bluuebunny/crossref_metadata_2025 huggingface dataset:
Heat-Priming during Somatic Embryogenesis Increased Resilience to Drought Stress in the Generated Maritime Pine (Pinus pinaster) Plants
Authors: Pérez-Oliver María Amparo , González-Mas María del Carmen , Renau-Morata Begoña , Arrillaga Isabel , Sales Ester
Published: May 2023

Drought stress is becoming the most important factor of global warming in forests, hampering the production of reproductive material with improved resilience. Previously, we reported that heat-priming maritime pine (Pinus pinaster) megagametophytes during SE produced epigenetic changes that generated plants better adapted to subsequent heat stress. In this work, we tested, in an experiment performed under greenhouse conditions, whether heat-priming will produce cross-tolerance to mild drought stress (30 days) in 3-year-old priming-derived plants. We found that they maintain constitutive physiological differences as compared to controls, such as higher proline, abscisic acid, starch, and reduced glutathione and total protein contents, as well as higher ΦPSII yield. Primed plants also displayed a constitutive upregulation of the WRKY transcription factor and the Responsive to Dehydration 22 (RD22) genes, as well as of those coding for antioxidant enzymes (APX, SOD, and GST) and for proteins that avoid cell damage (HSP70 and DHNs). Furthermore, osmoprotectants as total soluble sugars and proteins were early accumulated in primed plants during the stress. Prolongated water withdrawal increased ABA accumulation and negatively affected photosynthesis in all plants but primed-derived plants recovered faster than controls. We concluded that high temperature pulses during somatic embryogenesis resulted in transcriptomic and physiological changes in maritime pine plants that can increase their resilience to drought stress, since heat-primed plants exhibit permanent activation of mechanisms for cell protection and overexpression of stress pathways that pre-adapt them to respond more efficiently to soil water deficit.
Effects of Heavy Metals on Stomata in Plants: A Review
Authors: Guo Zhaolai , Gao Yuhan , Yuan Xinqi , Yuan Mengxiang , Huang Lv , Wang Sichen , Liu Chang’e , Duan Changqun
Published: May 2023

Stomata are one of the important structures for plants to alleviate metal stress and improve plant resistance. Therefore, a study on the effects and mechanisms of heavy metal toxicity to stomata is indispensable in clarifying the adaptation mechanism of plants to heavy metals. With the rapid pace of industrialization and urbanization, heavy metal pollution has been an environmental issue of global concern. Stomata, a special physiological structure of plants, play an important role in maintaining plant physiological and ecological functions. Recent studies have shown that heavy metals can affect the structure and function of stomata, leading to changes in plant physiology and ecology. However, although the scientific community has accumulated some data on the effects of heavy metals on plant stomata, the systematic understanding of the effects of heavy metals on plant stomata remains limited. Therefore, in this review, we present the sources and migration pathways of heavy metals in plant stomata, analyze systematically the physiological and ecological responses of stomata on heavy metal exposure, and summarize the current mechanisms of heavy metal toxicity on stomata. Finally, the future research perspectives of the effects of heavy metals on plant stomata are identified. This paper can serve as a reference for the ecological assessment of heavy metals and the protection of plant resources.
Expected and Unexpected Effects of Pharmacological Antioxidants
Authors: Tyuryaeva Irina , Lyublinskaya Olga
Published: May 2023

In this review, we have collected the existing data on the bioactivity of antioxidants (N-acetylcysteine, polyphenols, vitamin C) which are traditionally used in experimental biology and, in some cases, in the clinic. Presented data show that, despite the capacity of these substances to scavenge peroxides and free radicals in cell-free systems, their ability to exhibit these properties in vivo, upon pharmacological supplementation, has not been confirmed so far. Their cytoprotective activity is explained mainly by the ability not to suppress, but to activate multiple redox pathways, which causes biphasic hormetic responses and highly pleiotropic effects in cells. N-acetylcysteine, polyphenols, and vitamin C affect redox homeostasis by generating low-molecular-weight redox-active compounds (H2O2 or H2S), known for their ability to stimulate cellular endogenous antioxidant defense and promote cytoprotection at low concentrations but exert deleterious effects at high concentrations. Moreover, the activity of antioxidants strongly depends on the biological context and mode of their application. We show here that considering the biphasic and context-dependent response of cells on the pleiotropic action of antioxidants can help explain many of the conflicting results obtained in basic and applied research and build a more logical strategy for their use.
DNA Deamination Is Required for Human APOBEC3A-Driven Hepatocellular Carcinoma In Vivo
Authors: Naumann Jordan A. , Argyris Prokopios P. , Carpenter Michael A. , Gupta Harshita B. , Chen Yanjun , Temiz Nuri A. , Zhou Yufan , Durfee Cameron , Proehl Joshua , Koniar Brenda L. , Conticello Silvestro G. , Largaespada David A. , Brown William L. , Aihara Hideki , Vogel Rachel I. , Harris Reuben S.
Published: May 2023

Although the APOBEC3 family of single-stranded DNA cytosine deaminases is well-known for its antiviral factors, these enzymes are rapidly gaining attention as prominent sources of mutation in cancer. APOBEC3′s signature single-base substitutions, C-to-T and C-to-G in TCA and TCT motifs, are evident in over 70% of human malignancies and dominate the mutational landscape of numerous individual tumors. Recent murine studies have established cause-and-effect relationships, with both human APOBEC3A and APOBEC3B proving capable of promoting tumor formation in vivo. Here, we investigate the molecular mechanism of APOBEC3A-driven tumor development using the murine Fah liver complementation and regeneration system. First, we show that APOBEC3A alone is capable of driving tumor development (without Tp53 knockdown as utilized in prior studies). Second, we show that the catalytic glutamic acid residue of APOBEC3A (E72) is required for tumor formation. Third, we show that an APOBEC3A separation-of-function mutant with compromised DNA deamination activity and wildtype RNA-editing activity is defective in promoting tumor formation. Collectively, these results demonstrate that APOBEC3A is a “master driver” that fuels tumor formation through a DNA deamination-dependent mechanism.
Intersection of Coagulation and Fibrinolysis by the Glycosylphosphatidylinositol (GPI)-Anchored Serine Protease Testisin
Authors: Buzza Marguerite S. , Pawar Nisha R. , Strong Amando A. , Antalis Toni M.
Published: May 2023

Hemostasis is a delicate balance between coagulation and fibrinolysis that regulates the formation and removal of fibrin, respectively. Positive and negative feedback loops and crosstalk between coagulation and fibrinolytic serine proteases maintain the hemostatic balance to prevent both excessive bleeding and thrombosis. Here, we identify a novel role for the glycosylphosphatidylinositol (GPI)-anchored serine protease testisin in the regulation of pericellular hemostasis. Using in vitro cell-based fibrin generation assays, we found that the expression of catalytically active testisin on the cell surface accelerates thrombin-dependent fibrin polymerization, and intriguingly, that it subsequently promotes accelerated fibrinolysis. We find that the testisin-dependent fibrin formation is inhibited by rivaroxaban, a specific inhibitor of the central prothrombin-activating serine protease factor Xa (FXa), demonstrating that cell-surface testisin acts upstream of factor X (FX) to promote fibrin formation at the cell surface. Unexpectedly, testisin was also found to accelerate fibrinolysis by stimulating the plasmin-dependent degradation of fibrin and enhancing plasmin-dependent cell invasion through polymerized fibrin. Testisin was not a direct activator of plasminogen, but it is able to induce zymogen cleavage and the activation of pro-urokinase plasminogen activator (pro-uPA), which converts plasminogen to plasmin. These data identify a new proteolytic component that can regulate pericellular hemostatic cascades at the cell surface, which has implications for angiogenesis, cancer biology, and male fertility.
Preliminary Study on the Effect of a Night Shift on Blood Pressure and Clock Gene Expression
Authors: Toffoli Barbara , Tonon Federica , Giudici Fabiola , Ferretti Tommaso , Ghirigato Elena , Contessa Matilde , Francica Morena , Candido Riccardo , Puato Massimo , Grillo Andrea , Fabris Bruno , Bernardi Stella
Published: May 2023

Night shift work has been found to be associated with a higher risk of cardiovascular and cerebrovascular disease. One of the underlying mechanisms seems to be that shift work promotes hypertension, but results have been variable. This cross-sectional study was carried out in a group of internists with the aim of performing a paired analysis of 24 h blood pressure in the same physicians working a day shift and then a night shift, and a paired analysis of clock gene expression after a night of rest and a night of work. Each participant wore an ambulatory blood pressure monitor (ABPM) twice. The first time was for a 24 h period that included a 12 h day shift (08.00–20.00) and a night of rest. The second time was for a 30 h period that included a day of rest, a night shift (20.00–08.00), and a subsequent period of rest (08.00–14.00). Subjects underwent fasting blood sampling twice: after the night of rest and after the night shift. Night shift work significantly increased night systolic blood pressure (SBP), night diastolic blood pressure (DBP), and heart rate (HR) and decreased their respective nocturnal decline. Clock gene expression increased after the night shift. There was a direct association between night blood pressure and clock gene expression. Night shifts lead to an increase in blood pressure, non-dipping status, and circadian rhythm misalignment. Blood pressure is associated with clock genes and circadian rhythm misalignement.
Anti-Tumor Immunity and Preoperative Radiovaccination: Emerging New Concepts in the Treatment of Breast Cancer
Authors: Koukourakis Ioannis M. , Papadimitriou Marios , Desse Dimitra , Zygogianni Anna , Papadimitriou Christos
Published: May 2023

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological “coldness”, however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This “radiovaccination” effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC.
Integrative Analysis Reveals the Diverse Effects of 3D Stiffness upon Stem Cell Fate
Authors: Yue Muxin , Liu Yunsong , Zhang Ping , Li Zheng , Zhou Yongsheng
Published: May 2023

The origin of life and native tissue development are dependent on the heterogeneity of pluripotent stem cells. Bone marrow mesenchymal stem cells (BMMSCs) are located in a complicated niche with variable matrix stiffnesses, resulting in divergent stem cell fates. However, how stiffness drives stem cell fate remains unknown. For this study, we performed whole-gene transcriptomics and precise untargeted metabolomics sequencing to elucidate the complex interaction network of stem cell transcriptional and metabolic signals in extracellular matrices (ECMs) with different stiffnesses, and we propose a potential mechanism involved in stem cell fate decision. In a stiff (39~45 kPa) ECM, biosynthesis of aminoacyl-tRNA was up-regulated, and increased osteogenesis was also observed. In a soft (7~10 kPa) ECM, biosynthesis of unsaturated fatty acids and deposition of glycosaminoglycans were increased, accompanied by enhanced adipogenic/chondrogenic differentiation of BMMSCs. In addition, a panel of genes responding to the stiffness of the ECM were validated in vitro, mapping out the key signaling network that regulates stem cells’ fate decisions. This finding of “stiffness-dependent manipulation of stem cell fate” provides a novel molecular biological basis for development of potential therapeutic targets within tissue engineering, from both a cellular metabolic and a biomechanical perspective.
Mesoscale Simulations of Structure Formation in Polyacrylonitrile Nascent Fibers Induced by Binary Solvent Mixture
Authors: Komarov Pavel , Malyshev Maxim , Baburkin Pavel , Guseva Daria
Published: May 2023

Polyacrylonitrile (PAN) is widely used as a raw material for the production of high-modulus carbon fibers, the internal structure of which is directly affected by the spinning of the precursor. Although PAN fibers have been studied for a long time, the formation of their internal structure has not been sufficiently investigated theoretically. This is due to the large number of stages in the process and the parameters controlling them. In this study, we present a mesoscale model describing the evolution of nascent PAN fibers during the coagulation. It is constructed within the framework of a mesoscale dynamic density functional theory. We use the model to study the influence of a combined solvent of dimethyl sulfoxide (DMSO, a good solvent) and water (a non-solvent) on the microstructure of the fibers. A porous structure of PAN is formed as a result of the microphase separation of the polymer and the residual combined solvent at a high water content in the system. The model shows that one of the possible ways to obtain the homogeneous fiber structure is to slow down the coagulation by increasing the amount of good solvent in the system. This result is in agreement with the existing experimental data and confirms the efficiency of the presented model.
KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy
Authors: Gurreri Enrico , Genovese Giannicola , Perelli Luigi , Agostini Antonio , Piro Geny , Carbone Carmine , Tortora Giampaolo
Published: May 2023

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in oncology because of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein extremely difficult. KRAS regulates development, cell growth, epigenetically dysregulated differentiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indirect inhibitors of KRAS signaling. Therefore, KRAS dependency is so essential in KRASmu PDAC that cancer cells have secured several compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors, such as activation of MEK/ERK signaling or YAP1 upregulation. This review will provide insights into KRAS dependency in PDAC and analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms.
Recent Developments in the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors Incorporating Pyridine Moiety
Authors: Starosotnikov Alexey M. , Bastrakov Maxim A.
Published: May 2023

Human immunodeficiency virus (HIV) causes one of the most dangerous diseases—acquired immunodeficiency syndrome (AIDS). An estimated about 40 million people are currently living with HIV worldwide, most of whom are already on antiretroviral therapy. This makes the development of effective drugs to combat this virus very relevant. Currently, one of the dynamically developing areas of organic and medicinal chemistry is the synthesis and identification of new compounds capable of inhibiting HIV-1 integrase—one of the HIV enzymes. A significant number of studies on this topic are published annually. Many compounds inhibiting integrase incorporate pyridine core. Therefore, this review is an analysis of the literature on the methods for the synthesis of pyridine-containing HIV-1 integrase inhibitors since 2003 to the present.
The Pharmacological Efficacy of Baicalin in Inflammatory Diseases
Authors: Wen Yongqiang , Wang Yazhou , Zhao Chenxu , Zhao Baoyu , Wang Jianguo
Published: May 2023

Baicalin is one of the most abundant flavonoids found in the dried roots of Scutellaria baicalensis Georgi (SBG) belonging to the genus Scutellaria. While baicalin is demonstrated to have anti-inflammatory, antiviral, antitumor, antibacterial, anticonvulsant, antioxidant, hepatoprotective, and neuroprotective effects, its low hydrophilicity and lipophilicity limit the bioavailability and pharmacological functions. Therefore, an in-depth study of baicalin’s bioavailability and pharmacokinetics contributes to laying the theoretical foundation for applied research in disease treatment. In this view, the physicochemical properties and anti-inflammatory activity of baicalin are summarized in terms of bioavailability, drug interaction, and inflammatory conditions.
Direct Measurement of the Four-Phase Equilibrium Coexistence Vapor–Aqueous Solution–Ice–Gas Hydrate in Water–Carbon Dioxide System
Authors: Semenov Anton , Mendgaziev Rais , Stoporev Andrey , Istomin Vladimir , Tulegenov Timur , Yarakhmedov Murtazali , Novikov Andrei , Vinokurov Vladimir
Published: May 2023

Precise data on the non-variant equilibrium of the four phases (vapor–aqueous solution–ice–gas hydrate) in P–T coordinates are highly desired for developing accurate thermodynamic models and can be used as reference points (similar to the triple point of water). Using the two-component hydrate-forming system CO2–H2O, we have proposed and validated a new express procedure for determining the temperature and pressure of the lower quadruple point Q1. The essence of the method is the direct measurement of these parameters after the successive formation of the gas hydrate and ice phases in the initial two-phase gas–water solution system under intense agitation of the fluids. After relaxation, the system occurs in the same equilibrium state (T = 271.60 K, P = 1.044 MPa), regardless of the initial parameters and the order of crystallization of the CO2 hydrate and ice phases. Considering the combined standard uncertainties (±0.023 K, ±0.021 MPa), the determined P and T values agree with the results of other authors obtained by a more sophisticated indirect method. Validating the developed approach for systems with other hydrate-forming gases is of great interest.
The Expression of the StNRAMP2 Gene Determined the Accumulation of Cadmium in Different Tissues of Potato
Authors: Zhang Yule , He Tengbing , Tian Weijun , Xia Yabei , He Yeqing , Su Minmin , He Guandi
Published: May 2023

Cadmium (Cd) is a toxic metal that threatens human health when enriched in crops. NRAMPs are a family of natural macrophage proteins reported to play a key role in Cd transport in plants. In order to explore the gene regulation mechanism of potato under Cd stress and the role of NRAMPs family in it, this study analyzed the gene expression differences of two different Cd accumulation levels in potato after 7 days of 50 mg/kg Cd stress and screened out the key genes that may play a major role in the differential accumulation of Cd in different varieties. Additionally, StNRAMP2 was selected for verification. Further verification showed that the StNRAMP2 gene plays an important role in the accumulation of Cd in potato. Interestingly, silencing StNRAMP2 increased Cd accumulation in tubers but significantly decreased Cd accumulation in other sites, suggesting a critical role of StNRAMP2 in Cd uptake and transport in potatoes. To further confirm this conclusion, we performed heterologous expression experiments in which overexpression of StNRAMP2 gene in tomato resulted in a threefold increase in Cd content, which further confirmed the important role of StNRAMP2 in the process of Cd accumulation compared with wild-type plants. In addition, we found that the addition of Cd to the soil increased the activity of the plant antioxidant enzyme system, and silencing StNRAMP2 partially reversed this effect. This suggests that the StNRAMP2 gene plays an important role in plant stress tolerance, and future studies could further explore the role of this gene in other environmental stresses. In conclusion, the results of this study improve the understanding of the mechanism of Cd accumulation in potato and provide experimental basis for remediation of Cd pollution.
Identification of Driver Epistatic Gene Pairs Combining Germline and Somatic Mutations in Cancer
Authors: Rocha Jairo , Sastre Jaume , Amengual-Cladera Emilia , Hernandez-Rodriguez Jessica , Asensio-Landa Victor , Heine-Suñer Damià , Capriotti Emidio
Published: May 2023

Cancer arises from the complex interplay of various factors. Traditionally, the identification of driver genes focuses primarily on the analysis of somatic mutations. We describe a new method for the detection of driver gene pairs based on an epistasis analysis that considers both germline and somatic variations. Specifically, the identification of significantly mutated gene pairs entails the calculation of a contingency table, wherein one of the co-mutated genes can exhibit a germline variant. By adopting this approach, it is possible to select gene pairs in which the individual genes do not exhibit significant associations with cancer. Finally, a survival analysis is used to select clinically relevant gene pairs. To test the efficacy of the new algorithm, we analyzed the colon adenocarcinoma (COAD) and lung adenocarcinoma (LUAD) samples available at The Cancer Genome Atlas (TCGA). In the analysis of the COAD and LUAD samples, we identify epistatic gene pairs significantly mutated in tumor tissue with respect to normal tissue. We believe that further analysis of the gene pairs detected by our method will unveil new biological insights, enhancing a better description of the cancer mechanism.
Therapeutic Mechanisms and Clinical Effects of Glucagon-like Peptide 1 Receptor Agonists in Nonalcoholic Fatty Liver Disease
Authors: Lee Han Ah , Kim Hwi Young
Published: May 2023

Nonalcoholic fatty liver disease (NAFLD) can lead to liver fibrosis and cirrhosis. Recently, glucagon-like peptide 1 receptor agonists (GLP-1RAs), a class of drugs used to treat type 2 diabetes and obesity, have shown therapeutic effects against NAFLD. In addition to reducing blood glucose levels and body weight, GLP-1RAs are effective in improving the clinical, biochemical, and histological markers of hepatic steatosis, inflammation, and fibrosis in patients with NAFLD. Additionally, GLP-1RAs have a good safety profile with minor side effects, such as nausea and vomiting. Overall, GLP-1RAs show promise as a potential treatment for NAFLD, and further studies are required to determine their long-term safety and efficacy.
A Comparative Study of Nanobio Interaction of Zn-Doped CdTe Quantum Dots with Lactoferrin Using Different Spectroscopic Methods
Authors: Ji Meng , Ren Liwei , Tian Chunyuan , Zhuang Xuming , Luan Feng
Published: May 2023

In this paper, glutathione (GSH)-coated Zn-doped CdTe quantum dots (QDs) with different particle sizes were synthesized using the “reflow method”, and the interaction mechanism between the two QDs and lactoferrin (LF) was investigated systemically with different spectroscopic methods. The steady-state fluorescence spectra showed that the LF formed a tight complex with the two QDs through static bursting and that the electrostatic force was the main driving force between the two LF–QDs systems. The complex generation process was found to be spontaneous (ΔG < 0) and accompanied by exothermic and increasing degrees of freedom (ΔH < 0, ΔS > 0) by using the temperature-dependent fluorescence spectroscopy. The critical transfer distance (R0) and donor–acceptor distance (r) of the two LF–QDs systems were obtained based on the fluorescence resonance energy transfer theory. In addition, it was observed that the QDs changed the secondary and tertiary structures of LF, leading to an increase in the hydrophobicity of LF. Further, the nano-effect of orange QDs on LF is much larger than that of green QDs. The above results provide a basis for metal-doped QDs with LF in safe nano-bio applications.
Selective Encapsulation of the Polyphenols on Silk Fibroin Nanoparticles: Optimization Approaches
Authors: Bayraktar Oguz , Oder Gizem , Erdem Cansu , Kose Merve Deniz , Cheaburu-Yilmaz Catalina N.
Published: May 2023

The present study proposes a method for designing small bioactive nanoparticles using silk fibroin as a carrier to deliver hydrophobic polyphenols. Quercetin and trans-resveratrol, widely distributed in vegetables and plants, are used here as model compounds with hydrophobic properties. Silk fibroin nanoparticles were prepared by desolvation method and using various concentrations of ethanol solutions. The optimization of the nanoparticle formation was achieved by applying Central Composite Design (CCD) and the response surface methodology (RSM). The effects of silk fibroin and ethanol solution concentrations together with the pH on the selective encapsulation of phenolic compounds from a mixture were reported. The obtained results showed that nanoparticles with an average particle size of 40 to 105 nm can be prepared. The optimized system for the selective encapsulation of the polyphenols on the silk fibroin substrate was determined to be 60% ethanol solution and 1 mg/mL silk fibroin concentration at neutral pH. The selective encapsulation of the polyphenols was achieved, with the best results being obtained in the case of resveratrol and quercetin and encapsulation of gallic and vanillic acids being rather poor. Thin-layer chromatography confirmed the selective encapsulation and the loaded silk fibroin nanoparticles exhibited antioxidant activity.
An Update on the Molecular and Cellular Basis of Pharmacotherapy in Type 2 Diabetes Mellitus
Authors: Mahgoub Mohamed Omer , Ali Ifrah Ismail , Adeghate Jennifer O. , Tekes Kornélia , Kalász Huba , Adeghate Ernest A.
Published: May 2023

Diabetes mellitus (DM) is a chronic illness with an increasing global prevalence. More than 537 million cases of diabetes were reported worldwide in 2021, and the number is steadily increasing. The worldwide number of people suffering from DM is projected to reach 783 million in 2045. In 2021 alone, more than USD 966 billion was spent on the management of DM. Reduced physical activity due to urbanization is believed to be the major cause of the increase in the incidence of the disease, as it is associated with higher rates of obesity. Diabetes poses a risk for chronic complications such as nephropathy, angiopathy, neuropathy and retinopathy. Hence, the successful management of blood glucose is the cornerstone of DM therapy. The effective management of the hyperglycemia associated with type 2 diabetes includes physical exercise, diet and therapeutic interventions (insulin, biguanides, second generation sulfonylureas, glucagon-like peptide 1 agonists, dipeptidyl-peptidase 4 inhibitors, thiazolidinediones, amylin mimetics, meglitinides, α-glucosidase inhibitors, sodium-glucose cotransporter-2 inhibitors and bile acid sequestrants). The optimal and timely treatment of DM improves the quality of life and reduces the severe burden of the disease for patients. Genetic testing, examining the roles of different genes involved in the pathogenesis of DM, may also help to achieve optimal DM management in the future by reducing the incidence of DM and by enhancing the use of individualized treatment regimens.
Genetically Engineered Mice Unveil In Vivo Roles of the Mediator Complex
Authors: Ilchuk Leonid A. , Kubekina Marina V. , Okulova Yulia D. , Silaeva Yulia Yu. , Tatarskiy Victor V. , Filatov Maxim A. , Bruter Alexandra V.
Published: May 2023

The Mediator complex is a multi-subunit protein complex which plays a significant role in the regulation of eukaryotic gene transcription. It provides a platform for the interaction of transcriptional factors and RNA polymerase II, thus coupling external and internal stimuli with transcriptional programs. Molecular mechanisms underlying Mediator functioning are intensively studied, although most often using simple models such as tumor cell lines and yeast. Transgenic mouse models are required to study the role of Mediator components in physiological processes, disease, and development. As constitutive knockouts of most of the Mediator protein coding genes are embryonically lethal, conditional knockouts and corresponding activator strains are needed for these studies. Recently, they have become more easily available with the development of modern genetic engineering techniques. Here, we review existing mouse models for studying the Mediator, and data obtained in corresponding experiments.
DNA Polymerases for Whole Genome Amplification: Considerations and Future Directions
Authors: Ordóñez Carlos D. , Redrejo-Rodríguez Modesto
Published: May 2023

In the same way that specialized DNA polymerases (DNAPs) replicate cellular and viral genomes, only a handful of dedicated proteins from various natural origins as well as engineered versions are appropriate for competent exponential amplification of whole genomes and metagenomes (WGA). Different applications have led to the development of diverse protocols, based on various DNAPs. Isothermal WGA is currently widely used due to the high performance of Φ29 DNA polymerase, but PCR-based methods are also available and can provide competent amplification of certain samples. Replication fidelity and processivity must be considered when selecting a suitable enzyme for WGA. However, other properties, such as thermostability, capacity to couple replication, and double helix unwinding, or the ability to maintain DNA replication opposite to damaged bases, are also very relevant for some applications. In this review, we provide an overview of the different properties of DNAPs widely used in WGA and discuss their limitations and future research directions.
Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies
Authors: Yasir Muhammad , Park Jinyoung , Han Eun-Taek , Park Won Sun , Han Jin-Hee , Kwon Yong-Soo , Lee Hee-Jae , Hassan Mubashir , Kloczkowski Andrzej , Chun Wanjoo
Published: May 2023

Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1) is an orphan nuclear receptor encoded by the NR0B1 gene. The functional study showed that DAX1 is a physiologically significant target for EWS/FLI1-mediated oncogenesis, particularly Ewing Sarcoma (ES). In this study, a three-dimensional DAX1 structure was modeled by employing a homology modeling approach. Furthermore, the network analysis of genes involved in Ewing Sarcoma was also carried out to evaluate the association of DAX1 and other genes with ES. Moreover, a molecular docking study was carried out to check the binding profile of screened flavonoid compounds against DAX1. Therefore, 132 flavonoids were docked in the predicted active binding pocket of DAX1. Moreover, the pharmacogenomics analysis was performed for the top ten docked compounds to evaluate the ES-related gene clusters. As a result, the five best flavonoid-docked complexes were selected and further evaluated by Molecular Dynamics (MD) simulation studies at 100 ns. The MD simulation trajectories were evaluated by generating RMSD, hydrogen bond plot analysis, and interaction energy graphs. Our results demonstrate that flavonoids showed interactive profiles in the active region of DAX1 and can be used as potential therapeutic agents against DAX1-mediated augmentation of ES after in-vitro and in-vivo evaluations.
Resistance to Resveratrol Treatment in Experimental PTSD Is Associated with Abnormalities in Hepatic Metabolism of Glucocorticoids
Authors: Tseilikman Vadim E. , Fedotova Julia O. , Tseilikman Olga B. , Novak Jurica , Karpenko Marina N. , Maistrenko Victoria A. , Lazuko Svetlana S. , Belyeva Lyudmila E. , Kamel Mustapha , Buhler Alexey V. , Kovaleva Elena G.
Published: May 2023

Glucocorticoids are metabolized by the CYP3A isoform of cytochrome P450 and by 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1). Experimental data suggest that post-traumatic stress disorder (PTSD) is associated with an increase in hepatic 11β-HSD-1 activity and a concomitant decrease in hepatic CYP3A activity. Trans-resveratrol, a natural polyphenol, has been extensively studied for its antipsychiatric properties. Recently, protective effects of trans-resveratrol were found in relation to PTSD. Treatment of PTSD rats with trans-resveratrol allowed the rats to be divided into two phenotypes. The first phenotype is treatment-sensitive rats (TSR), and the second phenotype is treatment-resistant rats (TRRs). In TSR rats, trans-resveratrol ameliorated anxiety-like behavior and reversed plasma corticosterone concentration abnormalities. In contrast, in TRR rats, trans-resveratrol aggravated anxiety-like behavior and decreased plasma corticosterone concentration. In TSR rats, hepatic 11β-HSD-1 activity was suppressed, with a concomitant increase in CYP3A activity. In TRR rats, the activities of both enzymes were suppressed. Thus, the resistance of PTSD rats to trans-resveratrol treatment is associated with abnormalities in hepatic metabolism of glucocorticoids. The free energy of binding of resveratrol, cortisol, and corticosterone to the human CYP3A protein was determined using the molecular mechanics Poisson–Boltzmann surface area approach, indicating that resveratrol could affect CYP3A activity.
Non-Antigenic Modulation of Antigen Receptor (TCR) Cβ-FG Loop Modulates Signalling: Implications of External Factors Influencing T-Cell Responses
Authors: Manolios Nicholas , Pham Son , Hou Guojiang , Du Jonathan , Quek Camelia , Hibbs David
Published: May 2023

T-cell recognition of antigens is complex, leading to biochemical and cellular events that impart both specific and targeted immune responses. The end result is an array of cytokines that facilitate the direction and intensity of the immune reaction—such as T-cell proliferation, differentiation, macrophage activation, and B-cell isotype switching—all of which may be necessary and appropriate to eliminate the antigen and induce adaptive immunity. Using in silico docking to identify small molecules that putatively bind to the T-cell Cβ-FG loop, we have shown in vitro using an antigen presentation assay that T-cell signalling is altered. The idea of modulating T-cell signalling independently of antigens by directly targeting the FG loop is novel and warrants further study.
Antifungal Activities of Fluorinated Pyrazole Aldehydes on Phytopathogenic Fungi, and Their Effect on Entomopathogenic Nematodes, and Soil-Beneficial Bacteria
Authors: Rastija Vesna , Vrandečić Karolina , Ćosić Jasenka , Kanižai Šarić Gabriella , Majić Ivana , Agić Dejan , Šubarić Domagoj , Karnaš Maja , Bešlo Drago , Brahmbhatt Harshad , Komar Mario
Published: May 2023

Fluoro-substituted pyrazoles have a wide range of biological activities, such as antibacterial, antiviral, and antifungal activities. The aim of this study was to evaluate the antifungal activities of fluorinated 4,5-dihydro-1H-pyrazole derivatives on four phytopathogenic fungi: Sclerotinia sclerotiorum, Macrophomina phaseolina, Fusarium oxysporum f. sp. lycopersici, and F. culmorum. Moreover, they were tested on two soil beneficial bacteria—Bacillus mycoides and Bradyrhizobium japonicum—as well as two entomopathogenic nematodes (EPNs)—Heterorhabditis bacteriophora and Steinernema feltiae. The molecular docking was performed on the three enzymes responsible for fungal growth, the three plant cell wall-degrading enzymes, and acetylcholinesterase (AChE). The most active compounds against fungi S. sclerotiorum were 2-chlorophenyl derivative (H9) (43.07% of inhibition) and 2,5-dimethoxyphenyl derivative (H7) (42.23% of inhibition), as well as H9 against F. culmorum (46.75% of inhibition). Compounds were shown to be safe for beneficial soil bacteria and nematodes, except for compound H9 on EPN H. bacteriophora (18.75% mortality), which also showed the strongest inhibition against AChE (79.50% of inhibition). The molecular docking study revealed that antifungal activity is possible through the inhibition of proteinase K, and nematicidal activity is possible through the inhibition of AChE. The fluorinated pyrazole aldehydes are promising components of future plant protection products that could be environmentally and toxicologically acceptable.
State-of-the-Art Molecular Oncology in UK
Authors: Sandoughdaran Saleh , Mikropoulos Christos , Boussios Stergios
Published: May 2023

Molecular oncology is a rapidly evolving field that focuses on the genetic and molecular basis of cancer [...]
Fluorene Thiophene α-Cyanostilbene Hexacatenar-Generating LCs with Hexagonal Columnar Phases and Gels with Helical Morphologies as Well as a Light-Emitting LC Display
Authors: Zhao Hongmei , Cheng Xiaohong
Published: May 2023

Two series of novel synthesized hexacatenars, O/n and M/n, containing two thiophene-cyanostilbene units interconnected by central fluorene units (fluorenone or dicyanovinyl fluorene) using a donor–acceptor–acceptor–donor (A–D–A–D–A) rigid core, with three alkoxy chains at each end, can self-assemble into hexagonal columnar mesophases with wide liquid crystal (LC) ranges and aggregate into organogels with flowerlike and helical cylinder morphologies, as revealed via POM, DSC, XRD and SEM investigation. Furthermore, these compounds were observed to emit yellow luminescence in both solution and solid states which can be adopted to manufacture a light-emitting liquid crystal display (LE-LCD) by doping with commercially available nematic LC.
Regulation of Acetylation States by Nutrients in the Inhibition of Vascular Inflammation and Atherosclerosis
Authors: Kang Hyunju
Published: May 2023

Atherosclerosis (AS) is a chronic metabolic disorder and primary cause of cardiovascular diseases, resulting in substantial morbidity and mortality worldwide. Initiated by endothelial cell stimulation, AS is characterized by arterial inflammation, lipid deposition, foam cell formation, and plaque development. Nutrients such as carotenoids, polyphenols, and vitamins can prevent the atherosclerotic process by modulating inflammation and metabolic disorders through the regulation of gene acetylation states mediated with histone deacetylases (HDACs). Nutrients can regulate AS-related epigenetic states via sirtuins (SIRTs) activation, specifically SIRT1 and SIRT3. Nutrient-driven alterations in the redox state and gene modulation in AS progression are linked to their protein deacetylating, anti-inflammatory, and antioxidant properties. Nutrients can also inhibit advanced oxidation protein product formation, reducing arterial intima-media thickness epigenetically. Nonetheless, knowledge gaps remain when it comes to understanding effective AS prevention through epigenetic regulation by nutrients. This work reviews and confirms the underlying mechanisms by which nutrients prevent arterial inflammation and AS, focusing on the epigenetic pathways that modify histones and non-histone proteins by regulating redox and acetylation states through HDACs such as SIRTs. These findings may serve as a foundation for developing potential therapeutic agents to prevent AS and cardiovascular diseases by employing nutrients based on epigenetic regulation.
TCDD-Induced Allosteric Perturbation of the AhR:ARNT Binding to DNA
Authors: Motta Stefano , Bonati Laura
Published: May 2023

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the biological and toxicological effects of structurally diverse chemicals, including halogenated aromatic hydrocarbons. In this work, we investigate the effects of the binding of the AhR prototypical ligand, TCDD, on the stability of the AhR:ARNT complex, as well as the mechanisms by which ligand-induced perturbations propagate to the DNA recognition site responsible for gene transcription. To this aim, a reliable structural model of the overall quaternary structure of the AhR:ARNT:DRE complex is proposed, based on homology modelling. The model shows very good agreement with a previous one and is supported by experimental evidence. Moreover, molecular dynamics simulations are performed to compare the dynamic behaviour of the AhR:ARNT heterodimer in the presence or absence of the TCDD. Analysis of the simulations, performed by an unsupervised machine learning method, shows that TCDD binding to the AhR PASB domain influences the stability of several inter-domain interactions, in particular at the PASA-PASB interface. The inter-domain communication network suggests a mechanism by which TCDD binding allosterically stabilizes the interactions at the DNA recognition site. These findings may have implications for the comprehension of the different toxic outcomes of AhR ligands and drug design.
Targeting the Inflammatory Hallmarks of Obesity-Associated Osteoarthritis: Towards Nutraceutical-Oriented Preventive and Complementary Therapeutic Strategies Based on n-3 Polyunsaturated Fatty Acids
Authors: Gambari Laura , Cellamare Antonella , Grassi Francesco , Grigolo Brunella , Panciera Alessandro , Ruffilli Alberto , Faldini Cesare , Desando Giovanna
Published: May 2023

Obesity (Ob), which has dramatically increased in the last decade, is one of the main risk factors that contribute to the incidence and progression of osteoarthritis (OA). Targeting the characteristics of obesity-associated osteoarthritis (ObOA) may offer new chances for precision medicine strategies in this patient cohort. First, this review outlines how the medical perspective of ObOA has shifted from a focus on biomechanics to the significant contribution of inflammation, mainly mediated by changes in the adipose tissue metabolism through the release of adipokines and the modification of fatty acid (FA) compositions in joint tissues. Preclinical and clinical studies on n-3 polyunsaturated FAs (PUFAs) are critically reviewed to outline the strengths and weaknesses of n-3 PUFAs’ role in alleviating inflammatory, catabolic and painful processes. Emphasis is placed on potential preventive and therapeutic nutritional strategies based on n-3 PUFAs, with a focus on ObOA patients who could specifically benefit from reformulating the dietary composition of FAs towards a protective phenotype. Finally, tissue engineering approaches that involve the delivery of n-3 PUFAs directly into the joint are explored to address the perspectives and current limitations, such as safety and stability issues, for implementing preventive and therapeutic strategies based on dietary compounds in ObOA patients.
The Use of ctDNA in the Diagnosis and Monitoring of Hepatocellular Carcinoma—Literature Review
Authors: Kopystecka Agnieszka , Patryn Rafał , Leśniewska Magdalena , Budzyńska Julia , Kozioł Ilona
Published: May 2023

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is one of the leading causes of cancer-related deaths worldwide. Despite advances in medicine, it is still a cancer with a very poor prognosis. Both imaging and liver biopsy still have important limitations, especially in very small nodules and those which show atypical imaging features. In recent years, liquid biopsy and molecular analysis of tumor breakdown products have become an attractive source of new biomarkers. Patients with liver and biliary malignancies, including hepatocellular carcinoma (HCC), may greatly benefit from ctDNA testing. These patients are often diagnosed at an advanced stage of the disease, and relapses are common. Molecular analysis may indicate the best cancer treatment tailored to particular patients with specific tumor DNA mutations. Liquid biopsy is a minimally invasive technique that facilitates the early detection of cancer. This review summarizes the knowledge of ctDNA in liquid biopsy as an indicator for early diagnosis and monitoring of hepatocellular cancer.
VE-Cadherin in Cancer-Associated Angiogenesis: A Deceptive Strategy of Blood Vessel Formation
Authors: Delgado-Bellido Daniel , Oliver F. J. , Vargas Padilla María Victoria , Lobo-Selma Laura , Chacón-Barrado Antonio , Díaz-Martin Juan , de Álava Enrique
Published: May 2023

Tumor growth depends on the vascular system, either through the expansion of blood vessels or novel adaptation by tumor cells. One of these novel pathways is vasculogenic mimicry (VM), which is defined as a tumor-provided vascular system apart from endothelial cell-lined vessels, and its origin is partly unknown. It involves highly aggressive tumor cells expressing endothelial cell markers that line the tumor irrigation. VM has been correlated with high tumor grade, cancer cell invasion, cancer cell metastasis, and reduced survival of cancer patients. In this review, we summarize the most relevant studies in the field of angiogenesis and cover the various aspects and functionality of aberrant angiogenesis by tumor cells. We also discuss the intracellular signaling mechanisms involved in the abnormal presence of VE-cadherin (CDH5) and its role in VM formation. Finally, we present the implications for the paradigm of tumor angiogenesis and how targeted therapy and individualized studies can be applied in scientific analysis and clinical settings.