bluuebunny/crossref_metadata_2025 huggingface dataset:
A Scoping Review of Nature, Land, and Environmental Connectedness and Relatedness
Authors: Keaulana Samantha , Kahili-Heede Melissa , Riley Lorinda , Park Mei Linn N. , Makua Kuaiwi Laka , Vegas Jetney Kahaulahilahi , Antonio Mapuana C. K.
Published: May 2021

The importance of nature and the environment in relation to human health is coalescing, as demonstrated by the increased research that attempts to measure nature connectedness and relatedness. These findings align with constructs of cultural connectedness that assess for land connectedness as part of Indigenous ways of knowing. From an Indigenous worldview, relationships with the environment are critical to wellbeing. The purpose of this comprehensive systematic scoping literature review was two-fold: (1) identify and summarize existing measures of land, nature, and/or environmental connectedness, relatedness, and attitudes and (2) evaluate the psychometric properties of these scales. In total, 1438 articles were retrieved from select databases including PubMed/MEDLINE, PsycINFO, CINAHL (EBSCO), and Academic Search Complete (EBSCO). The final searches and application of the inclusion/exclusion criteria resulted in 57 unique articles and 38 scales categorized as connectedness and relatedness scales (n = 9 scales), attitudinal and values-based scales (n = 16 scales), cultural and spiritually based scales (n = 9 scales), and paradigm-based scales (n = 4 scales) (articles could be placed in multiple categories). Psychometric properties and general outcomes associated with nature-related scales are reported, with implications for future education, research, practice, and policy.
Modeling System Risk in the South African Insurance Sector: A Dynamic Mixture Copula Approach
Authors: Muteba Mwamba John Weirstrass , Angaman Ehounou Serge Eloge Florentin
Published: May 2021

In this paper, a dynamic mixture copula model is used to estimate the marginal expected shortfall in the South African insurance sector. We also employ the generalized autoregressive score model (GAS) to capture the dynamic asymmetric dependence between the insurers’ returns and the stock market returns. Furthermore, the paper implements a ranking framework that expresses to what extent individual insurers are systemically important in the South African economy. We use the daily stock return of five South African insurers listed on the Johannesburg Stock Exchange from November 2007 to June 2020. We find that Sanlam and Discovery contribute the most to systemic risk, and Santam turns out to be the least systemically risky insurance company in the South African insurance sector. Our findings defy common belief whereby only banks are systemically risky financial institutions in South Africa and should undergo stricter regulatory measures. However, our results indicate that stricter regulations such as higher capital and loss absorbency requirements should be required for systemically risky insurers in South Africa.
Pedestrian Routing and Perspectives: WayFinder’s Route down the Lane—Come on with the Rain
Authors: Opach Tomasz , Navarra Carlo , Rød Jan Ketil , Neset Tina-Simone
Published: May 2021

People living in urban areas are often exposed to heat and inundation caused by heavy rains. Therefore, pedestrian routing in areas exposed to weather-related threats can be of value to citizens. In this study, water accumulated on roads, sidewalks and footpaths after rainfall and snowmelt was used as a case of adverse environmental conditions. Pedestrian routing was implemented in the web tool WayFinder and a group of 56 participants tested the tool in Trondheim, Norway. The study aimed to gain insight into their perspectives on the implemented pedestrian routing functionality to examine to what extent pedestrians find such functionality helpful for navigating in regions that are likely to be inundated. Each participant was asked to (1) use the tool in practice; (2) when walking, report on observed inundated areas; and (3) complete three questionnaires to provide feedback on the WayFinder tool. Although most of the participants were successful in using WayFinder, they preferred the selection of routes that passed through areas likely to be inundated and obtaining information about the risks than selecting a single route suggestion that already avoided exposed areas.
Paradigm of Geological Mapping of the Adıyaman Fault Zone of Eastern Turkey Using Landsat 8 Remotely Sensed Data Coupled with PCA, ICA, and MNFA Techniques
Authors: Khalifa Abdelrahman , Bashir Bashar , Çakir Ziyadin , Kaya Şinasi , Alsalman Abdullah , Henaish Ahmed
Published: May 2021

A principal and independent component analysis (PCA and ICA) and a minimum noise fraction analysis (MNFA) were applied in this study to Landsat 8 Operational Land Imager (OLI) images along the Adıyaman fault zone in Eastern Turkey. These analyses indicated that the lithologic units, fault patterns, and the morphological and structural features can be mapped highly accurately by using spectral-matching techniques in regions where rocks are well exposed. An inspection of all possible band combinations indicated that the PCA 134 and 231 and the ICA 132 band combinations give the best false color composite images for identifying the lithological units and contacts. The findings of the MNFA band combinations show that the MNFA 521 band combination also is robust for discriminating the lithological units, particularly Quaternary clastic units (colluvium/alluvium). MNFA band 1 alone provides the best image for tracing the tectonic and structural elements in the study area. The new up-to-date lithologic map of the Adıyaman fault zone we produced upon the interpretation of the processed OLI images reveals several river channels that are offset and beheaded by the Adıyaman fault, which verifies its Quaternary activity. This study demonstrated that, when used with the OLI data, the PCA, ICA, and MNFA are very powerful for lithological and structural mapping in actively deforming tectonic zones and hence can be applied to other regions elsewhere in the world where the climate is arid to semiarid, and the vegetation cover is scarce.
Renal Handling of Albumin—From Early Findings to Current Concepts
Authors: Gburek Jakub , Konopska Bogusława , Gołąb Krzysztof
Published: May 2021

Albumin is the main protein of blood plasma, lymph, cerebrospinal and interstitial fluid. The protein participates in a variety of important biological functions, such as maintenance of proper colloidal osmotic pressure, transport of important metabolites and antioxidant action. Synthesis of albumin takes place mainly in the liver, and its catabolism occurs mostly in vascular endothelium of muscle, skin and liver, as well as in the kidney tubular epithelium. Long-lasting investigation in this area has delineated the principal route of its catabolism involving glomerular filtration, tubular endocytic uptake via the multiligand scavenger receptor tandem—megalin and cubilin-amnionless complex, as well as lysosomal degradation to amino acids. However, the research of the last few decades indicates that also additional mechanisms may operate in this process to some extent. Direct uptake of albumin in glomerular podocytes via receptor for crystallizable region of immunoglobulins (neonatal FC receptor) was demonstrated. Additionally, luminal recycling of short peptides into the bloodstream and/or back into tubular lumen or transcytosis of whole molecules was suggested. The article discusses the molecular aspects of these processes and presents the major findings and controversies arising in the light of the research concerning the last decade. Their better characterization is essential for further research into pathophysiology of proteinuric renal failure and development of effective therapeutic strategies.
Acute and Chronic Pain from Facial Skin and Oral Mucosa: Unique Neurobiology and Challenging Treatment
Authors: Chung Man-Kyo , Wang Sheng , Oh Se-Lim , Kim Yu Shin
Published: May 2021

The oral cavity is a portal into the digestive system, which exhibits unique sensory properties. Like facial skin, the oral mucosa needs to be exquisitely sensitive and selective, in order to detect harmful toxins versus edible food. Chemosensation and somatosensation by multiple receptors, including transient receptor potential channels, are well-developed to meet these needs. In contrast to facial skin, however, the oral mucosa rarely exhibits itch responses. Like the gut, the oral cavity performs mechanical and chemical digestion. Therefore, the oral mucosa needs to be insensitive, to some degree, in order to endure noxious irritation. Persistent pain from the oral mucosa is often due to ulcers, involving both tissue injury and infection. Trigeminal nerve injury and trigeminal neuralgia produce intractable pain in the orofacial skin and the oral mucosa, through mechanisms distinct from those seen in the spinal area, which is particularly difficult to predict or treat. The diagnosis and treatment of idiopathic chronic pain, such as atypical odontalgia (idiopathic painful trigeminal neuropathy or post-traumatic trigeminal neuropathy) and burning mouth syndrome, remain especially challenging. The central integration of gustatory inputs might modulate chronic oral and facial pain. A lack of pain in chronic inflammation inside the oral cavity, such as chronic periodontitis, involves the specialized functioning of oral bacteria. A more detailed understanding of the unique neurobiology of pain from the orofacial skin and the oral mucosa should help us develop novel methods for better treating persistent orofacial pain.
Prostaglandin E2 Enhances Gap Junctional Intercellular Communication in Clonal Epithelial Cells
Authors: Ogazon del Toro Alejandro , Jimenez Lidia , Serrano Rubi Mauricio , Castillo Aida , Hinojosa Lorena , Martinez Rendon Jacqueline , Cereijido Marcelino , Ponce Arturo
Published: May 2021

Prostaglandins are a group of lipids that produce diverse physiological and pathological effects. Among them, prostaglandin E2 (PGE2) stands out for the wide variety of functions in which it participates. To date, there is little information about the influence of PGE2 on gap junctional intercellular communication (GJIC) in any type of tissue, including epithelia. In this work, we set out to determine whether PGE2 influences GJIC in epithelial cells (MDCK cells). To this end, we performed dye (Lucifer yellow) transfer assays to compare GJIC of MDCK cells treated with PGE2 and untreated cells. Our results indicated that (1) PGE2 induces a statistically significant increase in GJIC from 100 nM and from 15 min after its addition to the medium, (2) such effect does not require the synthesis of new mRNA or proteins subunits but rather trafficking of subunits already synthesized, and (3) such effect is mediated by the E2 receptor, which, in turn, triggers a signaling pathway that includes activation of adenylyl cyclase and protein kinase A (PKA). These results widen the knowledge regarding modulation of gap junctional intercellular communication by prostaglandins.
Genomic Characterization of Cisplatin Response Uncovers Priming of Cisplatin-Induced Genes in a Resistant Cell Line
Authors: Golan Berman Hadar , Chauhan Pooja , Shalev Shira , Hassanain Hiba , Parnas Avital , Adar Sheera
Published: May 2021

Cisplatin is a chemotherapy drug that kills cancer cells by damaging their DNA. In human cells, this damage is repaired primarily by nucleotide excision repair. While cisplatin is generally effective, many cancers exhibit initial or acquired resistance to it. Here, we studied cisplatin resistance in a defined cell line system. We conducted a comprehensive genomic characterization of the cisplatin-sensitive A2780 ovarian cancer cell line compared to A2780cis, its resistant derivative. The resistant cells acquired less damage, but had similar repair kinetics. Genome-wide mapping of nucleotide excision repair showed a shift in the resistant cells from global genome towards transcription-coupled repair. By mapping gene expression changes following cisplatin treatment, we identified 56 upregulated genes that have higher basal expression in the resistant cell line, suggesting they are primed for a cisplatin response. More than half of these genes are novel to cisplatin- or damage-response. Six out of seven primed genes tested were upregulated in response to cisplatin in additional cell lines, making them attractive candidates for future investigation. These novel candidates for cisplatin resistance could prove to be important prognostic markers or targets for tailored combined therapy in the future.
Microglia in Neurodegenerative Events—An Initiator or a Significant Other?
Authors: Harry Gaylia Jean
Published: May 2021

A change in microglia structure, signaling, or function is commonly associated with neurodegeneration. This is evident in the patient population, animal models, and targeted in vitro assays. While there is a clear association, it is not evident that microglia serve as an initiator of neurodegeneration. Rather, the dynamics imply a close interaction between the various cell types and structures in the brain that orchestrate the injury and repair responses. Communication between microglia and neurons contributes to the physiological phenotype of microglia maintaining cells in a surveillance state and allows the cells to respond to events occurring in their environment. Interactions between microglia and astrocytes is not as well characterized, nor are interactions with other members of the neurovascular unit; however, given the influence of systemic factors on neuroinflammation and disease progression, such interactions likely represent significant contributes to any neurodegenerative process. In addition, they offer multiple target sites/processes by which environmental exposures could contribute to neurodegenerative disease. Thus, microglia at least play a role as a significant other with an equal partnership; however, claiming a role as an initiator of neurodegeneration remains somewhat controversial.
Potency Assessment of Dendritic Cell Anticancer Vaccine: Validation of the Co-Flow DC Assay
Authors: Carloni Silvia , Piccinini Claudia , Pancisi Elena , Soldati Valentina , Stefanelli Monica , Granato Anna Maria , Ibrahim Toni , Petrini Massimiliano
Published: May 2021

For many years, oncological clinical trials have taken advantage of dendritic cells (DC) for the design of DC-based cellular therapies. This has required the design of suitable quality control assays to evaluate the potency of these products. The purpose of our work was to develop and validate a novel bioassay that uses flow cytometry as a read-out measurement. In this method, CD3+ cells are labeled with a fluorescent dye and the DC costimulatory activity is measured by the degree of T cell proliferation caused by the DC–T cell interaction. The validation of the method was achieved by the evaluation of essential analytical parameters defined by international guidelines. Our results demonstrated that the method could be considered specific, selective, and robust. The comparison between measured values and estimated true values confirmed a high level of accuracy and a lack of systematic error. Repeated experiments have shown the reproducibility of the assay and the proportionality between the potency and the DC amount has proven its linearity. Our results suggest that the method is compliant with the guidelines and could be adopted as a quality control assay or batch-release testing within GMP facilities.
Increased Expression of Retinol-Binding Protein 4 in Ovarian Endometrioma and Its Possible Role in the Pathogenesis of Endometriosis
Authors: Lee Jae Chul , Kim Sung Hoon , Oh Young Sang , Kim Ju Hee , Lee Sa Ra , Chae Hee Dong
Published: May 2021

Although endometriosis is a benign disease characterized by the presence of endometrial tissues outside the uterus, ectopic endometrial cells can exhibit malignant biological behaviors. Retinol-binding protein4 (RBP4) is a novel adipocyte-derived cytokine, which has important roles in regulating insulin sensitivity and energy metabolism. RBP4 is a potent modulator of gene transcription, and acts by directly controlling cell growth, invasiveness, proliferation and differentiation. Here, we evaluated the possible role of RBP4 in the pathogenesis of endometriosis. We compared the levels of RBP4 in the tissues and peritoneal fluid (PF) of women with and without endometriosis and evaluated the in vitro effects of RBP4 on the viability, invasiveness, and proliferation of endometrial stromal cells (ESCs). RBP4 levels were significantly higher in the PF of the women in the endometriosis group than in the controls. RBP4 immunoreactivity was significantly higher in the ovarian endometriomas of women with advanced stage endometriosis than those of controls. In vitro treatment with human recombinant-RBP4 significantly increased the viability, bromodeoxyuridine expression, and invasiveness of ESCs. Transfection with RBP4 siRNA significantly reduced ESC viability and invasiveness. These findings suggest that RBP4 partakes in the pathogenesis of endometriosis by increasing the viability, proliferation and invasion of endometrial cells.
Baicalein Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo
Authors: Lu Hao , Li Xiaodan , Wang Gaoyan , Wang Chenchen , Feng Jiajia , Lu Wenjia , Wang Xiangru , Chen Huanchun , Liu Manli , Tan Chen
Published: May 2021

As an important zoonotic pathogen, Streptococcus suis (S. suis) infection has been reported to be a causative agent for variety of diseases in humans and animals, especially Streptococcal toxic shock-like syndrome (STSLS), which is commonly seen in cases of severe S. suis infection. STSLS is often accompanied by excessive production of inflammatory cytokines, which is the main cause of death. This calls for development of new strategies to avert the damage caused by STSLS. In this study, we found for the first time that Baicalein, combined with ampicillin, effectively improved severe S. suis infection. Further experiments demonstrated that baicalein significantly inhibited the hemolytic activity of SLY by directly binding to SLY and destroying its secondary structure. Cell-based assays revealed that Baicalein did not exert toxic effects and conferred protection in S. suis-infected cells. Interestingly, compared with ampicillin alone, Baicalein combined with ampicillin resulted in a higher survival rate in mice severely infected with S. suis. At the same time, we found that baicalein can be combined with meropenem against MRSA. In conclusion, these results indicate that baicalein has a good application prospect.
Role Played by Receptors for Advanced Glycosylation End Products in Corneal Endothelial Cells after HSV-1 Infection
Authors: Miyazaki Dai , Kandori-Inoue Michiko , Shimizu Yumiko , Ohtani Fumie , Chono Ikuyo , Inoue Yoshitsugu , Yamagami Satoru
Published: May 2021

Senescence, sterile inflammation, and infection cause dysfunction of corneal endothelial cells, leading to visual morbidity that may require corneal transplantation. With increasing age, the extracellular matrix is modified by non-enzymatic glycation forming advanced glycation end products (AGEs). The modifications are primarily sensed by the receptors for the AGEs (RAGE) and are manifested as a type I interferon response. Interestingly, in our study, human corneal endothelial cells (HCEn) cells did not respond to the typical RAGE ligands, including the AGEs, high mobility group box 1 (HMGB1), and serum amyloid-A (SAA). Instead, HCEn cells responded exclusively to the CpG DNA, which is possessed by typical corneal pathogen, herpes simplex virus-1 (HSV-1). Upon HSV-1 infection, the surface expression of RAGE was increased, and endocytosed HSV-1 was associated with RAGE and CpG DNA receptor, TLR9. RAGE DNA transfection markedly increased interferon-β secretion by CpG DNA or HSV-1 infection. HSV-1 infection-induced interferon-β secretion was abolished by TLR9 inhibition and partially by RAGE inhibition. Global transcriptional response analysis confirmed that RAGE and TLR9 were both significantly involved in type I interferon responses. We conclude that RAGE is a sensor of HSV-1 infection and provokes a type I interferon response.
Aging-Related Metabolic Dysfunction in the Salivary Gland: A Review of the Literature
Authors: Toan Nguyen Khanh , Ahn Sang-Gun
Published: May 2021

Aging-related salivary dysfunction commonly induces the poor oral health, including decreased saliva flow and dental caries. Although the clinical significance of the salivary glands is well-known, the complex metabolic pathways contributing to the aging-dysfunction process are only beginning to be uncovered. Here, we provide a comprehensive overview of the metabolic changes in aging-mediated salivary gland dysfunction as a key aspect of oral physiology. Several metabolic neuropeptides or hormones are involved in causing or contributing to salivary gland dysfunction, including hyposalivation and age-related diseases. Thus, aging-related metabolism holds promise for early diagnosis, increased choice of therapy and the identification of new metabolic pathways that could potentially be targeted in salivary gland dysfunction.
Erythrocytes: Central Actors in Multiple Scenes of Atherosclerosis
Authors: Turpin Chloé , Catan Aurélie , Meilhac Olivier , Bourdon Emmanuel , Canonne-Hergaux François , Rondeau Philippe
Published: May 2021

The development and progression of atherosclerosis (ATH) involves lipid accumulation, oxidative stress and both vascular and blood cell dysfunction. Erythrocytes, the main circulating cells in the body, exert determinant roles in the gas transport between tissues. Erythrocytes have long been considered as simple bystanders in cardiovascular diseases, including ATH. This review highlights recent knowledge concerning the role of erythrocytes being more than just passive gas carriers, as potent contributors to atherosclerotic plaque progression. Erythrocyte physiology and ATH pathology is first described. Then, a specific chapter delineates the numerous links between erythrocytes and atherogenesis. In particular, we discuss the impact of extravasated erythrocytes in plaque iron homeostasis with potential pathological consequences. Hyperglycaemia is recognised as a significant aggravating contributor to the development of ATH. Then, a special focus is made on glycoxidative modifications of erythrocytes and their role in ATH. This chapter includes recent data proposing glycoxidised erythrocytes as putative contributors to enhanced atherothrombosis in diabetic patients.
Novel Characterization of Constipation Phenotypes in ICR Mice Orally Administrated with Polystyrene Microplastics
Authors: Choi Yun Ju , Park Jun Woo , Kim Ji Eun , Lee Su Jin , Gong Jeong Eun , Jung Young-Suk , Seo Sungbaek , Hwang Dae Youn
Published: May 2021

Indirect evidence has determined the possibility that microplastics (MP) induce constipation, although direct scientific proof for constipation induction in animals remains unclear. To investigate whether oral administration of polystyrene (PS)-MP causes constipation, an alteration in the constipation parameters and mechanisms was analyzed in ICR mice, treated with 0.5 μm PS-MP for 2 weeks. Significant alterations in water consumption, stool weight, stool water contents, and stool morphology were detected in MP treated ICR mice, as compared to Vehicle treated group. Also, the gastrointestinal (GI) motility and intestinal length were decreased, while the histopathological structure and cytological structure of the mid colon were remarkably altered in treated mice. Mice exposed to MP also showed a significant decrease in the GI hormone concentration, muscarinic acetylcholine receptors (mAChRs) expression, and their downstream signaling pathway. Subsequent to MP treatment, concentrations of chloride ion and expressions of its channel (CFTR and CIC-2) were decreased, whereas expressions of aquaporin (AQP)3 and 8 for water transportation were downregulated by activation of the mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB signaling pathway. These results are the first to suggest that oral administration of PS-MP induces chronic constipation through the dysregulation of GI motility, mucin secretion, and chloride ion and water transportation in the mid colon.
Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis
Authors: Tamura Ryota
Published: May 2021

Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients.
Genetic Predisposition to the Mortality in Septic Shock Patients: From GWAS to the Identification of a Regulatory Variant Modulating the Activity of a CISH Enhancer
Authors: Rosier Florian , Brisebarre Audrey , Dupuis Claire , Baaklini Sabrina , Puthier Denis , Brun Christine , Pradel Lydie C. , Rihet Pascal , Payen Didier
Published: May 2021

The high mortality rate in septic shock patients is likely due to environmental and genetic factors, which influence the host response to infection. Two genome-wide association studies (GWAS) on 832 septic shock patients were performed. We used integrative bioinformatic approaches to annotate and prioritize the sepsis-associated single nucleotide polymorphisms (SNPs). An association of 139 SNPs with death based on a false discovery rate of 5% was detected. The most significant SNPs were within the CISH gene involved in cytokine regulation. Among the 139 SNPs associated with death and the 1311 SNPs in strong linkage disequilibrium with them, we investigated 1439 SNPs within non-coding regions to identify regulatory variants. The highest integrative weighted score (IW-score) was obtained for rs143356980, indicating that this SNP is a robust regulatory candidate. The rs143356980 region is located in a non-coding region close to the CISH gene. A CRISPR-Cas9-mediated deletion of this region and specific luciferase assays in K562 cells showed that rs143356980 modulates the enhancer activity in K562 cells. These analyses allowed us to identify several genes associated with death in patients with septic shock. They suggest that genetic variations in key genes, such as CISH, perturb relevant pathways, increasing the risk of death in sepsis patients.
Mitochondrial DNA Alterations in Glioblastoma (GBM)
Authors: Leão Barros Mariceli Baia , Pinheiro Danilo do Rosário , Borges Bárbara do Nascimento
Published: May 2021

Glioblastoma (GBM) is an extremely aggressive tumor originating from neural stem cells of the central nervous system, which has high histopathological and genomic diversity. Mitochondria are cellular organelles associated with the regulation of cellular metabolism, redox signaling, energy generation, regulation of cell proliferation, and apoptosis. Accumulation of mutations in mitochondrial DNA (mtDNA) leads to mitochondrial dysfunction that plays an important role in GBM pathogenesis, favoring abnormal energy and reactive oxygen species production and resistance to apoptosis and to chemotherapeutic agents. The present review summarizes the known mitochondrial DNA alterations related to GBM, their cellular and metabolic consequences, and their association with diagnosis, prognosis, and treatment.
Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects
Authors: Palmiero Giuseppe , Cesaro Arturo , Vetrano Erica , Pafundi Pia Clara , Galiero Raffaele , Caturano Alfredo , Moscarella Elisabetta , Gragnano Felice , Salvatore Teresa , Rinaldi Luca , Calabrò Paolo , Sasso Ferdinando Carlo
Published: May 2021

Heart failure (HF) affects up to over 20% of patients with type 2 diabetes (T2DM), even more in the elderly. Although, in T2DM, both hyperglycemia and the proinflammatory status induced by insulin resistance are crucial in cardiac function impairment, SGLT2i cardioprotective mechanisms against HF are several. In particular, these beneficial effects seem attributable to the significant reduction of intracellular sodium levels, well-known to exert a cardioprotective role in the prevention of oxidative stress and consequent cardiomyocyte death. From a molecular perspective, patients’ exposure to gliflozins’ treatment mimics nutrient and oxygen deprivation, with consequent autophagy stimulation. This allows to maintain the cellular homeostasis through different degradative pathways. Thus, since their introduction in the clinical practice, the hypotheses on SGLT2i mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. This provides their consequent cardioprotective effect, which justifies its significant reduction in CV events, especially in populations at higher risk. Finally, the updated clinical evidence of SGLT2i benefits on HF was summarized. Thus, this review aimed to analyze the cardioprotective mechanisms of sodium glucose transporter 2 inhibitors (SGLT2i) in patients with HF, as well as their clinical impact on cardiovascular events.
LEDGF/p75 Is Required for an Efficient DNA Damage Response
Authors: Liedtke Victoria , Schröder Christian , Roggenbuck Dirk , Weiss Romano , Stohwasser Ralf , Schierack Peter , Rödiger Stefan , Schenk Lysann
Published: May 2021

Lens epithelium-derived growth factor splice variant of 75 kDa (LEDGF/p75) plays an important role in cancer, but its DNA-damage repair (DDR)-related implications are still not completely understood. Different LEDGF model cell lines were generated: a complete knock-out of LEDGF (KO) and re-expression of LEDGF/p75 or LEDGF/p52 using CRISPR/Cas9 technology. Their proliferation and migration capacity as well as their chemosensitivity were determined, which was followed by investigation of the DDR signaling pathways by Western blot and immunofluorescence. LEDGF-deficient cells exhibited a decreased proliferation and migration as well as an increased sensitivity toward etoposide. Moreover, LEDGF-depleted cells showed a significant reduction in the recruitment of downstream DDR-related proteins such as replication protein A 32 kDa subunit (RPA32) after exposure to etoposide. The re-expression of LEDGF/p75 rescued all knock-out effects. Surprisingly, untreated LEDGF KO cells showed an increased amount of DNA fragmentation combined with an increased formation of γH2AX and BRCA1. In contrast, the protein levels of ubiquitin-conjugating enzyme UBC13 and nuclear proteasome activator PA28γ were substantially reduced upon LEDGF KO. This study provides for the first time an insight that LEDGF is not only involved in the recruitment of CtIP but has also an effect on the ubiquitin-dependent regulation of DDR signaling molecules and highlights the role of LEDGF/p75 in homology-directed DNA repair.
Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells
Authors: Valla Sofía , Hassan Nourhan , Vitale Daiana Luján , Madanes Daniela , Spinelli Fiorella Mercedes , Teixeira Felipe C. O. B. , Greve Burkhard , Espinoza-Sánchez Nancy Adriana , Cristina Carolina , Alaniz Laura , Götte Martin
Published: May 2021

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors.
The Role of Interleukin-1-Receptor-Antagonist in Bladder Cancer Cell Migration and Invasion
Authors: Schneider Lisa , Liu Junnan , Zhang Cheng , Azoitei Anca , Meessen Sabine , Zheng Xi , Cremer Catharina , Gorzelanny Christian , Kempe-Gonzales Sybille , Brunner Cornelia , Wezel Felix , Bolenz Christian , Gunes Cagatay , John Axel
Published: May 2021

Background: The interleukin-1-receptor antagonist IL1RA (encoded by the IL1RN gene) is a potent competitive antagonist to interleukin-1 (IL1) and thereby is mainly involved in the regulation of inflammation. Previous data indicated a role of IL1RA in muscle-invasive urothelial carcinoma of the bladder (UCB) as well as an IL1-dependent decrease in tissue barrier function, potentially contributing to cancer cell invasion. Objective: Based on these observations, here we investigated the potential roles of IL1RA, IL1A, and IL1B in bladder cancer cell invasion in vitro. Methods: Cell culture, real-time impedance sensing, invasion assays (Boyden chamber, pig bladder model), qPCR, Western blot, ELISA, gene overexpression. Results: We observed a loss of IL1RA expression in invasive, high-grade bladder cancer cell lines T24, UMUC-3, and HT1197 while IL1RA expression was readily detectable in the immortalized UROtsa cells, the non-invasive bladder cancer cell line RT4, and in benign patient urothelium. Thus, we modified the invasive human bladder cancer cell line T24 to ectopically express IL1RA, and measured changes in cell migration/invasion using the xCELLigence Real-Time-Cell-Analysis (RTCA) system and the Boyden chamber assay. The real-time observation data showed a significant decrease of cell migration and invasion in T24 cells overexpressing IL1RA (T24-IL1RA), compared to cells harboring an empty vector (T24-EV). Concurrently, tumor cytokines, e.g., IL1B, attenuated the vascular endothelial barrier, which resulted in a reduction of the Cell Index (CI), an impedance-based dimensionless unit. This reduction could be reverted by the simultaneous incubation with IL1RA. Moreover, we used an ex vivo porcine organ culture system to evaluate cell invasion capacity and showed that T24-IL1RA cells showed significantly less invasive capacity compared to parental T24 cells or T24-EV. Conclusions: Taken together, our results indicate an inverse correlation between IL1RA expression and tumor cell invasive capacity and migration, suggesting that IL1RA plays a role in bladder carcinogenesis, while the exact mechanisms by which IL1RA influences tumor cells migration/invasion remain to be clarified in future studies. Furthermore, we confirmed that real-time impedance sensing and the porcine ex vivo organ culture methods are powerful tools to discover differences in cancer cell migration and invasion.
Breast Cancer: Targeting of Steroid Hormones in Cancerogenesis and Diagnostics
Authors: Valko-Rokytovská Marcela , Očenáš Peter , Salayová Aneta , Kostecká Zuzana
Published: May 2021

Breast cancer is the most common malignancy in women with high mortality. Sensitive and specific methods for the detection, characterization and quantification of endogenous steroids in body fluids or tissues are needed for the diagnosis, treatment and prognosis of breast cancer and many other diseases. At present, non-invasive diagnostic methods are gaining more and more prominence, which enable a relatively fast and painless way of detecting many diseases. Metabolomics is a promising analytical method, the principle of which is the study and analysis of metabolites in biological material. It represents a comprehensive non-invasive diagnosis, which has a high potential for use in the diagnosis and prognosis of cancers, including breast cancer. This short review focuses on the targeted metabolomics of steroid hormones, which play an important role in the development and classification of breast cancer. The most commonly used diagnostic tool is the chromatographic method with mass spectrometry detection, which can simultaneously determine several steroid hormones and metabolites in one sample. This analytical procedure has a high potential in effective diagnosis of steroidogenesis disorders. Due to the association between steroidogenesis and breast cancer progression, steroid profiling is an important tool, as well as in monitoring disease progression, improving prognosis, and minimizing recurrence.
Proteome Changes Reveal the Protective Roles of Exogenous Citric Acid in Alleviating Cu Toxicity in Brassica napus L.
Authors: Ju Young-Hwan , Roy Swapan Kumar , Roy Choudhury Aritra , Kwon Soo-Jeong , Choi Ju-Young , Rahman Md Atikur , Katsube-Tanaka Tomoyuki , Shiraiwa Tatsuhiko , Lee Moon-Soon , Cho Kun , Woo Sun-Hee
Published: May 2021

Citric acid (CA), as an organic chelator, plays a vital role in alleviating copper (Cu) stress-mediated oxidative damage, wherein a number of molecular mechanisms alter in plants. However, it remains largely unknown how CA regulates differentially abundant proteins (DAPs) in response to Cu stress in Brassica napus L. In the present study, we aimed to investigate the proteome changes in the leaves of B. L. seedlings in response to CA-mediated alleviation of Cu stress. Exposure of 21-day-old seedlings to Cu (25 and 50 μM) and CA (1.0 mM) for 7 days exhibited a dramatic inhibition of overall growth and considerable increase in the enzymatic activities (POD, SOD, CAT). Using a label-free proteome approach, a total of 6345 proteins were identified in differentially treated leaves, from which 426 proteins were differentially expressed among the treatment groups. Gene ontology (GO) and KEGG pathways analysis revealed that most of the differential abundance proteins were found to be involved in energy and carbohydrate metabolism, photosynthesis, protein metabolism, stress and defense, metal detoxification, and cell wall reorganization. Our results suggest that the downregulation of chlorophyll biosynthetic proteins involved in photosynthesis were consistent with reduced chlorophyll content. The increased abundance of proteins involved in stress and defense indicates that these DAPs might provide significant insights into the adaptation of Brassica seedlings to Cu stress. The abundances of key proteins were further verified by monitoring the mRNA expression level of the respective transcripts. Taken together, these findings provide a potential molecular mechanism towards Cu stress tolerance and open a new route in accelerating the phytoextraction of Cu through exogenous application of CA in B. napus.
The CPGs for Limbed Locomotion–Facts and Fiction
Authors: Grillner Sten , Kozlov Alexander
Published: May 2021

The neuronal networks that generate locomotion are well understood in swimming animals such as the lamprey, zebrafish and tadpole. The networks controlling locomotion in tetrapods remain, however, still enigmatic with an intricate motor pattern required for the control of the entire limb during the support, lift off, and flexion phase, and most demandingly when the limb makes contact with ground again. It is clear that the inhibition that occurs between bursts in each step cycle is produced by V2b and V1 interneurons, and that a deletion of these interneurons leads to synchronous flexor–extensor bursting. The ability to generate rhythmic bursting is distributed over all segments comprising part of the central pattern generator network (CPG). It is unclear how the rhythmic bursting is generated; however, Shox2, V2a and HB9 interneurons do contribute. To deduce a possible organization of the locomotor CPG, simulations have been elaborated. The motor pattern has been simulated in considerable detail with a network composed of unit burst generators; one for each group of close synergistic muscle groups at each joint. This unit burst generator model can reproduce the complex burst pattern with a constant flexion phase and a shortened extensor phase as the speed increases. Moreover, the unit burst generator model is versatile and can generate both forward and backward locomotion.
Melatonin, Its Beneficial Effects on Embryogenesis from Mitigating Oxidative Stress to Regulating Gene Expression
Authors: Ivanov Dmitry , Mazzoccoli Gianluigi , Anderson George , Linkova Natalia , Dyatlova Anastasiia , Mironova Ekaterina , Polyakova Victoria , Kvetnoy Igor , Evsyukova Inna , Carbone Annalucia , Nasyrov Ruslan
Published: May 2021

Embryogenesis is a complex multi-stage process regulated by various signaling molecules including pineal and extrapineal melatonin (MT). Extrapineal MT is found in the placenta and ovaries, where it carries out local hormonal regulation. MT is necessary for normal development of oocytes, fertilization and subsequent development of human, animal and avian embryos. This review discusses the role of MT as a regulator of preimplantation development of the embryo and its implantation into endometrial tissue, followed by histo-, morpho- and organogenesis. MT possesses pronounced antioxidant properties and helps to protect the embryo from oxidative stress by regulating the expression of the NFE2L2, SOD1, and GPX1 genes. MT activates the expression of the ErbB1, ErbB4, GJA1, POU5F1, and Nanog genes which are necessary for embryo implantation and blastocyst growth. MT induces the expression of vascular endothelial growth factor (VEGF) and its type 1 receptor (VEGF-R1) in the ovaries, activating angiogenesis. Given the increased difficulties in successful fertilization and embryogenesis with age, it is of note that MT slows down ovarian aging by increasing the transcription of sirtuins. MT administration to patients suffering from infertility demonstrates an increase in the effectiveness of in vitro fertilization. Thus, MT may be viewed as a key factor in embryogenesis regulation, including having utility in the management of infertility.
Virus–Host Interaction Gets Curiouser and Curiouser. PART I: Phage P1vir Enhanced Development in an E. coli DksA-Deficient Cell
Authors: Cech Grzegorz M. , Kloska Anna , Krause Klaudyna , Potrykus Katarzyna , Cashel Michael , Szalewska-Pałasz Agnieszka
Published: May 2021

Bacteriophage P1 is among the best described bacterial viruses used in molecular biology. Here, we report that deficiency in the host cell DksA protein, an E. coli global transcription regulator, improves P1 lytic development. Using genetic and microbiological approaches, we investigated several aspects of P1vir biology in an attempt to understand the basis of this phenomenon. We found several minor improvements in phage development in the dksA mutant host, including more efficient adsorption to bacterial cell and phage DNA replication. In addition, gene expression of the main repressor of lysogeny C1, the late promoter activator Lpa, and lysozyme are downregulated in the dksA mutant. We also found nucleotide substitutions located in the phage immunity region immI, which may be responsible for permanent virulence of phage P1vir. We suggest that downregulation of C1 may lead to a less effective repression of lysogeny maintaining genes and that P1vir may be balancing between lysis and lysogeny, although finally it is able to enter the lytic pathway only. The mentioned improvements, such as more efficient replication and more “gentle” cell lysis, while considered minor individually, together may account for the phenomenon of a more efficient P1 phage development in a DksA-deficient host.
The Role of NLRP1, NLRP3, and AIM2 Inflammasomes in Psoriasis: Review
Authors: Ciążyńska Magdalena , Olejniczak-Staruch Irmina , Sobolewska-Sztychny Dorota , Narbutt Joanna , Skibińska Małgorzata , Lesiak Aleksandra
Published: May 2021

Inflammasomes are high-molecular-weight protein complexes that may cleave the two main proinflammatory cytokines, pro-interleukin-1β and pro-interleukin-18, into active forms, and contribute to psoriasis. Despite recent advances made in the pathogenesis of psoriasis, mainly studied as an autoimmune condition, activation of immune response triggers of psoriasis is still not completely understood. Recently, focus was placed on the role of inflammasomes in the pathogenesis of psoriasis. Multiple types of inhibitors and activators of various inflammasomes, inflammasome-related genes, and genetic susceptibility loci were recognized in psoriasis. In this systemic review, we collect recent and comprehensive evidence from the inflammasomes, NLRP1, NLRP3, and AIM2, in pathogenesis of psoriasis.
CAR-NK Cells in the Treatment of Solid Tumors
Authors: Wrona Ewa , Borowiec Maciej , Potemski Piotr
Published: May 2021

CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having unprecedented efficacy against hematological malignancies, the treatment is far from flawless. Its greatest drawbacks arise from a challenging and expensive production process, strict patient eligibility criteria and serious toxicity profile. One possible solution, supported by robust research, is the replacement of T lymphocytes with NK cells for CAR expression. NK cells seem to be an attractive vehicle for CAR expression as they can be derived from multiple sources and safely infused regardless of donor–patient matching, which greatly reduces the cost of the treatment. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have activity against non-hematological neoplasms. Here, we present a thorough overview of the current state of knowledge regarding the use of CAR-NK cells in treating various solid tumors.