Biomedicines

27 pages, 34030 KiB

Open AccessReview

Pharmacological Properties of Polyphenols: Bioavailability, Mechanisms of Action, and Biological Effects in In Vitro Studies, Animal Models, and Humans

by Kristine Stromsnes, Rudite Lagzdina, Gloria Olaso-Gonzalez, Lucia Gimeno-Mallench and Juan Gambini

Biomedicines 2021, 9(8), 1074; https://doi.org/10.3390/biomedicines9081074 - 23 Aug 2021

Cited by 31 | Viewed by 3853

Abstract

Drugs are bioactive compounds originally discovered from chemical structures present in both the plant and animal kingdoms. These have the ability to interact with molecules found in our body, blocking them, activating them, or increasing or decreasing their levels. Their actions have allowed [...] Read more.

Drugs are bioactive compounds originally discovered from chemical structures present in both the plant and animal kingdoms. These have the ability to interact with molecules found in our body, blocking them, activating them, or increasing or decreasing their levels. Their actions have allowed us to cure diseases and improve our state of health, which has led us to increase the longevity of our species. Among the molecules with pharmacological activity produced by plants are the polyphenols. These, due to their molecular structure, as drugs, also have the ability to interact with molecules in our body, presenting various pharmacological properties. In addition, these compounds are found in multiple foods in our diet. In this review, we focused on discussing the bioavailability of these compounds when we ingested them through diet and the specific mechanisms of action of polyphenols, focusing on studies carried out in vitro, in animals and in humans over the last five years. Knowing which foods have these pharmacological activities could allow us to prevent and aid as concomitant treatment against various pathologies. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation: From Mechanisms to Therapeutic Approaches 2.0)

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Graphical abstract

16 pages, 1249 KiB

Open AccessArticle

Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach

by Alessandro Di Minno, Roberta Clara Orsini, Mattia Chiesa, Viviana Cavalca, Ilenia Calcaterra, Maria Tripaldella, Andrea Anesi, Susanna Fiorelli, Sonia Eligini, Gualtiero I. Colombo, Elena Tremoli, Benedetta Porro and Matteo Nicola Dario Di Minno

Biomedicines 2021, 9(8), 1073; https://doi.org/10.3390/biomedicines9081073 - 23 Aug 2021

Cited by 8 | Viewed by 2525

Abstract

Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 [...] Read more.

Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. Methods: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. Results: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, p < 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (p-value = 0.041), indole (p-value = 0.045), and indoleacrylic acid (p-value= 0.045) concentrations. Conversely, significant decreases in choline (p-value = 0.045) and phosphatidylcholine (p-value < 0.01) together with a reduction in platelet activating factor (p-value = 0.041) were observed. Conclusions: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i. Full article

(This article belongs to the Special Issue Advanced and Innovative Therapies of Dyslipidemia)

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34 pages, 10203 KiB

Open AccessArticle

Optimized Manufacture of Lyophilized Dermal Fibroblasts for Next-Generation Off-the-Shelf Progenitor Biological Bandages in Topical Post-Burn Regenerative Medicine

by Alexis Laurent, Corinne Scaletta, Philippe Abdel-Sayed, Murielle Michetti, Marjorie Flahaut, Jeanne-Pascale Simon, Anthony de Buys Roessingh, Wassim Raffoul, Nathalie Hirt-Burri and Lee Ann Applegate

Biomedicines 2021, 9(8), 1072; https://doi.org/10.3390/biomedicines9081072 - 23 Aug 2021

Cited by 9 | Viewed by 2603

Abstract

Cultured fibroblast progenitor cells (FPC) have been studied in Swiss translational regenerative medicine for over two decades, wherein clinical experience was gathered for safely managing burns and refractory cutaneous ulcers. Inherent FPC advantages include high robustness, optimal adaptability to industrial manufacture, and potential [...] Read more.

Cultured fibroblast progenitor cells (FPC) have been studied in Swiss translational regenerative medicine for over two decades, wherein clinical experience was gathered for safely managing burns and refractory cutaneous ulcers. Inherent FPC advantages include high robustness, optimal adaptability to industrial manufacture, and potential for effective repair stimulation of wounded tissues. Major technical bottlenecks in cell therapy development comprise sustainability, stability, and logistics of biological material sources. Herein, we report stringently optimized and up-scaled processing (i.e., cell biobanking and stabilization by lyophilization) of dermal FPCs, with the objective of addressing potential cell source sustainability and stability issues with regard to active substance manufacturing in cutaneous regenerative medicine. Firstly, multi-tiered FPC banking was optimized in terms of overall quality and efficiency by benchmarking key reagents (e.g., medium supplement source, dissociation reagent), consumables (e.g., culture vessels), and technical specifications. Therein, fetal bovine serum batch identity and culture vessel surface were confirmed, among other parameters, to largely impact harvest cell yields. Secondly, FPC stabilization by lyophilization was undertaken and shown to maintain critical functions for devitalized cells in vitro, potentially enabling high logistical gains. Overall, this study provides the technical basis for the elaboration of next-generation off-the-shelf topical regenerative medicine therapeutic products for wound healing and post-burn care. Full article

(This article belongs to the Special Issue New Insights in Gene and Cell Therapy)

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14 pages, 5625 KiB

Open AccessArticle

Diffusion Weighted Imaging and T2 Mapping Detect Inflammatory Response in the Renal Tissue during Ischemia Induced Acute Kidney Injury in Different Mouse Strains and Predict Renal Outcome

by Robert Greite, Katja Derlin, Dagmar Hartung, Rongjun Chen, Martin Meier, Marcel Gutberlet, Bennet Hensen, Frank Wacker, Faikah Gueler and Susanne Hellms

Biomedicines 2021, 9(8), 1071; https://doi.org/10.3390/biomedicines9081071 - 23 Aug 2021

Cited by 5 | Viewed by 2250

Abstract

To characterize ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI) in C57BL/6 (B6) and CD1-mice by longitudinal functional MRI-measurement of edema formation (T2-mapping) and inflammation (diffusion weighted imaging (DWI)). IRI was induced with unilateral right renal pedicle clamping for 35min. 7T-MRI was performed [...] Read more.

To characterize ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI) in C57BL/6 (B6) and CD1-mice by longitudinal functional MRI-measurement of edema formation (T2-mapping) and inflammation (diffusion weighted imaging (DWI)). IRI was induced with unilateral right renal pedicle clamping for 35min. 7T-MRI was performed 1 and 14 days after surgery. DWI (7 b-values) and multiecho TSE sequences (7 TE) were acquired. Parameters were quantified in relation to the contralateral kidney on day 1 (d1). Renal MCP-1 and IL-6-levels were measured by qPCR and serum-CXCL13 by ELISA. Immunohistochemistry for fibronectin and collagen-4 was performed. T2-increase on d1 was higher in the renal cortex (127 ± 5% vs. 94 ± 6%, p < 0.01) and the outer stripe of the outer medulla (141 ± 9% vs. 111 ± 9%, p < 0.05) in CD1, indicating tissue edema. Medullary diffusivity was more restricted in CD1 than B6 (d1: 73 ± 3% vs. 90 ± 2%, p < 0.01 and d14: 77 ± 5% vs. 98 ± 3%, p < 0.01). Renal MCP-1 and IL-6-expression as well as systemic CXCL13-release were pronounced in CD1 on d1 after IRI. Renal fibrosis was detected in CD1 on d14. T2-increase and ADC-reduction on d1 correlated with kidney volume loss on d14 (r = 0.7, p < 0.05; r = 0.6, p < 0.05) and could serve as predictive markers. T2-mapping and DWI evidenced higher susceptibility to ischemic AKI in CD1 compared to B6. Full article

(This article belongs to the Special Issue Advanced Research in Molecular Imaging of Immunity and Inflammation)

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11 pages, 1564 KiB

Open AccessArticle

The Combined Effect of Branching and Elongation on the Bioactivity Profile of Phytocannabinoids. Part I: Thermo-TRPs

by Daiana Mattoteia, Aniello Schiano Moriello, Orazio Taglialatela-Scafati, Pietro Amodeo, Luciano De Petrocellis, Giovanni Appendino, Rosa Maria Vitale and Diego Caprioglio

Biomedicines 2021, 9(8), 1070; https://doi.org/10.3390/biomedicines9081070 - 23 Aug 2021

Cited by 4 | Viewed by 2039

Abstract

The affinity of cannabinoids for their CB₁ and CB₂ metabotropic receptors is dramatically affected by a combination of α-branching and elongation of their alkyl substituent, a maneuver exemplified by the n-pentyl -> α,α-dimethylheptyl (DMH) swap. The effect of this change [...] Read more.

The affinity of cannabinoids for their CB₁ and CB₂ metabotropic receptors is dramatically affected by a combination of α-branching and elongation of their alkyl substituent, a maneuver exemplified by the n-pentyl -> α,α-dimethylheptyl (DMH) swap. The effect of this change on other cannabinoid end-points is still unknown, an observation surprising since thermo-TRPs are targeted by phytocannabinoids with often sub-micromolar affinity. To fill this gap, the α,α-dimethylheptyl analogues of the five major phytocannabinoids [CBD (1a), Δ⁸-THC (6a), CBG (7a), CBC (8a) and CBN (9a)] were prepared by total synthesis, and their activity on thermo-TRPs (TRPV1-4, TRPM8, and TRPA1) was compared with that of one of their natural analogues. Surprisingly, the DMH chain promoted a shift in the selectivity toward TRPA1, a target involved in pain and inflammatory diseases, in all investigated compounds. A comparative study of the putative binding modes at TRPA1 between DMH-CBC (8b), the most active compound within the series, and CBC (8a) was carried out by molecular docking, allowing the rationalization of their activity in terms of structure–activity relationships. Taken together, these observations qualify DMH-CBC (8b) as a non-covalent TRPA1-selective cannabinoid lead that is worthy of additional investigation as an analgesic and anti-inflammatory agent. Full article

(This article belongs to the Special Issue Therapeutic Potential of Plant Secondary Metabolites in the Treatment of Diseases and Drug Development)

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22 pages, 4871 KiB

Open AccessArticle

AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats

by Ji-Eun Kim, Duk-Shin Lee, Hana Park, Tae-Hyun Kim and Tae-Cheon Kang

Biomedicines 2021, 9(8), 1069; https://doi.org/10.3390/biomedicines9081069 - 23 Aug 2021

Cited by 5 | Viewed by 2415

Abstract

The neural precursor cell expressed by developmentally downregulated gene 4-2 (NEDD4-2) is a ubiquitin E3 ligase that has a high affinity toward binding and ubiquitinating glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type subunit 1 (GRIA1, also referred to GluR1 or GluA1). Since dysregulation [...] Read more.

The neural precursor cell expressed by developmentally downregulated gene 4-2 (NEDD4-2) is a ubiquitin E3 ligase that has a high affinity toward binding and ubiquitinating glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type subunit 1 (GRIA1, also referred to GluR1 or GluA1). Since dysregulation of GRIA1 surface expression is relevant to the responsiveness to AMPA receptor (AMPAR) antagonists (perampanel and GYKI 52466) in chronic epilepsy rats, it is likely that NEDD4-2 may be involved in the pathogenesis of intractable epilepsy. However, the role of NEDD4-2-mediated GRIA1 ubiquitination in refractory seizures to AMPAR antagonists is still unknown. In the present study, both AMPAR antagonists recovered the impaired GRIA1 ubiquitination by regulating protein phosphatase 2B (PP2B)-extracellular signal-regulated kinase 1/2 (ERK1/2)-serum and glucocorticoid-regulated kinase 1 (SGK1)-NEDD4-2 signaling pathway in responders (whose seizure activities are responsive to AMPAR), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). In addition, cyclosporin A (CsA, a PP2B inhibitor) co-treatment improved the effects of AMPAR antagonists in non-responders, independent of AKT signaling pathway. Therefore, our findings suggest that dysregulation of PP2B-ERK1/2-SGK1-NEDD4-2-mediated GRIA1 ubiquitination may be responsible for refractory seizures and that this pathway may be a potential therapeutic target for improving the treatment of intractable epilepsy in response to AMPAR antagonists. Full article

(This article belongs to the Special Issue Pathogenesis and Targeted Therapy of Epilepsy)

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Graphical abstract

12 pages, 3087 KiB

Open AccessReview

Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease

by Shinya Ashizuka, Toshihiro Kita, Haruhiko Inatsu and Kazuo Kitamura

Biomedicines 2021, 9(8), 1068; https://doi.org/10.3390/biomedicines9081068 - 23 Aug 2021

Cited by 13 | Viewed by 2652

Abstract

Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the [...] Read more.

Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn’s disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment. Full article

(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases 2.0)

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12 pages, 1029 KiB

Open AccessSystematic Review

Sharing the Same Perspective. Mental Disorders and Central Serous Chorioretinopathy: A Systematic Review of Evidence from 2010 to 2020

by Gianluca Pandolfo, Giovanni Genovese, Antonio Bruno, Diletta Palumbo, Umberto Poli, Sebastiano Gangemi, Pasquale Aragona and Alessandro Meduri

Biomedicines 2021, 9(8), 1067; https://doi.org/10.3390/biomedicines9081067 - 23 Aug 2021

Cited by 6 | Viewed by 1930

Abstract

Background: The relevance of the association between mental disorders and other conditions might have been underestimated due to its complexity. Central Serous Chorioretinopathy (CSC) is an ophthalmological disorder associated with many psychiatric factors. The aim of this systematic review is to evaluate the [...] Read more.

Background: The relevance of the association between mental disorders and other conditions might have been underestimated due to its complexity. Central Serous Chorioretinopathy (CSC) is an ophthalmological disorder associated with many psychiatric factors. The aim of this systematic review is to evaluate the association between mental disorders and CSC. Methods: Articles about studies performed on humans on CSC published in peer-reviewed journals from 1 January 2010 to 31 December 2020 were included in the review. Results: We selected 21 research papers. Nine studies measured stress and anxious depressive symptoms, which are associated with CSC onset and recurrences, emerging as a state marker of the disease. Four out of the five studies focused on sleep disorders suggested a reliable association with CSC. Four studies evaluated other various psychiatric factors. The role of psychopharmacological medication has still not been elucidated (three studies). Conclusion: Multiple pieces of evidence highlights that CSC might arise in the context of systemic disease. This notion, together with the increasing evidence supporting a link between psychiatric disorders and choroidal thickness, suggests that CSC and mental disorders may share some etiopathogenetic pathways. Further research is needed to better investigate possible common etiopathogenetic pathways, especially vascular, immunological and endocrinological systems. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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18 pages, 2428 KiB

Open AccessArticle

Hydrolysable Tannins Exhibit Acetylcholinesterase Inhibitory and Anti-Glycation Activities In Vitro and Learning and Memory Function Improvements in Scopolamine-Induced Amnesiac Mice

by Lih-Geeng Chen, Shyr-Yi Lin, Yi-Shan Lee, Ching-Chiung Wang and Wen-Chi Hou

Biomedicines 2021, 9(8), 1066; https://doi.org/10.3390/biomedicines9081066 - 23 Aug 2021

Cited by 5 | Viewed by 2420

Abstract

Agricultural waste from the hulls of water caltrop (Trapa taiwanesis Nakai, TT-hull) was extracted by either steeping them in cold 95% ethanol (C95E), refluxing 95E, refluxing 50E, or refluxing hot water (HW) to obtain C95EE, 95EE, 50EE, and HWE, respectively. These four [...] Read more.

Agricultural waste from the hulls of water caltrop (Trapa taiwanesis Nakai, TT-hull) was extracted by either steeping them in cold 95% ethanol (C95E), refluxing 95E, refluxing 50E, or refluxing hot water (HW) to obtain C95EE, 95EE, 50EE, and HWE, respectively. These four extracts showed acetylcholinesterase (AChE) inhibitory activities and free radical scavenging activities, as well as anti-non-enzymatic protein glycation in vitro. Eight compounds were isolated from TT-hull-50EE and were used to plot the chromatographic fingerprints of the TT-hull extracts, among which tellimagrandin-I, tellimagrandin-II, and 1,2,3,6-tetra-galloylglucose showed the strongest AChE inhibitory activities, and they also exhibited anti-amyloid β peptide aggregations. The scopolamine-induced amnesiac ICR mice that were fed with TT-hull-50EE or TT-hull-HWE (100 and 200 mg/kg) or tellimagrandin-II (100 and 200 mg/kg) showed improved learning behavior when evaluated using passive avoidance or water maze evaluation, and they showed significant differences (p < 0.05) compared to those in the control group. The enriched hydrolysable tannins of the recycled TT-hull may be developed as functional foods for the treatment of degenerative disorders. Full article

(This article belongs to the Topic Bioactive Natural Products and Synthetic Small Molecules as Potential Investigational Treatments for Neurodegenerative Diseases)

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21 pages, 4289 KiB

Open AccessArticle

Clostridium butyricum MIYAIRI 588 Modifies Bacterial Composition under Antibiotic-Induced Dysbiosis for the Activation of Interactions via Lipid Metabolism between the Gut Microbiome and the Host

by Tadashi Ariyoshi, Mao Hagihara, Susumu Tomono, Shuhei Eguchi, Ayaka Minemura, Daiki Miura, Kentaro Oka, Motomichi Takahashi, Yuka Yamagishi and Hiroshige Mikamo

Biomedicines 2021, 9(8), 1065; https://doi.org/10.3390/biomedicines9081065 - 22 Aug 2021

Cited by 18 | Viewed by 3783

Abstract

The gut microbiome is closely related to gut metabolic functions, and the gut microbiome and host metabolic functions affect each other. Clostridium butyricum MIYAIRI 588 (CBM 588) upregulates protectin D1 production in host colon tissue following G protein-coupled receptor (GPR) 120 activation to [...] Read more.

The gut microbiome is closely related to gut metabolic functions, and the gut microbiome and host metabolic functions affect each other. Clostridium butyricum MIYAIRI 588 (CBM 588) upregulates protectin D1 production in host colon tissue following G protein-coupled receptor (GPR) 120 activation to protect gut epithelial cells under antibiotic-induced dysbiosis. However, how CBM 588 enhances polyunsaturated fatty acid (PUFA) metabolites remains unclear. Therefore, we focused on the metabolic function alterations of the gut microbiome after CBM 588 and protectin D1 administration to reveal the interaction between the host and gut microbiome through lipid metabolism during antibiotic-induced dysbiosis. Consequently, CBM 588 modified gut microbiome and increased the butyric acid and oleic acid content. These lipid metabolic modifications induced GPR activation, which is a trigger of ERK 1/2 signaling and directed differentiation of downstream immune cells in the host colon tissue. Moreover, endogenous protectin D1 modified the gut microbiome, similar to CBM 588. This is the first study to report that CBM 588 influences the interrelationship between colon tissue and the gut microbiome through lipid metabolism. These findings provide insights into the mechanisms of prevention and recovery from inflammation and the improvement of host metabolism by CBM 588. Full article

(This article belongs to the Special Issue Gut Dysbiosis: Molecular Mechanisms and Therapies)

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10 pages, 970 KiB

Open AccessReview

Clot Retraction: Cellular Mechanisms and Inhibitors, Measuring Methods, and Clinical Implications

by Ellen E. Jansen and Matthias Hartmann

Biomedicines 2021, 9(8), 1064; https://doi.org/10.3390/biomedicines9081064 - 21 Aug 2021

Cited by 16 | Viewed by 5118

Abstract

Platelets have important functions in hemostasis. Best investigated is the aggregation of platelets for primary hemostasis and their role as the surface for coagulation leading to fibrin- and clot-formation. Importantly, the function of platelets does not end with clot formation. Instead, platelets are [...] Read more.

Platelets have important functions in hemostasis. Best investigated is the aggregation of platelets for primary hemostasis and their role as the surface for coagulation leading to fibrin- and clot-formation. Importantly, the function of platelets does not end with clot formation. Instead, platelets are responsible for clot retraction through the concerted action of the activated αIIbβ3 receptors on the surface of filopodia and the platelet’s contractile apparatus binding and pulling at the fibrin strands. Meanwhile, the signal transduction events leading to clot retraction have been investigated thoroughly, and several targets to inhibit clot retraction have been demonstrated. Clot retraction is a physiologically important mechanism allowing: (1) the close contact of platelets in primary hemostasis, easing platelet aggregation and intercellular communication, (2) the reduction of wound size, (3) the compaction of red blood cells to a polyhedrocyte infection-barrier, and (4) reperfusion in case of thrombosis. Several methods have been developed to measure clot retraction that have been based on either the measurement of clot volume or platelet forces. Concerning the importance of clot retraction in inborn diseases, the failure of clot retraction in Glanzmann thrombasthenia is characterized by a bleeding phenotype. Concerning acquired diseases, altered clot retraction has been demonstrated in patients with coronary heart disease, stroke, bronchial asthma, uremia, lupus erythematodes, and other diseases. However, more studies on the diagnostic and prognostic value of clot retraction with methods that have to be standardized are necessary. Full article

(This article belongs to the Special Issue Biogenesis and Functions of Blood Platelets)

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13 pages, 10786 KiB

Open AccessArticle

Novel Biomimetic Human TLR2-Derived Peptides for Potential Targeting of Lipoteichoic Acid: An In Silico Assessment

by Nikita Devnarain, Ayman Y. Waddad, Beatriz G. de la Torre, Fernando Albericio and Thirumala Govender

Biomedicines 2021, 9(8), 1063; https://doi.org/10.3390/biomedicines9081063 - 21 Aug 2021

Cited by 1 | Viewed by 2175

Abstract

Antimicrobial resistance is one of the most significant threats to health and economy around the globe and has been compounded by the emergence of COVID-19, raising important consequences for antimicrobial resistance development. Contrary to conventional targeting approaches, the use of biomimetic application via [...] Read more.

Antimicrobial resistance is one of the most significant threats to health and economy around the globe and has been compounded by the emergence of COVID-19, raising important consequences for antimicrobial resistance development. Contrary to conventional targeting approaches, the use of biomimetic application via nanoparticles for enhanced cellular targeting, cell penetration and localized antibiotic delivery has been highlighted as a superior approach to identify novel targeting ligands for combatting antimicrobial resistance. Gram-positive bacterial cell walls contain lipoteichoic acid (LTA), which binds specifically to Toll-like receptor 2 (TLR2) on human macrophages. This phenomenon has the potential to be exploited for the design of biomimetic peptides for antibacterial application. In this study, we have derived peptides from sequences present in human TLR2 that bind to LTA with high affinity. In silico approaches including molecular modelling, molecular docking, molecular dynamics, and thermodynamics have enabled the identification of these crucial binding amino acids, the design of four novel biomimetic TLR2-derived peptides and their LTA binding potential. The outcomes of this study have revealed that one of these novel peptides binds to LTA more strongly and stably than the other three peptides and has the potential to enhance LTA targeting and bacterial cell penetration. Full article

(This article belongs to the Special Issue Peptides of Natural Origin as Leads for Drug Discovery: From Native Structures to Peptidomimetics, Peptide-Conjugates, and Peptide-Nanoparticles 2.0)

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33 pages, 6116 KiB

Open AccessArticle

Targeted Lipidomics of Mitochondria in a Cellular Alzheimer’s Disease Model

by Irina Kurokin, Anna Andrea Lauer, Daniel Janitschke, Jakob Winkler, Elena Leoni Theiss, Lea Victoria Griebsch, Sabrina Melanie Pilz, Veronika Matschke, Martin van der Laan, Heike Sabine Grimm, Tobias Hartmann and Marcus Otto Walter Grimm

Biomedicines 2021, 9(8), 1062; https://doi.org/10.3390/biomedicines9081062 - 21 Aug 2021

Cited by 10 | Viewed by 3899

Abstract

Alzheimer’s disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and [...] Read more.

Alzheimer’s disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and lipid-homeostasis exists, little is known about potential alterations in the lipid composition of mitochondria. Here, we investigate potential changes in the main mitochondrial phospholipid classes phosphatidylcholine, phosphatidylethanolamine and the corresponding plasmalogens and lyso-phospholipids of a cellular AD-model (SH-SY5Y APPswedish transfected cells), comparing these results with changes in cell-homogenates. Targeted shotgun-lipidomics revealed lipid alterations to be specific for mitochondria and cannot be predicted from total cell analysis. In particular, lipids containing three and four times unsaturated fatty acids (FA X:4), such as arachidonic-acid, are increased, whereas FA X:6 or X:5, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), are decreased. Additionally, PE plasmalogens are increased in contrast to homogenates. Results were confirmed in another cellular AD model, having a lower affinity to amyloidogenic APP processing. Besides several similarities, differences in particular in PE species exist, demonstrating that differences in APP processing might lead to specific changes in lipid homeostasis in mitochondria. Importantly, the observed lipid alterations are accompanied by changes in the carnitine carrier system, also suggesting an altered mitochondrial functionality. Full article

(This article belongs to the Special Issue Mitochondria and Brain Disease)

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48 pages, 1210 KiB

Open AccessReview

Exosomes: Potential Disease Biomarkers and New Therapeutic Targets

by Maria I. Mosquera-Heredia, Luis C. Morales, Oscar M. Vidal, Ernesto Barceló, Carlos Silvera-Redondo, Jorge I. Vélez and Pilar Garavito-Galofre

Biomedicines 2021, 9(8), 1061; https://doi.org/10.3390/biomedicines9081061 - 20 Aug 2021

Cited by 44 | Viewed by 6072

Abstract

Exosomes are extracellular vesicles released by cells, both constitutively and after cell activation, and are present in different types of biological fluid. Exosomes are involved in the pathogenesis of diseases, such as cancer, neurodegenerative diseases, pregnancy disorders and cardiovascular diseases, and have emerged [...] Read more.

Exosomes are extracellular vesicles released by cells, both constitutively and after cell activation, and are present in different types of biological fluid. Exosomes are involved in the pathogenesis of diseases, such as cancer, neurodegenerative diseases, pregnancy disorders and cardiovascular diseases, and have emerged as potential non-invasive biomarkers for the detection, prognosis and therapeutics of a myriad of diseases. In this review, we describe recent advances related to the regulatory mechanisms of exosome biogenesis, release and molecular composition, as well as their role in health and disease, and their potential use as disease biomarkers and therapeutic targets. In addition, the advantages and disadvantages of their main isolation methods, characterization and cargo analysis, as well as the experimental methods used for exosome-mediated drug delivery, are discussed. Finally, we present potential perspectives for the use of exosomes in future clinical practice. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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18 pages, 75519 KiB

Open AccessArticle

Oviductal Telocytes in Patients with Uterine Myoma

by Veronika Aleksandrovych, Anna Wrona, Tomasz Bereza, Kazimierz Pityński and Krzysztof Gil

Biomedicines 2021, 9(8), 1060; https://doi.org/10.3390/biomedicines9081060 - 20 Aug 2021

Cited by 9 | Viewed by 2248

Abstract

Tubal factor infertility occurs in 30–35% of infertile pairs and may be caused by impaired muscular contractility and ciliary beating as well as immunological imbalance and chronic inflammation. Newly discovered telocytes (TCs) have a wide palette of features, which play a role in [...] Read more.

Tubal factor infertility occurs in 30–35% of infertile pairs and may be caused by impaired muscular contractility and ciliary beating as well as immunological imbalance and chronic inflammation. Newly discovered telocytes (TCs) have a wide palette of features, which play a role in oviduct physiology. We have observed tissue samples from human fallopian tubes in patients with and without uterine myoma by immunolabelling. According to the immunohistochemical co-expression of markers, it has been determined that TCs are engaged in a wide range of physiological processes, including local innervation, sensitivity to hypoxia, regulation of calcium, and sex steroid hormones balances. Due to the proximity of NOS- and ChAT-positive nerve fibers and the expression of ion channels markers, tubal TCs might be considered conductor cells. Additionally, their integration in contractions and cilia physiology in the context of fertility has been revealed. We have observed the difference in telocytes expression in the human oviduct between groups of patients and attempted to describe this population of cells specifically in the case of infertility development, a clinically relevant avenue for further studies. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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17 pages, 5196 KiB

Open AccessArticle

A Novel Bispecific Antibody Targeting CD3 and Lewis Y with Potent Therapeutic Efficacy against Gastric Cancer

by Jie Chen, Zhidi Pan, Lei Han, Yuexian Zhou, Huifang Zong, Lei Wang, Rui Sun, Hua Jiang, Yueqing Xie, Yunsheng Yuan, Mingyuan Wu, Yanling Bian, Baohong Zhang and Jianwei Zhu

Biomedicines 2021, 9(8), 1059; https://doi.org/10.3390/biomedicines9081059 - 20 Aug 2021

Cited by 15 | Viewed by 3022

Abstract

Lewis Y antigen, a glycan highly expressed on most epithelial cancers, was targeted for cancer treatment but lacked satisfactory results in some intractable and refractory cancers. Thus, it is highly desirable to develop an effective therapy against these cancers, hopefully based on this [...] Read more.

Lewis Y antigen, a glycan highly expressed on most epithelial cancers, was targeted for cancer treatment but lacked satisfactory results in some intractable and refractory cancers. Thus, it is highly desirable to develop an effective therapy against these cancers, hopefully based on this target. In this work, we constructed a novel T cell-engaging bispecific antibody targeting Lewis Y and CD3 (m3s193 BsAb) with the IgG-[L]-scfv format. In vitro activity of m3s193 BsAb was evaluated by affinity assay to target cells, cytotoxicity assay, cytokines releasing assay, and T cells proliferation and recruiting assays. Anti-tumor activity against gastric cancer was evaluated in vivo by subcutaneous huPBMCs/tumor cells co-grafting model and huPBMCs intravenous injecting model. In vitro, m3s193 BsAb appeared to have a high binding affinity to Lewis Y positive cells and Jurkat cells. The BsAb showed stronger activity than its parent mAb in T cell recruiting, activation, proliferation, cytokine release, and cytotoxicity. In vivo, m3s193 BsAb not only demonstrated higher therapeutic efficacy in the huPBMCs/tumor co-grafting gastric carcinoma model than the parent mAb but also eliminated tumors in the model of intravenous injection with huPBMCs. Strong anti-tumor activity of m3s193 BsAb revealed that Lewis Y could be targeted in T cell-engaging BsAb for gastric cancer therapy. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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18 pages, 38297 KiB

Open AccessArticle

Proteomic Analysis Reveals Key Proteins in Extracellular Vesicles Cargo Associated with Idiopathic Pulmonary Fibrosis In Vitro

by Juan Manuel Velázquez-Enríquez, Jovito Cesar Santos-Álvarez, Alma Aurora Ramírez-Hernández, Edilburga Reyes-Jiménez, Armando López-Martínez, Socorro Pina-Canseco, Sergio Roberto Aguilar-Ruiz, María de los Ángeles Romero-Tlalolini, Luis Castro-Sánchez, Jaime Arellanes-Robledo, Verónica Rocío Vásquez-Garzón and Rafael Baltiérrez-Hoyos

Biomedicines 2021, 9(8), 1058; https://doi.org/10.3390/biomedicines9081058 - 20 Aug 2021

Cited by 16 | Viewed by 5290

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and highly fatal disease. It is characterized by the increased activation of both fibroblast and myofibroblast that results in excessive extracellular matrix (ECM) deposition. Extracellular vesicles (EVs) have been described as key mediators of [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and highly fatal disease. It is characterized by the increased activation of both fibroblast and myofibroblast that results in excessive extracellular matrix (ECM) deposition. Extracellular vesicles (EVs) have been described as key mediators of intercellular communication in various pathologies. However, the role of EVs in the development of IPF remains poorly understood. This study aimed to characterize the differentially expressed proteins contained within EVs cargo derived from the fibroblast cell lines LL97A (IPF-1) and LL29 (IPF-2) isolated from lungs bearing IPF as compared to those derived from the fibroblast cell lines CCD8Lu (NL-1) and CCD19Lu (NL-2) isolated from healthy donors. Isolated EVs were subjected to label-free quantitative proteomic analysis by LC-MS/MS, and as a result, 331 proteins were identified. Differentially expressed proteins were obtained after the pairwise comparison, including all experimental groups. A total of 86 differentially expressed proteins were identified in either one or more comparison groups. Of note, proteins involved in fibrogenic processes, such as tenascin-c (TNC), insulin-like-growth-factor-binding protein 7 (IGFBP7), fibrillin-1 (FBN1), alpha-2 collagen chain (I) (COL1A2), alpha-1 collagen chain (I) (COL1A1), and lysyl oxidase homolog 1 (LOXL1), were identified in EVs cargo isolated from IPF cell lines. Additionally, KEGG pathway enrichment analysis revealed that differentially expressed proteins participate in focal adhesion, PI3K-Akt, and ECM–receptor interaction signaling pathways. In conclusion, our findings reveal that proteins contained within EVs cargo might play key roles during IPF pathogenesis. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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22 pages, 3424 KiB

Open AccessArticle

The Histone Variant MacroH2A1 Impacts Circadian Gene Expression and Cell Phenotype in an In Vitro Model of Hepatocellular Carcinoma

by Annalucia Carbone, Elisabetta De Santis, Olga Cela, Vincenzo Giambra, Luca Miele, Giuseppe Marrone, Antonio Grieco, Marcus Buschbeck, Nazzareno Capitanio, Tommaso Mazza and Gianluigi Mazzoccoli

Biomedicines 2021, 9(8), 1057; https://doi.org/10.3390/biomedicines9081057 - 20 Aug 2021

Cited by 2 | Viewed by 2615

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. A foremost risk factor for HCC is obesity/metabolic syndrome-related non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which is prompted by remarkable changes in transcription patterns of genes enriching metabolic, immune/inflammatory, [...] Read more.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. A foremost risk factor for HCC is obesity/metabolic syndrome-related non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which is prompted by remarkable changes in transcription patterns of genes enriching metabolic, immune/inflammatory, and circadian pathways. Epigenetic mechanisms play a role in NAFLD-associated HCC, and macroH2A1, a variant of histone H2A, is involved in the pathogenesis modulating the expression of oncogenes and/or tumor suppressor genes and interacting with SIRT1, which crucially impacts the circadian clock circuitry. Hence, we aimed to appraise if and how macroH2A1 regulated the expression patterns of circadian genes in the setting of NAFLD-associated HCC. We took advantage of an in vitro model of liver cancer represented by HepG2 (human hepatocarcinoma) cells stably knocked down for macroH2A1 and conducted whole transcriptome profiling and deep phenotyping analysis. We found up-regulation of PER1 along with several deregulated circadian genes, enriching several important pathways and functions related to cancer onset and progression, such as epithelial-to-mesenchymal transition, cell cycle deregulation, and DNA damage. PER1 silencing partially mitigated the malignant phenotype induced by the loss of macroH2A1 in HCC cells. In conclusion, our findings suggest a modulatory role for the core circadian protein PER1 in liver carcinogenesis in the context of a lack of the macroH2A1 epigenetic and transcriptional landscape. Full article

(This article belongs to the Topic Cancer Biology and Therapy)

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17 pages, 3036 KiB

Open AccessArticle

African Trypanosomiasis: Extracellular Vesicles Shed by Trypanosoma brucei brucei Manipulate Host Mononuclear Cells

by Tatiana Dias-Guerreiro, Joana Palma-Marques, Patrícia Mourata-Gonçalves, Graça Alexandre-Pires, Ana Valério-Bolas, Áurea Gabriel, Telmo Nunes, Wilson Antunes, Isabel Pereira da Fonseca, Marcelo Sousa-Silva and Gabriela Santos-Gomes

Biomedicines 2021, 9(8), 1056; https://doi.org/10.3390/biomedicines9081056 - 20 Aug 2021

Cited by 9 | Viewed by 3488

Abstract

African trypanosomiasis or sleeping sickness is a zoonotic disease caused by Trypanosoma brucei, a protozoan parasite transmitted by Glossina spp. (tsetse fly). Parasite introduction into mammal hosts triggers a succession of events, involving both innate and adaptive immunity. Macrophages (MΦ) have a [...] Read more.

African trypanosomiasis or sleeping sickness is a zoonotic disease caused by Trypanosoma brucei, a protozoan parasite transmitted by Glossina spp. (tsetse fly). Parasite introduction into mammal hosts triggers a succession of events, involving both innate and adaptive immunity. Macrophages (MΦ) have a key role in innate defence since they are antigen-presenting cells and have a microbicidal function essential for trypanosome clearance. Adaptive immune defence is carried out by lymphocytes, especially by T cells that promote an integrated immune response. Like mammal cells, T. b. brucei parasites release extracellular vesicles (TbEVs), which carry macromolecules that can be transferred to host cells, transmitting biological information able to manipulate cell immune response. However, the exact role of TbEVs in host immune response remains poorly understood. Thus, the current study examined the effect elicited by TbEVs on MΦ and T lymphocytes. A combined approach of microscopy, nanoparticle tracking analysis, multiparametric flow cytometry, colourimetric assays and detailed statistical analyses were used to evaluate the influence of TbEVs in mouse mononuclear cells. It was shown that TbEVs can establish direct communication with cells of innate and adaptative immunity. TbEVs induce the differentiation of both M1- and M2-MΦ and elicit the expansion of MHCI⁺, MHCII⁺ and MHCI⁺MHCII⁺ MΦ subpopulations. In T lymphocytes, TbEVs drive the overexpression of cell-surface CD3 and the nuclear factor FoxP3, which lead to the differentiation of regulatory CD4⁺ and CD8⁺ T cells. Moreover, this study indicates that T. b. brucei and TbEVs seem to display opposite but complementary effects in the host, establishing a balance between parasite growth and controlled immune response, at least during the early phase of infection. Full article

(This article belongs to the Special Issue Parasitic Infection and Immunity)

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12 pages, 1524 KiB

Open AccessArticle

Expression of miR-1-3p, miR-16-5p and miR-122-5p as Possible Risk Factors of Secondary Cardiovascular Events

by Rafał Badacz, Paweł Kleczyński, Jacek Legutko, Krzysztof Żmudka, Jacek Gacoń, Tadeusz Przewłocki and Anna Kabłak-Ziembicka

Biomedicines 2021, 9(8), 1055; https://doi.org/10.3390/biomedicines9081055 - 20 Aug 2021

Cited by 23 | Viewed by 2882

Abstract

Ischemic event in one arterial territory increases the risk of a subsequent ischemic event. Circulating microRNAs (miRs) emerge as a potential clinical tool to assess risk of subsequent atherothrombotic events such as cardiovascular death (CVD), myocardial infarction (MI) and ischemic stroke (IS). In [...] Read more.

Ischemic event in one arterial territory increases the risk of a subsequent ischemic event. Circulating microRNAs (miRs) emerge as a potential clinical tool to assess risk of subsequent atherothrombotic events such as cardiovascular death (CVD), myocardial infarction (MI) and ischemic stroke (IS). In this prospective study, we searched for athero-specific miRs related to cardiovascular event risk in patients with symptomatic coronary, carotid lesion, or both territories involvements. The choice of particular miRs was based on database research (Pub-Med, Bethesda, MD, USA) taking into consideration the relationship with development of atherosclerosis and potential prognostic value. Levels of circulating miRs (miR-1-3p, miR-16-5p, miR-34a-5p, mir-122-5p, miR-124-3p, miR-133a-3p, miR-133b, miR-134-5p, miR-208b-3p, miR-375 and miR-499-5p) were compared in 142 patients with an acute ischemic event resulting from carotid and/or coronary artery stenosis, who underwent revascularization for symptomatic lesion. A 6-year prospective evaluation of CVD/MI/IS risk was performed. Patients with two-territory as compared to single-territory involvement differed in levels of miR-1-3p (p = 0.016), miR-16-5p (p < 0.001), miR-34a-5p (p = 0.018), miR-122-5p (p = 0.007), miR-124-3p (p < 0.001) and miR-499-5p (p < 0.001). During follow-up, 62 (43.7%) episodes of CVD/MI/IS occurred. In multivariate Cox analysis, miR-122-5p (HR = 1.0006, 95%CI = 1.0001–1.0011) and peripheral artery disease (PAD) (HR = 2.16, 95%CI = 1.26–3.70) were associated with CVD/MI/IS risk; miR-1-3p (HR = 2.73, 95%CI = 1.22–6.12) and PAD (HR = 3.47, 95%CI = 1.88–6.41) with CVD; miR-122-5p (HR = 1.0001, 95%CI = 1.000–1.0002) and creatinine level (HR = 1.02, 95%CI = 1.01–1.04) with IS, and miR-16-5p (HR = 1.0004, 95%CI = 1.0001–1.0008) with MI. Expression of miR-1-3p, miR-16-5p and miR-122-5p during incident ischemia may be possible risk factors of secondary cardiovascular event(s). Full article

(This article belongs to the Special Issue microRNAs as Biomarkers of Cardiovascular Diseases)

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14 pages, 1913 KiB

Open AccessArticle

Prognostic Significance of ROR2 Expression in Patients with Urothelial Carcinoma

by Cheng-Fa Yeh, Ti-Chun Chan, Hung-Lung Ke, Tzu-Ju Chen, Li-Ching Wu, Hsiang-Ying Lee, Yu-Ching Wei, Wen-Jeng Wu, Chien-Feng Li and Wei-Ming Li

Biomedicines 2021, 9(8), 1054; https://doi.org/10.3390/biomedicines9081054 - 20 Aug 2021

Cited by 5 | Viewed by 2349

Abstract

We investigated the association of receptor tyrosine kinase-like orphan receptor 2 (ROR2) expression with clinicopathological features and oncologic outcomes in large urothelial carcinoma (UC) of the upper tract (UTUC) and urinary bladder (UBUC) cohorts. Through transcriptomic profiling of a published dataset (GSE31684), ROR2 [...] Read more.

We investigated the association of receptor tyrosine kinase-like orphan receptor 2 (ROR2) expression with clinicopathological features and oncologic outcomes in large urothelial carcinoma (UC) of the upper tract (UTUC) and urinary bladder (UBUC) cohorts. Through transcriptomic profiling of a published dataset (GSE31684), ROR2 was discovered to be the most upregulated gene during UC progression, focusing on the JNK cascade (GO:0007254). Initially, the evaluation of ROR2 mRNA expression in 50 frozen UBUCs showed significantly upregulated levels in high-stage UC. Moreover, high ROR2 immunoexpression significantly correlated with high tumor stage, high tumor grade, lymph node metastasis, and vascular invasion (all p < 0.05). In multivariate analysis, after adjusting for standard clinicopathological features, ROR2 expression status was an independent prognosticator of cancer-specific survival and metastasis-free survival in UTUC and UBUC (all p < 0.01). In the subgroup analysis, it also significantly predicted bladder tumor recurrence in non-muscle invasive UBUC. Furthermore, the GO enrichment analysis showed that fatty acid, monocarboxylic acid, carboxylic acid metabolic processes, negative regulation of neutrophil migration, and negative regulation of granulocyte and neutrophil chemotaxis were significantly enriched by ROR2 dysregulation. In conclusion, high ROR2 immunoexpression was associated with aggressive pathological characteristics in UC and independently predicted worse prognosis, suggesting it could play roles in clinical risk stratification and therapy decisions. Full article

(This article belongs to the Topic Cancer Biology and Therapy)

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28 pages, 2300 KiB

Open AccessArticle

Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation

by Petr Kala, Matúš Miklovič, Šárka Jíchová, Petra Škaroupková, Zdeňka Vaňourková, Hana Maxová, Olga Gawrys, Elzbieta Kompanowska-Jezierska, Janusz Sadowski, John D. Imig, John R. Falck, Josef Veselka, Luděk Červenka, Renáta Aiglová, Marek Vícha, Vít Gloger and Miloš Táborský

Biomedicines 2021, 9(8), 1053; https://doi.org/10.3390/biomedicines9081053 - 20 Aug 2021

Cited by 11 | Viewed by 2645

Abstract

This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin [...] Read more.

This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin system (RAS). The results were compared with standard pharmacological blockade of the RAS using angiotensin-converting enzyme inhibitor (ACEi). The rationale for employing EET-A as a new treatment approach is based on our findings that apart from increased RAS activity, untreated ACF TGR also shows kidney and left ventricle (LV) tissue deficiency of EETs. Untreated ACF TGR began to die 17 days after creating ACF and were all dead by day 84. The treatment with EET-A alone or ACEi alone improved the survival rate: in 156 days after ACF creation, it was 45.5% and 59.4%, respectively. The combined treatment with EET-A and ACEi appeared to improve the final survival to 71%; however, the difference from either single treatment regimen did not reach significance. Nevertheless, our findings support the notion that targeting the cytochrome P-450-dependent epoxygenase pathway of arachidonic acid metabolism should be considered for the treatment of HF. Full article

(This article belongs to the Special Issue Hypertension and Cardiovascular Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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21 pages, 7739 KiB

Open AccessArticle

Impact of Plasma Xanthine Oxidoreductase Activity on the Mechanisms of Distal Symmetric Polyneuropathy Development in Patients with Type 2 Diabetes

by Midori Fujishiro, Hisamitsu Ishihara, Katsuhiko Ogawa, Takayo Murase, Takashi Nakamura, Kentaro Watanabe, Hideyuki Sakoda, Hiraku Ono, Takeshi Yamamotoya, Yusuke Nakatsu, Tomoichiro Asano and Akifumi Kushiyama

Biomedicines 2021, 9(8), 1052; https://doi.org/10.3390/biomedicines9081052 - 19 Aug 2021

Cited by 2 | Viewed by 2227

Abstract

To unravel associations between plasma xanthine oxidoreductase (XOR) and diabetic vascular complications, especially distal symmetric polyneuropathy (DSP), we investigated plasma XOR activities using a novel assay. Patients with type 2 diabetes mellitus (T2DM) with available nerve conduction study (NCS) data were analyzed. None [...] Read more.

To unravel associations between plasma xanthine oxidoreductase (XOR) and diabetic vascular complications, especially distal symmetric polyneuropathy (DSP), we investigated plasma XOR activities using a novel assay. Patients with type 2 diabetes mellitus (T2DM) with available nerve conduction study (NCS) data were analyzed. None were currently taking XOR inhibitors. XOR activity of fasting blood samples was assayed using a stable isotope-labeled substrate and LC-TQMS. JMP Clinical version 5.0. was used for analysis. We analyzed 54 patients. Mean age was 64.7 years, mean body mass index was 26.0 kg/m², and mean glycated hemoglobin was 9.4%. The logarithmically transformed plasma XOR activity (ln-XOR) correlated positively with hypoxanthine, xanthine, visceral fatty area, and liver dysfunction but negatively with HDL cholesterol. ln-XOR correlated negatively with diabetes duration and maximum intima-media thickness. Stepwise multiple regression analysis revealed ln-XOR to be among selected explanatory factors for various NCS parameters. Receiver operating characteristic curves showed the discriminatory power of ln-XOR. Principal component analysis revealed a negative relationship of ln-XOR with F-waves as well as positive relationships of ln-XOR with hepatic steatosis and obesity-related disorders. Taken together, our results show plasma XOR activity to be among potential disease status predictors in T2DM patients. Plasma XOR activity measurements might reliably detect pre-symptomatic DSP. Full article

(This article belongs to the Special Issue Pathological Mechanisms in Diabetes)

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22 pages, 3000 KiB

Open AccessReview

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

by Bernhard Moser, Sophie Edtmayer, Agnieszka Witalisz-Siepracka and Dagmar Stoiber

Biomedicines 2021, 9(8), 1051; https://doi.org/10.3390/biomedicines9081051 - 19 Aug 2021

Cited by 10 | Viewed by 5644

Abstract

Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival [...] Read more.

Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management. Full article

(This article belongs to the Special Issue Acute Myeloid Leukemia: From Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 1800 KiB

Open AccessReview

Gait Analysis Using Animal Models of Peripheral Nerve and Spinal Cord Injuries

by Gheorghita Isvoranu, Emilia Manole and Monica Neagu

Biomedicines 2021, 9(8), 1050; https://doi.org/10.3390/biomedicines9081050 - 19 Aug 2021

Cited by 11 | Viewed by 3077

Abstract

The present review discusses recent data regarding rodent models of spinal cord and peripheral nerve injuries in terms of gait analysis using the CatWalk system (CW), an automated and exceptionally reliable system for assessing gait abnormalities and motor coordination. CW is a good [...] Read more.

The present review discusses recent data regarding rodent models of spinal cord and peripheral nerve injuries in terms of gait analysis using the CatWalk system (CW), an automated and exceptionally reliable system for assessing gait abnormalities and motor coordination. CW is a good tool for both studying improvements in the walking of animals after suffering a peripheral nerve and spinal cord lesion and to select the best therapies and procedures after tissue destruction, given that it provides objective and quantifiable data. Most studies using CW for gait analysis that were published in recent years focus on injuries inflicted in the peripheral nerve, spinal cord, and brain. CW has been used in the assessment of rodent motor function through high-resolution videos, whereby specialized software was used to measure several aspects of the animal’s gait, and the main characteristics of the automated system are presented here. CW was developed to assess footfall and gait changes, and it can calculate many parameters based on footprints and time. However, given the multitude of parameters, it is necessary to evaluate which are the most important under the employed experimental circumstances. By selecting appropriate animal models and evaluating peripheral nerve and spinal cord lesion regeneration using standardized methods, suggestions for new therapies can be provided, which represents the translation of this methodology into clinical application. Full article

(This article belongs to the Topic Animal Model in Biomedical Research)

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15 pages, 4712 KiB

Open AccessArticle

Increasing Odontoblast-like Differentiation from Dental Pulp Stem Cells through Increase of β-Catenin/p-GSK-3β Expression by Low-Frequency Electromagnetic Field

by Han-Moi Lim, Myeong-Hyun Nam, Yu-Mi Kim and Young-Kwon Seo

Biomedicines 2021, 9(8), 1049; https://doi.org/10.3390/biomedicines9081049 - 19 Aug 2021

Cited by 9 | Viewed by 2538

Abstract

Odontoblasts produce proteins that form the dentinal extracellular matrix, which can protect the dental pulp from external stimuli and is required for tooth regeneration. This study showed that a pulsed electromagnetic field (PEMF) can regulate cell metabolism and induce cell differentiation. This study [...] Read more.

Odontoblasts produce proteins that form the dentinal extracellular matrix, which can protect the dental pulp from external stimuli and is required for tooth regeneration. This study showed that a pulsed electromagnetic field (PEMF) can regulate cell metabolism and induce cell differentiation. This study determined the frequency of PEMF that is effective for odontoblast differentiation. Human dental pulp stem cells (hDPSCs) were cultured in odontoblast differentiation medium containing dexamethasone, BMP2, TGF-β1, and FGF-2, and then exposed to 10 mT intensity of PEMF at 40, 60, 70, and 150 Hz for 15 min/day. The MTT assay, LDH assay, flow cytometry, protein and gene expression, and immunofluorescence were performed to check if hDPSCs differentiated into odontoblast-like cells. The hDPSCs showed frequency-dependent differences in protein and gene expression. The mesenchymal stem cell markers were reduced to a greater extent at 60 and 70 Hz than at other frequencies, and odontoblast-related markers, particularly β-catenin, p-GSK-3β, and p-p38, were increased at 60 and 70 Hz. Exposure to 10 mT intensity of PEMF at 70 Hz influenced the differentiation of hDPSCs considerably. Taken together, PEMF treatment can promote differentiation of hDPSCs into odontoblast-like cells by increasing p-GSK-3β and β-catenin expression. Full article

(This article belongs to the Special Issue Tissue Engineering Updates and Perspective in Dentistry)

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19 pages, 1800 KiB

Open AccessReview

Linking Immunity with Genomics in Sarcomas: Is Genomic Complexity an Immunogenic Trigger?

by Siddh van Oost, Debora M. Meijer, Marieke L. Kuijjer, Judith V. M. G. Bovée and Noel F. C. C. de Miranda

Biomedicines 2021, 9(8), 1048; https://doi.org/10.3390/biomedicines9081048 - 19 Aug 2021

Cited by 4 | Viewed by 3762

Abstract

Sarcomas comprise a collection of highly heterogeneous malignancies that can be grossly grouped in the categories of sarcomas with simple or complex genomes. Since the outcome for most sarcoma patients has barely improved in the last decades, there is an urgent need for [...] Read more.

Sarcomas comprise a collection of highly heterogeneous malignancies that can be grossly grouped in the categories of sarcomas with simple or complex genomes. Since the outcome for most sarcoma patients has barely improved in the last decades, there is an urgent need for improved therapies. Immunotherapy, and especially T cell checkpoint blockade, has recently been a game-changer in cancer therapy as it produced significant and durable treatment responses in several cancer types. Currently, only a small fraction of sarcoma patients benefit from immunotherapy, supposedly due to a general lack of somatically mutated antigens (neoantigens) and spontaneous T cell immunity in most cancers. However, genomic events resulting from chromosomal instability are frequent in sarcomas with complex genomes and could drive immunity in those tumors. Improving our understanding of the mechanisms that shape the immune landscape of sarcomas will be crucial to overcoming the current challenges of sarcoma immunotherapy. This review focuses on what is currently known about the tumor microenvironment in sarcomas and how this relates to their genomic features. Moreover, we discuss novel therapeutic strategies that leverage the tumor microenvironment to increase the clinical efficacy of immunotherapy, and which could provide new avenues for the treatment of sarcomas. Full article

(This article belongs to the Special Issue Pathogenic Mechanisms and Novel Therapeutic Approaches for Sarcomas)

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20 pages, 1333 KiB

Open AccessArticle

Soluble Guanylate Cyclase Stimulator Vericiguat Enhances Long-Term Memory in Rats without Altering Cerebral Blood Volume

by Ellis Nelissen, Elentina K. Argyrousi, Nick P. Van Goethem, Fuqiang Zhao, Catherine D. G. Hines, Gayathri Swaminath, Michael Gerisch, Joerg Hueser, Peter Sandner and Jos Prickaerts

Biomedicines 2021, 9(8), 1047; https://doi.org/10.3390/biomedicines9081047 - 19 Aug 2021

Cited by 10 | Viewed by 3336

Abstract

Vascular cognitive impairment (VCI) is characterized by impairments in cerebral blood flow (CBF), endothelial function and blood–brain barrier (BBB) integrity. These processes are all physiologically regulated by the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling pathway. Additionally, cGMP signaling plays an important role [...] Read more.

Vascular cognitive impairment (VCI) is characterized by impairments in cerebral blood flow (CBF), endothelial function and blood–brain barrier (BBB) integrity. These processes are all physiologically regulated by the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling pathway. Additionally, cGMP signaling plays an important role in long-term potentiation (LTP) underlying memory formation. Therefore, targeting the NO-sGC-cGMP pathway may be a therapeutic strategy for treating VCI. Hence, in this study we investigated whether sGC stimulator vericiguat has potential as a cognitive enhancer. The effects of vericiguat on long-term memory were measured in rats using an object location task. Due to the low brain-penetrance of vericiguat found in this study, it was investigated whether in the absence of BBB limitations, vericiguat enhanced hippocampal plasticity using an ex vivo memory acquisition-like chemical LTP model. Finally, peripheral effects were measured by means of blood pressure and cerebral blood volume. Vericiguat successfully enhanced long-term memory and increased hippocampal plasticity via enhanced translocation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to the cell membrane, while blood pressure and cerebral blood volume were unaltered. Although the memory enhancing effects in this study are likely due to peripheral effects on the cerebral microvasculature, sGC stimulation may provide a new therapeutic strategy for treating VCI, especially when BBB integrity is reduced. Full article

(This article belongs to the Special Issue Recent Advances in Brain Vascular Diseases Management and Therapy)

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17 pages, 2570 KiB

Open AccessArticle

Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo

by Safa Bazaz, Tõnis Lehto, Rahel Tops, Olof Gissberg, Dhanu Gupta, Burcu Bestas, Jeremy Bost, Oscar P. B. Wiklander, Helena Sork, Eman M. Zaghloul, Doste R. Mamand, Mattias Hällbrink, Rannar Sillard, Osama Saher, Kariem Ezzat, C. I. Edvard Smith, Samir EL Andaloussi and Taavi Lehto

Biomedicines 2021, 9(8), 1046; https://doi.org/10.3390/biomedicines9081046 - 19 Aug 2021

Cited by 4 | Viewed by 2891

Abstract

Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) [...] Read more.

Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) are a class of drug delivery systems (DDSs) that have recently gained considerable attention for improving the uptake of various oligonucleotide (ON)-based compounds, including SSOs. One strategy that has been successfully applied to develop effective CPP vectors is the introduction of various lipid modifications into the peptide. Here, we repurpose hydrocarbon-modified amino acids used in peptide stapling for the orthogonal introduction of hydrophobic modifications into the CPP structure during peptide synthesis. Our data show that α,α-disubstituted alkenyl-alanines can be successfully utilized to introduce hydrophobic modifications into CPPs to improve their ability to formulate SSOs into nanoparticles (NPs), and to mediate high delivery efficacy and tolerability both in vitro and in vivo. Conclusively, our results offer a new flexible approach for the sequence-specific introduction of hydrophobicity into the structure of CPPs and for improving their delivery properties. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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Open AccessReview

Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors

by Morena Fasano, Francesco Perri, Carminia Maria Della Corte, Raimondo Di Liello, Giuseppina Della Vittoria Scarpati, Marco Cascella, Alessandro Ottaiano, Fortunato Ciardiello and Raffaele Solla

Biomedicines 2021, 9(8), 1045; https://doi.org/10.3390/biomedicines9081045 - 19 Aug 2021

Cited by 3 | Viewed by 7497

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by a high mortality rate owing to very few available oncological treatments. For many years, a combination of platinum-based chemotherapy and anti-EGFR antibody cetuximab has represented the only available option for first-line therapy. Recently, [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is characterized by a high mortality rate owing to very few available oncological treatments. For many years, a combination of platinum-based chemotherapy and anti-EGFR antibody cetuximab has represented the only available option for first-line therapy. Recently, immunotherapy has been presented an alternative for positive PD-L1 HNSCC. However, the oncologists’ community foresees that a new therapeutic era is approaching. In fact, no-chemo options and some molecular targets are on the horizon. This narrative review addresses past, present, and future therapeutic options for HNSCC from a translational point of view. Full article

(This article belongs to the Topic Cancer Biology and Therapy)

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Biomedicines, Volume 9, Issue 8 (August 2021) – 226 articles

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