bluuebunny/crossref_metadata_2025 huggingface dataset:
Post Zygotic, Somatic, Deletion in KERATIN 1 V1 Domain Generates Structural Alteration of the K1/K10 Dimer, Producing a Monolateral Palmar Epidermolytic Nevus
Authors: Caporali Sabrina , Didona Biagio , Paradisi Mauro , Mauriello Alessandro , Campione Elena , Falconi Mattia , Iacovelli Federico , Minieri Marilena , Pieri Massimo , Bernardini Sergio , Terrinoni Alessandro
Published: June 2021

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.
Prevention of High Glucose-Mediated EMT by Inhibition of Hsp70 Chaperone
Authors: Nikotina Alina D. , Vladimirova Snezhana A. , Komarova Elena Y. , Alexeev Dmitry , Efremov Sergey , Leonova Elizaveta , Pavlov Rostislav , Kartsev Viktor G. , Polonik Sergey G. , Margulis Boris A. , Guzhova Irina V.
Published: June 2021

Hyperglycemia may contribute to the progression of carcinomas by triggering epithelial-to-mesenchymal transition (EMT). Some proteostasis systems are involved in metastasis; in this paper, we sought to explore the mechanism of Hsp70 chaperone in EMT. We showed that knockdown of Hsp70 reduced cell migration capacity concomitantly with levels of mRNA of the Slug, Snail, and Twist markers of EMT, in colon cancer cells incubated in high glucose medium. Conversely, treatment of cells with Hsp70 inducer U-133 were found to elevate cell motility, along with the other EMT markers. To prove that inhibiting Hsp70 may reduce EMT efficiency, we treated cells with a CL-43 inhibitor of the HSF1 transcription factor, which lowered Hsp70 and HSF1 content in the control and induced EMT in carcinoma cells. Importantly, CL-43 reduced migration capacity, EMT-linked transcription factors, and increased content of epithelial marker E-cadherin in colon cancer cells of three lines, including one derived from a clinical sample. To prove that Hsp70 chaperone should be targeted when inhibiting the EMT pathway, we treated cancer cells with 2-phenylethynesulfonamide (PES) and demonstrated that the compound inhibited substrate-binding capacity of Hsp70. Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.
Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors
Authors: Kim Hyeon Jin , Jeong Mi Suk , Jang Se Bok
Published: June 2021

Receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily. RAGE binds and mediates cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as AGEs, HMGB1, and S100/calgranulins, and as an innate immune sensor, can recognize microbial PAMPs (pathogen-associated molecular pattern molecules), including bacterial LPS, bacterial DNA, and viral and parasitic proteins. RAGE and its ligands stimulate the activations of diverse pathways, such as p38MAPK, ERK1/2, Cdc42/Rac, and JNK, and trigger cascades of diverse signaling events that are involved in a wide spectrum of diseases, including diabetes mellitus, inflammatory, vascular and neurodegenerative diseases, atherothrombosis, and cancer. Thus, the targeted inhibition of RAGE or its ligands is considered an important strategy for the treatment of cancer and chronic inflammatory diseases.
Biphasic α2β1 Integrin Expression in Breast Cancer Metastasis to Bone
Authors: Moritz Milene N.O. , Merkel Alyssa R. , Feldman Ean G. , Selistre-de-Araujo Heloisa S. , Rhoades (Sterling) Julie A.
Published: June 2021

Integrins participate in the pathogenesis and progression of tumors at many stages during the metastatic cascade. However, current evidence for the role of integrins in breast cancer progression is contradictory and seems to be dependent on tumor stage, differentiation status, and microenvironmental influences. While some studies suggest that loss of α2β1 enhances cancer metastasis, other studies suggest that this integrin is pro-tumorigenic. However, few studies have looked at α2β1 in the context of bone metastasis. In this study, we aimed to understand the role of α2β1 integrin in breast cancer metastasis to bone. To address this, we utilized in vivo models of breast cancer metastasis to bone using MDA-MB-231 cells transfected with an α2 expression plasmid (MDA-OEα2). MDA cells overexpressing the α2 integrin subunit had increased primary tumor growth and dissemination to bone but had no change in tumor establishment and bone destruction. Further in vitro analysis revealed that tumors in the bone have decreased α2β1 expression and increased osteolytic signaling compared to primary tumors. Taken together, these data suggest an inverse correlation between α2β1 expression and bone-metastatic potential. Inhibiting α2β1 expression may be beneficial to limit the expansion of primary tumors but could be harmful once tumors have established in bone.
Western Diet Decreases the Liver Mitochondrial Oxidative Flux of Succinate: Insight from a Murine NAFLD Model
Authors: Staňková Pavla , Kučera Otto , Peterová Eva , Elkalaf Moustafa , Rychtrmoc David , Melek Jan , Podhola Miroslav , Zubáňová Veronika , Červinková Zuzana
Published: June 2021

Mitochondria play an essential role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Previously, we found that succinate-activated respiration was the most affected mitochondrial parameter in mice with mild NAFLD. In this study, we focused on the role of succinate dehydrogenase (SDH) in NAFLD pathogenesis. To induce the progression of NAFLD to nonalcoholic steatohepatitis (NASH), C57BL/6J mice were fed a Western-style diet (WD) or control diet for 30 weeks. NAFLD severity was evaluated histologically and the expression of selected proteins and genes was assessed. Mitochondrial respiration was measured by high-resolution respirometry. Liver redox status was assessed using glutathione, malondialdehyde, and mitochondrial production of reactive oxygen species (ROS). Metabolomic analysis was performed by GC/MS. WD consumption for 30 weeks led to reduced succinate-activated respiration. We also observed decreased SDH activity, decreased expression of the SDH activator sirtuin 3, decreased gene expression of SDH subunits, and increased levels of hepatic succinate, an important signaling molecule. Succinate receptor 1 (SUCNR1) gene and protein expression were reduced in the livers of WD-fed mice. We did not observe signs of oxidative damage compared to the control group. The changes observed in WD-fed mice appear to be adaptive to prevent mitochondrial respiratory chain overload and massive ROS production.
Cyanine Dyes for Photo-Thermal Therapy: A Comparison of Synthetic Liposomes and Natural Erythrocyte-Based Carriers
Authors: Della Pelle Giulia , Delgado López Andrea , Salord Fiol Marina , Kostevšek Nina
Published: June 2021

Cyanine fluorescent dyes are attractive diagnostic or therapeutic agents due to their excellent optical properties. However, in free form, their use in biological applications is limited due to the short circulation time, instability, and toxicity. Therefore, their encapsulation into nano-carriers might help overcome the above-mentioned issues. In addition to indocyanine green (ICG), which is clinically approved and therefore the most widely used fluorescent dye, we tested the structurally similar and cheaper alternative called IR-820. Both dyes were encapsulated into liposomes. However, due to the synthetic origin of liposomes, they can induce an immunogenic response. To address this challenge, we proposed to use erythrocyte membrane vesicles (EMVs) as “new era” nano-carriers for cyanine dyes. The optical properties of both dyes were investigated in different biological relevant media. Then, the temperature stability and photo-stability of dyes in free form and encapsulated into liposomes and EMVs were evaluated. Nano-carriers efficiently protected dyes from thermal degradation, as well as from photo-induced degradation. Finally, a hemotoxicity study revealed that EMVs seem less hemotoxic dye carriers than clinically approved liposomes. Herein, we showed that EMVs exhibit great potential as nano-carriers for dyes with improved stability and hemocompatibility without losing excellent optical properties.
Brain Mechanisms of COVID-19-Sleep Disorders
Authors: Semyachkina-Glushkovskaya Oxana , Mamedova Aysel , Vinnik Valeria , Klimova Maria , Saranceva Elena , Ageev Vasily , Yu Tingting , Zhu Dan , Penzel Thomas , Kurths Jürgen
Published: June 2021

2020 and 2021 have been unprecedented years due to the rapid spread of the modified severe acute respiratory syndrome coronavirus around the world. The coronavirus disease 2019 (COVID-19) causes atypical infiltrated pneumonia with many neurological symptoms, and major sleep changes. The exposure of people to stress, such as social confinement and changes in daily routines, is accompanied by various sleep disturbances, known as ‘coronasomnia’ phenomenon. Sleep disorders induce neuroinflammation, which promotes the blood–brain barrier (BBB) disruption and entry of antigens and inflammatory factors into the brain. Here, we review findings and trends in sleep research in 2020–2021, demonstrating how COVID-19 and sleep disorders can induce BBB leakage via neuroinflammation, which might contribute to the ‘coronasomnia’ phenomenon. The new studies suggest that the control of sleep hygiene and quality should be incorporated into the rehabilitation of COVID-19 patients. We also discuss perspective strategies for the prevention of COVID-19-related BBB disorders. We demonstrate that sleep might be a novel biomarker of BBB leakage, and the analysis of sleep EEG patterns can be a breakthrough non-invasive technology for diagnosis of the COVID-19-caused BBB disruption.
Disruption of O-Linked N-Acetylglucosamine Signaling in Placenta Induces Insulin Sensitivity in Female Offspring
Authors: Moore Mackenzie , Avula Nandini , Jo Seokwon , Beetch Megan , Alejandro Emilyn U.
Published: June 2021

Placental dysfunction can lead to fetal growth restriction which is associated with perinatal morbidity and mortality. Fetal growth restriction increases the risk of obesity and diabetes later in life. Placental O-GlcNAc transferase (OGT) has been identified as a marker and a mediator of placental insufficiency in the setting of prenatal stress, however, its role in the fetal programming of metabolism and glucose homeostasis remains unknown. We aim to determine the long-term metabolic outcomes of offspring with a reduction in placental OGT. Mice with a partial reduction and a full knockout of placenta-specific OGT were generated utilizing the Cre-Lox system. Glucose homeostasis and metabolic parameters were assessed on a normal chow and a high-fat diet in both male and female adult offspring. A reduction in placental OGT did not demonstrate differences in the metabolic parameters or glucose homeostasis compared to the controls on a standard chow. The high-fat diet provided a metabolic challenge that revealed a decrease in body weight gain (p = 0.02) and an improved insulin tolerance (p = 0.03) for offspring with a partially reduced placental OGT but not when OGT was fully knocked out. Changes in body weight were not associated with changes in energy homeostasis. Offspring with a partial reduction in placental OGT demonstrated increased hepatic Akt phosphorylation in response to insulin treatment (p = 0.02). A partial reduction in placental OGT was protective from weight gain and insulin intolerance when faced with the metabolic challenge of a high-fat diet. This appears to be, in part, due to increased hepatic insulin signaling. The findings of this study contribute to the greater understanding of fetal metabolic programming and the effect of placental OGT on peripheral insulin sensitivity and provides a target for future investigation and clinical applications.
The Influence of Cell Cycle Regulation on Chemotherapy
Authors: Sun Ying , Liu Yang , Ma Xiaoli , Hu Hao
Published: June 2021

Cell cycle regulation is orchestrated by a complex network of interactions between proteins, enzymes, cytokines, and cell cycle signaling pathways, and is vital for cell proliferation, growth, and repair. The occurrence, development, and metastasis of tumors are closely related to the cell cycle. Cell cycle regulation can be synergistic with chemotherapy in two aspects: inhibition or promotion. The sensitivity of tumor cells to chemotherapeutic drugs can be improved with the cooperation of cell cycle regulation strategies. This review presented the mechanism of the commonly used chemotherapeutic drugs and the effect of the cell cycle on tumorigenesis and development, and the interaction between chemotherapy and cell cycle regulation in cancer treatment was briefly introduced. The current collaborative strategies of chemotherapy and cell cycle regulation are discussed in detail. Finally, we outline the challenges and perspectives about the improvement of combination strategies for cancer therapy.
Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against Trypanosoma cruzi
Authors: Scarim Cauê , Olmo Francisco , Ferreira Elizabeth , Chin Chung , Kelly John , Francisco Amanda
Published: June 2021

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using Trypanosoma cruzi strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic. The in vitro activity was assessed by exploiting the fluorescent reporter strain using wash-out assays and real-time microscopy. For animal experimentation, BALB/c mice were inoculated with the bioluminescent reporter strain and assessed by highly sensitive in vivo and ex vivo imaging. Cyclophosphamide treatment was used to promote parasite relapse in the chronic stage of infection. Our data show that NFOH acts by a trypanostatic mechanism, and that it is more active than BZN in vitro against the infectious trypomastigote form of Trypanosoma cruzi. We also found that it is more effective at curing experimental infections in the chronic stage, compared with the acute stage, a feature that it shares with BZN. Therefore, given its reduced toxicity, enhanced anti-trypomastigote activity, and curative properties, NFOH can be considered as a potential therapeutic option for Chagas disease, perhaps in combination with other trypanocidal agents.
Effect of Plasma Treatment on Titanium Surface on the Tissue Surrounding Implant Material
Authors: Tsujita Hitomi , Nishizaki Hiroshi , Miyake Akiko , Takao Seiji , Komasa Satoshi
Published: June 2021

Early osseointegration is important to achieve initial stability after implant placement. We have previously reported that atmospheric-pressure plasma treatment confers superhydrophilicity to titanium. Herein, we examined the effects of titanium implant material, which was conferred superhydrophilicity by atmospheric-pressure plasma treatment, on the surrounding tissue in rat femur. Control and experimental groups included untreated screws and those irradiated with atmospheric-pressure plasma using piezobrush, respectively. The femurs of 8-week-old male Sprague-Dawley rats were used for in vivo experiments. Various data prepared from the Micro-CT analysis showed results showing that more new bone was formed in the test group than in the control group. Similar results were shown in histological analysis. Thus, titanium screw, treated with atmospheric-pressure plasma, could induce high hard tissue differentiation even at the in vivo level. This method may be useful to achieve initial stability after implant placement.
The Comprehensive “Omics” Approach from Metabolomics to Advanced Omics for Development of Immune Checkpoint Inhibitors: Potential Strategies for Next Generation of Cancer Immunotherapy
Authors: Yoon Sang Jun , Lee Chae Bin , Chae Soon Uk , Jo Seong Jun , Bae Soo Kyung
Published: June 2021

In the past decade, immunotherapies have been emerging as an effective way to treat cancer. Among several categories of immunotherapies, immune checkpoint inhibitors (ICIs) are the most well-known and widely used options for cancer treatment. Although several studies continue, this treatment option has yet to be developed into a precise application in the clinical setting. Recently, omics as a high-throughput technique for understanding the genome, transcriptome, proteome, and metabolome has revolutionized medical research and led to integrative interpretation to advance our understanding of biological systems. Advanced omics techniques, such as multi-omics, single-cell omics, and typical omics approaches, have been adopted to investigate various cancer immunotherapies. In this review, we highlight metabolomic studies regarding the development of ICIs involved in the discovery of targets or mechanisms of action and assessment of clinical outcomes, including drug response and resistance and propose biomarkers. Furthermore, we also discuss the genomics, proteomics, and advanced omics studies providing insights and comprehensive or novel approaches for ICI development. The overview of ICI studies suggests potential strategies for the development of other cancer immunotherapies using omics techniques in future studies.
The V-ATPase a3 Subunit: Structure, Function and Therapeutic Potential of an Essential Biomolecule in Osteoclastic Bone Resorption
Authors: Chu Anh , Zirngibl Ralph A. , Manolson Morris F.
Published: June 2021

This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting its critical role in bone physiology. Despite its essential role in bone remodeling and its involvement in bone diseases, little is known about the way in which this subunit is targeted and regulated within osteoclasts. To this end, this review is broadened to include the three other mammalian paralogues (a1, a2 and a4) and the two yeast orthologs (Vph1p and Stv1p). By examining the literature on all of the paralogues/orthologs of the V-ATPase a subunit, we hope to provide insight into the molecular mechanisms and future research directions specific to a3. This review starts with an overview on bone, highlighting the role of V-ATPases in osteoclastic bone resorption. We then cover V-ATPases in other location/functions, highlighting the roles which the four mammalian a subunit paralogues might play in differential targeting and/or regulation. We review the ways in which the energy of ATP hydrolysis is converted into proton translocation, and go in depth into the diverse role of the a subunit, not only in proton translocation but also in lipid binding, cell signaling and human diseases. Finally, the therapeutic implication of targeting a3 specifically for bone diseases and cancer is discussed, with concluding remarks on future directions.
Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation
Authors: Lim Wei-Wen , Neo Melissa , Thanigaimani Shivshankar , Kuklik Pawel , Ganesan Anand N. , Lau Dennis H. , Tsoutsman Tatiana , Kalman Jonathan M. , Semsarian Christopher , Saint David A. , Sanders Prashanthan
Published: June 2021

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.
CDC2 Is an Important Driver of Vascular Smooth Muscle Cell Proliferation via FOXM1 and PLK1 in Pulmonary Arterial Hypertension
Authors: Pal-Ghosh Ruma , Xue Danfeng , Warburton Rod , Hill Nicholas , Polgar Peter , Wilson Jamie L.
Published: June 2021

A key feature of pulmonary arterial hypertension (PAH) is the hyperplastic proliferation exhibited by the vascular smooth muscle cells from patients (HPASMC). The growth inducers FOXM1 and PLK1 are highly upregulated in these cells. The mechanism by which these two proteins direct aberrant growth in these cells is not clear. Herein, we identify cyclin-dependent kinase 1 (CDK1), also termed cell division cycle protein 2 (CDC2), as having a primary role in promoting progress of the cell cycle leading to proliferation in HPASMC. HPASMC obtained from PAH patients and pulmonary arteries from Sugen/hypoxia rats were investigated for their expression of CDC2. Protein levels of CDC2 were much higher in PAH than in cells from normal donors. Knocking down FOXM1 or PLK1 protein expression with siRNA or pharmacological inhibitors lowered the cellular expression of CDC2 considerably. However, knockdown of CDC2 with siRNA or inhibiting its activity with RO-3306 did not reduce the protein expression of FOXM1 or PLK1. Expression of CDC2 and FOXM1 reached its maximum at G1/S, while PLK1 reached its maximum at G2/M phase of the cell cycle. The expression of other CDKs such as CDK2, CDK4, CDK6, CDK7, and CDK9 did not change in PAH HPASMC. Moreover, inhibition via Wee1 inhibitor adavosertib or siRNAs targeting Wee1, Myt1, CDC25A, CDC25B, or CDC25C led to dramatic decreases in CDC2 protein expression. Lastly, we found CDC2 expression at the RNA and protein level to be upregulated in pulmonary arteries during disease progression Sugen/hypoxia rats. In sum, our present results illustrate that the increased expression of FOXM1 and PLK1 in PAH leads directly to increased expression of CDC2 resulting in potentiated growth hyperactivity of PASMC from patients with pulmonary hypertension. Our results further suggest that the regulation of CDC2, or associated regulatory proteins, will prove beneficial in the treatment of this disease.
Feedback, Crosstalk and Competition: Ingredients for Emergent Non-Linear Behaviour in the PI3K/mTOR Signalling Network
Authors: Ghomlaghi Milad , Hart Anthony , Hoang Nhan , Shin Sungyoung , Nguyen Lan K.
Published: June 2021

The PI3K/mTOR signalling pathway plays a central role in the governing of cell growth, survival and metabolism. As such, it must integrate and decode information from both external and internal sources to guide efficient decision-making by the cell. To facilitate this, the pathway has evolved an intricate web of complex regulatory mechanisms and elaborate crosstalk with neighbouring signalling pathways, making it a highly non-linear system. Here, we describe the mechanistic biological details that underpin these regulatory mechanisms, covering a multitude of negative and positive feedback loops, feed-forward loops, competing protein interactions, and crosstalk with major signalling pathways. Further, we highlight the non-linear and dynamic network behaviours that arise from these regulations, uncovered through computational and experimental studies. Given the pivotal role of the PI3K/mTOR network in cellular homeostasis and its frequent dysregulation in pathologies including cancer and diabetes, a coherent and systems-level understanding of the complex regulation and consequential dynamic signalling behaviours within this network is imperative for advancing biology and development of new therapeutic approaches.
Ethanol Extract of Maclura tricuspidata Fruit Protects SH-SY5Y Neuroblastoma Cells against H2O2-Induced Oxidative Damage via Inhibiting MAPK and NF-κB Signaling
Authors: Tian Weishun , Heo Suyoung , Kim Dae-Woon , Kim In-Shik , Ahn Dongchoon , Tae Hyun-Jin , Kim Myung-Kon , Park Byung-Yong
Published: June 2021

Free radical generation and oxidative stress push forward an immense influence on the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Maclura tricuspidata fruit (MT) contains many biologically active substances, including compounds with antioxidant properties. The current study aimed to investigate the neuroprotective effects of MT fruit on hydrogen peroxide (H2O2)-induced neurotoxicity in SH-SY5Y cells. SH-SY5Y cells were pretreated with MT, and cell damage was induced by H2O2. First, the chemical composition and free radical scavenging properties of MT were analyzed. MT attenuated oxidative stress-induced damage in cells based on the assessment of cell viability. The H2O2-induced toxicity caused by ROS production and lactate dehydrogenase (LDH) release was ameliorated by MT pretreatment. MT also promoted an increase in the expression of genes encoding the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). MT pretreatment was associated with an increase in the expression of neuronal genes downregulated by H2O2. Mechanistically, MT dramatically suppressed H2O2-induced Bcl-2 downregulation, Bax upregulation, apoptotic factor caspase-3 activation, Mitogen-activated protein kinase (MAPK) (JNK, ERK, and p38), and Nuclear factor-κB (NF-κB) activation, thereby preventing H2O2-induced neurotoxicity. These results indicate that MT has protective effects against H2O2-induced oxidative damage in SH-SY5Y cells and can be used to prevent and protect against neurodegeneration.
Synthesis of the Bacteriostatic Poly(l-Lactide) by Using Zinc (II)[(acac)(L)H2O] (L = Aminoacid-Based Chelate Ligands) as an Effective ROP Initiator
Authors: Barczyńska-Felusiak Renata , Pastusiak Małgorzata , Rychter Piotr , Kaczmarczyk Bożena , Sobota Michał , Wanic Andrzej , Kaps Anna , Jaworska-Kik Marzena , Orchel Arkadiusz , Dobrzyński Piotr
Published: June 2021

The paper presents a synthesis of poly(l-lactide) with bacteriostatic properties. This polymer was obtained by ring-opening polymerization of the lactide initiated by selected low-toxic zinc complexes, Zn[(acac)(L)H2O], where L represents N-(pyridin-4-ylmethylene) tryptophan or N-(2-pyridin-4-ylethylidene) phenylalanine. These complexes were obtained by reaction of Zn[(acac)2 H2O] and Schiff bases, the products of the condensation of amino acids and 4-pyridinecarboxaldehyde. The composition, structure, and geometry of the synthesized complexes were determined by NMR and FTIR spectroscopy, elemental analysis, and molecular modeling. Both complexes showed the geometry of a distorted trigonal bipyramid. The antibacterial and antifungal activities of both complexes were found to be much stronger than those of the primary Schiff bases. The present study showed a higher efficiency of polymerization when initiated by the obtained zinc complexes than when initiated by the zinc(II) acetylacetonate complex. The synthesized polylactide showed antibacterial properties, especially the product obtained by polymerization initiated by a zinc(II) complex with a ligand based on l-phenylalanine. The polylactide showed a particularly strong antimicrobial effect against Pseudomonas aeruginosa, Staphylococcus aureus, and Aspergillus brasiliensis. At the same time, this polymer does not exhibit fibroblast cytotoxicity.
Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice
Authors: Gaja-Capdevila Núria , Hernández Neus , Zamanillo Daniel , Vela Jose Miguel , Merlos Manuel , Navarro Xavier , Herrando-Grabulosa Mireia
Published: June 2021

Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries.
Genetic Ancestry Inference and Its Application for the Genetic Mapping of Human Diseases
Authors: Suarez-Pajes Eva , Díaz-de Usera Ana , Marcelino-Rodríguez Itahisa , Guillen-Guio Beatriz , Flores Carlos
Published: June 2021

Admixed populations arise when two or more ancestral populations interbreed. As a result of this admixture, the genome of admixed populations is defined by tracts of variable size inherited from these parental groups and has particular genetic features that provide valuable information about their demographic history. Diverse methods can be used to derive the ancestry apportionment of admixed individuals, and such inferences can be leveraged for the discovery of genetic loci associated with diseases and traits, therefore having important biomedical implications. In this review article, we summarize the most common methods of global and local genetic ancestry estimation and discuss the use of admixture mapping studies in human diseases.
Effects of Dietary n–3 and n–6 Polyunsaturated Fatty Acids in Inflammation and Cancerogenesis
Authors: Liput Kamila P. , Lepczyński Adam , Ogłuszka Magdalena , Nawrocka Agata , Poławska Ewa , Grzesiak Agata , Ślaska Brygida , Pareek Chandra S. , Czarnik Urszula , Pierzchała Mariusz
Published: June 2021

The dietary recommendation encourages reducing saturated fatty acids (SFA) in diet and replacing them with polyunsaturated fatty acids (PUFAs) n–3 (omega–3) and n–6 (omega–6) to decrease the risk of metabolic disturbances. Consequently, excessive n–6 PUFAs content and high n–6/n–3 ratio are found in Western-type diet. The importance of a dietary n–6/n–3 ratio to prevent chronic diseases is linked with anti-inflammatory functions of linolenic acid (ALA, 18:3n–3) and longer-chain n–3 PUFAs. Thus, this review provides an overview of the role of oxylipins derived from n–3 PUFAs and oxylipins formed from n–6 PUFAs on inflammation. Evidence of PUFAs’ role in carcinogenesis was also discussed. In vitro studies, animal cancer models and epidemiological studies demonstrate that these two PUFA groups have different effects on the cell growth, proliferation and progression of neoplastic lesions.
Chitinases and Chitinase-Like Proteins as Therapeutic Targets in Inflammatory Diseases, with a Special Focus on Inflammatory Bowel Diseases
Authors: Mazur Marzena , Zielińska Anna , Grzybowski Marcin M. , Olczak Jacek , Fichna Jakub
Published: June 2021

Chitinases belong to the evolutionarily conserved glycosyl hydrolase family 18 (GH18). They catalyze degradation of chitin to N-acetylglucosamine by hydrolysis of the β-(1-4)-glycosidic bonds. Although mammals do not synthesize chitin, they possess two enzymatically active chitinases, i.e., chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase), as well as several chitinase-like proteins (YKL-40, YKL-39, oviductin, and stabilin-interacting protein). The latter lack enzymatic activity but still display oligosaccharides-binding ability. The physiologic functions of chitinases are still unclear, but they have been shown to be involved in the pathogenesis of various human fibrotic and inflammatory disorders, particularly those of the lung (idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, sarcoidosis, and asthma) and the gastrointestinal tract (inflammatory bowel diseases (IBDs) and colon cancer). In this review, we summarize the current knowledge about chitinases, particularly in IBDs, and demonstrate that chitinases can serve as prognostic biomarkers of disease progression. Moreover, we suggest that the inhibition of chitinase activity may be considered as a novel therapeutic strategy for the treatment of IBDs.
Therapeutic Effect of BDNF-Overexpressing Human Neural Stem Cells (F3.BDNF) in a Contusion Model of Spinal Cord Injury in Rats
Authors: Chang Da-Jeong , Cho Hwi-Young , Hwang Seyoung , Lee Nayeon , Choi Chunggab , Lee Hyunseung , Hong Kwan Soo , Oh Seung-Hun , Kim Hyun Sook , Shin Dong Ah , Yoon Young Wook , Song Jihwan
Published: June 2021

The most common type of spinal cord injury is the contusion of the spinal cord, which causes progressive secondary tissue degeneration. In this study, we applied genetically modified human neural stem cells overexpressing BDNF (brain-derived neurotrophic factor) (F3.BDNF) to determine whether they can promote functional recovery in the spinal cord injury (SCI) model in rats. We transplanted F3.BDNF cells via intrathecal catheter delivery after a contusion of the thoracic spinal cord and found that they were migrated toward the injured spinal cord area by MR imaging. Transplanted F3.BDNF cells expressed neural lineage markers, such as NeuN, MBP, and GFAP and were functionally connected to the host neurons. The F3.BDNF-transplanted rats exhibited significantly improved locomotor functions compared with the sham group. This functional recovery was accompanied by an increased volume of spared myelination and decreased area of cystic cavity in the F3.BDNF group. We also observed that the F3.BDNF-transplanted rats showed reduced numbers of Iba1- and iNOS-positive inflammatory cells as well as GFAP-positive astrocytes. These results strongly suggest the transplantation of F3.BDNF cells can modulate inflammatory cells and glia activation and also improve the hyperalgesia following SCI.
The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies
Authors: Özdirik Burcin , Müller Tobias , Wree Alexander , Tacke Frank , Sigal Michael
Published: June 2021

Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.
Systematic Review of Alexithymia in the Population of Hemodialysis Patients
Authors: Pojatić Đorđe , Tolj Ivana , Pezerović Davorin , Degmečić Dunja
Published: June 2021

Alexithymia is a construct defined as the inability to differentiate between emotional experiences and bodily sensations. According to existing knowledge, alexithymia may have a major effect on the process of treatment and the outcome of the hemodialysis disease. The objective of this literature review was to determine the significance that alexithymia has for compliance and variables of clinical and mental health in the population of hemodialysis patients. For the above purpose, bibliographic databases “MEDLINE” and “Web of Science” were searched. The matrix method was used in analysis of articles. Searching both databases resulted in 248 articles. After applying exclusion and inclusion criteria, we included results of 13 articles in the literature review. The results of the search are findings regarding the prevalence and correlation of alexithymia with variables of clinical and mental health in hemodialysis patients. Alexithymia is significantly more common in the population of hemodialysis patients, and it has a negative effect on their mental and somatic health. Alexithymia levels in hemodialysis patients are more pronounced in cases where there is a greater number of comorbidities. Alexithymia is the predictor of high mortality rate in the population of hemodialysis patients, independent of other comorbidities.
Responding to Negative Electronic Word of Mouth to Improve Purchase Intention
Authors: Zinko Robert , Patrick Angela , Furner Christopher P. , Gaines Shalanda , Kim Mi Dya , Negri Matthew , Orellana Elsy , Torres Shelby , Villarreal Carmen
Published: June 2021

Retailers have little control over what their customers say about their products and services online. Review platforms (e.g., Yelp and Travelocity) are rife with negativity, from both real customers with bad experiences and from fake reviews created by competitors. These negative reviews have been shown to influence the purchasing behavior of future consumers. Many platforms do afford companies some control by including them in the online conversation about their products or services. Crafting a response to a poor review which appeals to future consumers may mitigate some of the negative outcomes associated with that review. This study advances our knowledge of responding to negative reviews by adding to the growing body of research, using a simulation-based experiment to test the influence of three elements of a review response on purchase intention (i.e., an apology, an explanation and a pledge to correct the problem identified in the review). In doing so, the data show that purchase intention increases only when a response contains all three elements. Implications for e-commerce researchers and review platform developers are discussed.
The Energy System of an Ecovillage: Barriers and Enablers
Authors: Szabó Zita , Prohászka Viola , Sallay Ágnes
Published: June 2021

Nowadays, in the context of climate change, efficient energy management and increasing the share of renewable energy sources in the energy mix are helping to reduce greenhouse gases. In this research, we present the energy system and its management and the possibilities of its development through the example of an ecovillage. The basic goal of such a community is to be economically, socially, and ecologically sustainable, so the study of energy system of an ecovillage is especially justified. As the goal of this community is sustainability, potential technological and efficiency barriers to the use of renewable energy sources will also become visible. Our sample area is Visnyeszéplak ecovillage, where we examined the energy production and consumption habits and possibilities of the community with the help of interviews, literature, and map databases. By examining the spatial structure of the settlement, we examined the spatial structure of energy management. We formulated development proposals that can make the community’s energy management system more efficient.
Dynamic Mechanical Properties of Several High-Performance Single Fibers
Authors: Lei Xudong , Xiao Kailu , Wu Xianqian , Huang Chenguang
Published: June 2021

High-performance fiber-reinforced composites (FRCs) are widely used in bulletproof structures, in which the mechanical properties of the single fibers play a crucial role in ballistic resistance. In this paper, the quasi-static and dynamic mechanical properties of three commonly used fibers, single aramid III, polyimide (PI), and poly-p-phenylenebenzobisoxazole (PBO) fibers are measured by a small-scale tensile testing machine and mini-split Hopkinson tension bar (mini-SHTB), respectively. The results show that the PBO fiber is superior to the other two fibers in terms of strength and elongation. Both the PBO and aramid III fibers exhibit an obvious strain-rate strengthening effect, while the tensile strength of the PI fiber increases initially, then decreases with the increase in strain rate. In addition, the PBO and aramid III fibers show ductile-to-brittle transition with increasing strain rate, and the PI fiber possesses plasticity in the employed strain rate range. Under a high strain rate, a noticeable radial splitting and fibrillation is observed for the PBO fiber, which can explain the strain-rate strengthening effect. Moreover, the large dispersion of the strength at the same strain rate is observed for all the single fibers, and it increases with increasing strain rate, which can be ascribed to the defects in the fibers. Considering the effect of strain rate, only the PBO fiber follows the Weibull distribution, suggesting that the hypothesis of Weibull distribution for single fibers needs to be revisited.
Tri-Planar Geometric Dimensioning and Tolerancing Characteristics of SS 316L Laser Powder Bed Fusion Process Test Artifacts and Effect of Base Plate Removal
Authors: Rupal Baltej Singh , Singh Tegbir , Wolfe Tonya , Secanell Marc , Qureshi Ahmed Jawad
Published: June 2021

The precision of LPBF manufactured parts is quantified by characterizing the geometric tolerances based on the ISO 1101 standard. However, there are research gaps in the characterization of geometric tolerance of LPBF parts. A literature survey reveals three significant research gaps: (1) systematic design of benchmarks for geometric tolerance characterization with minimum experimentation; (2) holistic geometric tolerance characterization in different orientations and with varying feature sizes; and (3) a comparison of results, with and without the base plate. This research article focuses on addressing these issues by systematically designing a benchmark that can characterize geometric tolerances in three principal planar directions. The designed benchmark was simulated using the finite element method, manufactured using a commercial LPBF process using stainless steel (SS 316L) powder, and the geometric tolerances were characterized. The effect of base plate removal on the geometric tolerances was quantified. Simulation and experimental results were compared to understand tolerance variations using process variations such as base plate removal, orientation, and size. The tolerance zone variations not only validate the need for systematically designed benchmarks, but also for tri-planar characterization. Simulation and experimental result comparisons provide quantitative information about the applicability of numerical simulation for geometric tolerance prediction for the LPBF process.
Analysis of the Crystallization Kinetics and Thermal Stability of the Amorphous Mg72Zn24Ca4 Alloy
Authors: Opitek Bartosz , Lelito Janusz , Szucki Michał , Piwowarski Grzegorz , Gondek Łukasz , Rogal Łukasz
Published: June 2021

The aim of this study was to analyze the crystallization of the Mg72Zn24Ca4 metallic glass alloy. The crystallization process of metallic glass Mg72Zn24Ca4 was investigated by means of the differential scanning calorimetry. The glass-forming ability and crystallization are both strongly dependent on the heating rate. The crystallization kinetics, during the isothermal annealing, were modelled by the Johnson–Mehl–Avrami equation. Avrami exponents were from 2.7 to 3.51, which indicates diffusion-controlled grain growth. Local exponents of the Johnson–Mehl–Avrami equation were also calculated. In addition, the Mg phase—being the isothermal crystallization product—was found, and the diagram of the time–temperature phase transformation was developed. This diagram enables the reading of the start and end times of the crystallization process, occurring in amorphous ribbons of the Mg72Zn24Ca4 alloy on the isothermal annealing temperature. The research showed high stability of the amorphous structure of Mg72Zn24Ca4 alloy at human body temperature.