bluuebunny/crossref_metadata_2025 huggingface dataset:
Streptozotocin-Induced Type 1 and 2 Diabetes Mellitus Mouse Models Show Different Functional, Cellular and Molecular Patterns of Diabetic Cardiomyopathy
Authors: Marino Fabiola , Salerno Nadia , Scalise Mariangela , Salerno Luca , Torella Annalaura , Molinaro Claudia , Chiefalo Antonio , Filardo Andrea , Siracusa Chiara , Panuccio Giuseppe , Ferravante Carlo , Giurato Giorgio , Rizzo Francesca , Torella Michele , Donniacuo Maria , De Angelis Antonella , Viglietto Giuseppe , Urbanek Konrad , Weisz Alessandro , Torella Daniele , Cianflone Eleonora
Published: January 2023

The main cause of morbidity and mortality in diabetes mellitus (DM) is cardiovascular complications. Diabetic cardiomyopathy (DCM) remains incompletely understood. Animal models have been crucial in exploring DCM pathophysiology while identifying potential therapeutic targets. Streptozotocin (STZ) has been widely used to produce experimental models of both type 1 and type 2 DM (T1DM and T2DM). Here, we compared these two models for their effects on cardiac structure, function and transcriptome. Different doses of STZ and diet chows were used to generate T1DM and T2DM in C57BL/6J mice. Normal euglycemic and nonobese sex- and age-matched mice served as controls (CTRL). Immunohistochemistry, RT-PCR and RNA-seq were employed to compare hearts from the three animal groups. STZ-induced T1DM and T2DM affected left ventricular function and myocardial performance differently. T1DM displayed exaggerated apoptotic cardiomyocyte (CM) death and reactive hypertrophy and fibrosis, along with increased cardiac oxidative stress, CM DNA damage and senescence, when compared to T2DM in mice. T1DM and T2DM affected the whole cardiac transcriptome differently. In conclusion, the STZ-induced T1DM and T2DM mouse models showed significant differences in cardiac remodeling, function and the whole transcriptome. These differences could be of key relevance when choosing an animal model to study specific features of DCM.
Pulsed Electromagnetic Field (PEMF) Treatment Ameliorates Murine Model of Collagen-Induced Arthritis
Authors: Hong Ju-Eun , Lee Chang-Gun , Hwang Soonjae , Kim Junyoung , Jo Minjeong , Kang Da-Hye , Yoo Sang-Hyeon , Kim Woo-Seung , Lee Yongheum , Rhee Ki-Jong
Published: January 2023

Rheumatoid arthritis (RA) is an autoimmune disease of the joint synovial membranes. RA is difficult to prevent or treat; however, blocking proinflammatory cytokines is a general therapeutic strategy. Pulsed electromagnetic field (PEMF) is reported to alleviate RA’s inflammatory response and is being studied as a non-invasive physical therapy. In this current study, PEMF decreased paw inflammation in a collagen-induced arthritis (CIA) murine model. PEMF treatment at 10 Hz was more effective in ameliorating arthritis than at 75 Hz. In the PEMF-treated CIA group, the gross inflammation score and cartilage destruction were lower than in the untreated CIA group. The CIA group treated with PEMF also showed lower serum levels of IL-1β but not IL-6, IL-17, or TNF-α. Serum levels of total anti-type II collagen IgG and IgG subclasses (IgG1, IgG2a, and IgG2b) remained unchanged. In contrast, tissue protein levels of IL-1β, IL-6, TNF-α, receptor activator of nuclear factor kappa-Β (RANK), RANK ligand (RANKL), IL-6 receptor (IL-6R), and TNF-α receptor1 (TNFR1) were all lower in the ankle joints of the PEMF-treated CIA group compared with the CIA group. The results of this study suggest that PEMF treatment can preserve joint morphology cartilage and delay the occurrence of CIA. PEMF has potential as an effective adjuvant therapy that can suppress the progression of RA.
Brassica napus Roots Use Different Strategies to Respond to Warm Temperatures
Authors: Boter Marta , Pozas Jenifer , Jarillo Jose A. , Piñeiro Manuel , Pernas Mónica
Published: January 2023

Elevated growth temperatures are negatively affecting crop productivity by increasing yield losses. The modulation of root traits associated with improved response to rising temperatures is a promising approach to generate new varieties better suited to face the environmental constraints caused by climate change. In this study, we identified several Brassica napus root traits altered in response to warm ambient temperatures. Different combinations of changes in specific root traits result in an extended and deeper root system. This overall root growth expansion facilitates root response by maximizing root–soil surface interaction and increasing roots’ ability to explore extended soil areas. We associated these traits with coordinated cellular events, including changes in cell division and elongation rates that drive root growth increases triggered by warm temperatures. Comparative transcriptomic analysis revealed the main genetic determinants of these root system architecture (RSA) changes and uncovered the necessity of a tight regulation of the heat-shock stress response to adjusting root growth to warm temperatures. Our work provides a phenotypic, cellular, and genetic framework of root response to warming temperatures that will help to harness root response mechanisms for crop yield improvement under the future climatic scenario.
Acute and Chronic Systemic Inflammation: Features and Differences in the Pathogenesis, and Integral Criteria for Verification and Differentiation
Authors: Zotova Natalya , Zhuravleva Yulia , Chereshnev Valeriy , Gusev Evgenii
Published: January 2023

Currently, there is rationale for separating the systemic manifestations of classical inflammation from systemic inflammation (SI) itself as an independent form of the general pathological process underlying the pathogenesis of the most severe acute and chronic diseases. With this aim in view, we used integral scales of acute and chronic SI (ChSI), including the following blood plasma parameters: interleukins 6, 8, 10; tumor necrosis factor alpha; C-reactive protein; D-dimer; cortisol; troponin I; myoglobin. The presence of multiple organ dysfunction according to the SOFA score was also taken into account. The effectiveness of the scales was tested in groups of intensive care patients during different periods of acute trauma, sepsis, and septic shock. The ChSI scale was applicable under systemic autoimmune diseases, chronic purulent infections, chronic limb threatening ischemia, and end-stage renal disease of various genesis. The number of examined patients was 764 in total. The scales allowed us to verify specific phases of acute SI and identify pathogenetic risk factors of lethal outcomes, as well as the most severe variants of the chronic pathologies course. These scales are open adaptable systems (in terms of the nomenclature and choice of indicators). They are primarily intended for scientific research. However, the SI verification methodology presented in this paper may be useful for developing advanced criteria for assessing both the typical links in the pathogenesis of many diseases and the severity of the overall condition of patients for clinical practice.
COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes
Authors: Vasichkina Elena , Alekseeva Daria , Kudryavtsev Igor , Glushkova Anzhela , Starshinova Anastasia Y. , Malkova Anna , Kudlay Dmitry , Starshinova Anna
Published: January 2023

In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient’s condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated—post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events.
Functional Endophytes Regulating Plant Secondary Metabolism: Current Status, Prospects and Applications
Authors: Li Zhaogao , Xiong Keyi , Wen Weie , Li Lin , Xu Delin
Published: January 2023

Endophytes, which are widely found in host plants and have no harmful effects, are a vital biological resource. Plant endophytes promote plant growth and enhance plants’ resistance to diseases, pests, and environmental stresses. In addition, they enhance the synthesis of important secondary metabolites in plants and improve the potential applicability of plants in agriculture, medicine, food, and horticulture. In this review, we summarize the recent progress in understanding the interaction between endophytes and plants and summarize the construction of synthetic microbial communities (SynComs) and metaomics analysis of the interaction between endophytes and plants. The application and development prospects of endophytes in agriculture, medicine, and other industries are also discussed to provide a reference for further study of the interaction between endophytes and plants and further development and utilization of endophytes.
Bioinformatics and Connectivity Map Analysis Suggest Viral Infection as a Critical Causative Factor of Hashimoto’s Thyroiditis
Authors: Lim Dong-Woo , Choi Min-Seo , Kim Seok-Mo
Published: January 2023

Hashimoto’s thyroiditis (HT) is a common autoimmune disease, and its prevalence is rapidly increasing. Both genetic and environmental risk factors contribute to the development of HT. Recently, viral infection has been suggested to act as a trigger of HT by eliciting the host immune response and subsequent autoreactivity. We analyzed the features of HT through bioinformatics analysis so as to identify the markers of HT development. We accessed public microarray data of HT patients from the Gene Expression Omnibus (GEO) and obtained differentially expressed genes (DEGs) under HT. Gene Ontology (GO) and KEGG-pathway-enrichment analyses were performed for functional clustering of our protein–protein interaction (PPI) network. Utilizing ranked gene lists, we performed a Gene Set Enrichment Analysis (GSEA) by using the clusterprofiler R package. By comparing the expression signatures of the huge perturbation database with the queried rank-ordered gene list, a connectivity map (CMap) analysis was performed to screen potential therapeutic targets and agents. The gene expression profile of the HT group was in line with the general characteristics of HT. Biological processes related to the immune response and viral infection pathways were obtained for the upregulated DEGs. The GSEA results revealed activation of autoimmune-disease-related pathways and several viral-infection pathways. Autoimmune-disease and viral-infection pathways were highly interconnected by common genes, while the HLA genes, which are shared by both, were significantly upregulated. The CMap analysis suggested that perturbagens, including SRRM1, NLK, and CCDC92, have the potential to reverse the HT expression profile. Several lines of evidence suggested that viral infection and the host immune response are activated during HT. Viral infection is suspected to act as a key trigger of HT by causing autoimmunity. SRRM1, an alternative splicing factor which responds to viral activity, might serve as potential marker of HT.
Tumor Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6): A Promising Immunomodulatory Target in Acute Neurodegenerative Diseases
Authors: La Russa Daniele , Di Santo Chiara , Lizasoain Ignacio , Moraga Ana , Bagetta Giacinto , Amantea Diana
Published: January 2023

Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), the first soluble chemokine-binding protein to be identified in mammals, inhibits chemotaxis and transendothelial migration of neutrophils and attenuates the inflammatory response of dendritic cells, macrophages, monocytes, and T cells. This immunoregulatory protein is a pivotal mediator of the therapeutic efficacy of mesenchymal stem/stromal cells (MSC) in diverse pathological conditions, including neuroinflammation. However, TSG-6 is also constitutively expressed in some tissues, such as the brain and spinal cord, and is generally upregulated in response to inflammation in monocytes/macrophages, dendritic cells, astrocytes, vascular smooth muscle cells and fibroblasts. Due to its ability to modulate sterile inflammation, TSG-6 exerts protective effects in diverse degenerative and inflammatory diseases, including brain disorders. Emerging evidence provides insights into the potential use of TSG-6 as a peripheral diagnostic and/or prognostic biomarker, especially in the context of ischemic stroke, whereby the pathobiological relevance of this protein has also been demonstrated in patients. Thus, in this review, we will discuss the most recent data on the involvement of TSG-6 in neurodegenerative diseases, particularly focusing on relevant anti-inflammatory and immunomodulatory functions. Furthermore, we will examine evidence suggesting novel therapeutic opportunities that can be afforded by modulating TSG-6-related pathways in neuropathological contexts and, most notably, in stroke.
Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation
Authors: Paulin Emily K. , Leung Euphemia , Pilkington Lisa I. , Barker David
Published: January 2023

Dibenzylbutyrolactone lignans (DBLs) are a class of natural products with a wide variety of biological activities. Due to their potential for the development of human therapeutic agents, DBLs have been subjected to various SAR studies in order to optimise activity. Previous reports have mainly considered changes on the aromatic rings and at the benzylic carbons of the compounds, whilst the effects of substituents in the lactone, at the C-9′ position, have been relatively unexplored. This position has an unexploited potential for the development of novel dibenzyl butyrolactone derivatives, with previous preliminary findings revealing C-9′-hydroxymethyl analogues inducing programmed cell cycle death. Using the core structure of the bioactive natural product arctigenin, C-9′ derivatives were synthesised using various synthetic pathways and with prepared derivatives providing more potent anti-proliferative activity than the C-9′-hydroxymethyl lead compound.
Liver Regeneration and Immunity: A Tale to Tell
Authors: Di-Iacovo Nicola , Pieroni Stefania , Piobbico Danilo , Castelli Marilena , Scopetti Damiano , Ferracchiato Simona , Della-Fazia Maria Agnese , Servillo Giuseppe
Published: January 2023

The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.
Melatonin Involved in Protective Effects against Cadmium Stress in Wolffia arrhiza
Authors: Chmur Magdalena , Bajguz Andrzej
Published: January 2023

Melatonin (MT) is a new plant hormone that protects against adverse environmental conditions. In the present study, the responses of Wolffia arrhiza exposed to cadmium (Cd) and MT were analyzed. Quantitative analysis of MT and precursors of its biosynthesis was performed using LC-MS-MS. The photosynthetic pigments and phytochelatins (PCs) contents were determined using HPLC, while protein and monosaccharides, stress markers, and antioxidant levels were determined using spectrophotometric methods. Interestingly, the endogenous level of MT and its substrates in W. arrhiza exposed to 1–100 µM Cd was significantly higher compared to the control. Additionally, the application of 25 µM MT and Cd intensified the biosynthesis of these compounds. The most stimulatory effect on the growth and content of pigments, protein, and sugars was observed in plants treated with 25 µM MT. In contrast, Cd treatment caused a decrease in plant weight and level of these compounds, while the application of 25 µM MT mitigated the inhibitory effect of Cd. Additionally, Cd enhanced the level of stress markers; simultaneously, MT reduced their content in duckweed exposed to Cd. In plants treated with Cd, PC levels were increased by Cd treatment and by 25 µM MT. These results confirmed that MT mitigated the adverse effect of Cd. Furthermore, MT presence was reported for the first time in W. arrhiza. In summary, MT is an essential phytohormone for plant growth and development, especially during heavy metal stress.
Cantharidin and Its Analogue Norcantharidin Inhibit Metastasis—Inducing Genes S100A4 and MACC1
Authors: Schöpe Paul Curtis , Zinnow Viktoria , Ishfaq Muhammad Ahtisham , Smith Janice , Herrmann Pia , Shoemaker Robert H. , Walther Wolfgang , Stein Ulrike
Published: January 2023

Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer worldwide. In addition, metastasis directly causes up to 90% of all CRC deaths, highlighting the metastatic burden of the disease. Biomarkers such as S100A4 and MACC1 aid in identifying patients with a high risk of metastasis formation. High expression of S100A4 or MACC1 and to a greater extent the combination of both biomarkers is a predictor for metastasis and poor patient survival in CRC. MACC1 is a tumor-initiating and metastasis-promoting oncogene, whereas S100A4 has not been shown to initiate tumor formation but can, nevertheless, promote malignant tumor growth and metastasis formation. Cantharidin is a natural drug extracted from various blister beetle species, and its demethylated analogue norcantharidin has been shown in several studies to have an anti-cancer and anti-metastatic effect in different cancer entities such as CRC, breast cancer, and lung cancer. The impact of the natural compound cantharidin and norcantharidin on S100A4 and MACC1 gene expression, cancer cell migration, motility, and colony formation in vitro was tested. Here, for the first time, we have demonstrated that cantharidin and norcantharidin are transcriptional inhibitors of S100A4 and MACC1 mRNA expression, protein expression, and motility in CRC cells. Our results clearly indicate that cantharidin and, to a lesser extent, its analogue norcantharidin are promising compounds for efficient anti-metastatic therapy targeting the metastasis-inducing genes S100A4 and MACC1 for personalized medicine for cancer patients.
Efficacy of Dabrafenib and Trametinib in a Patient with Squamous-Cell Carcinoma, with Mutation p.D594G in BRAF and p.R461* in NF1 Genes—A Case Report with Literature Review
Authors: Grenda Anna , Krawczyk Pawel , Targowska-Duda Katarzyna M. , Kieszko Robert , Paśnik Iwona , Milanowski Janusz
Published: January 2023

The 3rd class of BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) variants including G466, D594, and A581 mutations cause kinase death or impaired kinase activity. It is unlikely that RAF (Raf Proto-Oncogene, Serine/Threonine Kinase) inhibitors suppress ERK (Extracellular Signal-Regulated Kinase) signaling in class 3 mutant-driven tumors due to the fact that they preferentially inhibit activated BRAF V600 mutants. However, there are suggestions that class 3 mutations are still associated with enhanced RAS/MAPK (RAS Proto-Oncogene, GTPase/Mitogen-Activated Protein Kinase) activation, potentially due to other mechanisms such as the activation of growth factor signaling or concurrent MAPK pathway mutations, e.g., RAS or NF1 (Neurofibromin 1). A 75-year-old male patient with squamous-cell cancer (SqCC) of the lung and with metastases to the kidney and mediastinal lymph nodes received chemoimmunotherapy (expression of Programmed Cell Death 1 Ligand 1 (PD-L1) on 2% of tumor cells). The chemotherapy was limited due to the accompanying myelodysplastic syndrome (MDS), and pembrolizumab monotherapy was continued for up to seven cycles. At the time of progression, next-generation sequencing was performed and a c.1781A>G (p.Asp594Gly) mutation in the BRAF gene, a c.1381C>T (p.Arg461Ter) mutation in the NF1 gene, and a c.37C>T (p.Gln13Ter) mutation in the FANCC gene were identified. Combined therapy with BRAF (dabrafenib) and MEK (trametinib) inhibitors was used, which resulted in the achievement of partial remission of the primary lesion and lung nodules and the stabilization of metastatic lesions in the kidney and bones. The therapy was discontinued after five months due to myelosuppression associated with MDS. The molecular background was decisive for the patient’s fate. NSCLC patients with non-V600 mutations in the BRAF gene rarely respond to anti-BRAF and anti-MEK therapy. The achieved effectiveness of the treatment could be related to a mutation in the NF1 tumor suppressor gene. The loss of NF1 function causes the excessive activation of KRAS and overactivity of the signaling pathway containing BRAF and MEK, which were the targets of the therapy. Moreover, the mutation in the FANCC gene was probably related to MDS development. The NGS technique was crucial for the qualification to treatment and the prediction of the NSCLC course in our patient. The mutations in two genes—the BRAF oncogene and the NF1 tumor suppressor gene—were the reason for the use of dabrafenib and trametinib treatment. The patients achieved short-term disease stabilization. This proved that coexisting mutations in these genes affect the disease course and treatment efficacy.
The ABA/LANCL Hormone/Receptor System in the Control of Glycemia, of Cardiomyocyte Energy Metabolism, and in Neuroprotection: A New Ally in the Treatment of Diabetes Mellitus?
Authors: Spinelli Sonia , Magnone Mirko , Guida Lucrezia , Sturla Laura , Zocchi Elena
Published: January 2023

Abscisic acid (ABA), long known as a plant stress hormone, is present and functionally active in organisms other than those pertaining to the land plant kingdom, including cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. The ancient, cross-kingdom role of this stress hormone allows ABA and its signaling pathway to control cell responses to environmental stimuli in diverse organisms such as marine sponges, higher plants, and humans. Recent advances in our knowledge about the physiological role of ABA and of its mammalian receptors in the control of energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells allow us to foresee therapeutic applications for ABA in the fields of pre-diabetes, diabetes, and cardio- and neuro-protection. Vegetal extracts titrated in their ABA content have shown both efficacy and tolerability in preliminary clinical studies. As the prevalence of glucose intolerance, diabetes, and cardiovascular and neurodegenerative diseases is steadily increasing in both industrialized and rapidly developing countries, new and cost-efficient therapeutics to combat these ailments are much needed to ensure disease-free aging for the current and future working generations.
Single–Molecule Study of DNAzyme Reveals Its Intrinsic Conformational Dynamics
Authors: Zhang Yiming , Ji Zongzhou , Wang Xin , Cao Yi , Pan Hai
Published: January 2023

DNAzyme is a class of DNA molecules that can perform catalytic functions with high selectivity towards specific metal ions. Due to its potential applications for biosensors and medical therapeutics, DNAzyme has been extensively studied to characterize the relationships between its biochemical properties and functions. Similar to protein enzymes and ribozymes, DNAzymes have been found to undergo conformational changes in a metal–ion–dependent manner for catalysis. Despite the important role the conformation plays in the catalysis process, such structural and dynamic information might not be revealed by conventional approaches. Here, by using the single–molecule fluorescence resonance energy transfer (smFRET) technique, we were able to investigate the detailed conformational dynamics of a uranyl–specific DNAzyme 39E. We observed conformation switches of 39E to a folded state with the addition of Mg2+ and to an extended state with the addition of UO22+. Furthermore, 39E can switch to a more compact configuration with or without divalent metal ions. Our findings reveal that 39E can undergo conformational changes spontaneously between different configurations.
A Non-functional γ-Aminobutyric Acid Shunt Pathway in Cyanobacterium Synechocystis sp. PCC 6803 Enhances δ-Aminolevulinic Acid Accumulation under Modified Nutrient Conditions
Authors: Kanwal Simab , De-Eknamkul Wanchai
Published: January 2023

To redirect carbon flux from the γ-aminobutyric acid (GABA) shunt to the δ-aminolevulinic acid (ALA) biosynthetic pathway, we disrupted the GABA shunt route of the model cyanobacterium Synechocystis sp. PCC 6803 by inactivating Gdc, the gene-encoding glutamate decarboxylase. The generated ΔGdc strain exhibited lower intracellular GABA and higher ALA levels than the wild-type (WT) one. The ΔGdc strain’s ALA levels were ~2.8 times higher than those of the WT one when grown with levulinic acid (LA), a competitive inhibitor of porphobilinogen synthase. Abiotic stress conditions including salinity induced by 10 mM NaCl and cold at 4 °C increased the ALA levels in ΔGdc up to ~2.5 and 5 ng g−1 cell DW, respectively. The highest ALA production in the ΔGdc cyanobacteria grown in BG11 medium was triggered by glucose induction, followed by glutamate supplementation with 60 mM of LA, thereby resulting in ~360 ng g−1 cell DW of ALA, that is >300-fold higher ALA accumulation than that observed in ΔGdc cyanobacteria grown in normal medium. Increased levels of the gdhA (involved in the interconversion of α-ketoglutarate to glutamate) and the hemA (a major regulatory target of the ALA biosynthetic pathway) transcripts occurred in ΔGdc cyanobacteria grown under modified growth conditions. Our study provides critical insight into the facilitation of ALA production in cyanobacteria.
Montelukast Increased IL-25, IL-33, and TSLP via Epigenetic Regulation in Airway Epithelial Cells
Authors: Tsai Mei-Lan , Tsai Ming-Kai , Tsai Yi-Giien , Lin Yu-Chih , Hsu Ya-Ling , Chen Yi-Ting , Lin Yi-Ching , Hung Chih-Hsing
Published: January 2023

The epithelium-derived cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are important mediators that initiate innate type 2 immune responses in asthma. Leukotriene receptor antagonists (LTRAs) are commonly used to prevent asthma exacerbations. However, the effects of LTRAs on epithelium-derived cytokines expression in airway epithelial cells are unclear. This study aimed to investigate the effects of LTRAs on the expression of epithelium-derived cytokines in human airway epithelial cells and to explore possible underlying intracellular processes, including epigenetic regulation. A549 or HBE cells in air-liquid interface conditions were pretreated with different concentrations of LTRAs. The expression of epithelium-derived cytokines and intracellular signaling were investigated by real-time PCR, enzyme-linked immunosorbent assay, and Western blot. In addition, epigenetic regulation was investigated using chromatin immunoprecipitation analysis. The expression of IL-25, IL-33, and TSLP was increased under LTRAs treatment and suppressed by inhaled corticosteroid cotreatment. Montelukast-induced IL-25, IL-33, and TSLP expression were mediated by the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways and regulated by histone H3 acetylation and H3K36 and H3K79 trimethylation. LTRAs alone might increase inflammation and exacerbate asthma by inducing the production of IL-25, IL-33, and TSLP; therefore, LTRA monotherapy may not be an appropriate therapeutic option for asthma.
Adipose Tissue-Derived Extracellular Vesicles Contribute to Phenotypic Plasticity of Prostate Cancer Cells
Authors: Mathiesen Allison , Haynes Bronson , Huyck Ryan , Brown Michael , Dobrian Anca
Published: January 2023

Metastatic prostate cancer is one of the leading causes of male cancer deaths in the western world. Obesity significantly increases the risk of metastatic disease and is associated with a higher mortality rate. Systemic chronic inflammation can result from a variety of conditions, including obesity, where adipose tissue inflammation is a major contributor. Adipose tissue endothelial cells (EC) exposed to inflammation become dysfunctional and produce a secretome, including extracellular vesicles (EV), that can impact function of cells in distant tissues, including malignant cells. The aim of this study was to explore the potential role of EVs produced by obese adipose tissue and the ECs exposed to pro-inflammatory cytokines on prostate cancer phenotypic plasticity in vitro. We demonstrate that PC3ML metastatic prostate cancer cells exposed to EVs from adipose tissue ECs and to EVs from human adipose tissue total explants display reduced invasion and increased proliferation. The latter functional changes could be attributed to the EV miRNA cargo. We also show that the functional shift is TWIST1-dependent and is consistent with mesenchymal-to-epithelial transition, which is key to establishment of secondary tumor growth. Understanding the complex effects of EVs on prostate cancer cells of different phenotypes is key before their intended use as therapeutics.
Structural and Functional RNA Motifs of SARS-CoV-2 and Influenza A Virus as a Target of Viral Inhibitors
Authors: Szczesniak Izabela , Baliga-Gil Agnieszka , Jarmolowicz Aleksandra , Soszynska-Jozwiak Marta , Kierzek Elzbieta
Published: January 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic, whereas the influenza A virus (IAV) causes seasonal epidemics and occasional pandemics. Both viruses lead to widespread infection and death. SARS-CoV-2 and the influenza virus are RNA viruses. The SARS-CoV-2 genome is an approximately 30 kb, positive sense, 5′ capped single-stranded RNA molecule. The influenza A virus genome possesses eight single-stranded negative-sense segments. The RNA secondary structure in the untranslated and coding regions is crucial in the viral replication cycle. The secondary structure within the RNA of SARS-CoV-2 and the influenza virus has been intensively studied. Because the whole of the SARS-CoV-2 and influenza virus replication cycles are dependent on RNA with no DNA intermediate, the RNA is a natural and promising target for the development of inhibitors. There are a lot of RNA-targeting strategies for regulating pathogenic RNA, such as small interfering RNA for RNA interference, antisense oligonucleotides, catalytic nucleic acids, and small molecules. In this review, we summarized the knowledge about the inhibition of SARS-CoV-2 and influenza A virus propagation by targeting their RNA secondary structure.
New 3,4-seco-3,19-Dinor- and Spongian-Based Diterpenoid Lactones from the Marine Sponge Spongia sp.
Authors: Tai Chi-Jen , Chao Chih-Hua , Ahmed Atallah F. , Yen Chia-Hung , Hwang Tsong-Long , Chang Fang-Rong , Huang Yusheng M. , Sheu Jyh-Horng
Published: January 2023

Continuing chemical investigation of the Red Sea sponge Spongia sp. led to the isolation of four new 3,4-seco-3,19-dinorspongian diterpenoid lactones, secodinorspongins A−D (1−4), along with a classical spongian diterpenoid lactone, sponginolide (5). The chemical structures, including the absolute configurations of these compounds, were elucidated using the extensive spectroscopic study composed of 1D and 2D NMR data analyses, and a comparison between calculated-electronic-circular-dichroism (ECD) and experimental-circular-dichroism (CD) spectra. A plausible biosynthetic pathway of 1−4 was also proposed. Furthermore, the cytotoxicity, antibacterial and anti-inflammatory activities of 1−5 were evaluated. Compound 1 was found to exhibit inhibitory activity against the growth of Staphylococcus aureus (S. aureus), and 4 and 5 exhibited suppression of superoxide-anion generation and elastase release in fMLF/CB-induced human neutrophils.
A Mixture of Dietary Plant Sterols at Nutritional Relevant Serum Concentration Inhibits Extrinsic Pathway of Eryptosis Induced by Cigarette Smoke Extract
Authors: Restivo Ignazio , Attanzio Alessandro , Tesoriere Luisa , Allegra Mario , Garcia-Llatas Guadalupe , Cilla Antonio
Published: January 2023

Cell death program of red blood cells (RBCs), called eryptosis, is characterized by activation of caspases and scrambling of membrane phospholipids with externalization of phosphatidylserine (PS). Excessive eryptosis confers a procoagulant phenotype and is implicated in impairment of microcirculation and increased prothrombotic risk. It has recently been reported that cigarette smokers have high levels of circulating eryptotic erythrocytes, and a possible contribution of eryptosis to the vaso-occlusive complications associated to cigarette smoke has been postulated. In this study, we demonstrate how a mixture of plant sterols (MPtS) consisting of β-sitosterol, campesterol and stigmasterol, at serum concentration reached after ingestion of a drink enriched with plant sterols, inhibits eryptosis induced by cigarette smoke extract (CSE). Isolated RBCs were exposed for 4 h to CSE (10–20% v/v). When RBCs were co-treated with CSE in the presence of 22 µM MPtS, a significant reduction of the measured hallmarks of apoptotic death like assembly of the death-inducing signaling complex (DISC), PS outsourced, ceramide production, cleaved forms of caspase 8/caspase 3, and phosphorylated p38 MAPK, was evident. The new beneficial properties of plant sterols on CSE-induced eryptosis presented in this work open new perspectives to prevent the negative physio-pathological events caused by the eryptotic red blood cells circulating in smokers.
Retinal Proteome Analysis Reveals a Region-Specific Change in the Rabbit Myopia Model
Authors: Moon Chae-Eun , Ji Yong Woo , Lee Jun-ki , Han Kyusun , Kim Hyunjin , Byeon Seok Ho , Han Suenghan , Han Jinu , Seo Yuri
Published: January 2023

Uncovering region-specific changes in the myopic retina can provide clues to the pathogenesis of myopia progression. After imposing form deprivation myopia in the right eye of 6-week-old rabbits, we investigated the proteome profile of each retinal region (central, mid-periphery, and far-periphery retina), using accurate high-resolution mass spectrometry. Protein expression was analyzed using gene ontology and network analysis compared with that of the control, the left eyes. Among 2065 proteins detected from whole retinal samples, 249 differentially expressed proteins (DEPs) were identified: 164 DEPs in the far-periphery, 39 in the mid-periphery, and 83 in the central retina. In network analysis, the far-periphery retina showed the most significant connectivity between DEPs. The regulation of coagulation was the most significant biological process in upregulated DEPs in the far-periphery retina. Proteasome was the most significant Kyoto Encyclopedia of Genes and Genomes pathway in downregulated DEPs in the central retina. Antithrombin-III, fibrinogen gamma chain, and fibrinogen beta chain were identified as hub proteins for myopia progression, which were upregulated in the far-periphery retina. Proteomic analysis in this study suggested that oxidative stress can be the primary pathogenesis of myopia progression and that the far-periphery retina plays a role as the key responder.
Shaping the Future of Immunotherapy Targets and Biomarkers in Melanoma and Non-Melanoma Cutaneous Cancers
Authors: Spiliopoulou Pavlina , Vornicova Olga , Genta Sofia , Spreafico Anna
Published: January 2023

Recent advances in treating cutaneous melanoma have resulted in impressive patient survival gains. Refinement of disease staging and accurate patient risk classification have significantly improved our prognostic knowledge and ability to accurately stratify treatment. Undoubtedly, the most important step towards optimizing patient outcomes has been the advent of cancer immunotherapy, in the form of immune checkpoint inhibition (ICI). Immunotherapy has established its cardinal role in the management of both early and late-stage melanoma. Through leveraging outcomes in melanoma, immunotherapy has also extended its benefit to other types of skin cancers. In this review, we endeavor to summarize the current role of immunotherapy in melanoma and non-melanoma skin cancers, highlight the most pertinent immunotherapy-related molecular biomarkers, and lastly, shed light on future research directions.
Low-Temperature Synthesis Approach for Calcium Hydroxyapatite Coatings on Titanium Substrate
Authors: Karalkeviciene Rasa , Briedyte Greta , Popov Anton , Tutliene Skirmante , Zarkov Aleksej , Kareiva Aivaras
Published: January 2023

In this study, a low-temperature synthetic approach was developed for the fabrication of calcium hydroxyapatite (CHAp) coatings on a titanium substrate. The titanium substrates were first coated with CaCO3 by a spin-coating technique using a sol–gel chemistry approach, and the obtained product was transformed into CHAp during a dissolution–precipitation reaction. The phase purity and structural and morphological features of the obtained CHAp coatings were evaluated by X-ray diffraction (XRD) analysis, FTIR spectroscopy, Raman spectroscopy, scanning electron microscopy (SEM) and using a 3D optical profilometer. It was demonstrated that almost-single-phase CHAp formed on the titanium substrate with a negligible number of side phases, such as Na2HPO4 (starting material) and TiO2. In the Raman spectrum of the CHAp coating, the peaks of phosphate group vibrations were clearly seen. Thus, the obtained results of Raman spectroscopy correlated well with the results of X-ray diffraction analysis. The corrosive behaviour of CHAp coatings on a titanium substrate was also evaluated using electrochemical methods. It was found that the corrosion resistance of titanium coated with CHAp increased significantly. These CHAp thin films may be potential candidates for use in not only in regenerative medicine but also in the development of different sensors.
How Epinephrine Administration Interval Impacts the Outcomes of Resuscitation during Adult Cardiac Arrest: A Systematic Review and Meta-Analysis
Authors: Wongtanasarasin Wachira , Srisurapanont Karan , Nishijima Daniel K.
Published: January 2023

Current guidelines for treating cardiac arrest recommend administering 1 mg of epinephrine every 3–5 min. However, this interval is based solely on expert opinion. We aimed to investigate the impact of the epinephrine administration interval (EAI) on resuscitation outcomes in adults with cardiac arrest. We systematically reviewed the PubMed, EMBASE, and Scopus databases. We included studies comparing different EAIs in adult cardiac arrest patients with reported neurological outcomes. Pooled estimates were calculated using the IVhet meta-analysis, and the heterogeneities were assessed using Q and I2 statistics. We evaluated the study risk of bias and overall quality using validated bias assessment tools. Three studies were included. All were classified as “good quality” studies. Only two reported the primary outcome. Compared with a recommended EAI of 3–5 min, a favorable neurological outcome was not significantly different in patients with the other frequencies: for <3 min, odds ratio (OR) 1.93 (95% CI: 0.82–4.54); for >5 min, OR 1.01 (95% CI: 0.55–1.87). For survival to hospital discharge, administering epinephrine for less than 3 min was not associated with a good outcome (OR 1.66, 95% CI: 0.89–3.10). Moreover, EAI of >5 min did not pose a benefit (OR 0.87, 95% CI: 0.68–1.11). Our review showed that EAI during CPR was not associated with better hospital outcomes. Further clinical trials are necessary to determine the optimal dosing interval for epinephrine in adults with cardiac arrest.
Metabolomic Approach to Screening Homozygotes in Chinese Patients with Severe Familial Hypercholesterolemia
Authors: Du Zhiyong , Du Yunhui , Li Linyi , Sun Haili , Hu Chaowei , Jiang Long , Wang Luya , Qin Yanwen
Published: January 2023

Homozygous familial hypercholesterolemia (HoFH) is a rare inborn-errors-of-metabolism disorder characterized by devastatingly elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. The gold standard for screening and diagnosing HoFH is genetic testing. In China, it is expensive and is always recommended for the most likely HoFH subjects with aggressive LDL-C phenotype. However, the LDL-C levels of HoFH patients and a substantial proportion of heterozygous FH (HeFH) patients overlapped considerably. Here, we performed a cost-effective metabolomic profiling on genetically diagnosed HoFH (n = 69) and HeFH patients (n = 101) with overlapping LDL-C levels, aiming to discovery a unique metabolic pattern for screening homozygotes in patients with severe FH. We demonstrated a differential serum metabolome profile in HoFH patients compared to HeFH patients. Twenty-one metabolomic alterations showed independent capability in differentiating HoFH from severe HeFH. The combined model based on seven identified metabolites yielded a corrected diagnosis in 91.3% of HoFH cases with an area under the curve value of 0.939. Collectively, this study demonstrated that metabolomic profiling serves as a useful and economical approach to preselecting homozygotes in FH patients with severe hypercholesterolemia and may help clinicians to conduct selective genetic confirmation testing and familial cascade screening.
A Prospective Study of Genetic Variants in Infants with Congenital Unilateral Sensorineural Hearing Loss
Authors: Johansson Marlin , Karltorp Eva , Asp Filip , Berninger Erik
Published: January 2023

Children with unilateral sensorineural hearing loss (uSNHL) have a high risk of speech-language delays and academic difficulties. Still, challenges remain in the diagnosis of uSNHL. With a prospective cross-sectional design, 20 infants were consecutively recruited from a universal newborn hearing screening program and invited to genetic testing. Eighteen of the subjects agreed to genetic testing, 15 subjects with OtoSCOPE® v.9 screening 224 genes, and four subjects underwent targeted testing, screening for chromosomal abnormalities or 105–137 gene mutations. The genetic results were described together with the 20 infants’ previously published auditory profiles and imaging results. Genetic causes for the uSNHL were found in 28% of subjects (5/18) including CHARGE syndrome (CHD7), autosomal recessive non-syndromic hearing loss (GJB2), Townes–Brocks syndrome (SALL1), Pendred Syndrome (SLC26A4) and Chromosome 8P inverted duplication and deletion syndrome. In subjects with comorbidities (malformation of fingers, anus, brain, and heart), 100% were diagnosed with a genetic cause for uSNHL (3/3 subjects), while 13% (2/15 subjects) were diagnosed without comorbidities observed at birth (p = 0.002). Genetic testing for congenital uSNHL is currently efficient for alleged syndromes, whereas genetic variants for non-syndromic congenital uSNHL need further research.
Delayed Leucoencephalopathy as a Complication after Endovascular Therapy of Intracranial Aneurysms—A Case Series
Authors: Bakola Eleni , Papagiannopoulou Georgia , Palaiodimou Lina , Lagios Konstantinos , Archontakis Eftychios , Theodorou Aikaterini , Katsanos Aristeidis H. , Triantafyllou Sokratis , Zouvelou Vasiliki , Lachanis Stefanos , Tzanetakos Dimitrios , Tzartos John S. , Giannopoulos Sotirios , Tsivgoulis Georgios
Published: January 2023

We describe the clinical presentation, radiological findings, treatment and outcomes of three patients with delayed leukoencephalopathy occurring after endovascular treatment (EVT) for cerebral aneurysms—a rare, albeit recurring, complication. The symptoms occurred 6 to 12 months following the EVT of the cerebral aneurysm. Characteristic imaging findings included high-signal changes on T2 images in the white matter without diffusion restriction predominantly at the distribution of the vascular territory of the catheterized arteries, coupled with patchy gadolinium enhancement or low susceptibility weighted imaging (SWI) signals within the white-matter lesions. Steroid pulse therapy is the treatment of choice and promptly improves clinical and imaging findings. Tapering or cessation of steroids may result in clinical and imaging relapses; close- and long-term follow-up for patients presenting this complication is warranted.
Assisted Reproductive Technology without Embryo Discarding or Freezing in Women ≥40 Years: A 5-Year Retrospective Study at a Single Center in Italy
Authors: Manna Claudio , Barbagallo Federica , Sagnella Francesca , Farrag Ashraf , Calogero Aldo E.
Published: January 2023

The protocols commonly used in assisted reproductive technology (ART) consist of long-term embryo culture up to the blastocyst stage after the insemination of all mature oocytes, the freezing of all the embryos produced, and their subsequent transfer one by one. These practices, along with preimplantation genetic testing, although developed to improve the live birth rate (LBR) and reduce the risk of multiple pregnancies, are drawing attention to the possible increase in obstetric and perinatal risks, and adverse epigenetic consequences in offspring. Furthermore, ethical–legal concerns are growing regarding the increase in cryopreservation and storage of frozen embryos. In an attempt to reduce the risk associated with prolonged embryo culture and avoid embryo storage, we have chosen to inseminate a limited number of oocytes not exceeding the number of embryos to be transferred, after two days or less of culture. We retrospectively analyzed 245 ICSI cycles performed in 184 infertile couples with a female partner aged ≥40 from January 2016 to July 2021. The results showed a fertilization rate of 95.7%, a miscarriage rate of 48.9%, and a LBR of 10% with twin pregnancies of 16.7%. The cumulative LBR in our group of couples was 13%. No embryos were frozen. In conclusion, these results suggest that oocyte selection and embryo transfer at the cleaving stage constitute a practice that has a LBR comparable to that of the more commonly used protocols in older women who have reduced ovarian reserve.