bluuebunny/crossref_metadata_2025 huggingface dataset:
Natural Product-Derived Compounds for Targeting Multidrug Resistance in Cancer and Microorganisms
Authors: U. Ferreira Maria-José
Published: September 2023

Natural products, characterized by huge scaffold diversity, complexity, and bioactivity, have long played a crucial role in drug discovery and development, particularly as anticancer and anti-infective agents [...]
Regulation of Human Sortilin Alternative Splicing by Glucagon-like Peptide-1 (GLP1) in Adipocytes
Authors: Lui Ashley , Patel Rekha S. , Krause-Hauch Meredith , Sparks Robert P. , Patel Niketa A.
Published: September 2023

Type 2 diabetes mellitus is a chronic metabolic disease with no cure. Adipose tissue is a major site of systemic insulin resistance. Sortilin is a central component of the glucose transporter -Glut4 storage vesicles (GSV) which translocate to the plasma membrane to uptake glucose from circulation. Here, using human adipocytes we demonstrate the presence of the alternatively spliced, truncated sortilin variant (Sort_T) whose expression is significantly increased in diabetic adipose tissue. Artificial-intelligence-based modeling, molecular dynamics, intrinsically disordered region analysis, and co-immunoprecipitation demonstrated association of Sort_T with Glut4 and decreased glucose uptake in adipocytes. The results show that glucagon-like peptide-1 (GLP1) hormone decreases Sort_T. We deciphered the molecular mechanism underlying GLP1 regulation of alternative splicing of human sortilin. Using splicing minigenes and RNA-immunoprecipitation assays, the results show that GLP1 regulates Sort_T alternative splicing via the splice factor, TRA2B. We demonstrate that targeted antisense oligonucleotide morpholinos reduces Sort_T levels and improves glucose uptake in diabetic adipocytes. Thus, we demonstrate that GLP1 regulates alternative splicing of sortilin in human diabetic adipocytes.
Novel Therapeutic Approaches to Prevent Atherothrombotic Ischemic Stroke in Patients with Carotid Atherosclerosis
Authors: Puig Núria , Solé Arnau , Aguilera-Simon Ana , Griñán Raquel , Rotllan Noemi , Camps-Renom Pol , Benitez Sonia
Published: September 2023

Atherothrombotic stroke represents approximately 20% of all ischemic strokes. It is caused by large-artery atherosclerosis, mostly in the internal carotid artery, and it is associated with a high risk of early recurrence. After an ischemic stroke, tissue plasminogen activator is used in clinical practice, although it is not possible in all patients. In severe clinical situations, such as high carotid stenosis (≥70%), revascularization by carotid endarterectomy or by stent placement is carried out to avoid recurrences. In stroke prevention, the pharmacological recommendations are based on antithrombotic, lipid-lowering, and antihypertensive therapy. Inflammation is a promising target in stroke prevention, particularly in ischemic strokes associated with atherosclerosis. However, the use of anti-inflammatory strategies has been scarcely studied. No clinical trials are clearly successful and most preclinical studies are focused on protection after a stroke. The present review describes novel therapies addressed to counteract inflammation in the prevention of the first-ever or recurrent stroke. The putative clinical use of broad-spectrum and specific anti-inflammatory drugs, such as monoclonal antibodies and microRNAs (miRNAs) as regulators of atherosclerosis, will be outlined. Further studies are necessary to ascertain which patients may benefit from anti-inflammatory agents and how.
Reducing Sialylation Enhances Electrotaxis of Corneal Epithelial Cells
Authors: Le Bryan , Zhu Kan , Brown Chelsea , Reid Brian , Cressman Amin , Zhao Min , Fierro Fernando A.
Published: September 2023

Corneal wound healing is a complex biological process that integrates a host of different signals to coordinate cell behavior. Upon wounding, there is the generation of an endogenous wound electric field that serves as a powerful cue to guide cell migration. Concurrently, the corneal epithelium reduces sialylated glycoforms, suggesting that sialylation plays an important role during electrotaxis. Here, we show that pretreating human telomerase-immortalized corneal epithelial (hTCEpi) cells with a sialyltransferase inhibitor, P-3FAX-Neu5Ac (3F-Neu5Ac), improves electrotaxis by enhancing directionality, but not speed. This was recapitulated using Kifunensine, which inhibits cleavage of mannoses and therefore precludes sialylation on N-glycans. We also identified that 3F-Neu5Ac enhanced the responsiveness of the hTCEpi cell population to the electric field and that pretreated hTCEpi cells showed increased directionality even at low voltages. Furthermore, when we increased sialylation using N-azidoacetylmannosamine-tetraacylated (Ac4ManNAz), hTCEpi cells showed a decrease in both speed and directionality. Importantly, pretreating enucleated eyes with 3F-Neu5Ac significantly improved re-epithelialization in an ex vivo model of a corneal injury. Finally, we show that in hTCEpi cells, sialylation is increased by growth factor deprivation and reduced by PDGF-BB. Taken together, our results suggest that during corneal wound healing, reduced sialylated glycoforms enhance electrotaxis and re-epithelialization, potentially opening new avenues to promote corneal wound healing.
Identification of Novel Glycans in the Mucus Layer of Shark and Skate Skin
Authors: Bachar-Wikstrom Etty , Thomsson Kristina A. , Sihlbom Carina , Abbo Lisa , Tartor Haitham , Lindén Sara K. , Wikstrom Jakob D.
Published: September 2023

The mucus layer covering the skin of fish has several roles, including protection against pathogens and mechanical damage. While the mucus layers of various bony fish species have been investigated, the composition and glycan profiles of shark skin mucus remain relatively unexplored. In this pilot study, we aimed to explore the structure and composition of shark skin mucus through histological analysis and glycan profiling. Histological examination of skin samples from Atlantic spiny dogfish (Squalus acanthias) sharks and chain catsharks (Scyliorhinus retifer) revealed distinct mucin-producing cells and a mucus layer, indicating the presence of a functional mucus layer similar to bony fish mucus albeit thinner. Glycan profiling using liquid chromatography–electrospray ionization tandem mass spectrometry unveiled a diverse repertoire of mostly O-glycans in the mucus of the two sharks as well as little skate (Leucoraja erinacea). Elasmobranch glycans differ significantly from bony fish, especially in being more sulfated, and some bear resemblance to human glycans, such as gastric mucin O-glycans and H blood group-type glycans. This study contributes to the concept of shark skin having unique properties and provides a foundation for further research into the functional roles and potential biomedical implications of shark skin mucus glycans.
Human γS-Crystallin Mutation F10_Y11delinsLN in the First Greek Key Pair Destabilizes and Impairs Tight Packing Causing Cortical Lamellar Cataract
Authors: Vendra Venkata Pulla Rao , Ostrowski Christian , Dyba Marzena A. , Tarasov Sergey G. , Hejtmancik J. Fielding
Published: September 2023

Aromatic residues forming tyrosine corners within Greek key motifs are critical for the folding, stability, and order of βγ-crystallins and thus lens transparency. To delineate how a double amino acid substitution in an N-terminal-domain tyrosine corner of the CRYGS mutant p.F10_Y11delinsLN causes juvenile autosomal dominant cortical lamellar cataracts, human γS-crystallin c-DNA was cloned into pET-20b (+) and a p.F10_Y11delinsLN mutant was generated via site-directed mutagenesis, overexpressed, and purified using ion-exchange and size-exclusion chromatography. Structure, stability, and aggregation properties in solution under thermal and chemical stress were determined using spectrofluorimetry and circular dichroism. In benign conditions, the p.F10_Y11delinsLN mutation does not affect the protein backbone but alters its tryptophan microenvironment slightly. The mutant is less stable to thermal and GuHCl-induced stress, undergoing a two-state transition with a midpoint of 60.4 °C (wild type 73.1 °C) under thermal stress and exhibiting a three-state transition with midpoints of 1.25 and 2.59 M GuHCl (wild type: two-state transition with Cm = 2.72 M GuHCl). The mutant self-aggregates upon heating at 60 °C, which is inhibited by α-crystallin and reducing agents. Thus, the F10_Y11delinsLN mutation in human γS-crystallin impairs the protein’s tryptophan microenvironment, weakening its stability under thermal and chemical stress, resulting in self-aggregation, lens opacification, and cataract.
Mapping QTL for Mineral Accumulation and Shoot Dry Biomass in Barley under Different Levels of Zinc Supply
Authors: Khan Waleed Amjad , Penrose Beth , Shabala Sergey , Zhang Xueqing , Cao Fangbin , Zhou Meixue
Published: September 2023

Zinc (Zn) deficiency is a common limiting factor in agricultural soils, which leads to significant reduction in both the yield and nutritional quality of agricultural produce. Exploring the quantitative trait loci (QTL) for shoot and grain Zn accumulation would help to develop new barley cultivars with greater Zn accumulation efficiency. In this study, two glasshouse experiments were conducted by growing plants under adequate and low Zn supply. From the preliminary screening of ten barley cultivars, Sahara (0.05 mg/pot) and Yerong (0.06 mg/pot) showed the lowest change in shoot Zn accumulation, while Franklin (0.16 mg/pot) had the highest change due to changes in Zn supply for plant growth. Therefore, the double haploid (DH) population derived from Yerong × Franklin was selected to identify QTL for shoot mineral accumulation and biomass production. A major QTL hotspot was detected on chromosome 2H between 31.91 and 73.12 cM encoding genes for regulating shoot mineral accumulations of Zn, Fe, Ca, K and P, and the biomass. Further investigation demonstrated 16 potential candidate genes for mineral accumulation, in addition to a single candidate gene for shoot biomass in the identified QTL region. This study provides a useful resource for enhancing nutritional quality and yield potential in future barley breeding programs.
Activation of 5-HT1A Receptors Normalizes the Overexpression of Presynaptic 5-HT1A Receptors and Alleviates Diabetic Neuropathic Pain
Authors: Munawar Neha , Bitar Milad S. , Masocha Willias
Published: September 2023

Neuropathic pain is a well-documented phenomenon in experimental and clinical diabetes; however, current treatment is unsatisfactory. Serotoninergic-containing neurons are key components of the descending autoinhibitory pathway, and a decrease in their activity may contribute at least in part to diabetic neuropathic pain (DNP). A streptozotocin (STZ)-treated rat was used as a model for type 1 diabetes mellitus (T1DM). Pain transmission was evaluated using well-established nociceptive-based techniques, including the Hargreaves apparatus, cold plate and dynamic plantar aesthesiometer. Using qRT-PCR, Western blotting, immunohistochemistry, and HPLC-based techniques, we also measured in the central nervous system and peripheral nervous system of diabetic animals the expression and localization of 5-HT1A receptors (5-HT1AR), levels of key enzymes involved in the synthesis and degradation of tryptophan and 5-HT, including tryptophan hydroxylase-2 (Tph-2), tryptophan 2,3-dioxygenase (Tdo), indoleamine 2,3-dioxygenase 1 (Ido1) and Ido2. Moreover, spinal concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT) and quinolinic acid (QA, a metabolite of tryptophan) were also quantified. Diabetic rats developed thermal hyperalgesia and cold/mechanical allodynia, and these behavioral abnormalities appear to be associated with the upregulation in the levels of expression of critical molecules related to the serotoninergic nervous system, including presynaptic 5-HT1AR and the enzymes Tph-2, Tdo, Ido1 and Ido2. Interestingly, the level of postsynaptic 5-HT1AR remains unaltered in STZ-induced T1DM. Chronic treatment of diabetic animals with 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), a selective 5-HT1AR agonist, downregulated the upregulation of neuronal presynaptic 5-HT1AR, increased spinal release of 5-HT (↑ 5-HIAA/5-HT) and reduced the concentration of QA, decreased mRNA expression of Tdo, Ido1 and Ido2, arrested neuronal degeneration and ameliorated pain-related behavior as exemplified by thermal hyperalgesia and cold/mechanical allodynia. These data show that 8-OH-DPAT alleviates DNP and other components of the serotoninergic system, including the ratio of 5-HIAA/5-HT and 5-HT1AR, and could be a useful therapeutic agent for managing DNP.
Nuclear NPM-ALK Protects Myc from Proteasomal Degradation and Contributes to Its High Expression in Cancer Stem-Like Cells in ALK-Positive Anaplastic Large Cell Lymphoma
Authors: Shang Chuquan , Lai Justine , Haque Moinul , Chen Will , Wang Peng , Lai Raymond
Published: September 2023

In ALK-positive anaplastic large cell lymphoma (ALK+ALCL), a small subset of cancer stem-like (or RR) cells characterized by high Myc expression have been identified. We hypothesize that NPM-ALK contributes to their high Myc expression. While transfection of NPM-ALK into HEK293 cells effectively increased Myc by inhibiting its proteasomal degradation (PD-Myc), this effect was dramatically attenuated when the full-length NPM1 (FL-NPM1) was downregulated using shRNA, highlighting the importance of the NPM-ALK:FL-NPM1 heterodimers in this context. Consistent with this concept, immunoprecipitation experiments showed that the heterodimers are abundant only in RR cells, in which the half-life of Myc is substantially longer than the bulk cells. Fbw7γ, a key player in PD-Myc, is sequestered by the heterodimers in RR cells, and this finding correlates with a Myc phosphorylation pattern indicative of ineffective PD-Myc. Using confocal microscopy and immunofluorescence staining, we found that the fusion signal between ALK and FL-NPM1, characteristic of the heterodimers, correlates with the Myc level in ALK+ALCL cells from cell lines and patient samples. To conclude, our findings have revealed a novel oncogenic function of NPM-ALK in the nucleus. Specifically, the NPM-ALK:FL-NPM1 heterodimers increase cancer stemness by blocking PD-Myc and promoting Myc accumulation in the cancer stem-like cell subset.
The Combination of Glucocorticoids and Hyaluronic Acid Enhances Efficacy in IL-1β/IL-17-Treated Bovine Osteochondral Grafts Compared with Individual Application
Authors: Bauer Christoph , Moser Lukas B. , Kern Daniela , Jeyakumar Vivek , Nehrer Stefan
Published: September 2023

Patients with knee osteoarthritis often receive glucocorticoid (GC) or hyaluronic acid (HA) injections to alleviate symptoms. This study evaluated the impact of Triamcinolone Hexacetonide (a GC), HA, and a combination of both on bovine osteochondral grafts exposed to IL-1β and IL-17 in an ex vivo culture. Metabolic activity increased with GC treatment. GCs and GCs/HA counteracted cytokine effects, with gene expressions similar to untreated controls, while HA alone did not. However, HA improved the coefficient of friction after two weeks. The highest friction values were observed in GC-containing and cytokine-treated groups. Cytokine treatment reduced tissue proteoglycan content, which HA could mitigate, especially in the GC/HA combination. This combo also effectively controlled proteoglycan release, supported by reduced sGAG release. Cytokine treatment led to surface cell death, while GCs, HA, or their combination showed protective effects against inflammation. The GC/HA combination had the best overall results, suggesting its potential as a superior treatment option for osteoarthritis.
A Short Review of the Toxicity of Dentifrices—Zebrafish Model as a Useful Tool in Ecotoxicological Studies
Authors: Stachurski Piotr , Świątkowski Wojciech , Ciszewski Andrzej , Sarna-Boś Katarzyna , Michalak Agnieszka
Published: September 2023

This review aims to summarize the literature data regarding the effects of different toothpaste compounds in the zebrafish model. Danio rerio provides an insight into the mechanisms of the ecotoxicity of chemicals as well as an assessment of their fate in the environment to determine long-term environmental impact. The regular use of adequate toothpaste with safe active ingredients possessing anti-bacterial, anti-inflammatory, anti-oxidant, and regenerative properties is one of the most effective strategies for oral healthcare. In addition to water, a typical toothpaste consists of a variety of components, among which three are of predominant importance, i.e., abrasive substances, fluoride, and detergents. These ingredients provide healthy teeth, but their environmental impact on living organisms are often not well-known. Each of them can influence a higher level of organization: subcellular, cellular, tissue, organ, individual, and population. Therefore, it is very important that the properties of a chemical are detected before it is released into the environment to minimize damage. An important part of a chemical risk assessment is the estimation of the ecotoxicity of a compound. The zebrafish model has unique advantages in environmental ecotoxicity research and has been used to study vertebrate developmental biology. Among others, the advantages of this model include its external, visually accessible development, which allows for providing many experimental manipulations. The zebrafish has a significant genetic similarity with other vertebrates. Nevertheless, translating findings from zebrafish studies to human risk assessment requires careful consideration of these differences.
From Homeostasis to Pathology: Decoding the Multifaceted Impact of Aquaporins in the Central Nervous System
Authors: Toader Corneliu , Tataru Calin Petru , Florian Ioan-Alexandru , Covache-Busuioc Razvan-Adrian , Dumitrascu David-Ioan , Glavan Luca Andrei , Costin Horia Petre , Bratu Bogdan-Gabriel , Ciurea Alexandru Vlad
Published: September 2023

Aquaporins (AQPs), integral membrane proteins facilitating selective water and solute transport across cell membranes, have been the focus of extensive research over the past few decades. Particularly noteworthy is their role in maintaining cellular homeostasis and fluid balance in neural compartments, as dysregulated AQP expression is implicated in various degenerative and acute brain pathologies. This article provides an exhaustive review on the evolutionary history, molecular classification, and physiological relevance of aquaporins, emphasizing their significance in the central nervous system (CNS). The paper journeys through the early studies of water transport to the groundbreaking discovery of Aquaporin 1, charting the molecular intricacies that make AQPs unique. It delves into AQP distribution in mammalian systems, detailing their selective permeability through permeability assays. The article provides an in-depth exploration of AQP4 and AQP1 in the brain, examining their contribution to fluid homeostasis. Furthermore, it elucidates the interplay between AQPs and the glymphatic system, a critical framework for waste clearance and fluid balance in the brain. The dysregulation of AQP-mediated processes in this system hints at a strong association with neurodegenerative disorders such as Parkinson’s Disease, idiopathic normal pressure hydrocephalus, and Alzheimer’s Disease. This relationship is further explored in the context of acute cerebral events such as stroke and autoimmune conditions such as neuromyelitis optica (NMO). Moreover, the article scrutinizes AQPs at the intersection of oncology and neurology, exploring their role in tumorigenesis, cell migration, invasiveness, and angiogenesis. Lastly, the article outlines emerging aquaporin-targeted therapies, offering a glimpse into future directions in combatting CNS malignancies and neurodegenerative diseases.
Limited Cheese Intake Paradigm Replaces Patterns of Behavioral Disorders in Experimental PTSD: Focus on Resveratrol Supplementation
Authors: Tseilikman Vadim E. , Shatilov Vladislav A. , Zhukov Maxim S. , Buksha Irina A. , Epitashvily Alexandr E. , Lipatov Ilya A. , Aristov Maxim R. , Koshelev Alexandr G. , Karpenko Marina N. , Traktirov Dmitrii S. , Maistrenko Viktoriya A. , Kamel Mustapha , Buhler Alexey V. , Kovaleva Elena G. , Kalinina Tatyana S. , Pashkov Anton A. , Kon’kov Vadim V. , Novak Jurica , Tseilikman Olga B.
Published: September 2023

Currently, the efficacy of drug therapy for post-traumatic stress disorder or PTSD leaves much to be desired, making nutraceutical support a promising avenue for treatment. Recent research has identified the protective effects of resveratrol in PTSD. Here, we tested the behavioral and neurobiological effects of combining cheese consumption with resveratrol supplements in an experimental PTSD model. Using the elevated plus maze test, we observed that cheese intake resulted in a shift from anxiety-like behavior to depressive behavior, evident in increased freezing acts. However, no significant changes in the anxiety index value were observed. Interestingly, supplementation with cheese and resveratrol only led to the elimination of freezing behavior in half of the PTSD rats. We further segregated the rats into two groups based on freezing behavior: Freezing+ and Freezing0 phenotypes. Resveratrol ameliorated the abnormalities in Monoamine Oxidize -A and Brain-Derived Neurotrophic Factor gene expression in the hippocampus, but only in the Freezing0 rats. Moreover, a negative correlation was found between the number of freezing acts and the levels of Monoamine Oxidize-A and Brain-Derived Neurotrophic Factor mRNAs in the hippocampus. The study results show promise for resveratrol supplementation in PTSD treatment. Further research is warranted to better understand the underlying mechanisms and optimize the potential benefits of resveratrol supplementation for PTSD.
Emerging Immunotherapy Approaches for Treating Prostate Cancer
Authors: Meng Lingbin , Yang Yuanquan , Mortazavi Amir , Zhang Jingsong
Published: September 2023

Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy has been limited in prostate cancer compared to other malignancies. This review summarizes key immunotherapy strategies under evaluation for prostate cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, chimeric antigen receptor (CAR) T cells, therapeutic vaccines, and cytokines. For each modality, the rationale stemming from preclinical studies is discussed along with outcomes from completed clinical trials and strategies to improve clinical efficacy that are being tested in ongoing clinical trials. Imperative endeavors include biomarker discovery for patient selection, deciphering resistance mechanisms, refining cellular therapies such as CAR T cells, and early-stage intervention were reviewed. These ongoing efforts instill optimism that immunotherapy may eventually deliver significant clinical benefits and expand treatment options for patients with advanced prostate cancer.
Advancing Spinal Cord Injury Treatment through Stem Cell Therapy: A Comprehensive Review of Cell Types, Challenges, and Emerging Technologies in Regenerative Medicine
Authors: Zeng Chih-Wei
Published: September 2023

Spinal cord injuries (SCIs) can lead to significant neurological deficits and lifelong disability, with far-reaching physical, psychological, and economic consequences for affected individuals and their families. Current treatments for SCIs are limited in their ability to restore function, and there is a pressing need for innovative therapeutic approaches. Stem cell therapy has emerged as a promising strategy to promote the regeneration and repair of damaged neural tissue following SCIs. This review article comprehensively discusses the potential of different stem cell types, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and neural stem/progenitor cells (NSPCs), in SCI treatment. We provide an in-depth analysis of the unique advantages and challenges associated with each stem cell type, as well as the latest advancements in the field. Furthermore, we address the critical challenges faced in stem cell therapy for SCIs, including safety concerns, ethical considerations, standardization of protocols, optimization of transplantation parameters, and the development of effective outcome measures. We also discuss the integration of novel technologies such as gene editing, biomaterials, and tissue engineering to enhance the therapeutic potential of stem cells. The article concludes by emphasizing the importance of collaborative efforts among various stakeholders in the scientific community, including researchers, clinicians, bioengineers, industry partners, and patients, to overcome these challenges and realize the full potential of stem cell therapy for SCI patients. By fostering such collaborations and advancing our understanding of stem cell biology and regenerative medicine, we can pave the way for the development of groundbreaking therapies that improve the lives of those affected by SCIs.
Exploring the Potential of Proteome Analysis as a Promising Tool for Evaluation of Sudden Cardiac Death (SCD) in Forensic Settings: A Literature Review
Authors: Sacco Matteo Antonio , Gualtieri Saverio , Calanna Luca , Ricci Pietrantonio , Aquila Isabella
Published: September 2023

Sudden cardiac death (SCD) represents a global emergency, with a high number of cases affecting all age groups every year. The prevention of these fatal events requires an accurate knowledge of etiology and pathogenesis, which can vary. Autopsy is an indispensable tool in cases of SCD for diagnostic purposes, as well as for judicial and preventive purposes for family members. Despite the completion of all routine post-mortem investigations, it is often complicated for the forensic pathologist to define the triggering cause of these events. The study of the proteome is proving to be extremely promising in the field of human cardiovascular disease. This paper aims to offer a literature review on the study of the proteome in post-mortem cadaveric biological samples obtained from SCD cases. The aim of this work is to outline the state of the art of the scientific advances that protein analysis can offer in the diagnosis of SCD and the limits that various studies have traced up to now. In conclusion, the work defines the future perspectives of this field in SCD, suggesting strategies to overcome the reported limits and improve the diagnostics of these events.
Choroideremia: The Endpoint Endgame
Authors: Abdalla Elsayed Maram E. A. , Taylor Laura J. , Josan Amandeep S. , Fischer M. Dominik , MacLaren Robert E.
Published: September 2023

Choroideremia is an X-linked retinal degeneration resulting from the progressive, centripetal loss of photoreceptors and choriocapillaris, secondary to the degeneration of the retinal pigment epithelium. Affected individuals present in late childhood or early teenage years with nyctalopia and progressive peripheral visual loss. Typically, by the fourth decade, the macula and fovea also degenerate, resulting in advanced sight loss. Currently, there are no approved treatments for this condition. Gene therapy offers the most promising therapeutic modality for halting or regressing functional loss. The aims of the current review are to highlight the lessons learnt from clinical trials in choroideremia, review endpoints, and propose a future strategy for clinical trials.
Exosomes in the Diagnosis and Treatment of Renal Cell Cancer
Authors: Boussios Stergios , Devo Perry , Goodall Iain C. A. , Sirlantzis Konstantinos , Ghose Aruni , Shinde Sayali D. , Papadopoulos Vasileios , Sanchez Elisabet , Rassy Elie , Ovsepian Saak V.
Published: September 2023

Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer originating from renal tubular epithelial cells, with clear cell RCC comprising approximately 80% of cases. The primary treatment modalities for RCC are surgery and targeted therapy, albeit with suboptimal efficacies. Despite progress in RCC research, significant challenges persist, including advanced distant metastasis, delayed diagnosis, and drug resistance. Growing evidence suggests that extracellular vesicles (EVs) play a pivotal role in multiple aspects of RCC, including tumorigenesis, metastasis, immune evasion, and drug response. These membrane-bound vesicles are released into the extracellular environment by nearly all cell types and are capable of transferring various bioactive molecules, including RNA, DNA, proteins, and lipids, aiding intercellular communication. The molecular cargo carried by EVs renders them an attractive resource for biomarker identification, while their multifarious role in the RCC offers opportunities for diagnosis and targeted interventions, including EV-based therapies. As the most versatile type of EVs, exosomes have attracted much attention as nanocarriers of biologicals, with multi-range signaling effects. Despite the growing interest in exosomes, there is currently no widely accepted consensus on their subtypes and properties. The emerging heterogeneity of exosomes presents both methodological challenges and exciting opportunities for diagnostic and clinical interventions. This article reviews the characteristics and functions of exosomes, with a particular reference to the recent advances in their application to the diagnosis and treatment of RCC.
Epitomics: Analysis of Plasma C9 Epitope Heterogeneity in the Plasma of Lung Cancer Patients and Control Subjects
Authors: Tornyi Ilona , Lazar Jozsef , Pettko-Szandtner Aladar , Hunyadi-Gulyas Eva , Takacs Laszlo
Published: September 2023

The human proteome is more complex than the genetic code predicts it to be. Epitomics, or protein epitome profiling, is a tool for understanding sub-protein level variation. With the ultimate goal to explore C9 proteoforms and their relevance to lung cancer, here we report plasma C9 epitope-associated molecular heterogeneity in plasma samples of lung cancer patients and control subjects. We show three C9 epitopes (BSI0449, BSI0581, BSI0639) with markedly different association with lung cancer (“unaltered”, “upregulated” and “downregulated”). In order to exclude confounding effects, we show first that the three epitope-defining mAbs recognize C9 in purified form and in the natural context, in the human plasma. Then, we present data demonstrating the lack of major epitope interdependence or overlap. The next experiments represent a quest toward the understanding of the molecular basis of apparent disparate association with lung cancer. Using immunochemistry, SDS PAGE and LC-MS/MS technologies, we demonstrate that epitope-specific immunoprecipitates of plasma C9 seem identical regarding peptide sequence. However, we found epitope-specific posttranslational modification and coprecipitated protein composition differences with respect to control and lung cancer plasma. Epitope profiling enabled the classification of hypothetical C9 proteoforms through differential association with lung cancer.
Defense Strategies of Rice in Response to the Attack of the Herbivorous Insect, Chilo suppressalis
Authors: Xiang Xing , Liu Shuhua , Li Hongjian , Danso Ofori Andrews , Yi Xiaoqun , Zheng Aiping
Published: September 2023

Chilo suppressalis is a notorious pest that attacks rice, feeding throughout the entire growth period of rice and posing a serious threat to rice production worldwide. Due to the boring behavior and overlapping generations of C. suppressalis, the pest is difficult to control. Moreover, no rice variety with high resistance to the striped stem borer (SSB) has been found in the available rice germplasm, which also poses a challenge to controlling the SSB. At present, chemical control is widely used in agricultural production to manage the problem, but its effect is limited and it also pollutes the environment. Therefore, developing genetic resistance is the only way to avoid the use of chemical insecticides. This article primarily focuses on the research status of the induced defense of rice against the SSB from the perspective of immunity, in which plant hormones (such as jasmonic acid and ethylene) and mitogen-activated protein kinases (MAPKs) play an important role in the immune response of rice to the SSB. The article also reviews progress in using transgenic technology to study the relationship between rice and the SSB as well as exploring the resistance genes. Lastly, the article discusses prospects for future research on rice’s resistance to the SSB.
Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas
Authors: Bingham Paul M. , Zachar Zuzana
Published: September 2023

We review extensive progress from the cancer metabolism community in understanding the specific properties of lipid metabolism as it is redesigned in advanced carcinomas. This redesigned lipid metabolism allows affected carcinomas to make enhanced catabolic use of lipids in ways that are regulated by oxygen availability and is implicated as a primary source of resistance to diverse treatment approaches. This oxygen control permits lipid catabolism to be an effective energy/reducing potential source under the relatively hypoxic conditions of the carcinoma microenvironment and to do so without intolerable redox side effects. The resulting robust access to energy and reduced potential apparently allow carcinoma cells to better survive and recover from therapeutic trauma. We surveyed the essential features of this advanced carcinoma-specific lipid catabolism in the context of treatment resistance and explored a provisional unifying hypothesis. This hypothesis is robustly supported by substantial preclinical and clinical evidence. This approach identifies plausible routes to the clinical targeting of many or most sources of carcinoma treatment resistance, including the application of existing FDA-approved agents.
Stachydrine Hydrochloride Regulates the NOX2-ROS-Signaling Axis in Pressure-Overload-Induced Heart Failure
Authors: Lu Shuang , Liang Yueyang , Yang Songru , Fu Mengwei , Shan Xiaoli , Zhang Chen , Chen Huihua , Zhao Pei , Lu Rong
Published: September 2023

Our previous studies revealed the protection of stachydrine hydrochloride (STA) against cardiopathological remodeling. One of the underlying mechanisms involves the calcium/calmodulin-dependent protein kinase Ⅱ (CaMKII). However, the way STA influences CaMKII needs to be further investigated. The nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-coupled reactive oxygen species (ROS) overproduction putatively induces the oxidative activation of CaMKII, resulting in the occurrence of pathological cardiac remodeling and dysfunction in experimental models of mice. Thus, in this study, we assessed the role of the NOX2-ROS signal axis in STA cardioprotection. The transverse aortic constriction (TAC)-induced heart failure model of mice, the phenylephrine-induced hypertrophic model of neonatal rat primary cardiomyocytes, and the H2O2-induced oxidative stress models of adult mouse primary cardiomyocytes and H9c2 cells were employed. The echocardiography and histological staining were applied to assess the cardiac effect of STA (6 mg/kg/d or 12 mg/kg/d), which was given by gavage. NOX2, ROS, and excitation-contraction (EC) coupling were detected by Western blotting, immunofluorescence, and calcium transient-contraction synchronous recordings. ROS and ROS-dependent cardiac fibrosis were alleviated in STA-treated TAC mice, demonstrating improved left ventricular ejection fraction and hypertrophy. In the heart failure model of mice and the hypertrophic model of cardiomyocytes, STA depressed NOX2 protein expression and activation, as shown by inhibited translocation of its phosphorylation, p67phox and p47phox, from the cytoplasm to the cell membrane. Furthermore, in cardiomyocytes under oxidative stress, STA suppressed NOX2-related cytosolic Ca2+ overload, enhanced cell contractility, and decreased Ca2+-dependent regulatory protein expression, including CaMKⅡ and Ryanodine receptor calcium release channels. Cardioprotection of STA against pressure overload-induced pathological cardiac remodeling correlates with the NOX2-coupled ROS signaling cascade.
Meta-Analysis of COVID-19 Metabolomics Identifies Variations in Robustness of Biomarkers
Authors: Onoja Anthony , von Gerichten Johanna , Lewis Holly-May , Bailey Melanie J. , Skene Debra J. , Geifman Nophar , Spick Matt
Published: September 2023

The global COVID-19 pandemic resulted in widespread harms but also rapid advances in vaccine development, diagnostic testing, and treatment. As the disease moves to endemic status, the need to identify characteristic biomarkers of the disease for diagnostics or therapeutics has lessened, but lessons can still be learned to inform biomarker research in dealing with future pathogens. In this work, we test five sets of research-derived biomarkers against an independent targeted and quantitative Liquid Chromatography–Mass Spectrometry metabolomics dataset to evaluate how robustly these proposed panels would distinguish between COVID-19-positive and negative patients in a hospital setting. We further evaluate a crowdsourced panel comprising the COVID-19 metabolomics biomarkers most commonly mentioned in the literature between 2020 and 2023. The best-performing panel in the independent dataset—measured by F1 score (0.76) and AUROC (0.77)—included nine biomarkers: lactic acid, glutamate, aspartate, phenylalanine, β-alanine, ornithine, arachidonic acid, choline, and hypoxanthine. Panels comprising fewer metabolites performed less well, showing weaker statistical significance in the independent cohort than originally reported in their respective discovery studies. Whilst the studies reviewed here were small and may be subject to confounders, it is desirable that biomarker panels be resilient across cohorts if they are to find use in the clinic, highlighting the importance of assessing the robustness and reproducibility of metabolomics analyses in independent populations.
Five Different Artemisia L. Species Ethanol Extracts’ Phytochemical Composition and Their Antimicrobial and Nematocide Activity
Authors: Nikitin Evgeny , Fitsev Igor , Egorova Anastasia , Logvinenko Lidia , Terenzhev Dmitriy , Bekmuratova Feruzakhon , Rakhmaeva Adelya , Shumatbaev Georgiy , Gatiyatullina Alsu , Shevchuk Oksana , Kalinnikova Tatiana
Published: September 2023

Among the plants that exhibit significant or established pharmacological activity, the genus Artemisia L. deserves special attention. This genus comprises over 500 species belonging to the largest Asteraceae family. Our study aimed at providing a comprehensive evaluation of the phytochemical composition of the ethanol extracts of five different Artemisia L. species (collected from the southwest of the Russian Federation) and their antimicrobial and nematocide activity as follows: A. annua cv. Novichok., A. dracunculus cv. Smaragd, A. santonica cv. Citral, A. abrotanum cv. Euxin, and A. scoparia cv. Tavrida. The study of the ethanol extracts of the five different Artemisia L. species using the methods of gas chromatography–mass spectrometry (GC–MS) and high-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (HPLC–MS/MS) allowed establishing their phytochemical profile. The obtained data on the of five different Artemisia L. species ethanol extracts’ phytochemical composition were used to predict the antibacterial and antifungal activity against phytopathogenic microorganisms and nematocidal activity against the free-living soil nematode Caenorhabditis elegans. The major compounds found in the composition of the Artemisia L. ethanol extracts were monoterpenes, sesquiterpenes, flavonoids, flavonoid glycosides, coumarins, and phenolic acids. The antibacterial and antifungal activity of the extracts began to manifest at a concentration of 150 µg/mL. The A. dracunculus cv. Smaragd extract had a selective effect against Gram-positive R. iranicus and B. subtilis bacteria, whereas the A. scoparia cv. Tavrida extract had a selective effect against Gram-negative A. tumefaciens and X. arboricola bacteria and A. solani, R. solani and F. graminearum fungi. The A. annua cv. Novichok, A. dracunculus cv. Smaragd, and A. santonica cv. Citral extracts in the concentration range of 31.3–1000 µg/mL caused the death of nematodes. It was established that A. annua cv. Novichok affects the UNC-63 protein, the molecular target of which is the nicotine receptor of the N-subtype.
A Decrease in Maternal Iron Levels Is the Predominant Factor Suppressing Hepcidin during Pregnancy in Mice
Authors: Helman Sheridan L. , Wilkins Sarah J. , Chan Jennifer C. J. , Hartel Gunter , Wallace Daniel F. , Anderson Gregory J. , Frazer David M.
Published: September 2023

In order to supply adequate iron during pregnancy, the levels of the iron regulatory hormone hepcidin in the maternal circulation are suppressed, thereby increasing dietary iron absorption and storage iron release. Whether this decrease in maternal hepcidin is caused by changes in factors known to regulate hepcidin expression, or by other unidentified pregnancy factors, is not known. To investigate this, we examined iron parameters during pregnancy in mice. We observed that hepatic iron stores and transferrin saturation, both established regulators of hepcidin production, were decreased in mid and late pregnancy in normal and iron loaded dams, indicating an increase in iron utilization. This can be explained by a significant increase in maternal erythropoiesis, a known suppressor of hepcidin production, by mid-pregnancy, as indicated by an elevation in circulating erythropoietin and an increase in spleen size and splenic iron uptake. Iron utilization increased further in late pregnancy due to elevated fetal iron demand. By increasing maternal iron levels in late gestation, we were able to stimulate the expression of the gene encoding hepcidin, suggesting that the iron status of the mother is the predominant factor influencing hepcidin levels during pregnancy. Our data indicate that pregnancy-induced hepcidin suppression likely occurs because of reductions in maternal iron reserves due to increased iron requirements, which predominantly reflect stimulated erythropoiesis in mid-gestation and increased fetal iron requirements in late gestation, and that there is no need to invoke other factors, including novel pregnancy factor(s), to explain these changes.
A Side-by-Side Comparison of Wildtype and Variant Melanocortin 1 Receptor Signaling with Emphasis on Protection against Oxidative Damage to DNA
Authors: Cerdido Sonia , Sánchez-Beltrán José , Lambertos Ana , Abrisqueta Marta , Padilla Lidia , Herraiz Cecilia , Olivares Conchi , Jiménez-Cervantes Celia , García-Borrón José C.
Published: September 2023

Common variants of the MC1R gene coding the α-melanocyte stimulating hormone receptor are associated with light skin, poor tanning, blond or red hair, and increased melanoma risk, due to pigment-dependent and -independent effects. This complex phenotype is usually attributed to impaired activation of cAMP signaling. However, several MC1R variants show significant residual coupling to cAMP and efficiently activate mitogenic extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling. Yet, residual signaling and the key actions of wildtype and variant MC1R have never been assessed under strictly comparable conditions in melanocytic cells of identical genetic background. We devised a strategy based on CRISPR-Cas9 knockout of endogenous MC1R in a human melanoma cell line wildtype for BRAF, NRAS and NF1, followed by reconstitution with epitope-labeled MC1R constructs, and functional analysis of clones expressing comparable levels of wildtype, R151C or D294H MC1R. The proliferation rate, shape, adhesion, motility and sensitivity to oxidative DNA damage were compared. The R151C and D294H RHC variants displayed impaired cAMP signaling, intracellular stability similar to the wildtype, triggered ERK1/2 activation as effectively as the wildtype, and afforded partial protection against oxidative DNA damage, although less efficiently than the wildtype. Therefore, common melanoma-associated MC1R variants display biased signaling and significant genoprotective activity.
Emerging Role of Decoy Receptor-2 as a Cancer Risk Predictor in Oral Potentially Malignant Disorders
Authors: de Villalaín Lucas , Álvarez-Teijeiro Saúl , Rodríguez-Santamarta Tania , Fernández del Valle Álvaro , Allonca Eva , Rodrigo Juan P. , de Vicente Juan Carlos , García-Pedrero Juana M.
Published: September 2023

The aim of this study was to evaluate the expression of the senescence markers, Decoy Receptor 2 (DcR2) and Differentiated Embryo-Chondrocyte expressed gen 1 (DEC1), in oral potentially malignant disorders (OPMDs) to ascertain their possible association with oral cancer risk. The immunohistochemical analysis of DcR2 and DEC1 expression (along with p16 and Ki67 expression) was carried out in 60 patients with clinically diagnosed oral leukoplakia. Fifteen cases (25%) subsequently developed an invasive carcinoma. Correlations between protein marker expression, histological grade and oral cancer risk were assessed. DcR2, DEC1 and Ki67 protein expressions were found to correlate significantly with increased oral cancer risk, and also with an increased grade of dysplasia. Multivariate analysis demonstrated that DcR2 and Ki67 expression are independent predictors of oral cancer development. Our results evidence for the first time the potential of DcR2 as an early biomarker to assess oral cancer risk in patients with oral leukoplakia (HR = 59.7, p = 0.015), showing a superior predictive value to histology (HR = 4.225, p = 0.08). These findings reveal that the increased expression of DcR2 and DEC1 occurred frequently in OPMDs. In addition, DcR2 expression emerges as a powerful biomarker for oral cancer risk assessment in patients with oral leukoplakia.
Multicaloric Effect in 0–3-Type MnAs/PMN–PT Composites
Authors: Amirov Abdulkarim A. , Anokhin Alexander S. , Talanov Mikhail V. , Sokolovskiy Vladimir V. , Kutzhanov Magzhan. K. , Huang Houbing , Reznichenko Larisa A. , Es’kov Andrey V. , Aliev Akhmed M.
Published: September 2023

The new xMnAs/(1 − x)PMN–PT (x = 0.2, 0.3) multicaloric composites, consisting of the modified PMN–PT-based relaxor-type ferroelectric ceramics and ferromagnetic compound of MnAs were fabricated, and their structure, magnetic, dielectric properties, and caloric effects were studied. Both components of the multicaloric composite have phase transition temperatures around 315 K, and large electrocaloric (~0.27 K at 20 kV/cm) and magnetocaloric (~13 K at 5 T) effects around this temperature were observed. As expected, composite samples exhibit a decrease in magnetocaloric effect (<1.4 K at 4 T) in comparison with an initial MnAs magnetic component (6.7 K at 4 T), but some interesting phenomena associated with magnetoelectric interaction between ferromagnetic and ferroelectric components were observed. Thus, a composite with x = 0.2 exhibits a double maximum in isothermal magnetic entropy changes, while a composite with x = 0.3 demonstrates behavior more similar to MnAs. Based on the results of experiments, the model of the multicaloric effect in an MnAs/PMN–PT composite was developed and different scenario observations of multicaloric response were modeled. In the framework of the proposed model, it was shown that boosting of caloric effect could be achieved by (1) compilation of ferromagnetic and ferroelectric components with large caloric effects in selected mass ratio and phase transition temperature; and (2) choosing of magnetic and electric field coapplying protocol. The 0.3MnAs/0.7PMN–PT composite was concluded to be the optimal multicaloric composite and a phase shift ∆φ = −π/4 between applied manetic fields can provide a synergetic caloric effect at a working point of 316 K.