (1–15) [GAL(1–15)] on escitalopram (ESC)-mediated effect in alcohol consumption using the alcohol self-administration test, the nuclei involved in the effect, and whether GAL(1–15) + ESC modulated the response in despair or anxiety tests in animals under chronic alcohol intake. GAL(1–15) + ESC combination substantially reduced alcohol intake in the alcohol self-administration test and, moreover, enhanced the reduction of reward capacity of ESC on different reinforcers such as sucrose or saccharine. GAL(1–15) + ESC coadministration significantly decreases the number of C-Fos-IR TH cell bodies in the VTA, and PCA analysis suggests that one functional network, including VTA, RMTg and DR, is involved in these effects. Significantly in rats with chronic alcohol consumption, GAL(1–15) reversed adverse ESC-mediated effects in the depression-related behavioural test and forced swimming test. The results open up the possibility of using GAL(1–15) in combination with the SSRI Escitalopram as a novel strategy in AUD comorbidity with depression.
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6.
  • Hill, Henrik, et al. (författare)
  • Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D. Using mass spectrometry, we have quantified the endogenous circulating levels of GABA in patients with new-onset and long-standing T1D and found that the levels are unaltered when compared to healthy controls, i.e., T1D patients do not have a deficit of systemic GABA levels. In T1D, GABA levels were negatively correlated with IL-1 beta, IL-12, and IL-15 15 and positively correlated to levels of IL-36 beta and IL-37. Interestingly, GABA levels were also correlated to the levels of GAD-autoantibodies. The unaltered levels of GABA in T1D patients suggest that the GABA secretion from beta-cells only has a minor impact on the circulating systemic levels. However, the local levels of GABA could be altered within pancreatic islets in the presence of GAD-autoantibodies.
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7.
  • Karlsson, D., et al. (författare)
  • Inhibition of SGLT2 Preserves Function and Promotes Proliferation of Human Islets Cells In Vivo in Diabetic Mice
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67+glucagon+ and Ki67+insulin+) while apoptosis was reduced (caspase3+glucagon+ and caspase3+insulin+). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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8.
  • Larsson, Anders, et al. (författare)
  • Plasma Leptin Is Increased in Intensive Care Patients with COVID-19—An Investigation Performed in the PronMed-Cohort
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:1, s. 4-4
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract: COVID-19 has shaken the world and intensive care units (ICU) have been challenged by numerous patients suffering from a previously unknown disease. Leptin is a polypeptide pleiotropic hormone, mainly expressed by adipocytes. It acts as a proinflammatory cytokine and is associated with several conditions, known to increase the risk of severe COVID-19. Very little is known about leptin in severe viral disorders. Plasma leptin was analyzed in 222 out of 229 patients with severe COVID-19 on admission to an ICU at Uppsala University Hospital, a tertiary care hospital in Sweden, and compared to plasma leptin in 25 healthy blood donors. COVID-19 was confirmed by positive PCR. Leptin levels were significantly higher in patients with COVID-19 (18.3 ng x mL-1; IQR = 30.4), than in healthy controls (7.8 ng x mL-1; IQR = 6.4). Women had significantly higher leptin values (22.9 ng x mL-1; IQR = 29.8) than men (17.5 ng x mL-1; IQR = 29.9). Mortality at 30 days was 23%, but was not associated with increased leptin levels. Neither median duration of COVID-19 before admission to ICU (10 days; IQR = 4) or median length of ICU stay (8 days; IQR = 11) correlated with the plasma leptin levels. Leptin levels in COVID-19 were higher in females than in males. Both treatment (e.g. use of corticosteroids) and prophylaxis (vaccines) have been improved since the start of the COVID-19 pandemic, which may contribute to some difficulties in deciphering relations between COVID-19 and leptin.
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9.
  • Norman, Daniel, et al. (författare)
  • Irisin-A Pancreatic Islet Hormone
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 alpha- and beta-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.
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10.
  • Portincasa, P, et al. (författare)
  • Intestinal Barrier and Permeability in Health, Obesity and NAFLD
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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11.
  • Schwäbe, Frederic V., et al. (författare)
  • Host Defense Peptides LL-37 and Lactoferrin Trigger ET Release from Blood-Derived Circulating Monocytes
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Neutrophils are commonly regarded as the first line of immune response during infection or in tissue injury-induced inflammation. The rapid influx of these cells results in the release of host defense proteins (HDPs) or formation of neutrophil extracellular traps (NETs). As a second wave during inflammation or infection, circulating monocytes arrive at the site. Earlier studies showed that HDPs LL-37 and Lactoferrin (LTF) activate monocytes while neutrophil elastase facilitates the formation of extracellular traps (ETs) in monocytes. However, the knowledge about the impact of HDPs on monocytes remains sparse. In the present study, we investigated the effect of LL-37 and LTF on blood-derived CD14+ monocytes. Both HDPs triggered a significant release of TNFα, nucleosomes, and monocyte ETs. Microscopic analysis indicated that ET formation by LL-37 depends on storage-operated calcium entry (SOCE), mitogen-activated protein kinase (MAPK), and ERK1/2, whereas the LTF-mediated ET release is not affected by any of the here used inhibitors. Quantitative proteomics mass spectrometry analysis of the neutrophil granular content (NGC) revealed a high abundance of Lactoferrin. The stimulation of CD14+ monocytes with NGC resulted in a significant secretion of TNFα and nucleosomes, and the formation of monocyte ETs. The findings of this study provide new insight into the complex interaction of HDPs, neutrophils, and monocytes during inflammation.
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12.
  • Serrano, J., et al. (författare)
  • Saccharin Stimulates Insulin Secretion Dependent on Sweet Taste Receptor-Induced Activation of PLC Signaling Axis
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Saccharin is a common artificial sweetener and a bona fide ligand for sweet taste receptors (STR). STR can regulate insulin secretion in beta cells, so we investigated whether saccharin can stimulate insulin secretion dependent on STR and the activation of phospholipase C (PLC) signaling. Methods: We performed in vivo and in vitro approaches in mice and cells with loss-of-function of STR signaling and specifically assessed the involvement of a PLC signaling cascade using real-time biosensors and calcium imaging. Results: We found that the ingestion of a physiological amount of saccharin can potentiate insulin secretion dependent on STR. Similar to natural sweeteners, saccharin triggers the activation of the PLC signaling cascade, leading to calcium influx and the vesicular exocytosis of insulin. The effects of saccharin also partially require transient receptor potential cation channel M5 (TRPM5) activity. Conclusions: Saccharin ingestion may transiently potentiate insulin secretion through the activation of the canonical STR signaling pathway. These physiological effects provide a framework for understanding the potential health impact of saccharin use and the contribution of STR in peripheral tissues. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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13.
  • Singh, Priyanka, et al. (författare)
  • Antibacterial Effect of Silver Nanoparticles Is Stronger If the Production Host and the Targeted Pathogen Are Closely Related
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Microbial resistance to antibiotics is one of the key challenges that lead to the search for alternate antimicrobial treatment approaches. Silver nanoparticles (AgNPs) are well known for their antimicrobial effects against a wide variety of drug-resistant microorganisms. AgNPs can be synthesized using microbial hosts, using a green and economical synthesis route, which produces extremely stable and highly active nanoparticles. Such green AgNPs are coated with a biological coating often referred to as a corona, originating from the production microorganism. In this study, we asked whether the composition of the biological corona might influence the antimicrobial activity of green AgNPs. To investigate this, we produced AgNPs in Pseudomonas putida KT2440 and Escherichia coli K12 MG1655, and tested them against pathogen species from the corresponding genera. AgNPs exhibited a size range of 15–40 nm for P. putida and 30–70 nm for E. coli, and both types of nanoparticles were surrounded by a thick biological corona layer, providing extreme stability. The nanoparticles remained stable over long periods and exhibited negative zeta potential values. P-AgNPs (obtained from P. putida) were tested against pathogenic Pseudomonas aeruginosa PAO1, and E-AgNPs (obtained from E. coli) were tested against pathogenic Escherichia coli UTI 89. Antimicrobial studies were conducted by Minimum bactericidal concentration (MBC), live/dead staining and SEM analysis. MBC of P-AgNPs against P. aeruginosa was 1 µg/mL, and MBC of E-AgNPs against E. coli UTI 89 was 8 µg/mL. In both cases, the MBC values were superior to those of green AgNPs produced in organisms unrelated to the target pathogens, available in the literature. Our results suggest that NPs produced in microorganisms closely related to the target pathogen may be more effective, indicating that the composition of the biological corona may play a crucial role in the antimicrobial mechanism of AgNPs.
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14.
  • Tavakoli, Shima, et al. (författare)
  • Immunomodulation of Skin Repair : Cell-Based Therapeutic Strategies for Skin Replacement (A Comprehensive Review)
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The immune system has a crucial role in skin wound healing and the application of specific cell-laden immunomodulating biomaterials emerged as a possible treatment option to drive skin tissue regeneration. Cell-laden tissue-engineered skin substitutes have the ability to activate immune pathways, even in the absence of other immune-stimulating signals. In particular, mesenchymal stem cells with their immunomodulatory properties can create a specific immune microenvironment to reduce inflammation, scarring, and support skin regeneration. This review presents an overview of current wound care techniques including skin tissue engineering and biomaterials as a novel and promising approach. We highlight the plasticity and different roles of immune cells, in particular macrophages during various stages of skin wound healing. These aspects are pivotal to promote the regeneration of nonhealing wounds such as ulcers in diabetic patients. We believe that a better understanding of the intrinsic immunomodulatory features of stem cells in implantable skin substitutes will lead to new translational opportunities. This, in turn, will improve skin tissue engineering and regenerative medicine applications.
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15.
  • Ågren, Richard, et al. (författare)
  • Evidence for two modes of binding of the negative allosteric modulator SB269,652 to the dopamine D2 receptor
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • SB269,652 has been described as the first negative allosteric modulator (NAM) of the dopamine D2 receptor (D2 R), however, the binding mode and allosteric mechanism of action of this ligand remain incompletely understood. SB269,652 comprises an orthosteric, primary pharmacophore and a secondary (or allosteric) pharmacophore joined by a hydrophilic cyclohexyl linker and is known to form corresponding interactions with the orthosteric binding site (OBS) and the secondary binding pocket (SBP) in the D2 R. Here, we observed a surprisingly low potency of SB269,652 to negatively modulate the D2 R-mediated activation of G protein-coupled inward-rectifier potassium channels (GIRK) and decided to perform a more detailed investigation of the interaction between dopamine and SB269,652. The results indicated that the SB269,652 inhibitory potency is increased 6.6-fold upon ligand pre-incubation, compared to the simultaneous co-application with dopamine. Mutagenesis experiments implicated both S193 in the OBS and E95 in the SBP in the effect of pre-application. The present findings extend previous knowledge about how SB269,652 competes with dopamine at the D2 R and may be useful for the development of novel D2 R ligands, such as antipsychotic drug candidates.
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16.
  • Antonopoulou, Io, 1989-, et al. (författare)
  • The Inhibitory Potential of Ferulic Acid Derivatives against the SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics, and ADMET Evaluation
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • The main protease (Mpro) of SARS-CoV-2 is an appealing target for the development of antiviral compounds, due to its critical role in the viral life cycle and its high conservation among different coronaviruses and the continuously emerging mutants of SARS-CoV-2. Ferulic acid (FA) is a phytochemical with several health benefits that is abundant in plant biomass and has been used as a basis for the enzymatic or chemical synthesis of derivatives with improved properties, including antiviral activity against a range of viruses. This study tested 54 reported FA derivatives for their inhibitory potential against Mpro by in silico simulations. Molecular docking was performed using Autodock Vina, resulting in comparable or better binding affinities for 14 compounds compared to the known inhibitors N3 and GC376. ADMET analysis showed limited bioavailability but significantly improved the solubility for the enzymatically synthesized hits while better bioavailability and druglikeness properties but higher toxicity were observed for the chemically synthesized ones. MD simulations confirmed the stability of the complexes of the most promising compounds with Mpro, highlighting FA rutinoside and compound e27 as the best candidates from each derivative category.
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17.
  • Bai, XN, et al. (författare)
  • Characterization of the Upper Respiratory Bacterial Microbiome in Critically Ill COVID-19 Patients
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • The upper respiratory tract (URT) microbiome can contribute to the acquisition and severity of respiratory viral infections. The described associations between URT microbiota and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited at microbiota genus level and by the lack of functional interpretation. Our study, therefore, characterized the URT bacterial microbiome at species level and their encoded pathways in patients with COVID-19 and correlated these to clinical outcomes. Whole metagenome sequencing was performed on nasopharyngeal samples from hospitalized patients with critical COVID-19 (n = 37) and SARS-CoV-2-negative individuals (n = 20). Decreased bacterial diversity, a reduction in commensal bacteria, and high abundance of pathogenic bacteria were observed in patients compared to negative controls. Several bacterial species and metabolic pathways were associated with better respiratory status and lower inflammation. Strong correlations were found between species biomarkers and metabolic pathways associated with better clinical outcome, especially Moraxella lincolnii and pathways of vitamin K2 biosynthesis. Our study demonstrates correlations between the URT microbiome and COVID-19 patient outcomes; further studies are warranted to validate these findings and to explore the causal roles of the identified microbiome biomarkers in COVID-19 pathogenesis.
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18.
  • Benetton, M., et al. (författare)
  • Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Hematopoietic stem cell transplantation (HSCT) is a curative post-remission treatment in patients with acute myeloid leukemia (AML), but relapse after transplant is still a challenging event. In recent year, several studies have investigated the molecular minimal residual disease (qPCR-MRD) as a predictor of relapse, but the lack of standardized protocols, cut-offs, and timepoints, especially in the pediatric setting, has prevented its use in several settings, including before HSCT. Here, we propose the first collaborative retrospective I-BFM-AML study assessing qPCR-MRD values in pretransplant bone marrow samples of 112 patients with a diagnosis of AML harboring t(8;21)(q22; q22)RUNX1::RUNX1T1, or inv(16)(p13q22)CBFB::MYH11, or t(9;11)(p21;q23)KMT2A::MLLT3, or FLT3-ITD genetic markers. We calculated an ROC cut-off of 2.1 x 10(-4) that revealed significantly increased OS (83.7% versus 57.1%) and EFS (80.2% versus 52.9%) for those patients with lower qPCR-MRD values. Then, we partitioned patients into three qPCR-MRD groups by combining two different thresholds, 2.1 x 10(-4) and one lower cut-off of 1 x 10(-2), and stratified patients into low-, intermediate-, and high-risk groups. We found that the 5-year OS (83.7%, 68.6%, and 39.2%, respectively) and relapse-free survival (89.2%, 73.9%, and 67.9%, respectively) were significantly different independent of the genetic lesion, conditioning regimen, donor, and stem cell source. These data support the PCR-based approach playing a clinical relevance in AML transplant management.
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19.
  • Berghäll, Elisabeth, et al. (författare)
  • The Evolution of Blood Cell Phenotypes, Intracellular and Plasma Cytokines and Morphological Changes in Critically Ill COVID-19 Patients
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Severe coronavirus disease 2019 (COVID-19) causes a strong inflammatory response. To obtain an overview of inflammatory mediators and effector cells, we studied 25 intensive-care-unit patients during the timeframe after off-label chloroquine treatment and before an introduction of immunomodulatory drugs.Material and methods: Blood samples were weekly examined with flow cytometry (FCM) for surface and intracytoplasmic markers, cytokine assays were analyzed for circulating interleukins (ILs), and blood smears were evaluated for morphological changes. Samples from healthy volunteers were used for comparison. Organ function data and 30-day mortality were obtained from medical records.Results: Compared to that of the healthy control group, the expression levels of leukocyte surface markers, i.e., the cluster of differentiation (CD) markers CD2, CD4, CD8, CD158d, CD25, CD127, and CD19, were lower (p < 0.001), while those of leukocytes expressing CD33 were increased (p < 0.05). An aberrant expression of CD158d on granulocytes was found on parts of the granulocyte population. The expression levels of intracellular tumor necrosis factor alpha (TNF alpha) and IL-1 receptor type 2 in leukocytes were higher (p < 0.001) as well as plasma levels of TNF alpha, IL-2, IL-6, IL-8, IL-10 (p < 0.001), interferon gamma (IFN gamma) (p < 0.01), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (p < 0.05). The expression levels of CD33+ leukocytes and circulating IL-6 were higher (p < 0.05) among patients with arterial oxygen partial pressure-to-fractional inspired oxygen (PaO2/FiO(2)) ratios below 13.3 kPa compared to in the remaining patients. The expression levels of TNF alpha, IL-2, IL-4, IL-6, IL-8, and IL-10 were higher in patients treated with continuous renal replacement therapy (CRRT) (p < 0.05), and the levels of the maximum plasma creatinine and TNF alpha Spearman's rank-order correlation coefficient (rho = 0.51, p < 0.05) and IL-8 (rho = 0.44, p < 0.05) correlated. Blood smears revealed neutrophil dysplasia with pseudo-Pelger forms being most common.Conclusion: These findings suggest that patients with severe COVID-19, in addition to augmented ILs, lymphopenia, and increased granulocytes, also had effects on the bone marrow.
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20.
  • Bodén, Embla, et al. (författare)
  • Quantitative Proteomics Indicate Radical Removal of Non-Small Cell Lung Cancer and Predict Outcome
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Non-small cell lung cancer (NSCLC) is associated with low survival rates, often due to late diagnosis and lack of personalized medicine. Diagnosing and monitoring NSCLC using blood samples has lately gained interest due to its less invasive nature. In the present study, plasma was collected at three timepoints and analyzed using proximity extension assay technology and quantitative real-time polymerase chain reaction in patients with primary NSCLC stages IA–IIIA undergoing surgery. Results were adjusted for patient demographics, tumor, node, metastasis (TNM) stage, and multiple testing. Major histocompatibility (MHC) class 1 polypeptide-related sequence A/B (MIC-A/B) and tumor necrosis factor ligand superfamily member 6 (FASLG) were significantly increased post-surgery, suggesting radical removal of cancerous cells. Levels of hepatocyte growth factor (HGF) initially increased postoperatively but were later lowered, potentially indicating radical removal of malignant cells. The levels of FASLG in patients who later died or had a relapse of NSCLC were lower at all three timepoints compared to surviving patients without relapse, indicating that FASLG may be used as a prognostic biomarker. The biomarkers were confirmed using microarray data. In conclusion, quantitative proteomics could be used for NSCLC identification but may also provide information on radical surgical removal of NSCLC and post-surgical prognosis.
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21.
  • Callesen, Katrine T., et al. (författare)
  • Characterization of Mast Cells from Healthy and Varicose Human Saphenous Vein
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Mast cells (MCs) are distributed in tissues throughout the body and are highly involved in many physiological and pathophysiological processes. The potential and involvement of different MC phenotypes are still not well understood. MCs are present in blood vessel walls, but their specific phenotypic features are unknown. We aimed at characterizing MCs from human saphenous veins for localization, mediator content, and receptor expression. This was done in MCs from both healthy and varicose human saphenous veins (hSV and vSV, respectively). For both vSV and hSV, we found that vein MCs are mainly present in the tunica adventitia (99% MCs in adventitia) and that the population consists of both MCT and MCTC phenotypes (vSV: 55% MCT, hSV: 64% MCT). The vein MCs contained high levels of histamine (vSV: 27 pg/MC, hSV: 55 pg/MC) and tryptase (vSV: 98 pg/MC, hSV: 111 pg/MC), indicating a strong potential for regulatory effects on blood vessels. The receptor expression of FcɛRI, MRGPRX2, PTAFR, C3aR, and C5aR was found, even though the percentage of positive cells differed between vSV and hSV MCs. We conclude that vein MCs from the blood vessel wall have a high potential to affect the tissue around them.
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22.
  • Dhiman, K., et al. (författare)
  • Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer's disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-beta [A beta]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]+/-; A+T+/N +/-). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR >= 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N +/-) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR >= 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR >= 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03-2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31-17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.
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23.
  • Dugic, A, et al. (författare)
  • The Clinical Utility of Soluble Serum Biomarkers in Autoimmune Pancreatitis: A Systematic Review
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Autoimmune pancreatitis (AIP) is a rare etiological type of chronic pancreatitis. The clinical and radiological presentation of AIP often resembles that of pancreatic cancer. Identifying non-invasive markers for their early distinction is of utmost importance to avoid unnecessary surgery or a delay in steroid therapy. Thus, this systematic review was conducted to revisit all current evidence on the clinical utility of different serum biomarkers in diagnosing AIP, distinguishing AIP from pancreatic cancer, and predicting disease course, steroid therapy response, and relapse. A systematic review was performed for articles published up to August 2021 by searching electronic databases such as MEDLINE, Web of Science, and EMBASE. Among 5123 identified records, 92 studies were included in the qualitative synthesis. Apart from immunoglobulin (Ig) G4, which was by far the most studied biomarker, we identified autoantibodies against the following: lactoferrin, carboanhydrase II, plasminogen-binding protein, amylase-α2A, cationic (PRSS1) and anionic (PRSS2) trypsinogens, pancreatic secretory trypsin inhibitor (PSTI/SPINK1), and type IV collagen. The identified novel autoantigens were laminin 511, annexin A11, HSP-10, and prohibitin. Other biomarkers included cytokines, decreased complement levels, circulating immune complexes, N-glycan profile changes, aberrant miRNAs expression, decreased IgA and IgM levels, increased IgE levels and/or peripheral eosinophil count, and changes in apolipoprotein isoforms levels. To our knowledge, this is the first systematic review that addresses biomarkers in AIP. Evolving research has recognized numerous biomarkers that could help elucidate the pathophysiological mechanisms of AIP, bringing us closer to AIP diagnosis and its preoperative distinction from pancreatic cancer.
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24.
  • Fernandez-de-las-Penas, C., et al. (författare)
  • Phenotyping Post-COVID Pain as a Nociceptive, Neuropathic, or Nociplastic Pain Condition
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Pain after an acute Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) condition (post-COVID pain) is becoming a new healthcare emergency. Precision medicine refers to an evidence-based method of grouping patients based on their diagnostic/symptom presentation and then tailoring specific treatments accordingly. Evidence suggests that post-COVID pain can be categorized as nociceptive (i.e., pain attributable to the activation of the peripheral receptive terminals of primary afferent neurons in response to noxious chemical, mechanical, or thermal stimuli), neuropathic (i.e., pain associated with a lesion or disease of the somatosensory nervous system and limited to a "neuroanatomically plausible" distribution of the system), nociplastic (i.e., pain arising from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain), or mixed type (when two pain phenotypes co-exist). Each of these pain phenotypes may require a different treatment approach to maximize treatment effectiveness. Accordingly, the ability to classify post-COVID pain patients into one of these phenotypes would likely be critical for producing successful treatment outcomes. The 2021 International Association for the Study of Pain (IASP) clinical criteria and grading system provide a framework for classifying pain within a precision pain medicine approach. Here we present data supporting the possibility of grouping patients with post-COVID pain into pain phenotypes, using the 2021 IASP classification criteria, with a specific focus on nociplastic pain, which is probably the primary mechanism involved in post-COVID pain. Nociplastic pain, which is usually associated with comorbid symptomology (e.g., poor sleep quality, fatigue, cognitive-emotional disturbances, etc.) and is considered to be more difficult to treat than other pain types, may require a more nuanced multimodal treatment approach to achieve better treatment outcomes.
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25.
  • Gravina, Giacomo, et al. (författare)
  • Association of N-Acetyl Asparagine with QTc in Diabetes: A Metabolomics Study
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Changes in the cardio-metabolomics profile and hormonal status have been associated with long QT syndrome, sudden cardiac death and increased mortality. The mechanisms underlying QTc duration are not fully understood. Therefore, an identification of novel markers that complement the diagnosis in these patients is needed. In the present study, we performed untargeted metabolomics on the sera of diabetic patients at a high risk of cardiovascular disease, followed up for 2.55 [2.34-2.88] years (NCT02431234), with the aim of identifying the metabolomic changes associated with QTc. We used independent weighted gene correlation network analysis (WGCNA) to explore the association between metabolites clusters and QTc at T1 (baseline) and T2 (follow up). The overlap of the highly correlated modules at T1 and T2 identified N-Acetyl asparagine as the only metabolite in common, which was involved with the urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine. This analysis was confirmed by applying mixed models, further highlighting its association with QTc. In the current study, we were able to identify a metabolite associated with QTc in diabetic patients at two chronological time points, suggesting a previously unrecognized potential role of N-Acetyl asparagine in diabetic patients suffering from long QTc.
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26.
  • Gurke, Robert, et al. (författare)
  • Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:10
  • Forskningsöversikt (refereegranskat)abstract
    • The definitive diagnosis and early treatment of many immune-mediated inflammatory diseases (IMIDs) is hindered by variable and overlapping clinical manifestations. Psoriatic arthritis (PsA), which develops in similar to 30% of people with psoriasis, is a key example. This mixed-pattern IMID is apparent in entheseal and synovial musculoskeletal structures, but a definitive diagnosis often can only be made by clinical experts or when an extensive progressive disease state is apparent. As with other IMIDs, the detection of multimodal molecular biomarkers offers some hope for the early diagnosis of PsA and the initiation of effective management and treatment strategies. However, specific biomarkers are not yet available for PsA. The assessment of new markers by genomic and epigenomic profiling, or the analysis of blood and synovial fluid/tissue samples using proteomics, metabolomics and lipidomics, provides hope that complex molecular biomarker profiles could be developed to diagnose PsA. Importantly, the integration of these markers with high-throughput histology, imaging and standardized clinical assessment data provides an important opportunity to develop molecular profiles that could improve the diagnosis of PsA, predict its occurrence in cohorts of individuals with psoriasis, differentiate PsA from other IMIDs, and improve therapeutic responses. In this review, we consider the technologies that are currently deployed in the EU IMI2 project HIPPOCRATES to define biomarker profiles specific for PsA and discuss the advantages of combining multi-omics data to improve the outcome of PsA patients.
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27.
  • Hammarlund, Maria, et al. (författare)
  • The Alpha 7 Nicotinic Acetylcholine Receptor Does Not Affect Neonatal Brain Injury
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Inflammation plays a central role in the development of neonatal brain injury. The alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) can modulate inflammation and has shown promising results as a treatment target in rodent models of adult brain injury. However, little is known about the role of the alpha 7nAChR in neonatal brain injury. Hypoxic-ischemic (HI) brain injury was induced in male and female C57BL/6 mice, alpha 7nAChR knock-out (KO) mice and their littermate controls on postnatal day (PND) 9-10. C57BL/6 pups received i.p. injections of alpha 7nAChR agonist PHA 568487 (8 mg/kg) or saline once daily, with the first dose given directly after HI. Caspase-3 activity and cytokine mRNA expression in the brain was analyzed 24 h after HI. Motor function was assessed 24 and 48 h after HI, and immunohistochemistry was used to assess tissue loss at 24 h and 7 days after HI and microglial activation 7 days after HI. Activation of alpha 7nAChR with the agonist PHA 568487 significantly decreased CCL2/MCP-1, CCL5/RANTES and IL-6 gene expression in the injured brain hemisphere 24 h after HI compared with saline controls in male, but not female, pups. However, alpha 7nAChR activation did not alter caspase-3 activity and TNF alpha, IL-1 beta and CD68 mRNA expression. Furthermore, agonist treatment did not affect motor function (24 or 48 h), neuronal tissue loss (24 h or 7 days) or microglia activation (7 days) after HI in either sex. Knock-out of alpha 7nAChR did not influence neuronal tissue loss 7 days after HI. In conclusion, targeting the alpha 7nAChR in neonatal brain injury shows some effect on dampening acute inflammatory responses in male pups. However, this does not lead to an effect on overall injury outcome.
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28.
  • Hande, Liv Nesse, et al. (författare)
  • Effect of N-3 Polyunsaturated Fatty Acids on Lipid Composition in Familial Hypercholesterolemia : A Randomized Crossover Trial
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Individuals with familial hypercholesterolemia (FH) have an increased risk of cardiovascular disease. Treatment is mainly low-density lipoprotein cholesterol (LDL-C) reduction. How omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplements affect lipoproteins in FH subjects is unknown. We hypothesized that a high-dose n-3 PUFA supplement would reduce atherogenic lipoproteins and influence the high-density lipoprotein cholesterol (HDL-C) function. We performed a randomized, double-blinded crossover study with 34 genetically verified FH individuals (18-75 years, clinically stable, statin treatment > 12 months). Treatment was 4 g n-3 PUFAs (1840 mg eicosapentaenoic acid and 1520 mg docosahexaenoic acid daily) or four capsules of olive oil for three months in a crossover design with a washout period of three months. The defined outcomes were changes in triglycerides, lipoproteins, lipoprotein subfractions, apolipoproteins, and HDL-C function. After treatment with n-3 PUFAs, total cholesterol, LDL-C, and triglycerides were reduced compared to placebo (p <= 0.01 for all). Total HDL-C levels were unchanged, but the subfraction of large HDL-C was higher (p <= 0.0001) after n-3 PUFAs than after placebo, and intermediate HDL-C and small HDL-C were reduced after n-3 PUFAs compared to placebo (p = 0.02 and p <= 0.001, respectively). No changes were found in apolipoproteins and HDL-C function. N-3 PUFAs supplements reduced atherogenic lipoproteins in FH subjects, leaving HDL-C function unaffected.
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29.
  • Hultström, Michael, 1978-, et al. (författare)
  • Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation : A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections, but the molecular mechanisms involved are unclear. Increased plasma levels of the inflammatory cytokine and TIE2 receptor antagonist Angiopoietin-2 were reported in severely ill COVID-19 patients. In vitro experiments suggest that Angiopoietin-2 bind and inhibits thrombomodulin. Thrombomodulin is expressed on the luminal surface of endothelial cells where it is an important member of the intrinsic anticoagulant pathway through activation of protein C. Using clinical data, mouse models, and in vitro assays, we tested if Angiopoietin-2 plays a causal role in COVID-19-associated hypercoagulation through direct inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Angiopoietin-2 was measured in 61 patients at admission, and after 10 days in the 40 patients remaining in the ICU. We found that Angiopoietin-2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. In support of a direct effect of Angiopoietin-2 on coagulation, we found that injected Angiopoietin-2 in mice associated to thrombomodulin and resulted in a shortened tail bleeding time, decreased circulating levels of activated protein C, and increased plasma thrombin/antithrombin complexes. Conversely, bleeding time was increased in endothelial-specific Angiopoietin-2 knockout mice, while knockout of Tie2 had no effect on tail bleeding. Using in vitro assays, we found that Angiopoietin-2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data suggest a novel in vivo mechanism for Angiopoietin-2 in COVID-19-associated hypercoagulation, implicating that Angiopoietin-2 inhibitors may be effective in the treatment of hypercoagulation in severe COVID-19 infection.
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30.
  • Huwait, E, et al. (författare)
  • Potential and Therapeutic Roles of Diosmin in Human Diseases
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Because of their medicinal characteristics, effectiveness, and importance, plant-derived flavonoids have been a possible subject of research for many years, particularly in the last decade. Plants contain a huge number of flavonoids, and Diosmin, a flavone glycoside, is one of them. Numerous in-vitro and in-vivo studies have validated Diosmin’s extensive range of biological capabilities which present antioxidative, antihyperglycemic, anti-inflammatory, antimutagenic, and antiulcer properties. We have presented this review work because of the greater biological properties and influences of Diosmin. We have provided a brief overview of Diosmin, its pharmacology, major biological properties, such as anti-cancer, anti-diabetic, antibacterial, anticardiovascular, liver protection, and neuroprotection, therapeutic approach, potential Diosmin targets, and pathways that are known to be associated with it.
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31.
  • Högman, Marieann, et al. (författare)
  • Alveolar Nitric Oxide in Chronic Obstructive Pulmonary Disease-A Two-Year Follow-Up
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic obstructive pulmonary disease (COPD) affects the airways and gas exchange areas. Nitric oxide (NO) production from the airways is presented as FENO50 and from the gas exchange areas as alveolar NO (CANO). We aimed to evaluate, over two years, the consistency of the CANO estimations in subjects with COPD. A total of 110 subjects (45 men) who completed the study were included from primary and secondary care settings. CANO was estimated using the two-compartment model. CANO increased slightly during the two-year follow-up (p = 0.01), but FENO50 remained unchanged (p = 0.24). Among the subjects with a low CANO (<1 ppb) at inclusion, only 2% remained at a low level. For those at a high level (>2 ppb), 29% remained so. The modified Medical Research Council dyspnoea scale (mMRC) score increased at least one point in 29% of the subjects, and those subjects also increased in CANO from 0.9 (0.5, 2.1) ppb to 1.8 (1.1, 2.3) ppb, p = 0.015. We conclude that alveolar NO increased slightly over two years, together with a small decline in lung function. The increase in CANO was found especially in those whose levels of dyspnoea increased over time.
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32.
  • Kamstrup, P, et al. (författare)
  • Biomarkers of Clot Activation and Degradation and Risk of Future Major Cardiovascular Events in Acute Exacerbation of COPD: A Cohort Sub-Study in a Randomized Trial Population
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Cardiovascular diseases are common in patients with chronic obstructive pulmonary disease (COPD). Clot formation and resolution secondary to systemic inflammation may be a part of the explanation. The aim was to determine whether biomarkers of clot formation (products of von Willebrand Factor formation and activation) and clot resolution (product of fibrin degeneration) during COPD exacerbation predicted major cardiovascular events (MACE). The cohort was based on clinical data and biobank plasma samples from a trial including patients admitted with an acute exacerbation of COPD (CORTICO-COP). Neo-epitope biomarkers of formation and the activation of von Willebrand factor (VWF-N and V-WFA, respectively) and cross-linked fibrin degradation (X-FIB) were assessed using ELISAs in EDTA plasma at the time of acute admission, and analyzed for time-to-first MACE within 36 months, using multivariable Cox proportional hazards models. In total, 299/318 participants had samples available for analysis. The risk of MACE for patients in the upper quartile of each biomarker versus the lower quartile was: X-FIB: HR 0.98 (95% CI 0.65–1.48), VWF-N: HR 1.56 (95% CI 1.07–2.27), and VWF-A: HR 0.78 (95% CI 0.52–1.16). Thus, in COPD patients with an acute exacerbation, VWF-N was associated with future MACE and warrants further studies in a larger population.
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33.
  • Larsson, Anders, et al. (författare)
  • Differential Bias for Creatinine- and Cystatin C- Derived Estimated Glomerular Filtration Rate in Critical COVID-19.
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:11
  • Tidskriftsartikel (refereegranskat)abstract
    • COVID-19 is a systemic disease, frequently affecting kidney function. Dexamethasone is standard treatment in severe COVID-19 cases, and is considered to increase plasma levels of cystatin C. However, this has not been studied in COVID-19. Glomerular filtration rate (GFR) is a clinically important indicator of renal function, but often estimated using equations (eGFR) based on filtered metabolites. This study focuses on sources of bias for eGFRs (mL/min) using a creatinine-based equation (eGFRLMR) and a cystatin C-based equation (eGFRCAPA) in intensive-care-treated patients with COVID-19. This study was performed on 351 patients aged 18 years old or above with severe COVID-19 infections, admitted to the intensive care unit (ICU) in Uppsala University Hospital, a tertiary care hospital in Uppsala, Sweden, between 14 March 2020 and 10 March 2021. Dexamethasone treatment (6 mg for up to 10 days) was introduced 22 June 2020 (n = 232). Values are presented as medians (IQR). eGFRCAPA in dexamethasone-treated patients was 69 (37), and 74 (46) in patients not given dexamethasone (p = 0.01). eGFRLMR was not affected by dexamethasone. eGFRLMR in females was 94 (20), and 75 (38) in males (p = 0.00001). Age and maximal CRP correlated negatively to eGFRCAPA and eGFRLMR, whereas both eGFR equations correlated positively to BMI. In ICU patients with COVID-19, dexamethasone treatment was associated with reduced eGFRCAPA. This finding may be explained by corticosteroid-induced increases in plasma cystatin C. This observation is important from a clinical perspective since adequate interpretation of laboratory results is crucial.
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34.
  • Li, Mei, et al. (författare)
  • The Performance of FDA-Approved PET Imaging Agents in the Detection of Prostate Cancer
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:10
  • Forskningsöversikt (refereegranskat)abstract
    • Positron emission tomography (PET) incorporated with X-ray computed tomography (PET/CT) or magnetic resonance imaging (PET/MRI) is increasingly being used as a diagnostic tool for prostate cancer (PCa). In this review, we describe and evaluate the clinical performance of some Food and Drug Administration (FDA)-approved agents used for visualizing PCa: [F-18]FDG, [C-11]choline, [F-18]FACBC, [Ga-68]Ga-PSMA-11, [F-18]DCFPyL, and [F-18]-NaF. We carried out a comprehensive literature search based on articles published from 1 January 2010 to 1 March 2022. We selected English language articles associated with the discovery, preclinical study, clinical study, and diagnostic performance of the imaging agents for the evaluation. Prostate-specific membrane antigen (PSMA)-targeted imaging agents demonstrated superior diagnostic performance in both primary and recurrent PCa, compared with [C-11]choline and [F-18]FACBC, both of which target dividing cells and are used especially in patients with low prostate-specific antigen (PSA) values. When compared to [F-18]-NaF (which is suitable for the detection of bone metastases), PSMA-targeted agents were also capable of detecting lesions in the lymph nodes, soft tissues, and bone. However, a limitation of PSMA-targeted imaging was the heterogeneity of PSMA expression in PCa, and consequently, a combination of two PET tracers was proposed to overcome this obstacle. The preliminary studies indicated that the use of PSMA-targeted scanning is more cost efficient than conventional imaging modalities for high-risk PCa patients. Furthering the development of imaging agents that target PCa-associated receptors and molecules could improve PET-based diagnosis of PCa.
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35.
  • Liew, B. X. W., et al. (författare)
  • Distress and Sensitization as Main Mediators of Severity in Women with Fibromyalgia: A Structural Equation Model
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • We aimed to explore a path model identified using a structural equation model (SEM) which best explains the multivariate contributions of sensitization, sensitivity, and emotional variables to clinical severity in women with FMS. Pain features, the Central Sensitization Inventory (CSI), painDETECT, S-LANSS, the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), the Pain Catastrophizing Scale (PCS), the Pain Vigilance and Awareness Questionnaire (PVAQ), the 11-item Tampa Scale for Kinesiophobia (TSK-11), and pressure pain thresholds (PPTs) were collected from 113 women with FMS. Four latent variables were created: severity (clinical pain features), sensitivity (PPTs), sensitization (S-LANSS, CSI, painDETECT), and distress (HADS-A, HADS-D, PCS, PVAQ, TSK-11). Data fit for the measurement model were considered excellent (RMSEA = 0.043, CFI = 0.966, SRMR = 0.067, and NNFI = 0.960). Distress had a significant relationship with the mediators of sleep (beta = 0.452, p = 0.031) and sensitization (beta = 0.618, p = 0.001). The only mediator with a significant effect (beta = 1.113, p < 0.001) on severity was sensitization. A significant indirect effect of sensitization (beta = 0.687, p = 0.001) that explained the relationship between distress and severity was also identified. The proposed model suggests that distress and sensitization, together with poor sleep, have a complex mediating effect on severity in women with FMS. The identified path model can be leveraged in clinical trials investigating treatment approaches for FMS.
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36.
  • Lipcsey, Miklós, et al. (författare)
  • Urine Hydrogen Peroxide Levels and Their Relation to Outcome in Patients with Sepsis, Septic Shock, and Major Burn Injury
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Hydrogen peroxide (H2O2) and oxidative stress have been suggested as possible instigators of both the systemic inflammatory response and the increased vascular permeability associated with sepsis and septic shock. We measured H2O2 concentrations in the urine of 82 patients with severe infections, such as sepsis, septic shock, and infections not fulfilling sepsis-3 criteria, in patients with major burn injury with associated systemic inflammation, and healthy subjects. The mean concentrations of H2O2 were found to be lower in patients with severe infections compared to burn injury patients and healthy subjects. Patients with acute kidney injury (AKI), vs. those without AKI, in all diagnostic groups displayed higher concentrations of urine H2O2 (p < 0.001). Likewise, urine concentrations of H2O2 were higher in non-survivors as compared to survivors (p < 0.001) at day 28 in all diagnostic groups, as well as in patients with severe infections and burn injury (p < 0.001 for both). In this cohort, increased H2O2 in urine is thus associated with mortality in patients with sepsis and septic shock as well as in patients with burn injury.
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37.
  • Liu, YX, et al. (författare)
  • Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5–10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of loss-of-function variants in more than twenty predisposing genes have been found, the majority of familial cases of HBC remain unexplained. The aim of this study was to identify new predisposing genes for HBC in three non-BRCA families with autosomal dominant inheritance pattern using whole-exome sequencing and functional prediction tools. No pathogenic variants in known hereditary cancer-related genes could explain the breast cancer susceptibility in these families. Among 2122 exonic variants with maximum minor allele frequency (MMAF) < 0.1%, between 17–35 variants with combined annotation-dependent depletion (CADD) > 20 segregated with disease in the three analyzed families. Selected candidate genes, i.e., UBASH3A, MYH13, UTP11L, and PAX7, were further evaluated using protein expression analysis but no alterations of cancer-related pathways were observed. In conclusion, identification of new high-risk cancer genes using whole-exome sequencing has been more challenging than initially anticipated, in spite of selected families with pronounced family history of breast cancer. A combination of low- and intermediate-genetic-risk variants may instead contribute the breast cancer susceptibility in these families.
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38.
  • Makam, A. A., et al. (författare)
  • Setting the Stage for Insulin Granule Dysfunction during Type-l-Diabetes: Is ER Stress the Culprit?
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:11
  • Forskningsöversikt (refereegranskat)abstract
    • Type-1-diabetes (T1D) is a multifactorial disorder with a global incidence of about 8.4 million individuals in 2021. It is primarily classified as an autoimmune disorder, where the pancreatic beta-cells are unable to secrete sufficient insulin. This leads to elevated blood glucose levels (hyperglycemia). The development of T1D is an intricate interplay between various risk factors, such as genetic, environmental, and cellular elements. In this review, we focus on the cellular elements, such as ER (endoplasmic reticulum) stress and its consequences for T1D pathogenesis. One of the major repercussions of ER stress is defective protein processing. A well-studied example is that of islet amyloid polypeptide (IAPP), which is known to form cytotoxic amyloid plaques when misfolded. This review discusses the possible association between ER stress, IAPP, and amyloid formation in beta-cells and its consequences in T1D. Additionally, ER stress also leads to autoantigen generation. This is driven by the loss of Ca++ ion homeostasis. Imbalanced Ca++ levels lead to abnormal activation of enzymes, causing post-translational modification of beta-cell proteins. These modified proteins act as autoantigens and trigger the autoimmune response seen in T1D islets. Several of these autoantigens are also crucial for insulin granule biogenesis, processing, and release. Here, we explore the possible associations between ER stress leading to defects in insulin secretion and ultimately beta-cell destruction.
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39.
  • Mirchandani-Duque, M, et al. (författare)
  • Galanin and Neuropeptide Y Interaction Enhances Proliferation of Granule Precursor Cells and Expression of Neuroprotective Factors in the Rat Hippocampus with Consequent Augmented Spatial Memory
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Dysregulation of hippocampal neurogenesis is linked to several neurodegenereative diseases, where boosting hippocampal neurogenesis in these patients emerges as a potential therapeutic approach. Accumulating evidence for a neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-, cellular-, and behavioral-specific levels. The purpose of the current work was to evaluate the role of the NPY and GAL interaction in the neurogenic actions on the dorsal hippocampus. We studied the Y1R agonist and GAL effects on: hippocampal cell proliferation through the proliferating cell nuclear antigen (PCNA), the expression of neuroprotective and anti-apoptotic factors, and the survival of neurons and neurite outgrowth on hippocampal neuronal cells. The functional outcome was evaluated in the object-in-place task. We demonstrated that the Y1R agonist and GAL promote cell proliferation and the induction of neuroprotective factors. These effects were mediated by the interaction of NPYY1 (Y1R) and GAL2 (GALR2) receptors, which mediate the increased survival and neurites’ outgrowth observed on neuronal hippocampal cells. These cellular effects are linked to the improved spatial-memory effects after the Y1R agonist and GAL co-injection at 24 h in the object-in-place task. Our results suggest the development of heterobivalent agonist pharmacophores, targeting Y1R–GALR2 heterocomplexes, therefore acting on the neuronal precursor cells of the DG in the dorsal hippocampus for the novel therapy of neurodegenerative cognitive-affecting diseases.
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40.
  • Nagy, D, et al. (författare)
  • Cardiac Amyloidosis with Normal Wall Thickness: Prevalence, Clinical Characteristics and Outcome in a Retrospective Analysis
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Cardiac amyloidosis (CA) is a rare, progressive, infiltrative cardiac disease. Light chain (AL) and transthyretin (ATTR) amyloidosis are in the background in almost all cases. New, easily available diagnostic tools and recently introduced novel therapies for both types of CA put this disease into the field of interest. Increased left ventricular wall thickness (IWT) detected by echocardiography is generally thought to be a necessary part of the diagnosis. We aimed to determine the proportion of CA patients without IWT, and to define the clinical characteristics of this cohort. Methods: In an academic tertiary center for CA, we identified patients diagnosed and treated for CA between January 2009 and February 2022. In a retrospective analysis we defined the proportion of patients with (≥12 mm) and without (<12 mm) IWT, and described their clinical features. Results: We identified 98 patients suitable for the analysis. In total, 70 had AL and 27 ATTR CA; 89 patients had CA with IWT and 9 patients (9%) had CA without IWT. All non-IWT patients had AL type CA. Both group of patients had clinically significant disease, which is supported by the relevant elevation in cardiac biomarker levels. There was no difference between the outcome of the two groups. Conclusion: Patients without IWT form a relevant subgroup among those with CA. Our results suggest that diagnostic algorithms and criteria should take these individuals into consideration, and, therefore, give them access to effective treatments.
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41.
  • Oliver, J, et al. (författare)
  • Association of Circular RNA and Long Non-Coding RNA Dysregulation with the Clinical Response to Immune Checkpoint Blockade in Cutaneous Metastatic Melanoma
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Cutaneous melanoma (CM) is the most lethal form of skin cancer if it becomes metastatic, where treatment options and survival chances decrease dramatically. Immunotherapy treatments based on the immunologic checkpoint inhibitors programmed death cell protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) constituted a main breakthrough in the treatment of metastatic CM, particularly for the achievement of long-term benefits. Even though it is a very promising therapy, resistance to primary immune checkpoint blockade (ICB) arises in about 70% of CM patients treated with a CTLA-4 inhibitor, and 40–65% of CM patients administered with a PD-1-targeting treatment. Some long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are implicated in triggering pro- and anti-tumorigenic responses to various cancer treatments. The relationship between lncRNAs, circRNAs and ICB immunotherapy has not been explored in cutaneous metastatic melanoma (CMM). The aim of this pilot study is to evaluate the potential role of circRNA and lncRNA expression variability as pre-treatment predictor of the clinical response to immunotherapy in CMM patients. RNA-seq from 12 formalin-fixed paraffin-embedded (FFPE) samples from the metastatic biopsies of CMM patients treated with nivolumab was used to identify response-associated transcripts. Our findings indicate that specific lncRNAs and circRNAs, probably acting as competitive endogenous RNAs (ceRNAs), are involved in the regulatory networks of the immune response against metastatic melanoma that these patients have under treatment with nivolumab. Moreover, we established a risk score that yields predictions of the overall survival (OS) and progression-free survival (PFS) of CMM patients with high accuracy. This proof-of-principle work provides a possible insight into the function of ceRNAs, contributing to efforts to decipher the complex molecular mechanisms of ICB cancer treatment response.
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42.
  • Pacini, Giovanni, et al. (författare)
  • Assessing the Effect of Incretin Hormones and Other Insulin Secretagogues on Pancreatic Beta-Cell Function : Review on Mathematical Modelling Approaches
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:5
  • Forskningsöversikt (refereegranskat)abstract
    • Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy. Among those model-based physiological parameters, an important role resides in those for the assessment of different functional aspects of the pancreatic beta cell. This study focuses on the mathematical models of incretin hormones and other endogenous substances with known effects on insulin secretion and beta-cell function, mainly amino acids, non-esterified fatty acids, and glucagon. We found that there is a relatively large number of mathematical models for the effects on the beta cells of incretin hormones, both at the cellular/organ level or at the higher, whole-body level. In contrast, very few models were identified for the assessment of the effect of other insulin secretagogues. Given the opportunities offered by mathematical modelling, we believe that novel models in the investigated field are certainly advisable.
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43.
  • Panezai, Jeneen, et al. (författare)
  • Periodontal Disease Augments Cardiovascular Disease Risk Biomarkers in Rheumatoid Arthritis
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:3
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Periodontal disease (PD) and rheumatoid arthritis (RA) are known chronic conditions with sustained inflammation leading to osteolysis. Cardiovascular diseases (CVD) are frequent comorbidities that may arise from sustained inflammation associated with both PD and RA. In order to determine CVD risk, alterations at the molecular level need to be identified. The objective of this study, therefore, was to assess the relationship of CVD associated biomarkers in RA patients and how it is influenced by PD.METHODS: The study consisted of patient (26 RA with PD, 21 RA without PD, 51 patients with PD only) and systemically and periodontally healthy control (n = 20) groups. Periodontal parameters bleeding on probing, probing pocket depth, and marginal bone loss were determined to characterize the patient groups. Proteomic analysis of 92 CVD-related protein biomarkers was performed using a multiplex proximity extension assay. Biomarkers were clustered using the search tool for retrieval of interacting genes (STRING) to determine protein-protein interaction (PPI) networks.RESULTS: RA patients with PD had higher detection levels for 47% of the measured markers (ANGPT1, BOC, CCL17, CCL3, CD4, CD84, CTRC, FGF-21, FGF-23, GLO1, HAOX1, HB-EGF, hOSCAR, HSP 27, IL16, IL-17D, IL18, IL-27, IL6, LEP, LPL, MERTK, MMP12, MMP7, NEMO, PAPPA, PAR-1, PARP-1, PD-L2, PGF, PIgR, PRELP, RAGE, SCF, SLAMF7, SRC, THBS2, THPO, TNFRSF13B, TRAIL-R2, VEGFD, VSIG2, and XCL1) as compared to RA without PD. Furthermore, a strong biological network was identified amongst these proteins (clustering coefficient = 0.52, PPI enrichment p-value < 0.0001). Coefficients for protein clusters involved in CVD (0.59), metabolic (0.53), and skeletal (0.51) diseases were strongest in the PD group.CONCLUSION: Periodontal disease augments CVD-related biomarkers in RA through shared pathological clusters, concurrently enhancing metabolic and skeletal disease protein interactions, independent of autoimmune status.
  •  
44.
  • Puthia, Manoj, et al. (författare)
  • Antibacterial and Anti-Inflammatory Effects of Apolipoprotein E
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:6, s. 1430-1430
  • Tidskriftsartikel (refereegranskat)abstract
    • Apolipoprotein E (APOE) is a lipid-transport protein that functions as a key mediator of lipid transport and cholesterol metabolism. Recent studies have shown that peptides derived from human APOE display anti-inflammatory and antimicrobial effects. Here, we applied in vitro assays and fluorescent microscopy to investigate the anti-bacterial effects of full-length APOE. The interaction of APOE with endotoxins from Escherichia coli was explored using surface plasmon resonance, binding assays, transmission electron microscopy and all-atom molecular dynamics (MD) simulations. We also studied the immunomodulatory activity of APOE using in vitro cell assays and an in vivo mouse model in combination with advanced imaging techniques. We observed that APOE exhibits anti-bacterial activity against several Gram-negative bacterial strains of Pseudomonas aeruginosa and Escherichia coli. In addition, we showed that APOE exhibits a significant binding affinity for lipopolysaccharide (LPS) and lipid A as well as heparin. MD simulations identified the low-density lipoprotein receptor (LDLR) binding region in helix 4 of APOE as a primary binding site for these molecules via electrostatic interactions. Together, our data suggest that APOE may have an important role in controlling inflammation during Gram-negative bacterial infection.
  •  
45.
  • Rinne, Sara S., et al. (författare)
  • Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Increasing evidence suggests that therapy targeting the human epidermal growth factor receptor 3 (HER3) could be a viable route for targeted cancer therapy. Here, we studied a novel drug conjugate, ZHER3-ABD-mcDM1, consisting of a HER3-targeting affibody molecule, coupled to the cytotoxic tubulin polymerization inhibitor DM1, and an albumin-binding domain for in vivo half-life extension. ZHER3-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (K-D 6 nM), and an even stronger affinity (KD 0.2 nM) to the HER3-overexpressing pancreatic carcinoma cell line, BxPC-3. The drug conjugate showed a potent cytotoxic effect on BxPC-3 cells with an IC50 value of 7 nM. Evaluation of a radiolabeled version, [99mTc]Tc-ZHER3-ABD-mcDM1, showed a relatively high rate of internalization, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could target BxPC-3 (pancreatic carcinoma) and DU145 (prostate carcinoma) xenografts in mice, with an uptake peaking at 6.3 +/- 0.4% IA/g at 6 h post-injection for the BxPC-3 xenografts. The general biodistribution showed uptake in the liver, lung, salivary gland, stomach, and small intestine, organs known to express murine ErbB3 naturally. The results from the study show that ZHER3-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3 overexpressing cells. Further pre-clinical and clinical development is discussed.
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46.
  • Schroeder, SK, et al. (författare)
  • Immunohistochemical Detection of Estrogen Receptor-Beta (ERβ) with PPZ0506 Antibody in Murine Tissue: From Pitfalls to Optimization
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:12
  • Tidskriftsartikel (refereegranskat)abstract
    • The estrogen receptor beta (ERβ) is physiologically essential for reproductive biology and is implicated in various diseases. However, despite more than 20 years of intensive research on ERβ, there are still uncertainties about its distribution in tissues and cellular expression. Several studies show contrasts between mRNA and protein levels, and the use of knockout strategies revealed that many commercially available antibodies gave false-positive expression results. Recently, a specific monoclonal antibody against human ERβ (PPZ0506) showed cross-reactivity with rodents and was optimized for the detection of rat ERβ. Herein, we established an immunohistochemical detection protocol for ERβ protein in mouse tissue. Staining was optimized on murine ovaries, as granulosa cells are known to strongly express ERβ. The staining results were confirmed by western blot analysis and RT-PCR. To obtain accurate and reliable staining results, different staining conditions were tested in paraffin-embedded tissues. Different pitfalls were encountered in immunohistochemical detection. Strong heat-induced epitope retrieval (HIER) and appropriate antibody dilution were required to visualize specific nuclear expression of ERβ. Finally, the specificity of the antibody was confirmed by using ovaries from Esr2-depleted mice. However, in some animals, strong (non-specific) background staining appeared. These signals could not be significantly alleviated with commercially available additional blocking solutions and are most likely due to estrus-dependent expression of endogenous immunoglobulins. In summary, our study showed that the antibody PPZ0506, originally directed against human ERβ, is also suitable for reliable detection of murine ERβ. An established staining protocol mitigated ambiguities regarding the expression and distribution of ERβ in different tissues and will contribute to an improved understanding of its role and functions in murine tissues in the future.
  •  
47.
  • Song, XY, et al. (författare)
  • Liver X Receptor Regulation of Glial Cell Functions in the CNS
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:9
  • Tidskriftsartikel (refereegranskat)abstract
    • In this review, we discuss the role of liver X receptors (LXRs) in glial cells (microglia, oligodendrocytes and astrocytes) in the central nervous system (CNS). LXRs are oxysterol-activated nuclear receptors that, in adults, regulate genes involved in cholesterol homeostasis, the modulation of inflammatory responses and glutamate homeostasis. The study of LXR knockout mice has revealed that LXRβ plays a key role in maintaining the health of dopaminergic neurons in the substantia nigra, large motor neurons in the spinal cord and retinal ganglion cells in the eye. In the peripheral nervous system (PNS), LXRβ is responsible for the health of the spiral ganglion neurons (SGNs) in the cochlea. In addition, LXRs are essential for the homeostasis of the cerebrospinal fluid (CSF), and in LXRαβ−/− mice, the lateral ventricles are empty and lined with lipid-laden cells. As LXRαβ−/− mice age, lipid vacuoles accumulate in astrocytes surrounding blood vessels. By seven months of age, motor coordination becomes impaired, and there is a loss of motor neurons in the spinal cord of LXRβ−/− mice. During development, migration of neurons in the cortex and cerebellum is retarded in LXRβ−/− mice. Since LXRs are not expressed in dopaminergic or motor neurons in adult mice, the neuroprotective effects of LXRs appear to come from LXRs in glial cells where they are expressed. However, despite the numerous neurological deficits in LXR−/− rodents, multiple sclerosis has the clear distinction of being the only human neurodegenerative disease in which defective LXR signaling has been identified. In this review, we summarize the regulation and functions of LXRs in glial cells and analyze how targeting LXRs in glial cells might, in the future, be used to treat neurodegenerative diseases and, perhaps, disorders caused by aberrant neuronal migration during development.
  •  
48.
  • Spratt, AN, et al. (författare)
  • Continued Complexity of Mutations in Omicron Sublineages
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:10
  • Tidskriftsartikel (refereegranskat)abstract
    • The latest SARS-CoV-2 variant of concern (VOC), Omicron (B.1.1.529), has diversified into more than 300 sublineages. With an expanding number of newly emerging sublineages, the mutation profile is also becoming complicated. There exist mutually exclusive and revertant mutations in different sublineages. Omicron sublineages share some common mutations with previous VOCs (Alpha, Beta, Gamma, and Delta), indicating an evolutionary relationship between these VOCs. A diverse mutation profile at the spike–antibody interface, flexibility of the regions harboring mutations, mutation types, and coexisting mutations suggest that SARS-CoV-2’s evolution is far from over.
  •  
49.
  • Stenman, Göran, 1953, et al. (författare)
  • Chromosome Translocations, Gene Fusions, and Their Molecular Consequences in Pleomorphic Salivary Gland Adenomas
  • 2022
  • Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Salivary gland tumors are a heterogeneous group of tumors originating from the major and minor salivary glands. The pleomorphic adenoma (PA), which is the most common subtype, is a benign lesion showing a remarkable morphologic diversity and that, upon recurrence or malignant transformation, can cause significant clinical problems. Cytogenetic studies of >500 PAs have revealed a complex and recurrent pattern of chromosome rearrangements. In this review, we discuss the specificity and frequency of these rearrangements and their molecular/clinical consequences. The genomic hallmark of PA is translocations with breakpoints in 8q12 and 12q13-15 resulting in gene fusions involving the transcription factor genes PLAG1 and HMGA2. Until recently, the association between these two oncogenic drivers was obscure. Studies of the Silver-Russel syndrome, a growth retardation condition infrequently caused by mutations in IGF2/HMGA2/PLAG1, have provided new clues to the understanding of the molecular pathogenesis of PA. These studies have demonstrated that HMGA2 is an upstream regulator of PLAG1 and that HMGA2 regulates the expression of IGF2 via PLAG1. This provides a novel explanation for the 8q12/12q13-15 aberrations in PA and identifies IGF2 as a major oncogenic driver and therapeutic target in PA. These studies have important diagnostic and therapeutic implications for patients with PA.
  •  
50.
  • Sun, Chengxi, et al. (författare)
  • Generation of Endogenous Promoter-Driven Luciferase Reporter System Using CRISPR/Cas9 for Investigating Transcriptional Regulation of the Core Clock Gene BMAL1
  • 2022
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 10:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Humans and other organisms are continuously exposed to thousands of chemicals through the atmosphere, drinking water, food, or direct contact. A large proportion of such chemicals are present in very low concentrations and may have synergistic effects, even at their no-observed-adverse-effect level (NOAEL). Complex mixtures of contaminants are very difficult to assess by traditional toxicological methods. There is increasing attention on how different pollutants induce adverse physiological functions in the human body through effects on the circadian rhythm. However, it is very difficult to screen for compounds with circadian-rhythm-disrupting effects from a large number of chemicals or their complex mixtures. We established a stable firefly luciferase reporter gene knock-in U2-OS cell line by CRISPR/Cas9 to screen circadian-rhythm-disrupting pollutants. The luciferase gene was inserted downstream of the core clock gene BMAL1 and controlled by an endogenous promoter. Compared to detection systems using exogenous promoters, these cells enable the detection of compounds that interfere with the circadian rhythm system mediated by BMAL1 gene expression. The U2-OS knock-in cells showed BMAL1 and luciferase activity had parallel changes when treated with BMAL1 inhibitor and activator. Furthermore, the luciferase reporter gene has high sensitivity and is faster and more cost-effective than classic toxicology methods. The knock-in cell line can be used for high-throughput and efficient screening of circadian-rhythm-disrupting chemicals such as drugs and pollutants.
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