bluuebunny/crossref_metadata_2025 huggingface dataset:
Photosystem I: A Paradigm for Understanding Biological Environmental Adaptation Mechanisms in Cyanobacteria and Algae
Authors: Tian Li-Rong , Chen Jing-Hua
Published: August 2024

The process of oxygenic photosynthesis is primarily driven by two multiprotein complexes known as photosystem II (PSII) and photosystem I (PSI). PSII facilitates the light-induced reactions of water-splitting and plastoquinone reduction, while PSI functions as the light-driven plastocyanin-ferredoxin oxidoreductase. In contrast to the highly conserved structure of PSII among all oxygen-evolving photosynthetic organisms, the structures of PSI exhibit remarkable variations, especially for photosynthetic organisms that grow in special environments. In this review, we make a concise overview of the recent investigations of PSI from photosynthetic microorganisms including prokaryotic cyanobacteria and eukaryotic algae from the perspective of structural biology. All known PSI complexes contain a highly conserved heterodimeric core; however, their pigment compositions and peripheral light-harvesting proteins are substantially flexible. This structural plasticity of PSI reveals the dynamic adaptation to environmental changes for photosynthetic organisms.
Effects of Ginsenoside Rb1 on the Crosstalk between Intestinal Stem Cells and Microbiota in a Simulated Weightlessness Mouse Model
Authors: Zong Beibei , Wang Jingyi , Wang Kai , Hao Jie , Han Jing-Yan , Jin Rong , Ge Qing
Published: August 2024

Exposure to the space microenvironment has been found to disrupt the homeostasis of intestinal epithelial cells and alter the composition of the microbiota. To investigate this in more detail and to examine the impact of ginsenoside Rb1, we utilized a mouse model of hindlimb unloading (HU) for four weeks to simulate the effects of microgravity. Our findings revealed that HU mice had ileum epithelial injury with a decrease in the number of intestinal stem cells (ISCs) and the level of cell proliferation. The niche functions for ISCs were also impaired in HU mice, including a reduction in Paneth cells and Wnt signaling, along with an increase in oxidative stress. The administration of Rb1 during the entire duration of HU alleviated the observed intestinal defects, suggesting its beneficial influence on epithelial cell homeostasis. Hindlimb unloading also resulted in gut dysbiosis. The supplementation of Rb1 in the HU mice or the addition of Rb1 derivative compound K in bacterial culture in vitro promoted the growth of beneficial probiotic species such as Akkermansia. The co-housing experiment further showed that Rb1 treatment in ground control mice alone could alleviate the defects in HU mice that were co-housed with Rb1-treated ground mice. Together, these results underscore a close relationship between dysbiosis and impaired ISC functions in the HU mouse model. It also highlights the beneficial effects of Rb1 in mitigating HU-induced epithelial injury by promoting the expansion of intestinal probiotics. These animal-based insights provide valuable knowledge for the development of improved approaches to maintaining ISC homeostasis in astronauts.
Indoxyl Sulfate Inhibits Osteogenesis in Bone Marrow Mesenchymal Stem Cells through the AhR/Hes1 Pathway
Authors: Hsieh Chin-Wen , Chang Ling-Hua , Wang Yan-Hsiung , Li Wei-Ting , Chang Je-Ken , Chen Chung-Hwan , Ho Mei-Ling
Published: August 2024

Uremic toxins cause bone disorders in patients with chronic kidney disease (CKD). These disorders are characterized by low turnover osteodystrophy and impaired bone formation in the early stages of CKD. Evidence indicates that the aryl hydrocarbon receptor (AhR) mediates signals that suppress early osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs). However, whether the AhR mediates the effects of indoxyl sulfate (IS), a uremic toxin, on BMSC osteogenesis remains unclear. We investigated whether IS affects osteogenesis through the AhR/Hes1 pathway. Expression levels of osteogenesis genes (Runx2, Bmp2, Alp, and Oc), AhR, and Hes1 were measured in mouse BMSCs (D1 cells). At concentrations of 2–50 μM, IS significantly reduced mineralization, particularly in the early stages of BMSC osteogenesis. Furthermore, IS significantly downregulated the expression of Runx2, Bmp2, Oc, and Alp. Notably, this downregulation could be prevented using an AhR antagonist and through Ahr knockdown. Mechanistically, IS induced the expression of Hes1 through AhR signaling, thereby suppressing the transcription of Runx2 and Bmp2. Our findings suggest that IS inhibits early osteogenesis of BMSCs through the AhR/Hes1 pathway, thus suppressing the transcription of Runx2 and Bmp2. Our findings may guide new therapeutic strategies against CKD-related bone disorders.
The Use of Photodynamic Therapy in the Treatment of Endometrial Cancer—A Review of the Literature
Authors: Żołyniak-Brzuchacz Aleksandra , Barnaś Edyta , Bartusik-Aebisher Dorota , Aebisher David
Published: August 2024

Endometrial cancer is the most common malignant tumor of the female reproductive system. It develops in the mucous membrane lining the inside of the uterine body—the endometrium, through the abnormal and continuous growth of cancer cells originating from the uterine mucosa. In recent years, there has been a significant increase in the number of cases in European countries. Photodynamic therapy (PDT) is an innovative and dynamically developing medical procedure, useful in the treatment of cancer and non-cancer tissue conditions. The PDT reaction involves the activation of a photosensitizing substance with visible light, which in turn leads to the formation of free oxygen radicals, which contribute to the destruction of the cell. PDT is minimally invasive, has few side effects, and preserves organ anatomy and function. Both diagnostics and photodynamic therapy as modern methods of treatment are becoming more and more popular in many research units around the world. They are most often practiced and tested in in vitro experimental conditions. In clinical practice, the use of PDT is rare. Comprehensive cooperation between scientists contributes to taking steps towards obtaining new, synthetic photosensitizers, directing their physicochemical properties, and showing the impact on a given organism. This review examines the evidence for the potential and usefulness of PDT in the treatment of endometrial cancer. This review highlights that PDT is gaining popularity and is becoming a promising field of medical research.
The Wdr5-H3K4me3 Epigenetic Axis Regulates Pancreatic Tumor Immunogenicity and Immune Suppression
Authors: Deng Kaidi , Liang Liyan , Yang Yingcui , Wu Yanmin , Li Yan , Zhang Rongrong , Tian Yulin , Lu Chunwan
Published: August 2024

The WDR5/MLL1-H3K4me3 epigenetic axis is often activated in both tumor cells and tumor-infiltrating immune cells to drive various cellular responses in the tumor microenvironment and has been extensively studied in hematopoietic cancer, but its respective functions in tumor cells and immune cells in the context of tumor growth regulation of solid tumor is still incompletely understood. We report here that WDR5 exhibits a higher expression level in human pancreatic tumor tissues compared with adjacent normal pancreas. Moreover, WDR5 expression is negatively correlated with patients’ response to chemotherapy or immunotherapy in human colon cancer and melanoma. However, WDR5 expression is positively correlated with the HLA level in human cancer cells, and H3K4me3 enrichment is observed at the promoter region of the HLA-A, HLA-B, and HLA-C genes in pancreatic cancer cells. Using mouse tumor cell lines and in vivo tumor models, we determined that WDR5 deficiency or inhibition significantly represses MHC I expression in vitro and in vivo in pancreatic tumor cells. Mechanistically, we determine that WDR5 deficiency inhibits H3K4me3 deposition at the MHC I (H2K) promoter region to repress MHC I (H2K) transcription. On the other hand, WDR5 depletion leads to the effective downregulation of immune checkpoints and immunosuppressive cytokines, including TGFβ and IL6, in the pancreatic tumor microenvironments. Our data determine that WDR5 not only regulates tumor cell immunogenicity to suppress tumor growth but also activates immune suppressive pathways to promote tumor immune evasion. Selective activation of the WDR5-MHC I pathway and/or selective inhibition of the WDR5–immune checkpoint and WDR5–cytokine pathways should be considered in WDR5-based epigenetic cancer immunotherapy.
Threshold Interphase Delay for Bipolar Pulses to Prevent Cancellation Phenomenon during Electrochemotherapy
Authors: Malyško-Ptašinskė Veronika , Nemeikaitė-Čėnienė Aušra , Radzevičiūtė-Valčiukė Eivina , Mickevičiūtė Eglė , Malakauskaitė Paulina , Lekešytė Barbora , Novickij Vitalij
Published: August 2024

Electroporation-based procedures employing nanosecond bipolar pulses are commonly linked to an undesirable phenomenon known as the cancelation effect. The cancellation effect arises when the second pulse partially or completely neutralizes the effects of the first pulse, simultaneously diminishing cells’ plasma membrane permeabilization and the overall efficiency of the procedure. Introducing a temporal gap between the positive and negative phases of the bipolar pulses during electroporation procedures may help to overcome the cancellation phenomenon; however, the exact thresholds are not yet known. Therefore, in this work, we have tested the influence of different interphase delay values (from 0 ms to 95 ms) using symmetric bipolar nanoseconds (300 and 500 ns) on cell permeabilization using 10 Hz, 100 Hz, and 1 kHz protocols. As a model mouse hepatoma, the MH-22a cell line was employed. Additionally, we conducted in vitro electrochemotherapy with cisplatin, employing reduced interphase delay values (0 ms and 0.1 ms) at 10 Hz. Cell plasma membrane permeabilization and viability dependence on a variety of bipolar pulsed electric field protocols were characterized. It was shown that it is possible to minimize bipolar cancellation, enabling treatment efficiency comparable to monophasic pulses with identical parameters. At the same time, it was highlighted that bipolar cancellation has a significant influence on permeabilization, while the effects on the outcome of electrochemotherapy are minimal.
Intrapleural Fibrinolytic Interventions for Retained Hemothoraces in Rabbits
Authors: De Vera Christian J. , Jacob Jincy , Sarva Krishna , Christudas Sunil , Emerine Rebekah L. , Florence Jon M. , Akiode Oluwaseyi , Gorthy Tanvi V. , Tucker Torry A. , Singh Karan P. , Azghani Ali O. , Komissarov Andrey A. , Florova Galina , Idell Steven
Published: August 2024

Bleeding within the pleural space may result in persistent clot formation called retained hemothorax (RH). RH is prone to organization, which compromises effective drainage, leading to lung restriction and dyspnea. Intrapleural fibrinolytic therapy is used to clear the persistent organizing clot in lieu of surgery, but fibrinolysin selection, delivery strategies, and dosing have yet to be identified. We used a recently established rabbit model of RH to test whether intrapleural delivery of single-chain urokinase (scuPA) can most effectively clear RH. scuPA, or single-chain tissue plasminogen activator (sctPA), was delivered via thoracostomy tube on day 7 as either one or two doses 8 h apart. Pleural clot dissolution was assessed using transthoracic ultrasonography, chest computed tomography, two-dimensional and clot displacement measurements, and gross analysis. Two doses of scuPA (1 mg/kg) were more effective than a bolus dose of 2 mg/kg in resolving RH and facilitating drainage of pleural fluids (PF). Red blood cell counts in the PF of scuPA, or sctPA-treated rabbits were comparable, and no gross intrapleural hemorrhage was observed. Both fibrinolysins were equally effective in clearing clots and promoting pleural drainage. Biomarkers of inflammation and organization were likewise comparable in PF from both groups. The findings suggest that single-agent therapy may be effective in clearing RH; however, the clinical advantage of intrapleural scuPA remains to be established by future clinical trials.
Construction and Stability of All-in-One Adenovirus Vectors Simultaneously Expressing Four and Eight Multiplex Guide RNAs and Cas9 Nickase
Authors: Nakahara Tomomi , Tabata Hirotaka , Kato Yuya , Fuse Ryoko , Nakamura Mariko , Yamaji Megumi , Hattori Nobutaka , Kiyono Tohru , Saito Izumu , Nakanishi Tomoko
Published: August 2024

CRISPR/Cas9 technology is expected to offer novel genome editing-related therapies for various diseases. We previously showed that an adenovirus vector (AdV) possessing eight expression units of multiplex guide RNAs (gRNAs) was obtained with no deletion of these units. Here, we attempted to construct “all-in-one” AdVs possessing expression units of four and eight gRNAs with Cas9 nickase, although we expected obstacles to obtain complete all-in-one AdVs. The first expected obstacle was that extremely high copies of viral genomes during replication may cause severe off-target cleavages of host cells and induce homologous recombination. However, surprisingly, four units in the all-in-one AdV genome were maintained completely intact. Second, for the all-in-one AdV containing eight gRNA units, we enlarged the E3 deletion in the vector backbone and shortened the U6 promoter of the gRNA expression units to shorten the AdV genome within the adenovirus packaging limits. The final size of the all-in-one AdV genome containing eight gRNA units still slightly exceeded the reported upper limit. Nevertheless, approximately one-third of the eight units remained intact, even upon preparation for in vivo experiments. Third, the genome editing efficiency unexpectedly decreased upon enlarging the E3 deletion. Our results suggested that complete all-in-one AdVs containing four gRNA units could be obtained if the problem of the low genome editing efficiency is solved, and those containing even eight gRNA units could be obtained if the obstacle of the vector size is also removed.
Increased Pan-Type, A1-Type, and A2-Type Astrocyte Activation and Upstream Inflammatory Markers Are Induced by the P2X7 Receptor
Authors: Campagno Keith E. , Sripinun Puttipong , See Lily P. , Li Jiaqi , Lu Wennan , Jassim Assraa Hassan , Más Gómez Néstor , Mitchell Claire H.
Published: August 2024

This study asked whether the P2X7 receptor was necessary and sufficient to trigger astrocyte polarization into neuroinflammatory activation states. Intravitreal injection of agonist BzATP increased gene expression of pan-astrocyte activation markers Gfap, Steap4, and Vim and A1-type astrocyte activation markers C3, Serping1, and H2T23, but also the Cd14 and Ptx3 genes usually associated with the A2-type astrocyte activation state and Tnfa, IL1a, and C1qa, assumed to be upstream of astrocyte activation in microglia. Correlation analysis of gene expression suggested the P2X7 receptor induced a mixed A1/A2-astrocyte activation state, although A1-state genes like C3 increased the most. A similar pattern of mixed glial activation genes occurred one day after intraocular pressure (IOP) was elevated in wild-type mice, but not in P2X7-/- mice, suggesting the P2X7 receptor is necessary for the glial activation that accompanies IOP elevation. In summary, this study suggests stimulation of the P2X7R is necessary and sufficient to trigger the astrocyte activation in the retina following IOP elevation, with a rise in markers for pan-, A1-, and A2-type astrocyte activation. The P2X7 receptor is expressed on microglia, optic nerve head astrocytes, and retinal ganglion cells (RGCs) in the retina, and can be stimulated by the mechanosensitive release of ATP that accompanies IOP elevation. Whether the P2X7 receptor connects this mechanosensitive ATP release to microglial and astrocyte polarization in glaucoma remains to be determined.
Correction: Russo et al. Involvement of Bax and Bcl-2 in Induction of Apoptosis by Essential Oils of Three Lebanese Salvia Species in Human Prostate Cancer Cells. Int. J. Mol. Sci. 2018, 19, 292
Authors: Russo Alessandra , Cardile Venera , Graziano Adriana C. E. , Avola Rosanna , Bruno Maurizio , Rigano Daniela
Published: August 2024

In the original publication [...]
Embryonic Lethal Phenotyping to Identify Candidate Genes Related with Birth Defects
Authors: Yan Bing , Gong Baoming , Wang Xue , Zheng Yufang , Sun Lei , Wu Xiaohui
Published: August 2024

Congenital birth defects contribute significantly to preterm birth, stillbirth, perinatal death, infant mortality, and adult disability. As a first step to exploring the mechanisms underlying this major clinical challenge, we analyzed the embryonic phenotypes of lethal strains generated by random mutagenesis. In this study, we report the gross embryonic and perinatal phenotypes of 55 lethal strains randomly picked from a collection of mutants that carry piggyBac (PB) transposon inserts. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested most of the analyzed mutations hit genes involved in heart and nervous development, or in Notch and Wnt signaling. Among them, 12 loci are known to be associated with human diseases. We confirmed 53 strains as embryonic or perinatal lethal, while others were subviable. Gross morphological phenotypes such as body size abnormality (29/55, 52.73%), growth or developmental delay (35/55, 63.64%), brain defects (9/55, 16.36%), vascular/heart development (31/55, 56.36%), and other structural defects (9/55, 16.36%) could be easily observed in the mutants, while three strains showed phenotypes similar to those of human patients. Furthermore, we detected body weight or body composition alterations in the heterozygotes of eight strains. One of them was the TGF-β signaling gene Smad2. The heterozygotes showed increased energy expenditure and a lower fat-to-body weight ratio compared to wild-type mice. This study provided new insights into mammalian embryonic development and will help understand the pathology of congenital birth defects in humans. In addition, it expanded our understanding of the etiology of obesity.
Phytochemicals in Drug Discovery—A Confluence of Tradition and Innovation
Authors: Chihomvu Patience , Ganesan A. , Gibbons Simon , Woollard Kevin , Hayes Martin A.
Published: August 2024

Phytochemicals have a long and successful history in drug discovery. With recent advancements in analytical techniques and methodologies, discovering bioactive leads from natural compounds has become easier. Computational techniques like molecular docking, QSAR modelling and machine learning, and network pharmacology are among the most promising new tools that allow researchers to make predictions concerning natural products’ potential targets, thereby guiding experimental validation efforts. Additionally, approaches like LC-MS or LC-NMR speed up compound identification by streamlining analytical processes. Integrating structural and computational biology aids in lead identification, thus providing invaluable information to understand how phytochemicals interact with potential targets in the body. An emerging computational approach is machine learning involving QSAR modelling and deep neural networks that interrelate phytochemical properties with diverse physiological activities such as antimicrobial or anticancer effects.
C-C Motif Chemokine Ligand 2 and Chemokine Receptor 2 in Cardiovascular and Neural Aging and Aging-Related Diseases
Authors: Guo David , Zhu Wuqiang , Qiu Hongyu
Published: August 2024

Aging is a prominent risk factor for numerous chronic diseases. Understanding the shared mechanisms of aging can aid in pinpointing therapeutic targets for age-related disorders. Chronic inflammation has emerged as a pivotal mediator of aging and a determinant in various age-related chronic conditions. Recent findings indicate that C-C motif chemokine ligand 2 and receptor 2 (CCL2-CCR2) signaling, an important physiological modulator in innate immune response and inflammatory defense, plays a crucial role in aging-related disorders and is increasingly recognized as a promising therapeutic target, highlighting its significance. This review summarizes recent advances in the investigation of CCL2-CCR2 signaling in cardiovascular and neural aging, as well as in various aging-related disorders. It also explores the underlying mechanisms and therapeutic potentials in these contexts. These insights aim to deepen our understanding of aging pathophysiology and the development of aging-related diseases.
Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review
Authors: Cao Yuan , Zhang Ding-Ding , Han Fei , Jiang Nan , Yao Ming , Zhu Yi-Cheng
Published: August 2024

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines. The pathogenic role of cysteine-sparing NOTCH3 mutations with typical clinical CADASIL syndrome is still debated. This review aimed to characterize NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL. Articles on NOTCH3 cysteine-sparing mutations with clinical suspicion of CADASIL were reviewed. Clinical and radiological cerebral phenotypes data were extracted and characterized across regions and compared with phenotypes of typical CADASIL patients. We screened 298 NOTCH3 cysteine-sparing mutation individuals from 20 publications, and mutations in exon 3 were the most frequently reported (21.46%). Gait impairment (76.47%), cognitive impairment (67.47%), and stroke (62.37%) were the three most common clinical phenotypes; the most frequent radiological cerebral phenotypes were lacunes (74.29%) and cerebral microbleeds (72.73%). Compared with CADASIL patients, cognitive impairment and cerebral microbleed frequencies were significantly higher in patients with NOTCH3 cysteine-sparing mutations, while the white matter hyperintensities in anterior temporal polar and external capsule were rarely observed. Compared with Western patients, radiological phenotypes were more common than clinical phenotypes in cysteine-sparing Asian patients. More than half of cysteine-sparing patients had positive granular osmiophilic material deposits. NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL mainly manifested with gait and cognitive impairment but rare white matter hyperintensities in anterior temporal pole and external capsule. Further studies are warranted to pay attention to atypical NOTCH3 variants, which could guide specific diagnosis and help unravel underlying mechanisms.
Candidate Signature miRNAs from Secreted miRNAome of Human Lung Microvascular Endothelial Cells in Response to Different Oxygen Conditions: A Pilot Study
Authors: Schaubmayr Wolfgang , Hackl Matthias , Pultar Marianne , Ghanim Bahil D. , Klein Klaus U. , Schmid Johannes A. , Mohr Thomas , Tretter Verena
Published: August 2024

Oxygen conditions in the lung determine downstream organ functionality by setting the partial pressure of oxygen, regulating the redox homeostasis and by activating mediators in the lung that can be propagated in the blood stream. Examples for such mediators are secreted soluble or vesicle-bound molecules (proteins and nucleic acids) that can be taken up by remote target cells impacting their metabolism and signaling pathways. MicroRNAs (miRNAs) have gained significant interest as intercellular communicators, biomarkers and therapeutic targets in this context. Due to their high stability in the blood stream, they have also been attributed a role as “memory molecules” that are able to modulate gene expression upon repeated (stress) exposures. In this study, we aimed to identify and quantify released miRNAs from lung microvascular endothelial cells in response to different oxygen conditions. We combined next-generation sequencing (NGS) of secreted miRNAs and cellular mRNA sequencing with bioinformatic analyses in order to delineate molecular events on the cellular and extracellular level and their putative interdependence. We show that the identified miRNA networks have the potential to co-mediate some of the molecular events, that have been observed in the context of hypoxia, hyperoxia, intermittent hypoxia and intermittent hypoxia/hyperoxia.
Inhibition of Ionic Currents by Fluoxetine in Vestibular Calyces in Different Epithelial Loci
Authors: Mohamed Nesrien M. M. , Meredith Frances L. , Rennie Katherine J.
Published: August 2024

Previous studies have suggested a role for selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac®) in the treatment of dizziness and inner ear vestibular dysfunction. The potential mechanism of action within the vestibular system remains unclear; however, fluoxetine has been reported to block certain types of K+ channel in other systems. Here, we investigated the direct actions of fluoxetine on membrane currents in presynaptic hair cells and postsynaptic calyx afferents of the gerbil peripheral vestibular system using whole cell patch clamp recordings in crista slices. We explored differences in K+ currents in peripheral zone (PZ) and central zone (CZ) calyces of the crista and their response to fluoxetine application. Outward K+ currents in PZ calyces showed greater inactivation at depolarized membrane potentials compared to CZ calyces. The application of 100 μM fluoxetine notably reduced K+ currents in calyx terminals within both zones of the crista, and the remaining currents exhibited distinct traits. In PZ cells, fluoxetine inhibited a non-inactivating K+ current and revealed a rapidly activating and inactivating K+ current, which was sensitive to blocking by 4-aminopyridine. This was in contrast to CZ calyces, where low-voltage-activated and non-inactivating K+ currents persisted following application of 100 μM fluoxetine. Additionally, marked inhibition of transient inward Na+ currents by fluoxetine was observed in calyces from both crista zones. Different concentrations of fluoxetine were tested, and the EC50 values were found to be 40 µM and 32 µM for K+ and Na+ currents, respectively. In contrast, 100 μM fluoxetine had no impact on voltage-dependent K+ currents in mechanosensory type I and type II vestibular hair cells. In summary, micromolar concentrations of fluoxetine are expected to strongly reduce both Na+ and K+ conductance in afferent neurons of the peripheral vestibular system in vivo. This would lead to inhibition of action potential firing in vestibular sensory neurons and has therapeutic implications for disorders of balance.
Molecular Characteristics of the Malate Dehydrogenase (MDH) Gene Family in Spirometra mansoni (Cestoda: Diphyllobothriidea)
Authors: Wang Ruijie , Hao Jie , Cao Chengyue , Li Jing , Zhang Xi
Published: August 2024

The plerocercoid larva of Spirometra mansoni can cause a parasitic zoonosis—sparganosis. Malate dehydrogenase (MDH) plays a very important role in the life activities of parasites. However, little is known about the MDH family in S. mansoni. We identified eight new MDH members in S. mansoni in this study. Clustering analysis divided SmMDHs into two groups and revealed patterns similar to the conserved motif organization. RT–qPCR suggested that five MDHs were highly expressed in the mature proglottid and that three MDHs were highly expressed in the gravid proglottid. Phylogenetic analysis revealed that SmMDHs contain both conserved family members and members in the process of further diversification. rSmMDH has an NAD binding domain, a dimer interface and a substrate binding domain. Natural SmMDH was immunolocalized in the tissues and follicles around the uterus in the mature or gravid proglottid and eggshells. The maximum forward and reverse reaction activities of rSmMDH were observed at pH 8.5 and 9.0, respectively. The optimum temperature for enzyme activity was 37 °C in the forward reaction and 40 °C in the reverse reaction. These results lay the foundation for studying the molecular functions and mechanisms of MDHs in S. mansoni and related taxa.
Protein Fold Usages in Ribosomes: Another Glance to the Past
Authors: Tanoz Inzhu , Timsit Youri
Published: August 2024

The analysis of protein fold usage, similar to codon usage, offers profound insights into the evolution of biological systems and the origins of modern proteomes. While previous studies have examined fold distribution in modern genomes, our study focuses on the comparative distribution and usage of protein folds in ribosomes across bacteria, archaea, and eukaryotes. We identify the prevalence of certain ‘super-ribosome folds,’ such as the OB fold in bacteria and the SH3 domain in archaea and eukaryotes. The observed protein fold distribution in the ribosomes announces the future power-law distribution where only a few folds are highly prevalent, and most are rare. Additionally, we highlight the presence of three copies of proto-Rossmann folds in ribosomes across all kingdoms, showing its ancient and fundamental role in ribosomal structure and function. Our study also explores early mechanisms of molecular convergence, where different protein folds bind equivalent ribosomal RNA structures in ribosomes across different kingdoms. This comparative analysis enhances our understanding of ribosomal evolution, particularly the distinct evolutionary paths of the large and small subunits, and underscores the complex interplay between RNA and protein components in the transition from the RNA world to modern cellular life. Transcending the concept of folds also makes it possible to group a large number of ribosomal proteins into five categories of urfolds or metafolds, which could attest to their ancestral character and common origins. This work also demonstrates that the gradual acquisition of extensions by simple but ordered folds constitutes an inexorable evolutionary mechanism. This observation supports the idea that simple but structured ribosomal proteins preceded the development of their disordered extensions.
Long Non-Coding RNAs and Their Potential Role as Biomarkers in Inflammatory Bowel Disease
Authors: Ortega Moreno Lorena , Chaparro María , Gisbert Javier P.
Published: August 2024

Inflammatory bowel disease is a chronic inflammatory disease that encompasses entities such as Crohn’s disease and ulcerative colitis. Its incidence has risen in newly industrialised countries over time, turning it into a global disease. Lately, studies on inflammatory bowel disease have focused on finding non-invasive and specific biomarkers. Long non-coding RNAs may play a role in the pathophysiology of inflammatory bowel disease and therefore they may be considered as potential biomarkers for this disease. In the present article, we review information in the literature on the relationship between long non-coding RNAs and inflammatory bowel disease. We especially focus on understanding the potential function of these RNAs as non-invasive biomarkers, providing information that may be helpful for future studies in the field.
Effects of SGLT2-Inhibitors on Comprehensive Geriatric Assessment, Biomarkers of Oxidative Stress, and Platelet Activation in Elderly Diabetic Patients with Heart Failure with Preserved Ejection Fraction
Authors: Magurno Marcello , Cassano Velia , Maruca Francesco , Pastura Carlo Alberto , Divino Marcello , Fazio Federica , Severini Giandomenico , Clausi Elvira , Armentaro Giuseppe , Miceli Sofia , Maio Raffaele , Imbalzano Egidio , Andreozzi Francesco , Hribal Marta Letizia , Sciacqua Angela
Published: August 2024

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major comorbidity in the elderly and is associated with cognitive impairment (CoI) and type 2 diabetes mellitus (T2DM). In this context, there is an increase in oxidative stress and platelet activation biomarkers. The aim of this study was to evaluate the effects of 6 months’ treatment with SGLT2i on functional, mood-related, and cognitive aspects, assessed by performing a comprehensive geriatric assessment (CGA), and on oxidative stress and platelet activation biomarkers, in a cohort of HFpEF elderly patients with T2DM. We recruited 150 elderly outpatients (mean age 75.8 ± 7.4 years). Results: At six-month follow-up, there was a significant improvement in MMSE (p < 0.0001), MoCA (p < 0.0001), GDS score (p < 0.0001), and SPPB (p < 0.0001). Moreover, we observed a significant reduction in Nox-2 (p < 0.0001), 8-Isoprostane (p < 0.0001), Sp-Selectin (p < 0.0001), and Gp-VI (p < 0.0001). Considering ΔMMSE as the dependent variable, ΔE/e’, ΔNox-2, ΔHOMA, Δ8-Isoprostane, and ΔUricemia were associated for 59.6% with ΔMMSE. When ΔMoCA was considered as the dependent variable, ΔHOMA, ΔE/e’, Δ8-Isoprostane, ΔNox-2 and ΔUricemia were associated for 59.2%. Considering ΔGDS as the dependent variable, ΔHOMA, ΔNox-2, Δ8-Isoprostane, and ΔUricemia were associated with 41.6% of ΔGDS variation. Finally, ΔHOMA was the main predictor of ΔSPPB, which was associated with 21.3% with ΔSPPB, Δ8-Isoprostane, ΔNox-2, ΔE/e’, and ΔUricemia added another 24.1%. Conclusion: The use of SGLT2i in elderly patients with T2DM and HFpEF significantly contributes to improving CGA scales and biomarkers of OS and PA.
Hypoxic Cardioprotection by New Antihypertensive Compounds in High Salt-Diet Hypertensive Rats: Glucose Transport Participation and Its Possible Pathway
Authors: Hernández-Serda Manuel A. , Alarcón-López Aldo Y. , Vázquez-Valadez Víctor H. , Briseño-Lugo Paola , Martínez-Soriano Pablo A. , Leguízamo Viridiana , Torres Nalleli , González-Terán Rodrigo , Cárdenas-Granados Luis A. , Sánchez Muñoz Fausto , Rodríguez Emma , Lerma Claudia , Zúñiga Muñoz Alejandra María , Ángeles Enrique , Carbó Roxana
Published: August 2024

Hypertension (HP) is a health condition that overloads the heart and increases the risk of heart attack and stroke. In an infarction, the lack of oxygen causes an exclusive use of glycolysis, which becomes a crucial source of ATP for the heart with a higher glucose uptake mediated by glucose transporters (GLUTs). Due to the unpleasant effects of antihypertensives, new drugs need to be researched to treat this disease. This study aimed to evaluate the cardioprotective effect of three novel antihypertensive compounds (LQMs, “Laboratorio de Química Medicinal”) synthesized from Changrolin under hypoxic conditions with the participation of two primary cardiac GLUT1 and GLUT4 using a high-salt diet HP model. The model used a diet with 10% salt to increase arterial blood pressure in Wistar rats. In isolated cardiomyocytes from these rats, glucose uptake was measured during hypoxia, evaluating the participation of GLUTs with or without the animals’ previous treatment with LQM312, 319, and 345 compounds. In silico calculations were performed to understand the affinity of the compounds for the trafficking of GLUTs. Results: Control cells do shift to glucose uptake exclusively in hypoxia (from 1.84 ± 0.09 µg/g/h to 2.67 ± 0.1 µg/g/h). Meanwhile, HP does not change its glucose uptake (from 2.38 ± 0.24 µg/g/h to 2.33 ± 0.26 µg/g/h), which is associated with cardiomyocyte damage. The new compounds lowered the systolic blood pressure (from 149 to 120 mmHg), but only LQM312 and LQM319 improved the metabolic state of hypoxic cardiomyocytes mediated by GLUT1 and GLUT4. In silico studies suggested that Captopril and LQM312 may mimic the interaction with the AMPK γ-subunit. Therefore, these compounds could activate AMPK, promoting the GLUT4 trafficking signaling pathway. These compounds are proposed to be cardioprotective during hypoxia under HP.
Is Exon Skipping a Viable Therapeutic Approach for Vascular Ehlers–Danlos Syndrome with Mutations in COL3A1 Exon 10 or 15?
Authors: Utama Sasiwimon , Cale Jessica M. , Mitrpant Chalermchai , Fletcher Sue , Wilton Steve D. , Aung-Htut May T.
Published: August 2024

Vascular Ehlers–Danlos syndrome or Ehlers–Danlos syndrome type IV (vEDS) is a connective tissue disorder characterised by skin hyperextensibility, joint hypermobility and fatal vascular rupture caused by COL3A1 mutations that affect collagen III expression, homo-trimer assembly and secretion. Along with collagens I, II, V and XI, collagen III plays an important role in the extracellular matrix, particularly in the inner organs. To date, only symptomatic treatment for vEDS patients is available. Fibroblasts derived from vEDS patients carrying dominant negative and/or haploinsufficiency mutations in COL3A1 deposit reduced collagen III in the extracellular matrix. This study explored the potential of an antisense oligonucleotide (ASO)-mediated splice modulating strategy to bypass disease-causing COL3A1 mutations reported in the in-frame exons 10 and 15. Antisense oligonucleotides designed to redirect COL3A1 pre-mRNA processing and excise exons 10 or 15 were transfected into dermal fibroblasts derived from vEDS patients and a healthy control subject. Efficient exon 10 or 15 excision from the mature COL3A1 mRNA was achieved and intracellular collagen III expression was increased after treatment with ASOs; however, collagen III deposition into the extracellular matrix was reduced in patient cells. The region encoded by exon 10 includes a glycosylation site, and exon 15 encodes hydroxyproline and hydroxylysine-containing triplet repeats, predicted to be crucial for collagen III assembly. These results emphasize the importance of post-translational modification for collagen III homo-trimer assembly. In conclusion, while efficient skipping of target COL3A1 exons was achieved, the induced collagen III isoforms generated showed defects in extracellular matrix formation. While therapeutic ASO-mediated exon skipping is not indicated for the patients in this study, the observations are restricted to exons 10 and 15 and may not be applicable to other collagen III in-frame exons.
BIO 300 Attenuates Whole Blood Transcriptome Changes in Mice Exposed to Total-Body Radiation
Authors: Serebrenik Artur A. , Fatanmi Oluseyi O. , Wise Stephen Y. , Petrus Sarah A. , Kaytor Michael D. , Singh Vijay K.
Published: August 2024

Development of radiation medical countermeasures under the U.S. Food and Drug Administration Animal Rule requires the capability to translate an effective animal-to-human drug dose. One method of human dose translation is using a biomarker and determining drug doses that modulate the biomarker to the desired level. BIO 300 Oral Powder (BIO 300) is a prophylactic radiation medical countermeasure that is currently being developed following the Animal Rule. The present study aimed to identify biomarkers that can be used for human dose conversion by conducting transcriptomics of whole blood collected from BIO 300-treated CD2F1 mice in the presence and absence of total-body irradiation (TBI). Unirradiated mice were treated with vehicle or 50, 100, or 200 mg/kg BIO 300, and irradiated mice were treated with 200 mg/kg or BIO 300 or vehicle prior to TBI. Whole-blood samples were collected after the last dose of the drug and after irradiation. RNA sequencing demonstrated 100 and 200 mg/kg of BIO 300 doses caused significantly more differential gene expression at 48 h after drug dose compared to 50 mg/kg of BIO 300 (7648, 7680, and 55 significantly differently expressed genes, respectively). Interestingly, following TBI, there were no significantly differentially expressed genes between vehicle- and BIO 300-treated mice. Despite the lack of significant changes in gene expression, the transcriptomic profiles in both groups indicated differential changes in signaling pathways. Pathway analysis of the transcriptome profile from vehicle-treated/TBI mice revealed that many inflammatory signaling pathways were activated in these animals. Signaling pathways enriched in BIO 300-treated/TBI mice were involved in cellular stress and immune response and were predicted to be inhibited. In all, four signaling pathways of interest were identified that were differentially enriched in irradiated animals treated with BIO 300: pathogen-induced cytokine storm signaling, S100 family signaling, pulmonary fibrosis idiopathic signaling, and wound-healing signaling. These pathways should be explored to identify potential biomarkers of BIO 300 that can be used for human dose translation.
Master Regulators of Causal Networks in Intestinal- and Diffuse-Type Gastric Cancer and the Relation to the RNA Virus Infection Pathway
Authors: Tanabe Shihori , Quader Sabina , Cabral Horacio , Perkins Edward J. , Yokozaki Hiroshi , Sasaki Hiroki
Published: August 2024

Causal networks are important for understanding disease signaling alterations. To reveal the network pathways affected in the epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs), which are related to the poor prognosis of cancer, the molecular networks and gene expression in diffuse- and intestinal-type gastric cancer (GC) were analyzed. The network pathways in GC were analyzed using Ingenuity Pathway Analysis (IPA). The analysis of the probe sets in which the gene expression had significant differences between diffuse- and intestinal-type GC in RNA sequencing of the publicly available data identified 1099 causal networks in diffuse- and intestinal-type GC. Master regulators of the causal networks included lenvatinib, pyrotinib, histone deacetylase 1 (HDAC1), mir-196, and erb-b2 receptor tyrosine kinase 2 (ERBB2). The analysis of the HDAC1-interacting network identified the involvement of EMT regulation via the growth factors pathway, the coronavirus pathogenesis pathway, and vorinostat. The network had RNA–RNA interactions with microRNAs such as mir-10, mir-15, mir-17, mir-19, mir-21, mir-223, mir-25, mir-27, mir-29, and mir-34. The molecular networks revealed in the study may lead to identifying drug targets for GC.
Molecular Iodine Improves the Efficacy and Reduces the Side Effects of Metronomic Cyclophosphamide Treatment against Mammary Cancer Progression
Authors: Delgado-González Evangelina , Ríos-Arellano Ericka de los , Anguiano Brenda , Aceves Carmen
Published: August 2024

Metronomic chemotherapy with cyclophosphamide (Cpp) has shown promising results in cancer protocols. These lower and prolonged doses have antiangiogenic, pro-cytotoxic, and moderate secondary effects. Molecular iodine (I2) reduces the viability of cancer cells and, with chemotherapeutic agents, activates the antitumoral immune response and diminishes side effects. The present work evaluates the adjuvant of oral I2 with Cpp using a murine model of mammary cancer. Female Sprague Dawley rats with 7,12-dimethylbenzantracene-induced tumors received Cpp intraperitoneal (50 and 70 mg/kg two times/week, iCpp50 and iCpp70) and oral (0.03%; 50 mg/Kg; oCpp50) doses. I2 (0.05%, 50 mg/100 mL) and oCpp50 were offered in drinking water for three weeks. iCpp70 was the most efficient antitumoral dose but generated severe body weight loss and hemorrhagic cystitis (HC). I2 prevented body weight loss, exhibited adjuvant actions with Cpp, decreasing tumor growth, and canceled HC mechanisms, including decreases in vascular endothelial growth factor (VEGF) and Survivin expression. oCpp50 + I2 diminished angiogenic signals (CD34, vessel-length, and VEGF content) and proinflammatory cytokines (interleukin-10 and tumor necrosis factor-alpha) and increased cytotoxic (lymphocytic infiltration, CD8+ cells, Tbet, and interferon-gamma) and antioxidant markers (nuclear erythroid factor-2 and glutathione peroxidase). I2 enhances the effectiveness of oCpp, making it a compelling candidate for a clinical protocol.
Designing a Candidate Multi-Epitope Vaccine against Transmissible Gastroenteritis Virus Based on Immunoinformatic and Molecular Dynamics
Authors: Bai Yihan , Zhou Mingxia , Wang Naidong , Yang Yi , Wang Dongliang
Published: August 2024

Transmissible gastroenteritis virus (TGEV) is an etiological agent of enteric disease that results in high mortality rates in piglets. The economic impact of the virus is considerable, causing significant losses to the pig industry. The development of an efficacious subunit vaccine to provide promising protection against TGEV is of the utmost importance. The viral antigen, spike glycoprotein (S), is widely regarded as one of the most effective antigenic components for vaccine research. In this study, we employed immunoinformatics and molecular dynamics approaches to develop an ‘ideal’ multi-epitope vaccine. Firstly, the dominant, non-toxic, highly antigenic T (Th, CTL) and B cell epitopes predicted from the TGEV S protein were artificially engineered in tandem to design candidate subunit vaccines. Molecular docking and dynamic simulation results demonstrate that it exhibits robust interactions with toll-like receptor 4 (TLR4). Of particular significance was the finding that the vaccine was capable of triggering an immune response in mammals, as evidenced by the immune simulation results. The humoral aspect is typified by elevated levels of IgG and IgM, whereas the cellular immune aspect is capable of eliciting the robust production of interleukins and cytokines (IFN-γ and IL-2). Furthermore, the adoption of E. coli expression systems for the preparation of vaccines will also result in cost savings. This study offers logical guidelines for the development of a secure and efficacious subunit vaccine against TGEV, in addition to providing a novel theoretical foundation and strategy to prevent associated CoV infections.
Phenotyping Tumor Heterogeneity through Proteogenomics: Study Models and Challenges
Authors: Piana Diletta , Iavarone Federica , De Paolis Elisa , Daniele Gennaro , Parisella Federico , Minucci Angelo , Greco Viviana , Urbani Andrea
Published: August 2024

Tumor heterogeneity refers to the diversity observed among tumor cells: both between different tumors (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). These cells can display distinct morphological and phenotypic characteristics, including variations in cellular morphology, metastatic potential and variability treatment responses among patients. Therefore, a comprehensive understanding of such heterogeneity is necessary for deciphering tumor-specific mechanisms that may be diagnostically and therapeutically valuable. Innovative and multidisciplinary approaches are needed to understand this complex feature. In this context, proteogenomics has been emerging as a significant resource for integrating omics fields such as genomics and proteomics. By combining data obtained from both Next-Generation Sequencing (NGS) technologies and mass spectrometry (MS) analyses, proteogenomics aims to provide a comprehensive view of tumor heterogeneity. This approach reveals molecular alterations and phenotypic features related to tumor subtypes, potentially identifying therapeutic biomarkers. Many achievements have been made; however, despite continuous advances in proteogenomics-based methodologies, several challenges remain: in particular the limitations in sensitivity and specificity and the lack of optimal study models. This review highlights the impact of proteogenomics on characterizing tumor phenotypes, focusing on the critical challenges and current limitations of its use in different clinical and preclinical models for tumor phenotypic characterization.