bluuebunny/crossref_metadata_2025 huggingface dataset:
Commutative Encryption and Reversible Watermarking Algorithm for Vector Maps Based on Virtual Coordinates
Authors: Dai Qianyi , Wu Baiyan , Liu Fanshuo , Bu Zixuan , Zhang Haodong
Published: September 2024

The combination of encryption and digital watermarking technologies is an increasingly popular approach to achieve full lifecycle data protection. Recently, reversible data hiding in the encrypted domain (RDHED) has greatly aroused the interest of many scholars. However, the fixed order of first encryption and then watermarking makes these algorithms unsuitable for many applications. Commutative encryption and watermarking (CEW) technology realizes the flexible combination of encryption and watermarking, and suits more applications. However, most existing CEW schemes for vector maps are not reversible and are unsuitable for high-precision maps. To solve this problem, here, we propose a commutative encryption and reversible watermarking (CERW) algorithm for vector maps based on virtual coordinates that are uniformly distributed on the number axis. The CERW algorithm consists of a virtual interval step-based encryption scheme and a coordinate difference-based reversible watermarking scheme. In the encryption scheme, the map coordinates are moved randomly by multiples of virtual interval steps defined as the distance between two adjacent virtual coordinates. In the reversible watermarking scheme, the difference expansion (DE) technique is used to embed the watermark bit into the coordinate difference, computed based on the relative position of a map coordinate in a virtual interval. As the relative position of a map coordinate in a virtual interval remains unchanged during the coordinate scrambling encryption process, the watermarking and encryption operations do not interfere with each other, and commutativity between encryption and watermarking is achieved. The results show that the proposed method has high security, high capacity, and good invisibility. In addition, the algorithm applies not only to polyline and polygon vector data, but also to sparsely distributed point data, which traditional DE watermarking algorithms often fail to watermark.
A Facile Route to Flavone-3-Carboxamides and Flavone-3-Carboxylates via Palladium-Catalyzed Amino- and Aryloxy-Carbonylation Reactions
Authors: Chniti Sami , Kollár László , Bényei Attila , Dörnyei Ágnes , Takács Attila
Published: September 2024

A library of C-3 functionalized flavones was successfully provided via palladium-catalyzed amino- and aryloxycarbonylation reactions of 3-iodoflavone (1), under mild conditions. This methodology showed good functional group tolerance using a variety of amines and phenols, under an atmospheric pressure of carbon monoxide as a carbonyl source. While the flavone-3-carboxamides (2a-t) were produced in 22–79%, the flavone-3-carboxylates (4a′-l′) were obtained in excellent yields (up to 88%), under identical reaction conditions, just by switching N-nucleophiles to O-nucleophiles. The convenient availability of the involved starting materials confers simplicity to this approach to design new C-3-substituted flavones of biological relevance. The solid-state structures of flavone-3-carboxamide (2r) and flavone-3-ester (4f′) were further studied by single-crystal XRD analysis.
Rice Husk Silica Liquid Enhances Autophagy and Reduces Overactive Immune Responses via TLR-7 Signaling in Lupus-Prone Models
Authors: Kao Chieh , Wang Shih-Wei , Chen Po-Chun , Huang Chun-Yung , Wei Yu-Feng , Ho Cheng-Hsun , Hong Yong-Han
Published: September 2024

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by widespread inflammation and multi-organ damage. Toll-like receptor 7 (TLR-7) and autophagy have been implicated in SLE pathogenesis. Rice husk silica liquid (RHSL) has shown potential for modulating inflammatory responses, but its effects on SLE have not been thoroughly investigated. This study aims to evaluate the impact of RHSL on immune responses and autophagy in cell culture experiments, focusing on its effects on TLR-7 signaling, cytokine production, and autophagy modulation. RAW264.7 cells and human peripheral blood mononuclear cells (PBMCs) from healthy donors and SLE patients were used. Cells were stimulated with LPS or TLR-7 agonists and treated with RHSL. Cell viability was assessed, and cytokine levels (TNF-α and IL-6) were measured by ELISA. Autophagy-related proteins (LC3II, ATG5-ATG12) were analyzed by Western blotting. The effect of autophagy inhibition was studied using 3-methyladenine (3-MA). A concentration of 100 μg/mL RHSL did not affect cell viability but significantly reduced the TNF-α production in TLR-7 agonist-stimulated RAW264.7 cells (compared to TLR-7 alone, 3.41 ± 0.54 vs. 6.72 ± 0.07 folds) and PBMCs (compared to TLR-7 alone, 0.97 ± 0.19 vs. 1.40 ± 0.33 folds). RHSL enhanced autophagy, as evidenced by increased LC3II (4.35 ± 1.08 folds) and ATG5-ATG12 (7.07 ± 1.30 folds) conjugation in both RAW264.7 cells and SLE patient-derived PBMCs. The reduction in TNF-α production by RHSL was attenuated by 3-MA, indicating that autophagy plays a role in this process. RHSL also inhibited the translocation of phosphorylated NF-κB into the nucleus, suggesting a mechanism for its anti-inflammatory effects. RHSL exhibits potential as an immunomodulatory agent in SLE by enhancing autophagy and modulating TLR-7 signaling pathways. These findings suggest that RHSL could offer therapeutic benefits for managing inflammatory responses in SLE and warrant further investigation into its clinical applications.
Interferon-Gamma-Inducible Protein-10 (IP-10) and Tumor Necrosis Factor-α (TNF-α) as Serological Predictors of Active Disease Status in Localized Scleroderma
Authors: Ashe Brittany , Zigler Christina Kelsey , Yabes Jonathan , Magee Kelsey , Kurzinski Katherine , Torok Kathryn S.
Published: September 2024

We investigated the ability of a panel of immune-related cytokines and chemokines to predict the disease activity state in localized scleroderma (LS) subjects followed longitudinally. A total of 194 sera samples were obtained from 45 LS subjects with diverse types of LS (40% linear, 20% mixed, 16% craniofacial, 13% generalized, and 11% circumscribed) in our cohort. Cytokines/chemokines that were significantly elevated at the baseline active disease visit compared to the inactive disease state at follow-up were Interferon-Gamma-Inducible Protein (IP)-10 (p < 0.021) and Tumor Necrosis Factor (TNF)-α (p < 0.033). Mixed effect logit modeling identified IP-10 (Odds Ratio (OR) [95% confidence interval] = 2.1 [1.4, 3.2], p < 0.001), TNF-α (OR = 1.8 [1.1, 3.0], p = 0.016), and Monocyte Chemoattractant Protein (MCP)-1 (OR = 2.0 [1.1, 3.9], p = 0.034) as significant predictors of active disease status. These findings support earlier correlations between IP-10 and TNF-α with disease activity parameters in a cross-sectional Luminex™ serological study and may enhance clinical decision-making when disease activity is challenging to assess by clinical examination alone.
Differential Effect of Omega-3 Fatty Acids on Platelet Inhibition by Antiplatelet Drugs In Vitro
Authors: Koutsaliaris Ioannis K. , Pantazi Despoina , Tsouka Aikaterini N. , Argyropoulou Ourania , Tellis Constantinos C. , Tselepis Alexandros D.
Published: September 2024

The omega-3 polyunsaturated fatty acids (PUFAs) Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) exert multiple cardioprotective effects, influencing inflammation, platelet activation, endothelial function and lipid metabolism, besides their well-established triglyceride lowering properties. It is not uncommon for omega-3 PUFAs to be prescribed for hypertriglyceridemia, alongside antiplatelet therapy in cardiovascular disease (CVD) patients. In this regard, we studied the effect of EPA and DHA, in combination with antiplatelet drugs, in platelet aggregation and P-selectin and αIIbβ3 membrane expression. The antiplatelet drugs aspirin and triflusal, inhibitors of cyclooxygenase-1 (COX-1); ticagrelor, an inhibitor of the receptor P2Y12; vorapaxar, an inhibitor of the PAR-1 receptor, were combined with DHA or EPA and evaluated against in vitro platelet aggregation induced by agonists arachidonic acid (AA), adenosine diphosphate (ADP) and TRAP-6. We further investigated procaspase-activating compound 1 (PAC-1) binding and P-selectin membrane expression in platelets stimulated with ADP and TRAP-6. Both DHA and EPA displayed a dose-dependent inhibitory effect on platelet aggregation induced by AA, ADP and TRAP-6. In platelet aggregation induced by AA, DHA significantly improved acetylsalicylic acid (ASA) and triflusal’s inhibitory activity, while EPA enhanced the inhibitory effect of ASA. In combination with EPA, ASA and ticagrelor expressed an increased inhibitory effect towards ADP-induced platelet activation. Both fatty acids could not improve the inhibitory effect of vorapaxar on AA- and ADP-induced platelet aggregation. In the presence of EPA, all antiplatelet drugs displayed a stronger inhibitory effect towards TRAP-6-induced platelet activation. Both omega-3 PUFAs inhibited the membrane expression of αIIbβ3, though they had no effect on P-selectin expression induced by ADP or TRAP-6. The antiplatelet drugs exhibited heterogeneity regarding their effect on P-selectin and αIIbβ3 membrane expression, while both omega-3 PUFAs inhibited the membrane expression of αIIbβ3, though had no effect on P-selectin expression induced by ADP or TRAP-6. The combinatory effect of DHA and EPA with the antiplatelet drugs did not result in enhanced inhibitory activity compared to the sum of the individual effects of each component.
Inhibition of NAMPT by PAK4 Inhibitors
Authors: Wang Yiling , Minden Audrey
Published: September 2024

The serine/threonine kinase PAK4 plays a crucial role in regulating cell proliferation, survival, migration, and invasion. Overexpression of PAK4 correlates with poor prognosis in some cancers. KPT-9274, a PAK4 inhibitor, significantly reduces the growth of triple-negative breast cancer cells and mammary tumors in mouse models, and it also inhibits the growth of several other types of cancer cells. Interestingly, although it was first identified as a PAK4 inhibitor, KPT-9274 was also found to inhibit the enzyme NAMPT (nicotinamide phosphoribosyltransferase), which is crucial for NAD (nicotinamide adenine dinucleotide) synthesis and vital for cellular energy and growth. These results made us question whether growth inhibition in response to KPT-9274 was due to PAK4 inhibition, NAMPT inhibition, or both. To address this, we tested several other PAK4 inhibitors that also inhibit cell growth, to determine whether they also inhibit NAMPT activity. Our findings confirm that multiple PAK4 inhibitors also inhibit NAMPT activity. This was assessed both in cell-free assays and in a breast cancer cell line. Molecular docking studies were also used to help us better understand the mechanism by which PAK4 inhibitors block PAK4 and NAMPT activity, and we identified specific residues on the PAK4 inhibitors that interact with NAMPT and PAK4. Our results suggest that PAK4 inhibitors may have a more complex mechanism of action than previously understood, necessitating further exploration of how they influence cancer cell growth.
A Comprehensive Review of Xanthan Gum-Based Oral Drug Delivery Systems
Authors: Layek Buddhadev
Published: September 2024

Xanthan gum (XG) is an exopolysaccharide synthesized by the aerobic fermentation of simple sugars using Xanthomonas bacteria. It comprises a cellulosic backbone with a trisaccharide side chain connected to alternative glucose residues in the main backbone through α (1→3) linkage. XG dissolves readily in cold and hot water to produce a viscous solution that behaves like a pseudoplastic fluid. It shows excellent resistance to enzymatic degradation and great stability throughout a broad temperature, pH, or salt concentration range. Additionally, XG is nontoxic, biocompatible, and biodegradable, making it a suitable carrier for drug delivery. Furthermore, the carboxylic functions of pyruvate and glucuronic acid offer a considerable opportunity for chemical modification to meet the desired criteria for a specific application. Therefore, XG or its derivatives in conjunction with other polymers have frequently been studied as matrices for tablets, nanoparticles, microparticles, and hydrogels. This review primarily focuses on the applications of XG in various oral delivery systems over the past decade, including sustained-release formulations, gastroretentive dosage forms, and colon-targeted drug delivery. Source, production methods, and physicochemical properties relevant to drug delivery applications of XG have also been discussed.
Biomarker Discovery in Liver Disease Using Untargeted Metabolomics in Plasma and Saliva
Authors: Daniels Noah J. , Hershberger Courtney E. , Kerosky Matthew , Wehrle Chase J. , Raj Roma , Aykun Nihal , Allende Daniela S. , Aucejo Federico N. , Rotroff Daniel M.
Published: September 2024

Chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC), continue to be a global health burden with a rise in incidence and mortality, necessitating a need for the discovery of novel biomarkers for HCC detection. This study aimed to identify novel non-invasive biomarkers for these different liver disease states. We performed untargeted metabolomics in plasma (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 34) and saliva samples (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 22) to test for significant metabolite associations with each disease state. Additionally, we identified enriched biochemical pathways and analyzed correlations of metabolites between, and within, the two biofluids. We identified two salivary metabolites and 28 plasma metabolites significantly associated with at least one liver disease state. No metabolites were significantly correlated between biofluids, but we did identify numerous metabolites correlated within saliva and plasma, respectively. Pathway analysis revealed significant pathways enriched within plasma metabolites for several disease states. Our work provides a detailed analysis of the altered metabolome at various stages of liver disease while providing some context to altered pathways and relationships between metabolites.
Temporal Dynamics of Oxidative Stress and Inflammation in Bronchopulmonary Dysplasia
Authors: Teng Michelle , Wu Tzong-Jin , Jing Xigang , Day Billy W. , Pritchard Kirkwood A. , Naylor Stephen , Teng Ru-Jeng
Published: September 2024

Bronchopulmonary dysplasia (BPD) is the most common lung complication of prematurity. Despite extensive research, our understanding of its pathophysiology remains limited, as reflected by the stable prevalence of BPD. Prematurity is the primary risk factor for BPD, with oxidative stress (OS) and inflammation playing significant roles and being closely linked to premature birth. Understanding the interplay and temporal relationship between OS and inflammation is crucial for developing new treatments for BPD. Animal studies suggest that OS and inflammation can exacerbate each other. Clinical trials focusing solely on antioxidants or anti-inflammatory therapies have been unsuccessful. In contrast, vitamin A and caffeine, with antioxidant and anti-inflammatory properties, have shown some efficacy, reducing BPD by about 10%. However, more than one-third of very preterm infants still suffer from BPD. New therapeutic agents are needed. A novel tripeptide, N-acetyl-lysyltyrosylcysteine amide (KYC), is a reversible myeloperoxidase inhibitor and a systems pharmacology agent. It reduces BPD severity by inhibiting MPO, enhancing antioxidative proteins, and alleviating endoplasmic reticulum stress and cellular senescence in a hyperoxia rat model. KYC represents a promising new approach to BPD treatment.
Enhancing Plant Stress Tolerance: The Role of LcWRKY40 Gene in Drought and Alkaline Salt Resistance in Tobacco and Yeast
Authors: Guo Jianan , Zhao Yipeng , Cheng Huihui , Yu Ruiqiang , Gu Baoxiang , Wang Qiuhui , Zhang Jitao , Li Shenglin , Guan Qingjie
Published: September 2024

Leymus chinensis, a halophytic perennial grass belonging to the Poaceae family, thrives in saline-alkali grasslands and harbors a rich repository of resistance-related genetic resources. This study focused on deciphering the stress-responsive mechanisms of L. chinensis by conducting transcriptomic sequencing under NaHCO3 stress, which resulted in the annotation of a segment corresponding to the 51WRKY gene. The alkali-induced gene LcWRKY40 (QIG37591) was identified by phylogenetic analysis. Real-time quantitative PCR analysis was performed on L. chinensis plants subjected to PEG6000 and alkaline salt (NaHCO3) stress, and the results indicated that the LcWRKY40 gene was upregulated in both the leaves and roots. The localization of the LcWRKY40 protein was confirmed by the use of green fluorescent protein (GFP) fusion technology in transformed rice protoplast cells. The GAL4-driven transformation of the LcWRKY40 gene in INVScI yeast cells, which exhibited enhanced tolerance upon overexpression of the LcWRKY40 gene under mannitol and alkaline salt (NaHCO3) stress conditions. Under drought stress using mannitol, the fresh weight of Nicotiana tabacum overexpressing the LcWRKY40 gene was significantly higher than that of wild-type(WT) tobacco. Through drought and salt alkali stress, we found that overexpressed tobacco at different stages always outperformed the wild type in terms of fresh weight, SOD, MDA, and Fv/Fm. This study provides preliminary insights into the involvement of the LcWRKY40 gene in responding to drought and alkaline salt stresses, highlighting its role in enhancing plant resistance to drought and saline-alkaline conditions. These findings lay the foundation for future molecular breeding strategies aimed at improving grass resistance from different aspects.
Synthesis and Mechanism of a Green Scale and Corrosion Inhibitor
Authors: Zhao Linlin , Han Yu , Zhang Xiaojuan , Cao Zhongyan , Zhao Xiaowei , Wang Yuxia , Cai Yonghong , Wu Yufeng , Xu Ying
Published: September 2024

A new green water treatment agent, a poly(aspartic acid)-modified polymer (PASP/5–AVA), was synthesized using polysuccinimide and 5-aminovaleric acid (5-AVA) in a hybrid system. The structure was characterized, and the scale and corrosion inhibition performance were carried out with standard static scale inhibition and electrochemical methods, respectively. The mechanism was explored using XRD, XPS, SEM, and quantum chemistry calculations. The results indicated that PASP/5–AVA exhibited better scale and corrosion inhibition performance than PASP and maintained efficacy and thermal stability of the scale inhibition effect for a long time. Mechanistic studies indicated that PASP/5–AVA interferes with the normal generation of CaCO3 and CaSO4 scales through lattice distortion and dispersion, respectively; the combined effect of an alkaline environment and terminal electron-withdrawing -COOH groups can induce the stable C- ionic state formation in -CH2- of the extended side chain, thus enhancing its chelating ability for Ca2+ ions. At the same time, the extension of the side chain length also enhances the adsorption ability of the agent on the metal surface, forming a thick film and delaying the corrosion of the metal surface. This study provides the necessary theoretical reference for the design of green scale and corrosion agents.
microRNA Temporal-Specific Expression Profiles Reveal longissimus dorsi Muscle Development in Tianzhu White Yak
Authors: Shi Bingang , Zhu Chune , Wang Xiangyan , Qi Youpeng , Hu Jiang , Liu Xiu , Wang Jiqing , Hao Zhiyun , Zhao Zhidong , Zhang Xiaolan
Published: September 2024

As a class of regulatory factors, microRNAs (miRNAs) play an important role in regulating normal muscle development and fat deposition. Muscle and adipose tissues, as major components of the animal organism, are also economically important traits in livestock production. However, the effect of miRNA expression profiles on the development of muscle and adipose tissues in yak is currently unknown. In this study, we performed RNA sequencing (RNA-Seq) on Tianzhu white yak longissimus dorsi muscle tissue obtained from calves (6 months of age, M6, n = 6) and young (30 months of age, M30, n = 6) and adult yak (54 months of age, M54, n = 6) to identify which miRNAs are differentially expressed and to investigate their temporal expression profiles, establishing a regulatory network of miRNAs associated with the development of muscle and adipose. The results showed that 1191 miRNAs and 22061 mRNAs were screened across the three stages, of which the numbers of differentially expressed miRNAs (DE miRNAs) and differentially expressed mRNAs (DE mRNAs) were 225 and 450, respectively. The expression levels of the nine DE miRNAs were confirmed using a reverse transcription quantitative PCR (RT-qPCR) assay, and the trend of the assay results was generally consistent with the trend of the transcriptome profiles. Based on the expression trend, DE miRNAs were categorized into eight different expression patterns. Regarding the expression of DE miRNAs in sub-trends Profile 1 and Profile 2 (p < 0.05), the gene expression patterns were upregulated (87 DE miRNAs). Gene ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) analyses showed that the identified DE miRNAs and DE mRNAs were enriched in pathway entries associated with muscle and intramuscular fat (IMF) growth and development. On this basis, we constructed a DE miRNA–mRNA interaction network. We found that some DE mRNAs of interest overlapped with miRNA target genes, such as ACSL3, FOXO3, FBXO30, FGFBP4, TSKU, MYH10 (muscle development), ACOX1, FADS2, EIF4E2, SCD1, EL0VL5, and ACACB (intramuscular fat deposition). These results provide a valuable resource for further studies on the molecular mechanisms of muscle tissue development in yak and also lay a foundation for investigating the interactions between genes and miRNAs.
Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology
Authors: Shirley Simona N. , Watson Abigail E. , Yusuf Nabiha
Published: September 2024

Many skin diseases begin with inflammatory changes on a molecular level. To develop a more thorough understanding of skin pathology and to identify new targets for therapeutic advancements, molecular mechanisms of inflammation in the context of skin disease should be studied. Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). This review seeks to summarize recent developments in our understanding of inflammatory processes in skin disease and to highlight opportunities for therapeutic advancements. With a focus on publications within the past 5 years (2019–2024), the databases PubMed and EBSCOhost were used to search for peer-reviewed papers regarding inflammatory molecular mechanisms and skin disease. Several themes of research interest regarding inflammatory processes in skin disease were determined through extensive review and were included based on their relative representation in current research and their focus on therapeutic potential. Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease.
Molecular Functions and Physiological Roles of Gustatory Receptors of the Silkworm Bombyx mori
Authors: Sato Ryoichi
Published: September 2024

Complete elucidation of members of the gustatory receptor (Gr) family in lepidopteran insects began in the silkworm Bombyx mori. Grs of lepidopteran insects were initially classified into four subfamilies based on the results of phylogenetic studies and analyses of a few ligands. However, with further ligand analysis, it has become clear that plant secondary metabolites are important targets not only for Grs in the bitter subfamily but also for the Drosophila melanogaster Gr43a orthologue subfamily and Grs in the sugar subfamily. Gene knockout experiments showed that B. mori Gr6 (BmGr6) and BmGr9 are involved in the recognition of the feeding-promoting compounds chlorogenic acid and isoquercetin in mulberry leaves by the maxillary palps, suggesting that these Grs are responsible for palpation-dependent host recognition without biting. On the other hand, BmGr expression was also confirmed in nonsensory organs. Midgut enteroendocrine cells that produce specific neuropeptides were shown to express specific BmGrs, suggesting that BmGrs are involved in the induction of endocrine secretion in response to changes in the midgut contents. Furthermore, gene knockout experiments indicated that BmGr6 is indeed involved in the secretion of myosuppressin. On the other hand, BmGr9 was shown to induce signal transduction that is not derived from the intracellular signaling cascade mediated by G proteins but from the fructose-regulated cation channel of BmGr9 itself. Cryogenic electron microscopy revealed the mechanism by which the ion channel of the BmGr9 homotetramer opens upon binding of fructose to the ligand-binding pocket. Research on BmGrs has contributed greatly to our understanding of the functions and roles of Grs in insects.
Solanesol Ameliorates Anxiety-like Behaviors via the Downregulation of Cingulate T Cell-Restricted Intracellular Antigen-1 in a Complete Freund’s Adjuvant-Induced Mouse Model
Authors: Ding Shufan , Li Yifan , Chen Zhichao , Hu Jingnan , Li Jiayi , Li Junlan , Wang Yongjie
Published: September 2024

Anxiety disorder is a universal disease related to neuro-inflammation. Solanesol has shown positive effects because of its anti-inflammatory, anti-tumor, and anti-ulcer properties. This study focused on determining whether solanesol could ameliorate anxiety-like behaviors in a mouse model of neuro-inflammation and identify its working targets. Complete Freund’s adjuvant (CFA)-induced mice that were intra-peritoneally administered with solanesol (50 mg/kg) for 1 week showed a statistically significant reduction in anxiety-like behaviors, as measured by open field and elevated plus-maze tests. Western blot analysis revealed that CFA-induced upregulation of the levels of pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor α (TNF-α), which played crucial roles in regulating anxiety, returned to normal in the anterior cingulate cortex (ACC) after solanesol treatment. The level of T cell-restricted intracellular antigen-1 (TIA1), a key component of stress granules, also decreased in the ACC. Moreover, immunofluorescence results indicated that solanesol suppressed CFA-induced microglial and astrocytic activation in the ACC. CFA was injected in the hind paws of TIA1Nestin conditional knockout (cKO) mice to confirm whether TIA1 is a potential modulatory molecule that influences pro-inflammatory cytokines and anxiety-like behaviors. Anxiety-like behaviors could not be observed in cKO mice after CFA injection with IL-1β and TNF-α levels not remarkedly increasing. Our findings suggest that solanesol inhibits neuro-inflammation by decreasing the TIA1 level to reduce IL-1β and TNF-α expression, meanwhile inhibiting microglial and astrocytic activation in the ACC and ultimately ameliorating anxiety-like behaviors in mice.
Development of mRNA Lipid Nanoparticles: Targeting and Therapeutic Aspects
Authors: Liu Yaping , Huang Yingying , He Guantao , Guo Chun , Dong Jinhua , Wu Linping
Published: September 2024

Lipid nanoparticles (LNPs) have emerged as leading non-viral carriers for messenger RNA (mRNA) delivery in clinical applications. Overcoming challenges in safe and effective mRNA delivery to target tissues and cells, along with controlling release from the delivery vehicle, remains pivotal in mRNA-based therapies. This review elucidates the structure of LNPs, the mechanism for mRNA delivery, and the targeted delivery of LNPs to various cells and tissues, including leukocytes, T-cells, dendritic cells, Kupffer cells, hepatic endothelial cells, and hepatic and extrahepatic tissues. Here, we discuss the applications of mRNA–LNP vaccines for the prevention of infectious diseases and for the treatment of cancer and various genetic diseases. Although challenges remain in terms of delivery efficiency, specific tissue targeting, toxicity, and storage stability, mRNA–LNP technology holds extensive potential for the treatment of diseases.
Sperm DNA Fragmentation: Unraveling Its Imperative Impact on Male Infertility Based on Recent Evidence
Authors: Stavros Sofoklis , Potiris Anastasios , Molopodi Ermioni , Mavrogianni Despoina , Zikopoulos Athanasios , Louis Konstantinos , Karampitsakos Theodoros , Nazou Eleni , Sioutis Dimdos , Christodoulaki Chrysi , Skentou Charikleia , Gerede Angeliki , Zachariou Athanasios , Christopoulos Panagiotis , Panagopoulos Periklis , Domali Ekaterini , Drakakis Peter
Published: September 2024

Male factors may be present in up to 50–70% of infertile couples and the prevalence of male infertility accounts for 20–30% of infertility cases. Understanding the mechanisms and causes behind male infertility remains a challenge, but new diagnostic tools such as DNA fragmentation might aid in cases where the routine semen analysis is insufficient. DNA fragmentation, which refers to damages or breaks of the genetic material of the spermatozoa, is considered one of the main causes of male infertility due to impaired functional capability of sperm. The aim of the present narrative review is to investigate and enlighten the potential correlation between DNA fragmentation and male infertility parameters such as the seminal profile and the reproductive outcomes. Comprehensive research in PubMed/Medline and Scopus databases was conducted and 28 studies were included in the present review. Fourteen studies provided data regarding the impact of DNA fragmentation and seminal parameters and showed a correlation of significantly lower sperm count, lower concentration, motility, and abnormal morphology with an increased DNA fragmentation index (DFI). Similarly, 15 studies provided data regarding the impact of DFI on reproductive outcomes. Two studies showed higher aneuploidy rates with higher DFI values, and seven studies showed significantly lower pregnancy rates and live birth rates with higher DFI values. Ultimately, the studies included in this review highlight, collectively, the importance of measuring sperm DFI in the assessment of male infertility. Further studies are needed to explore the effectiveness of interventions aiming to reduce DFI levels.
Augmented Global Protein Acetylation Diminishes Cell Growth and Migration of Cholangiocarcinoma Cells
Authors: Saisomboon Saowaluk , Kariya Ryusho , Mahalapbutr Panupong , Insawang Tonkla , Sawanyawisuth Kanlayanee , Cha’on Ubon , Rungrotmongkol Thanyada , Wongkham Sopit , Jitrapakdee Sarawut , Okada Seiji , Vaeteewoottacharn Kulthida
Published: September 2024

We have previously shown that the overexpression of acetyl-CoA carboxylase 1 (ACC1) was associated with the poor prognosis of cholangiocarcinoma (CCA) patients, and suppression of its expression in CCA cell lines deteriorated cell growth. The present study explored the mechanism by which ACC1 inhibition affects global protein acetylation, using genetic knockdown and pharmacological inhibition with an ACC1 inhibitor ND-646 as models. Both ACC1 knockdown and ACC1-inhibitor-treated cells displayed the hyperacetylation of proteins, accompanied by impaired growth and migration. The immunoprecipitation of hyperacetylated proteins using the anti-acetylated lysine antibody, followed by tandem mass spectrometry, identified three potential verification candidates, namely POTE ankyrin domain family member E, peroxisomal biogenesis factor 1, and heat shock protein 90 beta (HSP90B). HSP90 acetylation was the candidate selected for the verification of protein acetylation. To establish the effects of protein hyperacetylation, treatment with suberoylanilide hydroxamic acid (SAHA), a lysine deacetylase inhibitor, was conducted, and this served as an independent model. Decreased tumor growth but increased acetylated protein levels were observed in ACC1-KD xenograft tumors. Hyperacetylated-alleviated cell growth and migration were consistently observed in the SAHA-treated models. The molecular linkage between protein hyperacetylation and the AKT/GSK3β/Snail pathway was demonstrated. This study highlighted the importance of protein acetylation in CCA progression, suggesting that ACC1 and KDAC are potential targets for CCA treatment.
Advances in the Insulin–Heart Axis: Current Therapies and Future Directions
Authors: Caturano Alfredo , Vetrano Erica , Galiero Raffaele , Sardu Celestino , Rinaldi Luca , Russo Vincenzo , Monda Marcellino , Marfella Raffaele , Sasso Ferdinando Carlo
Published: September 2024

The insulin–heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin–heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor–neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin–heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations.
Novel Drug-like HsrA Inhibitors Exhibit Potent Narrow-Spectrum Antimicrobial Activities against Helicobacter pylori
Authors: Casado Javier , Olivan-Muro Irene , Algarate Sonia , Chueca Eduardo , Salillas Sandra , Velázquez-Campoy Adrián , Piazuelo Elena , Fillat María F. , Sancho Javier , Lanas Ángel , González Andrés
Published: September 2024

Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase in multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide. By using a high-throughput screening strategy, in combination with in vitro DNA binding assays and antibacterial activity testing, we identified a battery of novel drug-like HsrA inhibitors with MIC values ranging from 0.031 to 4 mg/L against several antibiotic-resistant strains of H. pylori, and minor effects against both Gram-negative and Gram-positive species of human microbiota. The most potent anti-H. pylori candidate demonstrated a high therapeutic index, an additive effect in combination with metronidazole and clarithromycin as well as a strong antimicrobial action against Campylobacter jejuni, another clinically relevant pathogen of phylum Campylobacterota. Transcriptomic analysis suggests that the in vivo inhibition of HsrA triggers lethal global disturbances in H. pylori physiology including the arrest of protein biosynthesis, malfunction of respiratory chain, detriment in ATP generation, and oxidative stress. The novel drug-like HsrA inhibitors described here constitute valuable candidates to a new family of narrow-spectrum antibiotics that allow overcoming the current resistome, protecting from dysbiosis, and increasing therapeutic options for novel personalized treatments against H. pylori.
Investigating the Link between STAT4 Genetic Variants, STAT4 Protein Concentrations, and Laryngeal Squamous Cell Carcinoma: A Comprehensive Analysis of Clinical Manifestations
Authors: Pileckaite Enrika , Vilkeviciute Alvita , Kriauciuniene Loresa , Liutkevicius Vykintas , Liutkeviciene Rasa
Published: September 2024

According to recent research, inflammatory STAT4 and its protein impact may be important factors in developing cancerous diseases. Still unanalyzed is this effect in patients with laryngeal squamous cell carcinoma (LSCC). In the present study, we evaluated four single nucleotide variants (SNVs) of STAT4 (rs10181656, rs7574865, rs7601754, and rs10168266) and STAT4 serum levels to determine their link between LSCC development and its clinical manifestations. A total of 632 men (324 LSCC patients and 338 healthy individuals) were involved in this study. The genotyping was carried out using real-time PCR. Additionally, we measured 80 study subjects’ (40 LSCC patients and 40 control subjects) STAT4 protein concentrations using an enzyme-linked immunosorbent assay (ELISA). In our study, the T allele of STAT4 rs7574865 significantly increases the likelihood of LSCC occurrence by 1.4-fold. Additionally, this SNV is associated with higher odds of early-stage disease, T1 size LSCC development, absence of metastasis to neck lymph nodes, and well-differentiated carcinoma. The G allele of rs10181656 is significantly associated with various clinical characteristics of LSCC, increasing the odds of early- and advanced-stage disease by 2.8-fold and 1.9-fold, respectively. Additionally, this allele is linked to an increased likelihood of developing tumors of different sizes and non-metastasized LSCC, as well as poorly differentiated carcinoma, highlighting its potential impact on the development and features of LSCC. Conclusion: The analysis of the STAT4 rs7574865 SNV revealed that the G allele is linked to a more favorable prognosis in LSCC. Additionally, it is hypothesized that the G allele of rs10181656 may be associated with the occurrence of LSCC but may not serve as a sensitive prognostic biomarker for distinguishing between disease stages, cell differentiation, or tumor size.
Genome-Wide Analysis of Aquaporins Gene Family in Populus euphratica and Its Expression Patterns in Response to Drought, Salt Stress, and Phytohormones
Authors: Ndayambaza Boniface , Si Jianhua , Zhou Dongmeng , Bai Xue , Jia Bing , He Xiaohui , Wang Chunlin , Qin Jie , Zhu Xinglin , Liu Zijin , Wang Boyang
Published: September 2024

Aquaporins (AQPs) play an essential role in membrane water transport during plant responses to water stresses centered on conventional upstream signals. Phytohormones (PHs) regulate plant growth and yield, working with transcription factors to help plants withstand environmental challenges and regulate physiological and chemical processes. The AQP gene family is important, so researchers have studied its function and regulatory system in numerous species. Yet, there is a critical gap the understanding of many of their molecular features, thus our full knowledge of AQPs is far-off. In this study, we undertook a broad examination of the AQP family gene in Populus euphratica via bioinformatics tools and analyzed the expression patterns of certain members in response to drought, salt, and hormone stress. A total of 22 AQP genes were examined in P. euphratica, and were categorized into four main groups, including TIPs, PIPs, SIPs, and NIPs based on phylogenetic analysis. Comparable exon–intron gene structures were found by gene structure examination, and similarities in motif number and pattern within the same subgroup was determined by motif analysis. The PeuAQP gene family has numerous duplications, and there is a distinct disparity in how the members of the PeuAQP family react to post-translational modifications. Abiotic stress and hormone responses may be mediated by AQPs, as indicated by the abundance of stress response elements found in 22 AQP genes, as revealed by the promoter’s cis-elements prediction. Expression pattern analysis reveals that selected six AQP genes from the PIP subgroup were all expressed in the leaves, stem, and roots with varying expression levels. Moreover, qRT-PCR analysis discovered that the majority of the selected AQP members were up- or down-regulated in response to hormone treatment and abiotic stress. Remarkably, PeuAQP14 and PeuAQP15 appeared to be highly responsive to drought stress and PeuAQP15 exhibited a high response to salt stress. The foliar application of the phytohormones (SA, IAA, GA3, MeJA, and ABA) were found to either activate or inhibit PeuAQP, suggesting that they may mitigate the effects of water shortage of poplar water stress. The present work enhances our knowledge of the practical roles of AQPs in stress reactions and offers fundamental information for the AQP genes in poplar species. It also highlights a direction for producing new varieties of poplar species with drought, salt, and hormone tolerance and holds substantial scientific and ecological importance, offering a potential contribution to the conservation of poplar species in arid regions.
Pathological Involvement of Protein Phase Separation and Aggregation in Neurodegenerative Diseases
Authors: Wu Yinuo , Ma Biao , Liu Chang , Li Dangdang , Sui Guangchao
Published: September 2024

Neurodegenerative diseases are the leading cause of human disability and immensely reduce patients’ life span and quality. The diseases are characterized by the functional loss of neuronal cells and share several common pathogenic mechanisms involving the malfunction, structural distortion, or aggregation of multiple key regulatory proteins. Cellular phase separation is the formation of biomolecular condensates that regulate numerous biological processes, including neuronal development and synaptic signaling transduction. Aberrant phase separation may cause protein aggregation that is a general phenomenon in the neuronal cells of patients suffering neurodegenerative diseases. In this review, we summarize the pathological causes of common neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, among others. We discuss the regulation of key amyloidogenic proteins with an emphasis of their aberrant phase separation and aggregation. We also introduce the approaches as potential therapeutic strategies to ameliorate neurodegenerative diseases through intervening protein aggregation. Overall, this review consolidates the research findings of phase separation and aggregation caused by misfolded proteins in a context of neurodegenerative diseases.
Helper T Cells are Hyperactive and Contribute to the Dysregulation of Antibody Production in Patients with Rheumatoid Arthritis
Authors: Talib Mustafa , Gyebrovszki Balázs , Bőgér Dorottya , Csomor Réka , Mészáros Anna , Fodor Anna , Rojkovich Bernadette , Sármay Gabriella
Published: September 2024

Rheumatoid arthritis (RA) is a systemic autoimmune disease, mediated by a complex interaction between B cells and various subsets of T cells. Dysfunction of helper T (Th) and regulatory T (Treg) cells may contribute to the breakdown of self-tolerance and the progression of autoimmune disease. In this study, we investigated the activity of Th and Treg cells on the differentiation of autologous B cells in vitro using cell cultures from the peripheral blood of healthy controls (HCs) and RA patients. The expressions of programmed death 1 (PD-1) and IL-21 were monitored as activation markers for Th cells. Unstimulated Th cells from RA patients showed remarkably higher PD-1 expression than HC samples. Stimulation of Th cells from RA patients with Staphylococcus enterotoxin B (SEB) in the presence of B cells significantly induced their PD-1 and IL-21 expression at a considerably higher level in RA compared to HCs, and Treg cells did not affect IL-21 production. When monitoring B-cell differentiation, a significantly higher frequency of plasma cells was observed, even in unstimulated samples of RA patients compared to HCs. In the SEB-stimulated co-cultures of the RA samples, plasma cell frequency and IgG production were considerably higher than in HCs and were not significantly affected by Tregs. These findings demonstrate that Th cells are constitutively active in RA, and their hyperactivity upon interaction with diseased B cells may lead to uncontrolled antibody production.
Autoimmunity-Associated SNP rs3024505 Disrupts STAT3 Binding in B Cells, Leading to IL10 Dysregulation
Authors: Uvarova Aksinya N. , Zheremyan Elina A. , Ustiugova Alina S. , Murashko Matvey M. , Bogomolova Elvina A. , Demin Denis E. , Stasevich Ekaterina M. , Kuprash Dmitry V. , Korneev Kirill V.
Published: September 2024

Interleukin 10 (IL10) is a major anti-inflammatory cytokine that acts as a master regulator of the immune response. A single nucleotide polymorphism rs3024505(C/T), located downstream of the IL10 gene, is associated with several aggressive inflammatory diseases, including systemic lupus erythematosus, Sjögren’s syndrome, Crohn’s disease, and ulcerative colitis. In such autoimmune pathologies, IL10-producing B cells play a protective role by decreasing the level of inflammation and restoring immune homeostasis. This study demonstrates that rs3024505 is located within an enhancer that augments the activity of the IL10 promoter in a reporter system based on a human B cell line. The common rs3024505(C) variant creates a functional binding site for the transcription factor STAT3, whereas the risk allele rs3024505(T) disrupts STAT3 binding, thereby reducing the IL10 promoter activity. Our findings indicate that B cells from individuals carrying the minor rs3024505(T) allele may produce less IL10 due to the disrupted STAT3 binding site, contributing to the progression of inflammatory pathologies.
Transplanted Murine Tumours SPECT Imaging with 99mTc Delivered with an Artificial Recombinant Protein
Authors: Pozdniakova Natalia V. , Lipengolts Alexey A. , Skribitsky Vsevolod A. , Shpakova Kristina E. , Finogenova Yulia A. , Smirnova Anna V. , Shevelev Alexei B. , Grigorieva Elena Y.
Published: September 2024

99mTc is a well-known radionuclide that is widely used and readily available for SPECT/CT (Single-Photon Emission Computed Tomography) diagnosis. However, commercial isotope carriers are not specific enough to tumours, rapidly clear from the bloodstream, and are not safe. To overcome these limitations, we suggest immunologically compatible recombinant proteins containing a combination of metal binding sites as 99mTc chelators and several different tumour-specific ligands for early detection of tumours. E1b protein containing metal-binding centres and tumour-specific ligands targeting integrin αvβ3 and nucleolin, as well as a short Cys-rich sequence, was artificially constructed. It was produced in E. coli, purified by metal-chelate chromatography, and used to obtain a complex with 99mTc. This was administered intravenously to healthy Balb/C mice at an activity dose of about 80 MBq per mouse, and the biodistribution was studied by SPECT/CT for 24 h. Free sodium 99mTc-pertechnetate at the same dose was used as a reference. The selectivity of 99mTc-E1b and the kinetics of isotope retention in tumours were then investigated in experiments in C57Bl/6 and Balb/C mice with subcutaneously transplanted lung carcinoma (LLC) or mammary adenocarcinoma (Ca755, EMT6, or 4T1). The radionuclide distribution ratio in tumour and adjacent normal tissue (T/N) steadily increased over 24 h, reaching 15.7 ± 4.2 for EMT6, 16.5 ± 3.8 for Ca755, 6.7 ± 4.2 for LLC, and 7.5 ± 3.1 for 4T1.