bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Descriptors Property Prediction Using Transformer-Based Approach
Authors: Tran Tuan , Ekenna Chinwe
Published: July 2023

In this study, we introduce semi-supervised machine learning models designed to predict molecular properties. Our model employs a two-stage approach, involving pre-training and fine-tuning. Particularly, our model leverages a substantial amount of labeled and unlabeled data consisting of SMILES strings, a text representation system for molecules. During the pre-training stage, our model capitalizes on the Masked Language Model, which is widely used in natural language processing, for learning molecular chemical space representations. During the fine-tuning stage, our model is trained on a smaller labeled dataset to tackle specific downstream tasks, such as classification or regression. Preliminary results indicate that our model demonstrates comparable performance to state-of-the-art models on the chosen downstream tasks from MoleculeNet. Additionally, to reduce the computational overhead, we propose a new approach taking advantage of 3D compound structures for calculating the attention score used in the end-to-end transformer model to predict anti-malaria drug candidates. The results show that using the proposed attention score, our end-to-end model is able to have comparable performance with pre-trained models.
Differential Gene and Protein Expression of Conjunctival Bleb Hyperfibrosis in Early Failure of Glaucoma Surgery
Authors: Millá Elena , Ventura-Abreu Néstor , Vendrell Cristina , Muniesa Maria Jesús , Pazos Marta , Gasull Xavier , Comes Núria
Published: July 2023

The early failure of glaucoma surgery is mainly caused by over-fibrosis at the subconjunctival space, causing obliteration of the filtration bleb. Because fibrosis has a suspected basis of genetic predisposition, we have undertaken a prospective study to identify upregulated profibrotic genes in a population of glaucoma patients with signs of conjunctival fibrosis and early postoperative surgical failure. Clinical data of re-operated fibrosis patients, hyperfibrosis patients who re-operated more than once in a short time, and control patients with no fibrosis were recorded and analyzed at each follow-up visit. Conjunctival-Tenon surgical specimens were obtained intraoperatively to evaluate the local expression of a panel of genes potentially associated with fibrosis. In order to correlate gene expression signatures with protein levels, we quantified secreted proteins in primary cultures of fibroblasts from patients. Expression of VEGFA, CXCL8, MYC, and CDKN1A was induced in the conjunctiva of hyperfibrosis patients. VEGFA and IL8 protein levels were also increased in fibroblast supernatants. We propose that an increase in these proteins could be useful in detecting conjunctival fibrosis in glaucoma patients undergoing filtering surgery. Molecular markers could be crucial for early detection of patients at high risk of failure of filtration surgery, leading to more optimal and personalized treatments.
Stringent Response Factor DksA Contributes to Fatty Acid Degradation Function to Influence Cell Membrane Stability and Polymyxin B Resistance of Yersinia enterocolitica
Authors: Huang Can , Li Wenqian , Chen Jingyu
Published: July 2023

DksA is a proteobacterial regulator that binds directly to the secondary channel of RNA polymerase with (p)ppGpp and is responsible for various bacterial physiological activities. While (p)ppGpp is known to be involved in the regulation and response of fatty acid metabolism pathways in many foodborne pathogens, the role of DksA in this process has yet to be clarified. This study aimed to characterize the function of DksA on fatty acid metabolism and cell membrane structure in Yersinia enterocolitica. Therefore, comparison analysis of gene expression, growth conditions, and membrane permeabilization among the wide-type (WT), DksA-deficient mutant (YEND), and the complemented strain was carried out. It confirmed that deletion of DksA led to a more than four-fold decrease in the expression of fatty acid degradation genes, including fadADEIJ. Additionally, YEND exhibited a smaller growth gap compared to the WT strain at low temperatures, indicating that DksA is not required for the growth of Y. enterocolitica in cold environments. Given that polymyxin B is a cationic antimicrobial peptide that targets the cell membrane, the roles of DksA under polymyxin B exposure were also characterized. It was found that DksA positively regulates the integrity of the inner and outer membranes of Y. enterocolitica under polymyxin B, preventing the leakage of intracellular nucleic acids and proteins and ultimately reducing the sensitivity of Y. enterocolitica to polymyxin B. Taken together, this study provides insights into the functions of DksA and paves the way for novel fungicide development.
CCR9/CXCR5 Co-Expressing CD4 T Cells Are Increased in Primary Sjögren’s Syndrome and Are Enriched in PD-1/ICOS-Expressing Effector T Cells
Authors: Hinrichs Anneline C. , Kruize Aike A. , Lafeber Floris P. J. G. , Leavis Helen L. , van Roon Joel A. G.
Published: July 2023

Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterised by B cell hyperactivity. CXCR5+ follicular helper T cells (Tfh), CXCR5-PD-1hi peripheral helper T cells (Tph) and CCR9+ Tfh-like cells have been implicated in driving B cell hyperactivity in pSS; however, their potential overlap has not been evaluated. Our aim was to study the overlap between the two CXCR5- cell subsets and to study their PD-1/ICOS expression compared to “true” CXCR5/PD-1/ICOS-expressing Tfh cells. CXCR5- Tph and CCR9+ Tfh-like cell populations from peripheral blood mononuclear cells of pSS patients and healthy controls (HC) were compared using flow cytometry. PD-1/ICOS expression from these cell subsets was compared to each other and to CXCR5+ Tfh cells, taking into account their differentiation status. CXCR5- Tph cells and CCR9+ Tfh-like cells, both in pSS patients and HC, showed limited overlap. PD-1/ICOS expression was higher in memory cells expressing CXCR5 or CCR9. However, the highest expression was found in CXCR5/CCR9 co-expressing T cells, which are enriched in the circulation of pSS patients. CXCR5- Tph and CCR9+ Tfh-like cells are two distinct cell populations that both are enriched in pSS patients and can drive B cell hyperactivity in pSS. The known upregulated expression of CCL25 and CXCL13, ligands of CCR9 and CXCR5, at pSS inflammatory sites suggests concerted action to facilitate the migration of CXCR5+CCR9+ T cells, which are characterised by the highest frequencies of PD-1/ICOS-positive cells. Hence, these co-expressing effector T cells may significantly contribute to the ongoing immune responses in pSS.
A Genetically Engineered Bivalent Vaccine Coexpressing a Molecular Adjuvant against Classical Swine Fever and Porcine Epidemic Diarrhea
Authors: Wang Hao , Yi Weicheng , Qin Huan , Wang Qin , Guo Rui , Pan Zishu
Published: July 2023

Classical swine fever (CSF) and porcine epidemic diarrhea (PED) are highly contagious viral diseases that pose a significant threat to piglets and cause substantial economic losses in the global swine industry. Therefore, the development of a bivalent vaccine capable of targeting both CSF and PED simultaneously is crucial. In this study, we genetically engineered a recombinant classical swine fever virus (rCSFV) expressing the antigenic domains of the porcine epidemic diarrhea virus (PEDV) based on the modified infectious cDNA clone of the vaccine strain C-strain. The S1N and COE domains of PEDV were inserted into C-strain cDNA clone harboring the mutated 136th residue of Npro and substituted 3′UTR to generate the recombinant chimeric virus vC/SM3′UTRN-S1NCOE. To improve the efficacy of the vaccine, we introduced the tissue plasminogen activator signal (tPAs) and CARD domain of the signaling molecule VISA into vC/SM3′UTRN-S1NCOE to obtain vC/SM3′UTRN-tPAsS1NCOE and vC/SM3′UTRN-CARD/tPAsS1NCOE, respectively. We characterized three vaccine candidates in vitro and investigated their immune responses in rabbits and pigs. The NproD136N mutant exhibited normal autoprotease activity and mitigated the inhibition of IFN-β induction. The introduction of tPAs and the CARD domain led to the secretory expression of the S1NCOE protein and upregulated IFN-β induction in infected cells. Immunization with recombinant CSFVs expressing secretory S1NCOE resulted in a significantly increased in PEDV-specific antibody production, and coexpression of the CARD domain of VISA upregulated the PEDV-specific IFN-γ level in the serum of vaccinated animals. Notably, vaccination with vC/SM3′UTRN-CARD/tPAsS1NCOE conferred protection against virulent CSFV and PEDV challenge in pigs. Collectively, these findings demonstrate that the engineered vC/SM3′UTRN-CARD/tPAsS1NCOE is a promising bivalent vaccine candidate against both CSFV and PEDV infections.
Physicochemical Study of the Molecular Signal Transfer of Ultra-High Diluted Antibodies to Interferon-Gamma
Authors: Jerman Igor , Ogrizek Linda , Periček Krapež Vesna , Jan Luka
Published: July 2023

Physicochemical investigations of (UHD) solutions subjected to certain physical factors (like shaking) are becoming more frequent and increasingly yielding convincing results. A much less studied phenomenon is the transfer of molecular information (UHD signals) from one fluid to another without an intermediate liquid phase. The purpose of this study was to investigate the possibility of such a UHD signal transfer from UHD solutions into the receiver fluid, especially when the molecular source used in solutions was a biologically active molecule of antibodies to interferon-gamma. We used physicochemical measurements and UV spectroscopy for this purpose. The results of this large pilot study confirm the possibility of such a transfer and a rough similarity to the original UHD signal donors, the weaker signal detection relative to the original donor fluids, and that exposure time improves the effect.
Indoxyl Sulfate Administration during Pregnancy Contributes to Renal Injury and Increased Blood–Brain Barrier Permeability
Authors: Griffin Ashley , Berry Brittany , Spencer Shauna-Kay , Bowles Teylor , Wallace Kedra
Published: July 2023

Rates of pregnancy-related acute kidney injury (PR-AKI) have increased in the U.S over the past two decades, but how PR-AKI affects the blood–brain barrier (BBB) is understudied. AKI is associated with increased amounts of uremic toxins, like indoxyl sulfate (I.S), whose chronic administration leads to BBB and cognitive changes. This study’s objective was to determine if (1) PR-AKI increases I.S and (2) if administration of I.S during pregnancy elicits renal injury and/or increases BBB permeability. From gestational day (GD) 11 to GD19, Sprague Dawley rats were given either 100 or 200 mg/kg body-weight dose of I.S. PR-AKI was induced on GD18 via 45 min bilateral renal ischemic reperfusion surgery. On GD18, metabolic cage metrics and metabolic waste was collected and on GD19 blood pressure, and BBB permeability (by Evan’s Blue infusion) were measured. I.S and creatinine were measured in both urine and circulation, respectively. One-way ANOVA or student t-tests were performed using GraphPad Prism with a p < 0.05 significance. I.S and PR-AKI led to oliguria. I.S administration led to increased BBB permeability compared to normal pregnant and PR-AKI animals. These results suggest that I.S administration during pregnancy leads to increased BBB permeability and evidence of renal injury comparable to PR-AKI animals.
Gut Microbiota Composition and Cardiovascular Disease: A Potential New Therapeutic Target?
Authors: Belli Martina , Barone Lucy , Longo Susanna , Prandi Francesca Romana , Lecis Dalgisio , Mollace Rocco , Margonato Davide , Muscoli Saverio , Sergi Domenico , Federici Massimo , Barillà Francesco
Published: July 2023

A great deal of evidence has revealed an important link between gut microbiota and the heart. In particular, the gut microbiota plays a key role in the onset of cardiovascular (CV) disease, including heart failure (HF). In HF, splanchnic hypoperfusion causes intestinal ischemia resulting in the translocation of bacteria and their metabolites into the blood circulation. Among these metabolites, the most important is Trimethylamine N-Oxide (TMAO), which is responsible, through various mechanisms, for pathological processes in different organs and tissues. In this review, we summarise the complex interaction between gut microbiota and CV disease, particularly with respect to HF, and the possible strategies for influencing its composition and function. Finally, we highlight the potential role of TMAO as a novel prognostic marker and a new therapeutic target for HF.
Aloe-Emodin Ameliorates Cecal Ligation and Puncture-Induced Sepsis
Authors: Su Jingqian , Chen Siyuan , Xiao Jianbin , Feng Zhihua , Hu Shan , Su Qiaofen , Chen Qi , Chen Duo
Published: July 2023

Sepsis remains a major challenge owing to its severe adverse effects and high mortality, against which specific pharmacological interventions with high efficacy are limited. Mitigation of hyperactive inflammatory responses is a key factor in enhancing the likelihood of survival in patients with sepsis. The Aloe genus has several health benefits, including anti-inflammatory properties. The toxicological implications of aloe-emodin (AE), extracted from various Aloe species, remain uncertain in clinical contexts. However, AE has been shown to inhibit inflammatory responses in lipopolysaccharide-induced mice, indicating its potential as a therapeutic approach for sepsis treatment. Nonetheless, there is a paucity of data regarding the therapeutic benefits of AE in the widely recognized cecal ligation and puncture (CLP)-induced sepsis model, which is commonly used as the gold standard model for sepsis research. This study demonstrates the potential benefits of AE in the treatment of CLP-induced sepsis and investigates its underlying mechanism, along with the efficacy of postoperative AE treatment in mice with CLP-induced sepsis. The results of this study suggest that AE can mitigate sepsis in mice by diminishing systemic inflammation and regulating the gut microbiota. The study provides novel insights into the molecular mechanisms underlying the anti-inflammatory effects of AE.
Triangular Silver Nanoplates as a Bioanalytical Tool: Potential COVID-19 Detection
Authors: Rodriguez Barroso Laura G. , Lanzagorta Garcia Eduardo , Mojicevic Marija , Alkan Tas Buket , Huerta Miriam , Pogue Robert , Devine Declan M. , Brennan-Fournet Margaret
Published: July 2023

Nanotechnology offers new possibilities in molecular diagnostics, with nanoparticles gaining attention as biosensor upgrades. This study evaluates gold-coated silver nanoplates coated with PEG for enhanced protection, aiming to detect Spike protein with higher sensitivity, and emphasizes the importance of considering complex environments and appropriate controls for specific binding and accurate analysis. The sensitivity of antibody-coated PEGAuTSNPs as tools for immunoassays is demonstrated through fibronectin (Fn)– anti-fibronectin binding within an isolated extracellular matrix as a complex and native environment of Fn. Moreover, the optimal functionalization volume of Spike protein was determined (4 µg/mL of PEGAuTSNP). Anti-Spike was added to confirm binding, while the TJP1 protein was used as a negative control. The same experiment was used in the presence of horse serum to simulate a complex environment. According to Localized Surface Plasmon Resonance analysis and Dynamic Light Scattering size measurements, anti-Spike exhibited a stronger affinity for the nanoplates, causing TJP1 to be replaced by the antibody on the nanoplates’ surface. Future research will involve exploring alternative complex environments, filtering larger molecules, and the optimization of immunoassay performance.
Paradox: Curcumin, a Natural Antioxidant, Suppresses Osteosarcoma Cells via Excessive Reactive Oxygen Species
Authors: Xu Chunfeng , Wang Mingjie , Zandieh Doulabi Behrouz , Sun Yuanyuan , Liu Yuelian
Published: July 2023

Osteosarcoma (OS) is an aggressive tumor with a rare incidence. Extended surgical resections are the prevalent treatment for OS, which may cause critical-size bone defects. These bone defects lead to dysfunction, weakening the post-surgical quality of patients’ life. Hence, an ideal therapeutic agent for OS should simultaneously possess anti-cancer and bone repair capacities. Curcumin (CUR) has been reported in OS therapy and bone regeneration. However, it is not clear how CUR suppresses OS development. Conventionally, CUR is considered a natural antioxidant in line with its capacity to promote the nuclear translocation of a nuclear transcription factor, nuclear factor erythroid 2 (NRF2). After nuclear translocation, NRF2 can activate the transcription of some antioxidases, thereby circumventing excess reactive oxygen species (ROS) that are deleterious to cells. Intriguingly, this research demonstrated that, in vitro, 10 and 20 μM CUR increased the intracellular ROS in MG-63 cells, damaged cells’ DNA, and finally caused apoptosis of MG-63 cells, although increased NRF2 protein level and the expression of NRF2-regulated antioxidase genes were identified in those two groups.
Microbial Reprogramming in Obsessive–Compulsive Disorders: A Review of Gut–Brain Communication and Emerging Evidence
Authors: Bendriss Ghizlane , MacDonald Ross , McVeigh Clare
Published: July 2023

Obsessive–compulsive disorder (OCD) is a debilitating mental health disorder characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions). Dysbiosis, an imbalance in the gut microbial composition, has been associated with various health conditions, including mental health disorders, autism, and inflammatory diseases. While the exact mechanisms underlying OCD remain unclear, this review presents a growing body of evidence suggesting a potential link between dysbiosis and the multifaceted etiology of OCD, interacting with genetic, neurobiological, immunological, and environmental factors. This review highlights the emerging evidence implicating the gut microbiota in the pathophysiology of OCD and its potential as a target for novel therapeutic approaches. We propose a model that positions dysbiosis as the central unifying element in the neurochemical, immunological, genetic, and environmental factors leading to OCD. The potential and challenges of microbial reprogramming strategies, such as probiotics and fecal transplants in OCD therapeutics, are discussed. This review raises awareness of the importance of adopting a holistic approach that considers the interplay between the gut and the brain to develop interventions that account for the multifaceted nature of OCD and contribute to the advancement of more personalized approaches.
Oxido-Reduction Potential as a Method to Determine Oxidative Stress in Semen Samples
Authors: Balló András , Czétány Péter , Busznyákné Kinga Székvári , Márk László , Mike Nóra , Török Attila , Szántó Árpád , Máté Gábor
Published: July 2023

There are different estimates for the incidence of infertility. Its occurrence may vary from area to area, but on average, it affects 15% of couples and 10–12% of men worldwide. Many aspects of infertility can be linked to reactive oxygen species (ROS) and the process of oxidative stress (OS). The association between poor semen quality and OS is well known. Unfortunately, there is no accepted protocol for the diagnosis and treatment of OS in andrology. Oxido-reduction potential (ORP) measurement is a new method for determining the ratio between oxidant and antioxidant molecules. Currently, ORP measurement is one of the fastest and most user-friendly methods of andrological OS determination and our goals were to confirm published correlations between ORP values and sperm parameters, examine how sperm concentration influences these results, and investigate whether intracellular ROS formations are also manifested in the ORP values or not after artificial ROS induction. Intracellular ROS formations were induced by menadione (superoxide anion inducer), hydrogen peroxide, and tert-butyl hydroperoxide (lipid peroxidation inducer) treatments; sperm parameters like motility and viability were determined with an SCA Scope system, and ORP changes were recorded by the Mioxsys system. Significant correlations were noticed among the ORP, spermatozoa concentration, motility, progressive motility, and viability. Nevertheless, only the ORP value after normalization with the sperm count correlated with these parameters. Due to normalization, very low and very high sperm concentrations can give misleading results. The means of the non-normalized ORP values were almost the same. All of the applied treatments resulted in decreases in the viability, motility, and progressive motility, and interestingly, altered ORP levels were detected. In addition, it was determined that seminal plasma had a significant protective effect on spermatozoa. The elimination of seminal plasma caused higher sensitivity of spermatozoa against used OS inducers, and higher ORP levels and decreased viabilities and motilities were measured. The ORP level could be a good indicator of male OS; however, in cases of low and high sperm counts, its result can be misleading. Overall, the conclusion can be drawn that ORP determination is a suitable method for detecting intracellular ROS accumulation, but it has limitations that still need to be clarified.
Castanopsis sieboldii Extract Alleviates Acute Liver Injury by Antagonizing Inflammasome-Mediated Pyroptosis
Authors: Kim Jae Min , Cho Sam Seok , Kang Sohi , Moon Changjong , Yang Ji Hye , Ki Sung Hwan
Published: July 2023

Castanopsis sieboldii (CS), a subtropical species, was reported to have antioxidant and antibacterial effects. However, the anti-inflammatory effects of CS have not been studied. This study aimed to investigate whether the 70% ethanol extract of the CS leaf (CSL3) inhibited lipopolysaccharide (LPS)-induced inflammatory responses and LPS and ATP-induced pyroptosis in macrophages. CSL3 treatment inhibited NO release and iNOS expression in LPS-stimulated cells. CSL3 antagonized NF-κB and AP-1 activation, which was due to MAPK (p38, ERK, and JNK) inhibition. CSL3 successfully decreased NLRP3 inflammasome activation and increased IL-1β expression. CSL3 treatment diminished LPS and ATP-induced pore formation in GSDMD. The in vivo effect of CSL3 on acute liver injury was evaluated in a CCl4-treated mouse model. CCl4 treatment increased the activity of serum alanine aminotransferase and aspartate aminotransferase, which decreased by CSL3. In addition, CCl4-induced an increase in TNF-α, and IL-6 levels decreased by CSL3 treatment. Furthermore, we verified that the CCl4-induced inflammasome and pyroptosis-related gene expression in liver tissue and release of IL-1β into serum were suppressed by CSL3 treatment. Our results suggest that CSL3 protects against acute liver injury by inhibiting inflammasome formation and pyroptosis.
Using A Protoplast Transformation System to Enable Functional Studies in Mangifera indica L.
Authors: Adjei Mark Owusu , Zhao Huan , Tao Xiaoguang , Yang Li , Deng Shuyue , Li Xiyan , Mao Xinjing , Li Shujiang , Huang Jianfeng , Luo Ruixiong , Gao Aiping , Ma Jun
Published: July 2023

Mangoes (Mangifera indica L.) are an important kind of perennial fruit tree, but their biochemical testing method and transformation technology were insufficient and had not been rigorously explored. The protoplast technology is an excellent method for creating a rapid and effective tool for transient expression and transformation assays, particularly in plants that lack an Agrobacterium-mediated plant transformation system. This study optimized the conditions of the protoplast isolation and transformation system, which can provide a lot of help in the gene expression regulation study of mango. The most beneficial protoplast isolation conditions were 150 mg/mL of cellulase R-10 and 180 mg/mL of macerozyme R-10 in the digestion solution at pH 5.6 and 12 h of digestion time. The 0.16 M and 0.08 M mannitol in wash solution (WI) and suspension for counting (MMG), respectively, were optimal for the protoplast isolation yield. The isolated leaf protoplasts (~5.4 × 105 cells/10 mL) were transfected for 30 min mediated by 40% calcium-chloride-based polyethylene glycol (PEG)-4000-CaCl2, from which 84.38% of the protoplasts were transformed. About 0.08 M and 0.12 M of mannitol concentration in MMG and transfection solutions, respectively, were optimal for protoplast viability. Under the florescence signal, GFP was seen in the transformed protoplasts. This showed that the target gene was successfully induced into the protoplast and that it can be transcribed and translated. Experimental results in this paper show that our high-efficiency protoplast isolation and PEG-mediated transformation protocols can provide excellent new methods for creating a rapid and effective tool for the molecular mechanism study of mangoes.
Phospho-DIGE Identified Phosphoproteins Involved in Pathways Related to Tumour Growth in Endometrial Cancer
Authors: Capaci Valeria , Arrigoni Giorgio , Monasta Lorenzo , Aloisio Michelangelo , Rocca Giulia , Di Lorenzo Giovanni , Licastro Danilo , Romano Federico , Ricci Giuseppe , Ura Blendi
Published: July 2023

Endometrial cancer (EC) is the most common gynecologic malignancy of the endometrium. This study focuses on EC and normal endometrium phosphoproteome to identify differentially phosphorylated proteins involved in tumorigenic signalling pathways which induce cancer growth. We obtained tissue samples from 8 types I EC at tumour stage 1 and 8 normal endometria. We analyzed the phosphoproteome by two-dimensional differential gel electrophoresis (2D-DIGE), combined with immobilized metal affinity chromatography (IMAC) and mass spectrometry for protein and phosphopeptide identification. Quantities of 34 phosphoproteins enriched by the IMAC approach were significantly different in the EC compared to the endometrium. Validation using Western blotting analysis on 13 patients with type I EC at tumour stage 1 and 13 endometria samples confirmed the altered abundance of HBB, CKB, LDHB, and HSPB1. Three EC samples were used for in-depth identification of phosphoproteins by LC-MS/MS analysis. Bioinformatic analysis revealed several tumorigenic signalling pathways. Our study highlights the involvement of the phosphoproteome in EC tumour growth. Further studies are needed to understand the role of phosphorylation in EC. Our data shed light on mechanisms that still need to be ascertained but could open the path to a new class of drugs that could hinder EC growth.
Viscum album Induces Apoptosis by Regulating STAT3 Signaling Pathway in Breast Cancer Cells
Authors: Park Ye-Rin , Jee Wona , Park So-Mi , Kim Seok Woo , Bae Hanbit , Jung Ji Hoon , Kim Hyungsuk , Kim Sangki , Chung Jong Sup , Jang Hyeung-Jin
Published: July 2023

In this study, we investigated the potential anticancer effects of Viscum album, a parasitic plant that grows on Malus domestica (VaM) on breast cancer cells, and explored the underlying mechanisms. VaM significantly inhibited cell viability and proliferation and induced apoptosis in a dose-dependent manner. VaM also regulated cell cycle progression and effectively inhibited activation of the STAT3 signaling pathway through SHP-1. Combining VaM with low-dose doxorubicin produced a synergistic effect, highlighting its potential as a promising therapeutic. In vivo, VaM administration inhibited tumor growth and modulated key molecular markers associated with breast cancer progression. Overall, our findings provide strong evidence for the therapeutic potential of VaM in breast cancer treatment and support further studies exploring clinical applications.
Molecular Mechanisms of Migraine: Nitric Oxide Synthase and Neuropeptides
Authors: Karsan Nazia , Gosalia Helin , Goadsby Peter J.
Published: July 2023

Migraine is a common condition with disabling attacks that burdens people in the prime of their working lives. Despite years of research into migraine pathophysiology and therapeutics, much remains to be learned about the mechanisms at play in this complex neurovascular condition. Additionally, there remains a relative paucity of specific and targeted therapies available. Many sufferers remain underserved by currently available broad action preventive strategies, which are also complicated by poor tolerance and adverse effects. The development of preclinical migraine models in the laboratory, and the advances in human experimental migraine provocation, have led to the identification of key molecules likely involved in the molecular circuity of migraine, and have provided novel therapeutic targets. Importantly, the identification that vasoconstriction is neither necessary nor required for headache abortion has changed the landscape of migraine treatment and has broadened the therapy targets for patients with vascular risk factors or vascular disease. These targets include nitric oxide synthase (NOS) and several neuropeptides that are involved in migraine. The ability of NO donors and infusion of some of these peptides into humans to trigger typical migraine-like attacks has supported the development of targeted therapies against these molecules. Some of these, such as those targeting calcitonin gene-related peptide (CGRP), have already reached clinical practice and are displaying a positive outcome in migraineurs for the better by offering targeted efficacy without significant adverse effects. Others, such as those targeting pituitary adenylate cyclase activating polypeptide (PACAP), are showing promise and are likely to enter phase 3 clinical trials in the near future. Understanding these nitrergic and peptidergic mechanisms in migraine and their interactions is likely to lead to further therapeutic strategies for migraine in the future.
Transcriptome Analysis Reveals the Molecular Basis of Overfeeding-Induced Diabetes in Zebrafish
Authors: Ge Guodong , Ren Jing , Song Guili , Li Qing , Cui Zongbin
Published: July 2023

Diabetes has gradually become a serious disease that threatens human health. It can induce various complications, and the pathogenesis of diabetes is quite complex and not yet fully elucidated. The zebrafish has been widely acknowledged as a useful model for investigating the mechanisms underlying the pathogenesis and therapeutic interventions of diabetes. However, the molecular basis of zebrafish diabetes induced by overfeeding remains unknown. In this study, a zebrafish diabetes model was established by overfeeding, and the molecular basis of zebrafish diabetes induced by overfeeding was explored. Compared with the control group, the body length, body weight, and condition factor index of zebrafish increased significantly after four weeks of overfeeding. There was a significant elevation in the fasting blood glucose level, accompanied by a large number of lipid droplets accumulated within the liver. The levels of triglycerides and cholesterol in both the serum and liver exhibited a statistically significant increase. Transcriptome sequencing was employed to investigate changes in the livers of overfed zebrafish. The number of up-regulated and down-regulated differentially expressed genes (DEGs) was 1582 and 2404, respectively, in the livers of overfed zebrafish. The DEGs were subjected to KEGG and GO enrichment analyses, and the hub signaling pathways and hub DEGs were identified. The results demonstrate that sixteen genes within the signal pathway associated with fatty acid metabolism were found to be significantly up-regulated. Specifically, these genes were found to mainly participate in fatty acid transport, fatty acid oxidation, and ketogenesis. Furthermore, thirteen genes that play a crucial role in glucose metabolism, particularly in the pathways of glycolysis and glycogenesis, were significantly down-regulated in the livers of overfed zebrafish. These results indicate insulin resistance and inhibition of glucose entry into liver cells in the livers of overfed zebrafish. These findings elucidate the underlying molecular basis of zebrafish diabetes induced by overfeeding and provide a model for further investigation of the pathogenesis and therapeutics of diabetes.
Expression and Characterization of Two α-l-Arabinofuranosidases from Talaromyces amestolkiae: Role of These Enzymes in Biomass Valorization
Authors: Méndez-Líter Juan A. , de Eugenio Laura I. , Nieto-Domínguez Manuel , Prieto Alicia , Martínez María Jesús
Published: July 2023

α-l-arabinofuranosidases are glycosyl hydrolases that catalyze the break between α-l-arabinofuranosyl substituents or between α-l-arabinofuranosides and xylose from xylan or xylooligosaccharide backbones. While they belong to several glycosyl hydrolase (GH) families, there are only 24 characterized GH62 arabinofuranosidases, making them a small and underrepresented group, with many of their features remaining unknown. Aside from their applications in the food industry, arabinofuranosidases can also aid in the processing of complex lignocellulosic materials, where cellulose, hemicelluloses, and lignin are closely linked. These materials can be fully converted into sugar monomers to produce secondary products like second-generation bioethanol. Alternatively, they can be partially hydrolyzed to release xylooligosaccharides, which have prebiotic properties. While endoxylanases and β-xylosidases are also necessary to fully break down the xylose backbone from xylan, these enzymes are limited when it comes to branched polysaccharides. In this article, two new GH62 α-l-arabinofuranosidases from Talaromyces amestolkiae (named ARA1 and ARA-2) have been heterologously expressed and characterized. ARA-1 is more sensitive to changes in pH and temperature, whereas ARA-2 is a robust enzyme with wide pH and temperature tolerance. Both enzymes preferentially act on arabinoxylan over arabinan, although ARA-1 has twice the catalytic efficiency of ARA-2 on this substrate. The production of xylooligosaccharides from arabinoxylan catalyzed by a T. amestolkiae endoxylanase was significantly increased upon pretreatment of the polysaccharide with ARA-1 or ARA-2, with the highest synergism values reported to date. Finally, both enzymes (ARA-1 or ARA-2 and endoxylanase) were successfully applied to enhance saccharification by combining them with a β-xylosidase already characterized from the same fungus.
Combined Metabolipidomic and Machine Learning Approach in a Rat Model of Stroke Reveals a Deleterious Impact of Brain Injury on Heart Metabolism
Authors: Dieu Xavier , Tamareille Sophie , Herbreteau Aglae , Lebeau Lucie , Chao De La Barca Juan Manuel , Chabrun Floris , Reynier Pascal , Mirebeau-Prunier Delphine , Prunier Fabrice
Published: July 2023

Cardiac complications are frequently found following a stroke in humans whose pathophysiological mechanism remains poorly understood. We used machine learning to analyse a large set of data from a metabolipidomic study assaying 630 metabolites in a rat stroke model to investigate metabolic changes affecting the heart within 72 h after a stroke. Twelve rats undergoing a stroke and 28 rats undergoing the sham procedure were investigated. A plasmatic signature consistent with the literature with notable lipid metabolism remodelling was identified. The post-stroke heart showed a discriminant metabolic signature, in comparison to the sham controls, involving increased collagen turnover, increased arginase activity with decreased nitric oxide synthase activity as well as an altered amino acid metabolism (including serine, asparagine, lysine and glycine). In conclusion, these results demonstrate that brain injury induces a metabolic remodelling in the heart potentially involved in the pathophysiology of stroke heart syndrome.
A Comprehensive Review of Inorganic Sonosensitizers for Sonodynamic Therapy
Authors: Chen Peng , Zhang Ping , Shah Navid Hussain , Cui Yanyan , Wang Yaling
Published: July 2023

Sonodynamic therapy (SDT) is an emerging non-invasive cancer treatment method in the field of nanomedicine, which has the advantages of deep penetration, good therapeutic efficacy, and minimal damage to normal tissues. Sonosensitizers play a crucial role in the process of SDT, as their structure and properties directly determine the treatment outcome. Inorganic sonosensitizers, with their high stability and longer circulation time in the human body, have great potential in SDT. In this review, the possible mechanisms of SDT including the ultrasonic cavitation, reactive oxygen species generation, and activation of immunity are briefly discussed. Then, the latest research progress on inorganic sonosensitizers is systematically summarized. Subsequently, strategies for optimizing treatment efficacy are introduced, including combination therapy and image-guided therapy. The challenges and future prospects of sonodynamic therapy are discussed. It is hoped that this review will provide some guidance for the screening of inorganic sonosensitizers.
Amyloid Beta Peptides Lead to Mast Cell Activation in a Novel 3D Hydrogel Model
Authors: Liu Jingshu , Liu Sihan , Zeng Li , Tsilioni Irene
Published: July 2023

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease and the world’s primary cause of dementia among the elderly population. The aggregation of toxic amyloid-beta (Aβ) is one of the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as one of the major features of AD, which involves a network of interactions between immune cells. The mast cell (MC) is an innate immune cell type known to serve as a first responder to pathological changes and crosstalk with microglia and neurons. Although an increased number of mast cells were found near the sites of Aβ deposition, how mast cells are activated in AD is not clear. We developed a 3D culture system to culture MCs and investigated the activation of MCs by Aβ peptides. Because collagen I is the major component of extracellular matrix (ECM) in the brain, we encapsulated human LADR MCs in gels formed by collagen I. We found that 3D-cultured MCs survived and proliferated at the same level as MCs in suspension. Additionally, they can be induced to secrete inflammatory cytokines as well as MC proteases tryptase and chymase by typical MC activators interleukin 33 (IL-33) and IgE/anti-IgE. Culturing with peptides Aβ1-42, Aβ1-40, and Aβ25-35 caused MCs to secrete inflammatory mediators, with Aβ1-42 inducing the maximum level of activation. These data indicate that MCs respond to amyloid deposition to elicit inflammatory responses and demonstrate the validity of collagen gel as a model system to investigate MCs in a 3D environment to understand neuroinflammation in AD.
RNA-Binding Proteins as Critical Post-Transcriptional Regulators of Cardiac Regeneration
Authors: Shi De-Li
Published: July 2023

Myocardial injury causes death to cardiomyocytes and leads to heart failure. The adult mammalian heart has very limited regenerative capacity. However, the heart from early postnatal mammals and from adult lower vertebrates can fully regenerate after apical resection or myocardial infarction. Thus, it is of particular interest to decipher the mechanism underlying cardiac regeneration that preserves heart structure and function. RNA-binding proteins, as key regulators of post-transcriptional gene expression to coordinate cell differentiation and maintain tissue homeostasis, display dynamic expression in fetal and adult hearts. Accumulating evidence has demonstrated their importance for the survival and proliferation of cardiomyocytes following neonatal and postnatal cardiac injury. Functional studies suggest that RNA-binding proteins relay damage-stimulated cell extrinsic or intrinsic signals to regulate heart regenerative capacity by reprogramming multiple molecular and cellular processes, such as global protein synthesis, metabolic changes, hypertrophic growth, and cellular plasticity. Since manipulating the activity of RNA-binding proteins can improve the formation of new cardiomyocytes and extend the window of the cardiac regenerative capacity in mammals, they are potential targets of therapeutic interventions for cardiovascular disease. This review discusses our evolving understanding of RNA-binding proteins in regulating cardiac repair and regeneration, with the aim to identify important open questions that merit further investigations.
Photoluminescent Lanthanide(III) Coordination Polymers with Bis(1,2,4-Triazol-1-yl)Methane Linker
Authors: Ivanova Elizaveta A. , Smirnova Ksenia S. , Pozdnyakov Ivan P. , Potapov Andrei S. , Lider Elizaveta V.
Published: July 2023

A series of new lanthanide(III) coordination polymers with the general formula [Ln(btrm)2(NO3)3]n, where btrm = bis(1,2,4-triazol-1-yl)methane and Ln = Eu3+, Tb3+, Sm3+, Dy3+, Gd3+ were synthesized and characterized by IR-spectroscopy, elemental, thermogravimetric, single-crystal, and powder X-ray diffraction analyses. Europium(III), samarium(III), terbium(III), and gadolinium(III) coordination polymers demonstrate thermal stability up to 250 °C, while dysprosium(III) is stable up to 275 °C. According to single-crystal X-ray diffraction analysis, the ligand exhibits a bidentate-bridging coordination mode, forming a polymeric chain of octagonal metallocycles. The photoluminescence of the free ligand in the polycrystalline state is observed in the ultraviolet range with a quantum yield of 13%. The energy transfer from the ligand to the lanthanide ions was not observed for all obtained coordination polymers. However, there are sharp bands of lanthanide(III) ions in the diffuse reflectance and excitation spectra of the obtained compounds. Therefore, Ln(III) luminescence arises, most probably, from the enhancement of f-f transition intensity under the influence of the ligand field and non-centrosymmetric interactions.
Half-Dose versus Single-Dose Gadobutrol for Extracellular Volume Measurements in Cardiac Magnetic Resonance
Authors: Doeblin Patrick , Steinbeis Fridolin , Witzenrath Martin , Hashemi Djawid , Chen Wensu , Weiss Karl Jakob , Stawowy Philipp , Kelle Sebastian
Published: July 2023

Background: Cardiac magnetic resonance (CMR) imaging with gadolinium-based contrast agents offers unique non-invasive insights into cardiac tissue composition. Myocardial extracellular volume (ECV) has evolved as an objective and robust parameter with broad diagnostic and prognostic implications. For the gadolinium compound gadobutrol, the recommended dose for cardiac imaging, including ECV measurements, is 0.1 mmol/kg (single dose). This dose was optimized for late enhancement imaging, a measure of focal fibrosis. Whether a lower dose is sufficient for ECV measurements is unknown. We aim to evaluate the accuracy of ECV measurements using a half dose of 0.05 mmol/kg gadobutrol compared to the standard single dose of 0.1 mmol/kg. Methods and results: From a contemporary trial (NCT04747366, registered 10 February 2021), a total of 25 examinations with available T1 mapping before and after 0.05 and 0.1 mmol/kg gadobutrol were analyzed. ECV values were calculated automatically from pre- and post-contrast T1 relaxation times. T1 and ECV Measurements were performed in the midventricular septum. ECV values after 0.05 and 0.1 mmol/kg gadobutrol were correlated (R2 = 0.920, p < 0.001). ECV values after 0.05 mmol/kg had a bias of +0.9% (95%-CI [0.4; 1.4], p = 0.002) compared to 0.1 mmol/kg gadobutrol, with limits of agreement from −1.5 to 3.3%. Conclusions: CMR with a half dose of 0.05 mmol/kg gadobutrol overestimated ECV by 0.9% compared with a full dose of 0.1 mmol/kg, necessitating adjustment of normal values when using half-dose ECV imaging.
Management of Acute Cholecystitis in High-Risk Patients: Percutaneous Gallbladder Drainage as a Definitive Treatment vs. Emergency Cholecystectomy—Systematic Review and Meta-Analysis
Authors: Cirocchi Roberto , Amato Lavinia , Ungania Serena , Buononato Massimo , Tebala Giovanni Domenico , Cirillo Bruno , Avenia Stefano , Cozza Valerio , Costa Gianluca , Davies Richard Justin , Sapienza Paolo , Coccolini Federico , Mingoli Andrea , Chiarugi Massimo , Brachini Gioia
Published: July 2023

Background: This systematic review aims to investigate whether percutaneous transhepatic gallbladder biliary drainage (PTGBD) is superior to emergency cholecystectomy (EC) as a definitive treatment in high-risk patients with acute cholecystitis (AC). Material and Methods: A systematic literature search was performed until December 2022 using the Scopus, Medline/PubMed and Web of Science databases. Results: Seventeen studies have been included with a total of 783,672 patients (32,634 treated with PTGBD vs. 4663 who underwent laparoscopic cholecystectomy, 343 who had open cholecystectomy and 746,032 who had some form of cholecystectomy, but without laparoscopic or open approach being specified). An analysis of the results shows that PTGBD, despite being less invasive, is not associated with lower morbidity with respect to EC (RR 0.77 95% CI [0.44 to 1.34]; I2 = 99%; p = 0.36). A lower postoperative mortality was reported in patients who underwent EC (2.37%) with respect to the PTGBD group (13.78%) (RR 4.21; 95% CI [2.69 to 6.58]; p < 0.00001); furthermore, the risk of hospital readmission for biliary complications (RR 2.19 95% CI [1.72 to 2.79]; I2 = 48%; p < 0.00001) and hospital stay (MD 4.29 95% CI [2.40 to 6.19]; p < 0.00001) were lower in the EC group. Conclusions: In our systematic review, the majority of studies have very low-quality evidence and more RCTs are needed; furthermore, PTGBD is inferior in the treatment of AC in high-risk patients. The definition of high-risk patients is important in interpreting the results, but the methods of assessment and definitions differ between studies. The results of our systematic review and meta-analysis failed to demonstrate any advantage of using PTGBD over ER as a definitive treatment of AC in critically ill patients, which suggests that EC should be considered as the treatment of choice even in very high-risk patients. Most likely, the inferiority of PTGBD versus early LC for high-risk patients is related to an association of various patient-side factor conditions and the severity of acute cholecystitis.
Differences between Hepatic and Cerebral Regional Tissue Oxygen Saturation at the Onset of Intradialytic Hypotension
Authors: Kaneko Shohei , Ookawara Susumu , Ito Kiyonori , Minato Saori , Mutsuyoshi Yuko , Ueda Yuichiro , Hirai Keiji , Morishita Yoshiyuki
Published: July 2023

Background: Intradialytic hypotension (IDH) is a critical pathological condition associated with all-cause mortality in patients undergoing hemodialysis (HD). However, few studies have investigated IDH-related changes in hepatic and cerebral regional tissue oxygen saturation (rSO2). This study investigated IDH-induced changes in hepatic and cerebral rSO2. Methods: Hepatic and cerebral rSO2 during HD were measured using an INVOS 5100C oxygen saturation monitor, and their percentage (%) changes during the development of IDH were analyzed. Ninety-one patients undergoing HD were investigated, including twenty with IDH. Results: In patients with IDH, % changes in hepatic and cerebral rSO2 decreased at the onset of IDH. Additionally, the % change in hepatic rSO2 was significantly larger than that in cerebral rSO2 (p < 0.001). In patients without IDH, no significant differences were found between the % changes in hepatic and cerebral rSO2 at the time of the lowest systolic blood pressure during HD. Multivariable linear regression analysis showed that the difference between the % changes in cerebral and hepatic rSO2 was significantly associated with the development of IDH (p < 0.001) and the ultrafiltration rate (p = 0.010). Conclusions: Hepatic and cerebral rSO2 significantly decreased during the development of IDH, and hepatic rSO2 was more significantly decreased than cerebral rSO2 at the onset of IDH.