bluuebunny/crossref_metadata_2025 huggingface dataset:
A Deep Transfer Learning Toponym Extraction and Geospatial Clustering Framework for Investigating Scenic Spots as Cognitive Regions
Authors: Zhang Chengkun , Zhang Yiran , Zhang Jiajun , Yao Junwei , Liu Hongjiu , He Tao , Zheng Xinyu , Xue Xingyu , Xu Liang , Yang Jing , Wang Yuanyuan , Xu Liuchang
Published: May 2023

In recent years, the Chinese tourism industry has developed rapidly, leading to significant changes in the relationship between people and space patterns in scenic regions. To attract more tourists, the surrounding environment of a scenic region is usually well developed, attracting a large number of human activities, which creates a cognitive range for the scenic region. From the perspective of tourism, tourists’ perceptions of the region in which tourist attractions are located in a city usually differ from the objective region of the scenic spots. Among them, social media serves as an important medium for tourists to share information about scenic spots and for potential tourists to learn scenic spot information, and it interacts to influence people’s perceptions of the destination image. Extracting the names of tourist attractions from social media data and exploring their spatial distribution patterns is the basis for research on the cognitive region of tourist attractions. This study takes Hangzhou, a well-known tourist city in China, as a case study to explore the human cognitive region of its popular scenic spots. First, we propose a Chinese tourist attraction name extraction model based on RoBERTa-BiLSTM-CRF to extract the names of tourist attractions from social media data. Then, we use a multi-distance spatial clustering method called Ripley’s K to filter the extracted tourist attraction names. Finally, we combine road network data and polygons generated using the chi-shape algorithm to construct the vague cognitive regions of each scenic spot. The results show that the classification indicators of our proposed tourist attraction name extraction model are significantly better than those of previous toponym extraction models and algorithms (precision = 0.7371, recall = 0.6926, F1 = 0.7141), and the extracted vague cognitive regions of tourist attractions also generally conform to people’s habitual cognition.
TRPV3 Ion Channel: From Gene to Pharmacology
Authors: Kalinovskii Aleksandr P. , Utkina Lyubov L. , Korolkova Yuliya V. , Andreev Yaroslav A.
Published: May 2023

Transient receptor potential vanilloid subtype 3 (TRPV3) is an ion channel with a sensory function that is most abundantly expressed in keratinocytes and peripheral neurons. TRPV3 plays a role in Ca2+ homeostasis due to non-selective ionic conductivity and participates in signaling pathways associated with itch, dermatitis, hair growth, and skin regeneration. TRPV3 is a marker of pathological dysfunctions, and its expression is increased in conditions of injury and inflammation. There are also pathogenic mutant forms of the channel associated with genetic diseases. TRPV3 is considered as a potential therapeutic target of pain and itch, but there is a rather limited range of natural and synthetic ligands for this channel, most of which do not have high affinity and selectivity. In this review, we discuss the progress in the understanding of the evolution, structure, and pharmacology of TRPV3 in the context of the channel’s function in normal and pathological states.
The Role of Cardiac Fibrosis in Diabetic Cardiomyopathy: From Pathophysiology to Clinical Diagnostic Tools
Authors: Pan Kuo-Li , Hsu Yung-Chien , Chang Shih-Tai , Chung Chang-Min , Lin Chun-Liang
Published: May 2023

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to inadequate insulin secretion, resistance, or both. The cardiovascular complications of DM are the leading cause of morbidity and mortality in diabetic patients. There are three major types of pathophysiologic cardiac remodeling including coronary artery atherosclerosis, cardiac autonomic neuropathy, and DM cardiomyopathy in patients with DM. DM cardiomyopathy is a distinct cardiomyopathy characterized by myocardial dysfunction in the absence of coronary artery disease, hypertension, and valvular heart disease. Cardiac fibrosis, defined as the excessive deposition of extracellular matrix (ECM) proteins, is a hallmark of DM cardiomyopathy. The pathophysiology of cardiac fibrosis in DM cardiomyopathy is complex and involves multiple cellular and molecular mechanisms. Cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction (HFpEF), which increases mortality and the incidence of hospitalizations. As medical technology advances, the severity of cardiac fibrosis in DM cardiomyopathy can be evaluated by non-invasive imaging modalities such as echocardiography, heart computed tomography (CT), cardiac magnetic resonance imaging (MRI), and nuclear imaging. In this review article, we will discuss the pathophysiology of cardiac fibrosis in DM cardiomyopathy, non-invasive imaging modalities to evaluate the severity of cardiac fibrosis, and therapeutic strategies for DM cardiomyopathy.
The miRNA Content of Bone Marrow-Derived Extracellular Vesicles Contributes to Protein Pathway Alterations Involved in Ionising Radiation-Induced Bystander Responses
Authors: Csordás Ilona Barbara , Rutten Eric Andreas , Szatmári Tünde , Subedi Prabal , Cruz-Garcia Lourdes , Kis Dávid , Jezsó Bálint , Toerne Christine von , Forgács Martina , Sáfrány Géza , Tapio Soile , Badie Christophe , Lumniczky Katalin
Published: May 2023

Extracellular vesicles (EVs), through their cargo, are important mediators of bystander responses in the irradiated bone marrow (BM). MiRNAs carried by EVs can potentially alter cellular pathways in EV-recipient cells by regulating their protein content. Using the CBA/Ca mouse model, we characterised the miRNA content of BM-derived EVs from mice irradiated with 0.1 Gy or 3 Gy using an nCounter analysis system. We also analysed proteomic changes in BM cells either directly irradiated or treated with EVs derived from the BM of irradiated mice. Our aim was to identify key cellular processes in the EV-acceptor cells regulated by miRNAs. The irradiation of BM cells with 0.1 Gy led to protein alterations involved in oxidative stress and immune and inflammatory processes. Oxidative stress-related pathways were also present in BM cells treated with EVs isolated from 0.1 Gy-irradiated mice, indicating the propagation of oxidative stress in a bystander manner. The irradiation of BM cells with 3 Gy led to protein pathway alterations involved in the DNA damage response, metabolism, cell death and immune and inflammatory processes. The majority of these pathways were also altered in BM cells treated with EVs from mice irradiated with 3 Gy. Certain pathways (cell cycle, acute and chronic myeloid leukaemia) regulated by miRNAs differentially expressed in EVs isolated from mice irradiated with 3 Gy overlapped with protein pathway alterations in BM cells treated with 3 Gy EVs. Six miRNAs were involved in these common pathways interacting with 11 proteins, suggesting the involvement of miRNAs in the EV-mediated bystander processes. In conclusion, we characterised proteomic changes in directly irradiated and EV-treated BM cells, identified processes transmitted in a bystander manner and suggested miRNA and protein candidates potentially involved in the regulation of these bystander processes.
Mitochondrial Trafficking of MLKL, Bak/Bax, and Drp1 Is Mediated by RIP1 and ROS which Leads to Decreased Mitochondrial Membrane Integrity during the Hyperglycemic Shift to Necroptosis
Authors: Deragon Matthew A. , McCaig William D. , Truong Phillip V. , Metz Kevin R. , Carron Katherine A. , Hughes Keven J. , Knapp Angeleigh R. , Dougherty Molly J. , LaRocca Timothy J.
Published: May 2023

Apoptosis and necroptosis overlap in their initial signaling but diverge to produce non-inflammatory and pro-inflammatory outcomes, respectively. High glucose pushes signaling in favor of necroptosis producing a hyperglycemic shift from apoptosis to necroptosis. This shift depends on receptor-interacting protein 1 (RIP1) and mitochondrial reactive oxygen species (ROS). Here, we show that RIP1, mixed lineage kinase domain-like (MLKL) protein, Bcl-2 agonist/killer (Bak), Bcl-2 associated x (Bax) protein, and dynamin-related protein 1 (Drp1) traffic to the mitochondria in high glucose. RIP1 and MLKL appear in the mitochondria in their activated, phosphorylated states while Drp1 appears in its activated, dephosphorylated state in high glucose. Mitochondrial trafficking is prevented in rip1 KO cells and upon treatment with N-acetylcysteine. Induction of ROS replicated the mitochondrial trafficking seen in high glucose. MLKL forms high MW oligomers in the outer and inner mitochondrial membranes while Bak and Bax form high MW oligomers in the outer mitochondrial membrane in high glucose, suggesting pore formation. MLKL, Bax, and Drp1 promoted cytochrome c release from the mitochondria as well as a decrease in mitochondrial membrane potential in high glucose. These results indicate that mitochondrial trafficking of RIP1, MLKL, Bak, Bax, and Drp1 are key events in the hyperglycemic shift from apoptosis to necroptosis. This is also the first report to show oligomerization of MLKL in the inner and outer mitochondrial membranes and dependence of mitochondrial permeability on MLKL.
Xenon’s Sedative Effect Is Mediated by Interaction with the Cyclic Nucleotide-Binding Domain (CNBD) of HCN2 Channels Expressed by Thalamocortical Neurons of the Ventrobasal Nucleus in Mice
Authors: Kassab Nour El Dine , Mehlfeld Verena , Kass Jennifer , Biel Martin , Schneider Gerhard , Rammes Gerhard
Published: May 2023

Previous studies have shown that xenon reduces hyperpolarization-activated cyclic nucleotide-gated channels type-2 (HCN2) channel-mediated current (Ih) amplitude and shifts the half-maximal activation voltage (V1/2) in thalamocortical circuits of acute brain slices to more hyperpolarized potentials. HCN2 channels are dually gated by the membrane voltage and via cyclic nucleotides binding to the cyclic nucleotide-binding domain (CNBD) on the channel. In this study, we hypothesize that xenon interferes with the HCN2 CNBD to mediate its effect. Using the transgenic mice model HCN2EA, in which the binding of cAMP to HCN2 was abolished by two amino acid mutations (R591E, T592A), we performed ex-vivo patch-clamp recordings and in-vivo open-field test to prove this hypothesis. Our data showed that xenon (1.9 mM) application to brain slices shifts the V1/2 of Ih to more hyperpolarized potentials in wild-type thalamocortical neurons (TC) (V1/2: −97.09 [−99.56–−95.04] mV compared to control −85.67 [−94.47–−82.10] mV; p = 0.0005). These effects were abolished in HCN2EA neurons (TC), whereby the V1/2 reached only −92.56 [−93.16– −89.68] mV with xenon compared to −90.03 [−98.99–−84.59] mV in the control (p = 0.84). After application of a xenon mixture (70% xenon, 30% O2), wild-type mice activity in the open-field test decreased to 5 [2–10] while in HCN2EA mice it remained at 30 [15–42]%, (p = 0.0006). In conclusion, we show that xenon impairs HCN2 channel function by interfering with the HCN2 CNBD site and provide in-vivo evidence that this mechanism contributes to xenon-mediated hypnotic properties.
Molecular Determinants of Species Specificity of α-Conotoxin TxIB towards Rat and Human α6/α3β4 Nicotinic Acetylcholine Receptors
Authors: Xie Ting , Qin Yuan , Zhao Jinyuan , Dong Jianying , Qi Panpan , Zhang Panpan , Zhangsun Dongting , Zhu Xiaopeng , Yu Jinpeng , Luo Sulan
Published: May 2023

Conotoxins are widely distributed and important for studying ligand-gated ion channels. TxIB, a conotoxin consisting of 16 amino acids derived from Conus textile, is a unique selective ligand that blocks rat α6/α3β2β3 nAChR (IC50 = 28 nM) without affecting other rat subtypes. However, when the activity of TxIB against human nAChRs was examined, it was unexpectedly found that TxIB had a significant blocking effect on not only human α6/α3β2β3 nAChR but also human α6/α3β4 nAChR, with an IC50 of 537 nM. To investigate the molecular mechanism of this species specificity and to establish a theoretical basis for drug development studies of TxIB and its analogs, different amino acid residues between human and rat α6/α3 and β4 nAChR subunits were identified. Each residue of the human species was then substituted with the corresponding residue of the rat species via PCR-directed mutagenesis. The potencies of TxIB towards the native α6/α3β4 nAChRs and their mutants were evaluated through electrophysiological experiments. The results showed that the IC50 of TxIB against h[α6V32L, K61R/α3]β4L107V, V115I was 22.5 μM, a 42-fold decrease in potency compared to the native hα6/α3β4 nAChR. Val-32 and Lys-61 in the human α6/α3 subunit and Leu-107 and Val-115 in the human β4 subunit, together, were found to determine the species differences in the α6/α3β4 nAChR. These results also demonstrate that the effects of species differences between humans and rats should be fully considered when evaluating the efficacy of drug candidates targeting nAChRs in rodent models.
Identification of Potential Biomarkers and Small Molecule Drugs for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ): An Integrated Bioinformatics Study Using Big Data
Authors: Balachandran Kumarendran , Ramli Roszalina , Karsani Saiful Anuar , Abdul Rahman Mariati
Published: May 2023

This study aimed to identify potential molecular mechanisms and therapeutic targets for bisphosphonate-related osteonecrosis of the jaw (BRONJ), a rare but serious side effect of bisphosphonate therapy. This study analyzed a microarray dataset (GSE7116) of multiple myeloma patients with BRONJ (n = 11) and controls (n = 10), and performed gene ontology, a pathway enrichment analysis, and a protein–protein interaction network analysis. A total of 1481 differentially expressed genes were identified, including 381 upregulated and 1100 downregulated genes, with enriched functions and pathways related to apoptosis, RNA splicing, signaling pathways, and lipid metabolism. Seven hub genes (FN1, TNF, JUN, STAT3, ACTB, GAPDH, and PTPRC) were also identified using the cytoHubba plugin in Cytoscape. This study further screened small-molecule drugs using CMap and verified the results using molecular docking methods. This study identified 3-(5-(4-(Cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxybenzo[d]isoxazol-6-yl) methoxy) phenyl) propanoic acid as a potential drug treatment and prognostic marker for BRONJ. The findings of this study provide reliable molecular insight for biomarker validation and potential drug development for the screening, diagnosis, and treatment of BRONJ. Further research is needed to validate these findings and develop an effective biomarker for BRONJ.
Meta-Inflammation and New Anti-Diabetic Drugs: A New Chance to Knock Down Residual Cardiovascular Risk
Authors: d’Aiello Alessia , Bonanni Alice , Vinci Ramona , Pedicino Daniela , Severino Anna , De Vita Antonio , Filomia Simone , Brecciaroli Mattia , Liuzzo Giovanna
Published: May 2023

Type 2 diabetes mellitus (DM) represents, with its macro and microvascular complications, one of the most critical healthcare issues for the next decades. Remarkably, in the context of regulatory approval trials, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) proved a reduced incidence of major adverse cardiovascular events (MACEs), i.e., cardiovascular death and heart failure (HF) hospitalizations. The cardioprotective abilities of these new anti-diabetic drugs seem to run beyond mere glycemic control, and a growing body of evidence disclosed a wide range of pleiotropic effects. The connection between diabetes and meta-inflammation seems to be the key to understanding how to knock down residual cardiovascular risk, especially in this high-risk population. The aim of this review is to explore the link between meta-inflammation and diabetes, the role of newer glucose-lowering medications in this field, and the possible connection with their unexpected cardiovascular benefits.
Development of Procathepsin L (pCTS-L)-Inhibiting Lanosterol-Carrying Liposome Nanoparticles to Treat Lethal Sepsis
Authors: Chen Weiqiang , Zhu Cassie Shu , Qiang Xiaoling , Chen Shujin , Li Jianhua , Wang Ping , Tracey Kevin J. , Wang Haichao
Published: May 2023

The pathogenesis of microbial infections and sepsis is partly attributable to dysregulated innate immune responses propagated by late-acting proinflammatory mediators such as procathepsin L (pCTS-L). It was previously not known whether any natural product could inhibit pCTS-L-mediated inflammation or could be strategically developed into a potential sepsis therapy. Here, we report that systemic screening of a NatProduct Collection of 800 natural products led to the identification of a lipophilic sterol, lanosterol (LAN), as a selective inhibitor of pCTS-L-induced production of cytokines [e.g., Tumor Necrosis Factor (TNF) and Interleukin-6 (IL-6)] and chemokines [e.g., Monocyte Chemoattractant Protein-1 (MCP-1) and Epithelial Neutrophil-Activating Peptide (ENA-78)] in innate immune cells. To improve its bioavailability, we generated LAN-carrying liposome nanoparticles and found that these LAN-containing liposomes (LAN-L) similarly inhibited pCTS-L-induced production of several chemokines [e.g., MCP-1, Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES) and Macrophage Inflammatory Protein-2 (MIP-2)] in human blood mononuclear cells (PBMCs). In vivo, these LAN-carrying liposomes effectively rescued mice from lethal sepsis even when the first dose was given at 24 h post the onset of this disease. This protection was associated with a significant attenuation of sepsis-induced tissue injury and systemic accumulation of serval surrogate biomarkers [e.g., IL-6, Keratinocyte-derived Chemokine (KC), and Soluble Tumor Necrosis Factor Receptor I (sTNFRI)]. These findings support an exciting possibility to develop liposome nanoparticles carrying anti-inflammatory sterols as potential therapies for human sepsis and other inflammatory diseases.
The Mechanism of Tigecycline Resistance in Acinetobacter baumannii Revealed by Proteomic and Genomic Analysis
Authors: Liu Cunwei , Wang Lei , Wang Ping , Xiao Di , Zou Qinghua
Published: May 2023

The mechanism of tigecycline resistance in A. baumannii remains largely unclear. In this study, we selected a tigecycline-resistant and a tigecycline-susceptible strain from a tigecycline-susceptible and a resistant strain, respectively. Proteomic and genomic analyses were performed to elucidate the variations associated with tigecycline resistance. Our study showed proteins associated with efflux pump, biofilm formation, iron acquisition, stress response, and metabolic ability are upregulated in tigecycline resistant strains, and efflux pump should be the key mechanism for tigecycline resistance. By genomic analysis, we found several changes in the genome that can explain the increased level of efflux pump, including the loss of the global negative regulator hns in the plasmid and the disruption of the hns gene and acrR gene on the chromosome by the insertion of IS5. Collectively, we not only revealed the phenomenon that the efflux pump is mainly responsible for tigecycline resistance, but also highlighted the mechanism at the genomic level, which will help in understanding the resistance mechanism in detail and provide clues for the treatment of clinical multiple drug-resistant A. baumannii.
5-ALA/SFC Ameliorates Endotoxin-Induced Ocular Inflammation in Rats by Inhibiting the NF-κB Signaling Pathway and Activating the HO-1/Nrf2 Signaling Pathway
Authors: Otaka Yuya , Kanai Kazutaka , Mori Arisa , Okada Daiki , Nagai Noriaki , Yamashita Yohei , Ichikawa Yoichiro , Tajima Kazuki
Published: May 2023

Sodium ferrous citrate (SFC) is involved in the metabolism of 5-aminolevulinic acid (5-ALA) and enhances its anti-inflammatory effects. The effects of 5-ALA/SFC on inflammation in rats with endotoxin-induced uveitis (EIU) have yet to be elucidated. In this study, during lipopolysaccharide injection, 5-ALA/SFC (10 mg/kg 5-ALA plus 15.7 mg/kg SFC) or 5-ALA (10 or 100 mg/kg) was administered via gastric gavage, wherein we saw that 5-ALA/SFC ameliorated ocular inflammation in EIU rats by suppressing clinical scores; by infiltrating cell counts, aqueous humor protein, and inflammatory cytokine levels; and by improving histopathological scores to the same extent as 100 mg/kg 5-ALA. Immunohistochemistry showed that 5-ALA/SFC suppressed iNOS and COX-2 expression, NF-κB activation, IκB-α degradation, and p-IKKα/β expression, and activated HO-1 and Nrf2 expression. Therefore, this study has investigated how 5-ALA/SFC reduces inflammation and revealed the pathways involved in EIU rats. 5-ALA/SFC is shown to inhibit ocular inflammation in EIU rats by inhibiting NF-κB and activating the HO-1/Nrf2 pathways.
Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment
Authors: Rodríguez Francisco D. , Sánchez Manuel Lisardo , Coveñas Rafael
Published: May 2023

Harmful alcohol use is responsible for a group of disorders collectively named alcohol use disorders (AUDs), according to the DSM-5 classification. The damage induced by alcohol depends on the amount, time, and consumption patterns (continuous and heavy episodic drinking). It affects individual global well-being and social and familial environments with variable impact. Alcohol addiction manifests with different degrees of organ and mental health detriment for the individual, exhibiting two main traits: compulsive drinking and negative emotional states occurring at withdrawal, frequently causing relapse episodes. Numerous individual and living conditions, including the concomitant use of other psychoactive substances, lie in the complexity of AUD. Ethanol and its metabolites directly impact the tissues and may cause local damage or alter the homeostasis of brain neurotransmission, immunity scaffolding, or cell repair biochemical pathways. Brain modulator and neurotransmitter-assembled neurocircuitries govern reward, reinforcement, social interaction, and consumption of alcohol behaviors in an intertwined manner. Experimental evidence supports the participation of neurotensin (NT) in preclinical models of alcohol addiction. For example, NT neurons in the central nucleus of the amygdala projecting to the parabrachial nucleus strengthen alcohol consumption and preference. In addition, the levels of NT in the frontal cortex were found to be lower in rats bred to prefer alcohol to water in a free alcohol–water choice compared to wild-type animals. NT receptors 1 and 2 seem to be involved in alcohol consumption and alcohol effects in several models of knockout mice. This review aims to present an updated picture of the role of NT systems in alcohol addiction and the possible use of nonpeptide ligands modulating the activity of the NT system, applied to experimental animal models of harmful drinking behavior mimicking alcohol addiction leading to health ruin in humans.
Modeling Duchenne Muscular Dystrophy Cardiomyopathy with Patients’ Induced Pluripotent Stem-Cell-Derived Cardiomyocytes
Authors: Eisen Binyamin , Binah Ofer
Published: May 2023

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease caused by mutations in the dystrophin gene, resulting in death by the end of the third decade of life at the latest. A key aspect of the DMD clinical phenotype is dilated cardiomyopathy, affecting virtually all patients by the end of the second decade of life. Furthermore, despite respiratory complications still being the leading cause of death, with advancements in medical care in recent years, cardiac involvement has become an increasing cause of mortality. Over the years, extensive research has been conducted using different DMD animal models, including the mdx mouse. While these models present certain important similarities to human DMD patients, they also have some differences which pose a challenge to researchers. The development of somatic cell reprograming technology has enabled generation of human induced pluripotent stem cells (hiPSCs) which can be differentiated into different cell types. This technology provides a potentially endless pool of human cells for research. Furthermore, hiPSCs can be generated from patients, thus providing patient-specific cells and enabling research tailored to different mutations. DMD cardiac involvement has been shown in animal models to include changes in gene expression of different proteins, abnormal cellular Ca2+ handling, and other aberrations. To gain a better understanding of the disease mechanisms, it is imperative to validate these findings in human cells. Furthermore, with the recent advancements in gene-editing technology, hiPSCs provide a valuable platform for research and development of new therapies including the possibility of regenerative medicine. In this article, we review the DMD cardiac-related research performed so far using human hiPSCs-derived cardiomyocytes (hiPSC-CMs) carrying DMD mutations.
Yeast Chaperone Hsp70-Ssb Modulates a Variety of Protein-Based Heritable Elements
Authors: Jay-Garcia Lina M. , Cornell Joseph L. , Howie Rebecca L. , Faber Quincy L. , Salas Abigail , Chernova Tatiana A. , Chernoff Yury O.
Published: May 2023

Prions are transmissible self-perpetuating protein isoforms associated with diseases and heritable traits. Yeast prions and non-transmissible protein aggregates (mnemons) are frequently based on cross-β ordered fibrous aggregates (amyloids). The formation and propagation of yeast prions are controlled by chaperone machinery. Ribosome-associated chaperone Hsp70-Ssb is known (and confirmed here) to modulate formation and propagation of the prion form of the Sup35 protein [PSI+]. Our new data show that both formation and mitotic transmission of the stress-inducible prion form of the Lsb2 protein ([LSB+]) are also significantly increased in the absence of Ssb. Notably, heat stress leads to a massive accumulation of [LSB+] cells in the absence of Ssb, implicating Ssb as a major downregulator of the [LSB+]-dependent memory of stress. Moreover, the aggregated form of Gγ subunit Ste18, [STE+], behaving as a non-heritable mnemon in the wild-type strain, is generated more efficiently and becomes heritable in the absence of Ssb. Lack of Ssb also facilitates mitotic transmission, while lack of the Ssb cochaperone Hsp40-Zuo1 facilitates both spontaneous formation and mitotic transmission of the Ure2 prion, [URE3]. These results demonstrate that Ssb is a general modulator of cytosolic amyloid aggregation, whose effect is not restricted only to [PSI+].
Consideration for Flavonoid-Containing Dietary Supplements to Tackle Deficiency and Optimize Health
Authors: Solnier Julia , Chang Chuck , Pizzorno Joseph
Published: May 2023

Randomized clinical trials (RCT) and observational studies have highlighted the importance of flavonoid consumption for human health. Several studies have associated a high intake of dietary flavonoids with (a) enhanced metabolic and cardiovascular health, (b) enhanced cognitive and vascular endothelial functions, (c) an improved glycemic response in type 2 diabetes mellitus, and (d) a reduced risk of breast cancer in postmenopausal women. Since flavonoids belong to a broad and diverse family of polyphenolic plant molecules—with more than 6000 compounds interspersed in the human diet—researchers are still uncertain whether the intake of single, individual polyphenols or a large combination of them (i.e., synergistic action) can produce the greatest health benefits for humans. Furthermore, studies have reported a poor bioavailability of flavonoid compounds in humans, which presents a major challenge for determining their optimal dosage, recommended intake, and, consequently, their therapeutic value. Especially because of their scarce bioavailability from foods—along with the overall declining food quality and nutrient density in foods—the role of flavonoid supplementation may become increasingly important for human health. Although research shows that dietary supplements can be a highly useful tool to complement diets that lack sufficient amounts of important nutrients, some caution is warranted regarding possible interactions with prescription and non-prescription drugs, especially when taken concurrently. Herein, we discuss the current scientific basis for using flavonoid supplementation to improve health as well as the limitations related to high intakes of dietary flavonoids.
Dental Pulp Stem Cells for Salivary Gland Regeneration—Where Are We Today?
Authors: Muallah David , Matschke Jan , Kappler Matthias , Kroschwald Lysann Michaela , Lauer Günter , Eckert Alexander W.
Published: May 2023

Xerostomia is the phenomenon of dry mouth and is mostly caused by hypofunction of the salivary glands. This hypofunction can be caused by tumors, head and neck irradiation, hormonal changes, inflammation or autoimmune disease such as Sjögren’s syndrome. It is associated with a tremendous decrease in health-related quality of life due to impairment of articulation, ingestion and oral immune defenses. Current treatment concepts mainly consist of saliva substitutes and parasympathomimetic drugs, but the outcome of these therapies is deficient. Regenerative medicine is a promising approach for the treatment of compromised tissue. For this purpose, stem cells can be utilized due to their ability to differentiate into various cell types. Dental pulp stem cells are adult stem cells that can be easily harvested from extracted teeth. They can form tissues of all three germ layers and are therefore becoming more and more popular for tissue engineering. Another potential benefit of these cells is their immunomodulatory effect. They suppress proinflammatory pathways of lymphocytes and could therefore probably be used for the treatment of chronic inflammation and autoimmune disease. These attributes make dental pulp stem cells an interesting tool for the regeneration of salivary glands and the treatment of xerostomia. Nevertheless, clinical studies are still missing. This review will highlight the current strategies for using dental pulp stem cells in the regeneration of salivary gland tissue.
UBASH3A Interacts with PTPN22 to Regulate IL2 Expression and Risk for Type 1 Diabetes
Authors: Newman Jeremy R. B. , Concannon Patrick , Ge Yan
Published: May 2023

UBASH3A is a negative regulator of T cell activation and IL-2 production and plays key roles in autoimmunity. Although previous studies revealed the individual effects of UBASH3A on risk for type 1 diabetes (T1D; a common autoimmune disease), the relationship of UBASH3A with other T1D risk factors remains largely unknown. Given that another well-known T1D risk factor, PTPN22, also inhibits T cell activation and IL-2 production, we investigated the relationship between UBASH3A and PTPN22. We found that UBASH3A, via its Src homology 3 (SH3) domain, physically interacts with PTPN22 in T cells, and that this interaction is not altered by the T1D risk coding variant rs2476601 in PTPN22. Furthermore, our analysis of RNA-seq data from T1D cases showed that the amounts of UBASH3A and PTPN22 transcripts exert a cooperative effect on IL2 expression in human primary CD8+ T cells. Finally, our genetic association analyses revealed that two independent T1D risk variants, rs11203203 in UBASH3A and rs2476601 in PTPN22, interact statistically, jointly affecting risk for T1D. In summary, our study reveals novel interactions, both biochemical and statistical, between two independent T1D risk loci, and suggests how these interactions may affect T cell function and increase risk for T1D.
Chitosan Membranes Containing Plant Extracts: Preparation, Characterization and Antimicrobial Properties
Authors: Gradinaru Luiza Madalina , Barbalata-Mandru Mihaela , Enache Alin Alexandru , Rimbu Cristina Mihaela , Badea Georgiana Ileana , Aflori Magdalena
Published: May 2023

The main strategy of this study was to combine the traditional perspective of using medicinal extracts with polymeric scaffolds manufactured by an engineering approach to fabricate a potential dressing product with antimicrobial properties. Thus, chitosan-based membranes containing S. officinalis and H. perforatum extracts were developed and their suitability as novel dressing materials was investigated. The morphology of the chitosan-based films was assessed by scanning electron microscopy (SEM) and the chemical structure characterization was performed via Fourier transform infrared spectroscopy (FTIR). The addition of the plant extracts increased the sorption capacity of the studied fluids, mainly at the membrane with S. officinalis extract. The membranes with 4% chitosan embedded with both plant extracts maintained their integrity after being immersed for 14 days in incubation media, especially in PBS. The antibacterial activities were determined by the modified Kirby–Bauer disk diffusion method for Gram-positive (S. aureus ATCC 25923, MRSA ATCC 43300) and Gram-negative (E. coli ATCC 25922, P. aeruginosa ATCC 27853) microorganisms. The antibacterial property was enhanced by incorporating the plant extracts into chitosan films. The outcome of the study reveals that the obtained chitosan-based membranes are promising candidates to be used as a wound dressing due to their good physico-chemical and antimicrobial properties.
TGF-β Type I Receptor Signaling in Melanoma Liver Metastases Increases Metastatic Outgrowth
Authors: Marvin Dieuwke L. , Dijkstra Jelmer , Zulfiqar Rabia M. , Vermeulen Michiel , ten Dijke Peter , Ritsma Laila
Published: May 2023

Despite advances in treatment for metastatic melanoma patients, patients with liver metastasis have an unfavorable prognosis. A better understanding of the development of liver metastasis is needed. The multifunctional cytokine Transforming Growth Factor β (TGF-β) plays various roles in melanoma tumors and metastasis, affecting both tumor cells and cells from the surrounding tumor microenvironment. To study the role of TGF-β in melanoma liver metastasis, we created a model to activate or repress the TGF-β receptor pathway in vitro and in vivo in an inducible manner. For this, we engineered B16F10 melanoma cells to have inducible ectopic expression of a constitutively active (ca) or kinase-inactive (ki) TGF-β receptor I, also termed activin receptor-like kinase (ALK5). In vitro, stimulation with TGF-β signaling and ectopic caALK5 expression reduced B16F10 cell proliferation and migration. Contrasting results were found in vivo; sustained caALK5 expression in B16F10 cells in vivo increased the metastatic outgrowth in liver. Blocking microenvironmental TGF-β did not affect metastatic liver outgrowth of both control and caALK5 expressing B16F10 cells. Upon characterizing the tumor microenvironment of control and caALk5 expressing B16F10 tumors, we observed reduced (cytotoxic) T cell presence and infiltration, as well as an increase in bone marrow-derived macrophages in caALK5 expressing B16F10 tumors. This suggests that caALK5 expression in B16F10 cells induces changes in the tumor microenvironment. A comparison of newly synthesized secreted proteins upon caALK5 expression by B16F10 cells revealed increased secretion of matrix remodeling proteins. Our results show that TGF-β receptor activation in B16F10 melanoma cells can increase metastatic outgrowth in liver in vivo, possibly through remodeling of the tumor microenvironment leading to altered infiltration of immune cells. These results provide insights in the role of TGF-β signaling in B16F10 liver metastasis and could have implications regarding the use of TGF-β inhibitors for the treatment of melanoma patients with liver metastasis.
Recent Advances on Affibody- and DARPin-Conjugated Nanomaterials in Cancer Therapy
Authors: Gabriele Federica , Palerma Marta , Ippoliti Rodolfo , Angelucci Francesco , Pitari Giuseppina , Ardini Matteo
Published: May 2023

Affibodies and designed ankyrin repeat proteins (DARPins) are synthetic proteins originally derived from the Staphylococcus aureus virulence factor protein A and the human ankyrin repeat proteins, respectively. The use of these molecules in healthcare has been recently proposed as they are endowed with biochemical and biophysical features heavily demanded to target and fight diseases, as they have a strong binding affinity, solubility, small size, multiple functionalization sites, biocompatibility, and are easy to produce; furthermore, impressive chemical and thermal stability can be achieved. especially when using affibodies. In this sense, several examples reporting on affibodies and DARPins conjugated to nanomaterials have been published, demonstrating their suitability and feasibility in nanomedicine for cancer therapy. This minireview provides a survey of the most recent studies describing affibody- and DARPin-conjugated zero-dimensional nanomaterials, including inorganic, organic, and biological nanoparticles, nanorods, quantum dots, liposomes, and protein- and DNA-based assemblies for targeted cancer therapy in vitro and in vivo.
Molecular Research on Migraine: From Pathogenesis to Treatment
Authors: Tuttolomondo Antonino , Simonetta Irene
Published: May 2023

Migraine is a common, multifactorial, disabling, recurrent, hereditary, neurovascular headache disorder [...]
Pirfenidone Inhibits Alveolar Bone Loss in Ligature-Induced Periodontitis by Suppressing the NF-κB Signaling Pathway in Mice
Authors: Zhang Zijiao , Song Juhan , Kwon Seung-Hee , Wang Zhao , Park Suk-Gyun , Piao Xianyu , Ryu Je-Hwang , Kim Nacksung , Kim Ok-Su , Kim Sun-Hun , Koh Jeong-Tae
Published: May 2023

There has been increasing interest in adjunctive use of anti-inflammatory drugs to control periodontitis. This study was performed to examine the effects of pirfenidone (PFD) on alveolar bone loss in ligature-induced periodontitis in mice and identify the relevant mechanisms. Experimental periodontitis was established by ligating the unilateral maxillary second molar for 7 days in mice (n = 8 per group), and PFD was administered daily via intraperitoneal injection. The micro-computed tomography and histology analyses were performed to determine changes in the alveolar bone following the PFD administration. For in vitro analysis, bone marrow macrophages (BMMs) were isolated from mice and cultured with PFD in the presence of RANKL or LPS. The effectiveness of PFD on osteoclastogenesis, inflammatory cytokine expression, and NF-κB activation was determined with RT-PCR, Western blot, and immunofluorescence analyses. PFD treatment significantly inhibited the ligature-induced alveolar bone loss, with decreases in TRAP-positive osteoclasts and expression of inflammatory cytokines in mice. In cultured BMM cells, PFD also inhibited RANKL-induced osteoclast differentiation and LPS-induced proinflammatory cytokine (IL-1β, IL-6, TNF-a) expression via suppressing the NF-κB signal pathway. These results suggest that PFD can suppress periodontitis progression by inhibiting osteoclastogenesis and inflammatory cytokine production via inhibiting the NF-κB signal pathway, and it may be a promising candidate for controlling periodontitis.
Vitamin A Promotes the Fusion of Autophagolysosomes and Prevents Excessive Inflammasome Activation in Dextran Sulfate Sodium-Induced Colitis
Authors: Hiraga Hiroto , Chinda Daisuke , Maeda Takato , Murai Yasuhisa , Ogasawara Kohei , Muramoto Ryutaro , Ota Shinji , Hasui Keisuke , Sakuraba Hirotake , Ishiguro Yoh , Yoshida Shukuko , Asano Krisana , Nakane Akio , Fukuda Shinsaku
Published: May 2023

Vitamin A ensures intestinal homeostasis, impacting acquired immunity and epithelial barrier function; however, its role in innate immunity is mostly unknown. Here, we studied the impact of vitamin A in different dextran sulfate sodium (DSS)-induced colitis animal models. Interestingly, more severe DSS-induced colitis was observed in vitamin A-deficient (VAD) mice than in vitamin A-sufficient (VAS) mice; the same was observed in VAD severe combined immunodeficient mice lacking T/B cells. Remarkably, IL-1β production, LC3B-II expression, and inflammasome activity in the lamina propria were significantly elevated in VAD mice. Electron microscopy revealed numerous swollen mitochondria with severely disrupted cristae. In vitro, non-canonical inflammasome signaling-induced pyroptosis, LC3B-II and p62 expression, and mitochondrial superoxide levels were increased in murine macrophages (RAW 264.7) pretreated with retinoic acid receptor antagonist (Ro41-5253). These findings suggest that vitamin A plays a crucial role in the efficient fusion of autophagosomes with lysosomes in colitis.
OsNPR1 Enhances Rice Resistance to Xanthomonas oryzae pv. oryzae by Upregulating Rice Defense Genes and Repressing Bacteria Virulence Genes
Authors: Dai Xing , Wang Yankai , Yu Kaili , Zhao Yonghui , Xiong Langyu , Wang Ruozhong , Li Shengben
Published: May 2023

The bacteria pathogen Xanthomonas oryzae pv. oryzae (Xoo) infects rice and causes the severe disease of rice bacteria blight. As the central regulator of the salic acid (SA) signaling pathway, NPR1 is responsible for sensing SA and inducing the expression of pathogen-related (PR) genes in plants. Overexpression of OsNPR1 significantly increases rice resistance to Xoo. Although some downstream rice genes were found to be regulated by OsNPR1, how OsNPR1 affects the interaction of rice-Xoo and alters Xoo gene expression remains unknown. In this study, we challenged the wild-type and OsNPR1-OE rice materials with Xoo and performed dual RNA-seq analyses for the rice and Xoo genomes simultaneously. In Xoo-infected OsNPR1-OE plants, rice genes involved in cell wall biosynthesis and SA signaling pathways, as well as PR genes and nucleotide-binding site-leucine-rich repeat (NBS-LRR) genes, were significantly upregulated compared to rice variety TP309. On the other hand, Xoo genes involved in energy metabolism, oxidative phosphorylation, biosynthesis of primary and secondary metabolism, and transportation were repressed. Many virulence genes of Xoo, including genes encoding components of type III and other secretion systems, were downregulated by OsNPR1 overexpression. Our results suggest that OsNPR1 enhances rice resistance to Xoo by bidirectionally regulating gene expression in rice and Xoo.
Development of a Prediction Model for Short-Term Remission of Patients with Crohn’s Disease Treated with Anti-TNF Drugs
Authors: Medina-Medina Rosario , Iglesias-Flores Eva , Benítez Jose M. , Marín-Pedrosa Sandra , Salgueiro-Rodríguez Isabel , Linares Clara I. , González-Rubio Sandra , Soto-Escribano Pilar , Gros Beatriz , Rodríguez-Perálvarez Manuel L. , Cabriada José L. , Chaparro María , Gisbert Javier P. , Chicano-Gálvez Eduardo , Ortea Ignacio , Ferrín Gustavo , García-Sánchez Valle , Aguilar-Melero Patricia
Published: May 2023

Therapy with anti-tumor necrosis factor (TNF) has dramatically changed the natural history of Crohn’s disease (CD). However, these drugs are not without adverse events, and up to 40% of patients could lose efficacy in the long term. We aimed to identify reliable markers of response to anti-TNF drugs in patients with CD. A consecutive cohort of 113 anti-TNF naive patients with CD was stratified according to clinical response as short-term remission (STR) or non-STR (NSTR) at 12 weeks of treatment. We compared the protein expression profiles of plasma samples in a subset of patients from both groups prior to anti-TNF therapy by SWATH proteomics. We identified 18 differentially expressed proteins (p ≤ 0.01, fold change ≥ 2.4) involved in the organization of the cytoskeleton and cell junction, hemostasis/platelet function, carbohydrate metabolism, and immune response as candidate biomarkers of STR. Among them, vinculin was one of the most deregulated proteins (p < 0.001), whose differential expression was confirmed by ELISA (p = 0.054). In the multivariate analysis, plasma vinculin levels along with basal CD Activity Index, corticosteroids induction, and bowel resection were factors predicting NSTR.
Mucin-Phenotype and Expression of the Protein V-Set and Immunoglobulin Domain Containing 1 (VSIG1): New Insights into Gastric Carcinogenesis
Authors: Satala Catalin-Bogdan , Jung Ioan , Gurzu Simona
Published: May 2023

In gastric cancer (GC), intestinal metaplasia (IM) is a common precursor lesion, but its relationship to the MUC2/MUC5AC/CDX2 axis is not completely understood. Although V-set and immunoglobulin domain containing 1 (VSIG1) is supposed to be a specific marker for gastric mucosa and GC, respectively, no data about its relationship with IM or mucin phenotype have been published. The aim of our study was to explore the possible linkage between IM and these four molecules. The clinicopathological features of 60 randomly selected GCs were examined in association with VSIG1, MUC2, MUC5AC and CDX2. Two online database platforms were also used to establish the transcription factors (TFs) network involved in MUC2/MUC5AC/CDX2 cascade. IM was more frequently encountered in females (11/16 cases) and in patients below 60 years old (10/16 cases). Poorly differentiated (G3) carcinomas tended to show a loss of CDX2 (27/33 cases) but not of MUC2 and MUC5AC. MUC5AC and CDX2 were lost in parallel with the depth of invasion of the pT4 stage (28/35 and 29/35 cases), while an advanced Dukes-MAC-like stage was only correlated with CDX2 and VSIG1 loss (20/37 and 30/37 cases). VSIG1 was directly correlated with MUC5AC (p = 0.04) as an indicator of gastric phenotype. MUC2-negative cases showed a propensity towards lymphatic invasion (37/40 cases) and distant metastases, while CDX2-negative cases tended to associate with hematogenous dissemination (30/40 cases). Regarding the molecular network, only 3 of the 19 TFs involved in this carcinogenic cascade (SP1, RELA, NFKB1) interacted with all targeted genes. In GC, VSIG1 can be considered an indicator of gastric phenotype carcinomas, where carcinogenesis is mainly driven by MUC5AC. Although infrequently encountered in GC, CDX2 positivity might indicate a locally advanced stage and risk for vascular invasion, especially in tumors developed against the background of IM. The loss of VSIG1 indicates a risk for lymph node metastases.
The Role of Dopamine D3 Receptors, Dysbindin, and Their Functional Interaction in the Expression of Key Genes for Neuroplasticity and Neuroinflammation in the Mouse Brain
Authors: Rivi Veronica , Benatti Cristina , Blom Joan M. C. , Pani Luca , Brunello Nicoletta , Drago Filippo , Papaleo Francesco , Caraci Filippo , Geraci Federica , Torrisi Sebastiano Alfio , Leggio Gian Marco , Tascedda Fabio
Published: May 2023

Cognitive impairment in schizophrenia remains a clinically and pharmacologically unsolved challenge. Clinical and preclinical studies have revealed that the concomitant reduction in dysbindin (DYS) and dopamine receptor D3 functionality improves cognitive functions. However, the molecular machinery underlying this epistatic interaction has not yet been fully elucidated. The glutamate NMDA receptors and the neurotrophin BDNF, with their established role in promoting neuroplasticity, may be involved in the complex network regulated by the D3/DYS interaction. Furthermore, as inflammation is involved in the etiopathogenesis of several psychiatric diseases, including schizophrenia, the D3/DYS interaction may affect the expression levels of pro−inflammatory cytokines. Thus, by employing mutant mice bearing selective heterozygosis for D3 and/or DYS, we provide new insights into the functional interactions (single and synergic) between these schizophrenia susceptibility genes and the expression levels of key genes for neuroplasticity and neuroinflammation in three key brain areas for schizophrenia: the prefrontal cortex, striatum, and hippocampus. In the hippocampus, the epistatic interaction between D3 and DYS reversed to the wild-type level the downregulated mRNA levels of GRIN1 and GRIN2A were observed in DYS +/− and D3 +/− mice. In all the areas investigated, double mutant mice had higher BDNF levels compared to their single heterozygote counterparts, whereas D3 hypofunction resulted in higher pro−inflammatory cytokines. These results may help to clarify the genetic mechanisms and functional interactions involved in the etiology and development of schizophrenia.