bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver
Authors: Ros Javier , Vaghi Caterina , Baraibar Iosune , Saoudi González Nadia , Rodríguez-Castells Marta , García Ariadna , Alcaraz Adriana , Salva Francesc , Tabernero Josep , Elez Elena
Published: March 2024

Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.
Physiological and Molecular Modulations to Drought Stress in the Brassica Species
Authors: Yoo Mi-Jeong , Hwang Yoojeong , Koh Yoo-Min , Zhu Fanchao , Deshpande Aaditya Sunil , Bechard Tyler , Andreescu Silvana
Published: March 2024

Climate change, particularly drought stress, significantly impacts plant growth and development, necessitating the development of resilient crops. This study investigated physiological and molecular modulations to drought stress between diploid parent species and their polyploid progeny in the Brassica species. While no significant phenotypic differences were observed among the six species, drought stress reduced growth parameters by 2.4% and increased oxidative stress markers by 1.4-fold. Drought also triggered the expression of genes related to stress responses and led to the accumulation of specific metabolites. We also conducted the first study of perfluorooctane sulfonic acid (PFOS) levels in leaves as a drought indicator. Lower levels of PFOS accumulation were linked to plants taking in less water under drought conditions. Both diploid and polyploid species responded to drought stress similarly, but there was a wide range of variation in their responses. In particular, responses were less variable in polyploid species than in diploid species. This suggests that their additional genomic components acquired through polyploidy may improve their flexibility to modulate stress responses. Despite the hybrid vigor common in polyploid species, Brassica polyploids demonstrated intermediate responses to drought stress. Overall, this study lays the framework for future omics-level research, including transcriptome and proteomic studies, to deepen our understanding of drought tolerance mechanisms in Brassica species.
Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia
Authors: Wu Andrew , Liu Xiaohu , Fruhstorfer Clark , Jiang Xiaoyan
Published: March 2024

Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.
Caffeine Decreases Topiramate Levels in Zebrafish Larvae in a Pentylenetetrazol-Induced Seizure Model
Authors: Bartoszek Adrian , Sumara Agata , Kozub-Pędrak Anna , Trzpil Alicja , Stachniuk Anna , Fornal Emilia
Published: March 2024

Epilepsy ranks as the second-most prevalent neurological disease, and is characterized by seizures resulting in neurobiological and behavioral impairment. Naturally occurring in coffee beans or tea leaves, the alkaloid caffeine (CAF) is the most prevalent global stimulant. Caffeine has been observed to influence epileptic seizures and the efficacy of antiepileptic medications, with a notable impact on topiramate (TPM). This study aimed to explore the influence of CAF on TPM’s anticonvulsant effects in zebrafish larvae within a PTZ-induced seizure model, concurrently determining TPM concentrations through a sophisticated analytical approach based on ultrahigh-performance liquid chromatography and subsequent mass spectrometric detection. Zebrafish larvae four days post-fertilization were incubated for 18 h with varying doses of TPM or combinations of CAF + TPM, and locomotor activity was then assessed. Seizures were induced by introducing a PTZ solution to achieve a final concentration of 20 mM. Utilizing liquid chromatography–mass spectrometry (LC–MS/MS), TPM levels in the larvae were quantified. CAF co-administration (especially in higher doses) with TPM caused a decrease in the average locomotor activity in the larvae compared to TPM alone. Moreover, CAF decreased TPM levels in the larvae at all investigated doses. In conclusion, these findings offer a novel perspective on the interplay between CAF and TPM, shedding light on previously unexplored facets. The potential impact of CAF consumption in assisting with epileptic seizure control, unless proven otherwise, suggests a noteworthy consideration for future research and clinical practices.
Osmotic Pressure and Its Biological Implications
Authors: Zheng Songjie , Li Yan , Shao Yingfeng , Li Long , Song Fan
Published: March 2024

Gaining insight into osmotic pressure and its biological implications is pivotal for revealing mechanisms underlying numerous fundamental biological processes across scales and will contribute to the biomedical and pharmaceutical fields. This review aims to provide an overview of the current understanding, focusing on two central issues: (i) how to determine theoretically osmotic pressure and (ii) how osmotic pressure affects important biological activities. More specifically, we discuss the representative theoretical equations and models for different solutions, emphasizing their applicability and limitations, and summarize the effect of osmotic pressure on lipid phase separation, cell division, and differentiation, focusing on the mechanisms underlying the osmotic pressure dependence of these biological processes. We highlight that new theory of osmotic pressure applicable for all experimentally feasible temperatures and solute concentrations needs to be developed, and further studies regarding the role of osmotic pressure in other biological processes should also be carried out to improve our comprehensive and in-depth understanding. Moreover, we point out the importance and challenges of developing techniques for the in vivo measurement of osmotic pressure.
Is There a Link between Thyroid Peroxidase Gene Promoter Polymorphisms and Autoimmune Thyroiditis in the Polish Population?
Authors: Lacka Katarzyna , Maciejewski Adam , Jarecki Piotr , Herman Waldemar , Lacki Jan K. , Żaba Ryszard , Kowalczyk Michał J.
Published: March 2024

(1) Autoimmune thyroiditis (AIT) is the most common cause of primary hypothyroidism and one of the most frequent organ-specific autoimmune diseases. Its pathogenesis is polygenic and still requires further research. The aim of the study was to assess, for the first time in the Caucasian population, the role of selected TPO gene promoter polymorphisms (rs2071399 G/A, rs2071400C/T, rs2071402 A/G, and rs2071403 A/G) in the development of AIT. A total of 237 patients diagnosed with AIT and 130 healthy controls were genotyped for four TPO gene polymorphisms, and the results were statistically analyzed to check for the role of these polymorphisms. There were no significant differences in the genotype and allele frequencies of the studied TPO gene promoter polymorphisms between patients and controls (p > 0.05). The haplotype distribution (rs2071400–rs2071402–rs2071403) between the two studied groups was similar for the most common variants (CGA, CAG, TGG). Only a rare haplotype (CGG) occurred more frequently among patients compared to controls (p = 0.04). The studied TPO gene promoter polymorphisms did not show an association with susceptibility to AIT in the Caucasian Polish population, contrary to the results in Japanese patients.
Vesicular Messages from Dental Biofilms for Neutrophils
Authors: Vitkov Ljubomir , Krunić Jelena , Dudek Johanna , Bobbili Madhusudhan Reddy , Grillari Johannes , Hausegger Bernhard , Mladenović Irena , Stojanović Nikola , Krautgartner Wolf Dietrich , Oberthaler Hannah , Schauer Christine , Herrmann Martin , Singh Jeeshan , Minnich Bernd , Hannig Matthias
Published: March 2024

The encounter between dental biofilm and neutrophils in periodontitis remains elusive, although it apparently plays a crucial role in the periodontal pathology and constitutes a key topic of periodontology. Dental biofilm and neutrophils were isolated from orally healthy persons and patients with periodontitis. We investigated biofilm and its particle-shedding phenomenon with electron microscopy and nanoparticle tracking analysis (NTA); biofilm shedding–neutrophil interactions were examined ex vivo with epi-fluorescence microscopy. For this purpose, we used acellular dental biofilm shedding, purified lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA) as activators, and the interleukin 8 receptor beta (CXCR2) inhibitor and the anti-interleukin 8 receptor alpha (CXCR1) antibody as modulators. The shedding of acellular dental biofilms overwhelmingly consists of bacterial extracellular vesicles (BEVs). The latter induced the moderate formation of neutrophil extracellular traps (NETs) in orally healthy subjects and a strong formation in patients with periodontitis. A CXCR2 inhibitor and an anti-CXCR1 antibody had a minor effect on NET formation. Neutrophils from patients with periodontitis exhibited NET hyper-responsiveness. BEVs were stronger inducers of NET formation than purified LPS and PMA. A plateau of neutrophil responsiveness is reached above the age of 40 years, indicating the abrupt switch of maladaptive trained immunity (TI) into the activated modus. Our results suggest that dental biofilms consist of and disseminate immense amounts of outer membrane vesicles (OMVs), which initiate NET formation via a non-canonical cytosolic LPS/caspase-4/11/Gasdermin D pathway. This modus of NET formation is independent of neutrophil elastase (NE), myeloperoxidase (MPO), peptidylarginine deiminase 4 (PAD4), and toll-like receptors (TLR). In periodontitis, the hyper-responsiveness of neutrophils to BEVs and the increased NET formation appear to be a consequence of TI.
NButGT Reinforces the Beneficial Effects of Epinephrine on Cardiac Mitochondrial Respiration, Lactatemia and Cardiac Output in Experimental Anaphylactic Shock
Authors: Oulehri Walid , Persello Antoine , Blangy-Letheule Angelique , Tacquard Charles , Rozec Bertrand , Charles Anne-Laure , Geny Bernard , Lauzier Benjamin , Mertes Paul Michel , Collange Olivier
Published: March 2024

Anaphylactic shock (AS) is the most severe form of acute systemic hypersensitivity reaction. Although epinephrine can restore patients’ hemodynamics, it might also be harmful, supporting the need for adjuvant treatment. We therefore investigated whether NButGT, enhancing O-GlcNAcylation and showing beneficial effects in acute heart failure might improve AS therapy. Ovalbumin-sensitized rats were randomly allocated to six groups: control (CON), shock (AS), shock treated with NButGT alone before (AS+pre-Nbut) or after (AS+post-Nbut) AS onset, shock treated with epinephrine alone (AS+EPI) and shock group treated with combination of epinephrine and NButGT (AS+EPI+preNBut). Induction of shock was performed with an intravenous (IV) ovalbumin. Cardiac protein and cycling enzymes O-GlcNAcylation levels, mean arterial pressure (MAP), heart rate, cardiac output (CO), left ventricle shortening fraction (LVSF), mitochondrial respiration, and lactatemia were evaluated using Western blotting experiments, invasive arterial monitoring, echocardiography, mitochondrial oximetry and arterial blood samples. AS decreased MAP (−77%, p < 0.001), CO (−90%, p < 0.001) and LVSF (−30%, p < 0.05). Epinephrine improved these parameters and, in particular, rats did not die in 15 min. But, cardiac mitochondrial respiration remained impaired (complexes I + II −29%, p < 0.05 and II −40%, p < 0.001) with hyperlactatemia. NButGT pretreatment (AS+pre-Nbut) efficiently increased cardiac O-GlcNAcylation level as compared to the AS+post-Nbut group. Compared to epinephrine alone, the adjunction of NButGT significantly improved CO, LVSF and mitochondrial respiration. MAP was not significantly increased but lactatemia decreased more markedly. Pretreatment with NButGT increases O-GlcNAcylation of cardiac proteins and has an additive effect on epinephrine, improving cardiac output and mitochondrial respiration and decreasing blood lactate levels. This new therapy might be useful when the risk of AS cannot be avoided.
Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions
Authors: Wang Shuo , El Jurdi Najla , Thyagarajan Bharat , Prizment Anna , Blaes Anne H.
Published: March 2024

The population of cancer survivors has markedly increased due to the rapid improvements in cancer treatment. However, cancer survivors experience accelerated aging, which leads to chronic diseases and other age-related conditions, such as frailty. Those conditions may persist years after cancer diagnosis and treatment. Cellular senescence, a hallmark of aging, is one of the mechanisms that contribute to accelerated aging in cancer survivors. Several aging measures, including measures based on clinical markers and biomarkers, have been proposed to estimate the aging process, and some of them have shown associations with mortality and frailty in cancer survivors. Several anti-aging interventions, including lifestyle changes and anti-aging drugs, have been proposed. Future research, particularly in large-scale studies, is needed to determine the efficiency of these aging measures and anti-aging interventions before considering their application in clinics. This review focuses on the mechanisms of cellular senescence and accelerated aging in cancer survivors, assessment of the aging process using clinical markers and biomarkers, and the high prevalence of frailty in that population, as well as possible opportunities for anti-aging interventions. A deeper understanding of aging measures and anti-aging interventions in cancer survivors will contribute to the development of effective strategies to mitigate accelerated aging in cancer survivors and improve their quality of life.
Radiation Dermatitis: Radiation-Induced Effects on the Structural and Immunological Barrier Function of the Epidermis
Authors: Rübe Claudia E. , Freyter Benjamin M. , Tewary Gargi , Roemer Klaus , Hecht Markus , Rübe Christian
Published: March 2024

An important hallmark of radiation dermatitis is the impairment of the mitotic ability of the stem/progenitor cells in the basal cell layers due to radiation-induced DNA damage, leading to suppressed cell renewal in the epidermis. However, this mechanism alone does not adequately explain the complex pathogenesis of radiation-induced skin injury. In this review, we summarize the latest findings on the complex pathogenesis of radiation dermatitis and correlate these with the clinical features of radiation-induced skin reactions. The current studies show that skin exposure to ionizing radiation induces cellular senescence in the epidermal keratinocytes. As part of their epithelial stress response, these senescent keratinocytes secrete pro-inflammatory mediators, thereby triggering skin inflammation. Keratinocyte-derived cytokines and chemokines modulate intercellular communication with the immune cells, activating skin-resident and recruiting skin-infiltrating immune cells within the epidermis and dermis, thereby orchestrating the inflammatory response to radiation-induced tissue damage. The increased expression of specific chemoattractant chemokines leads to increased recruitment of neutrophils into the irradiated skin, where they release cytotoxic granules that are responsible for the exacerbation of an inflammatory state. Moreover, the importance of IL-17-expressing γδ-T cells to the radiation-induced hyperproliferation of keratinocytes was demonstrated, leading to reactive hyperplasia of the epidermis. Radiation-induced, reactive hyperproliferation of the keratinocytes disturbs the fine-tuned keratinization and cornification processes, leading to structural dysfunction of the epidermal barrier. In summary, in response to ionizing radiation, epidermal keratinocytes have important structural and immunoregulatory barrier functions in the skin, coordinating interacting immune responses to eliminate radiation-induced damage and to initiate the healing process.
IFI16 Is Indispensable for Promoting HIF-1α-Mediated APOL1 Expression in Human Podocytes under Hypoxic Conditions
Authors: Randle Richaundra K. , Amara Venkateswara Rao , Popik Waldemar
Published: March 2024

Genetic variants in the protein-coding regions of APOL1 are associated with an increased risk and progression of chronic kidney disease (CKD) in African Americans. Hypoxia exacerbates CKD progression by stabilizing HIF-1α, which induces APOL1 transcription in kidney podocytes. However, the contribution of additional mediators to regulating APOL1 expression under hypoxia in podocytes is unknown. Here, we report that a transient accumulation of HIF-1α in hypoxia is sufficient to upregulate APOL1 expression in podocytes through a cGAS/STING/IRF3-independent pathway. Notably, IFI16 ablation impedes hypoxia-driven APOL1 expression despite the nuclear accumulation of HIF-1α. Co-immunoprecipitation assays indicate no direct interaction between IFI16 and HIF-1α. Our studies identify hypoxia response elements (HREs) in the APOL1 gene enhancer/promoter region, showing increased HIF-1α binding to HREs located in the APOL1 gene enhancer. Luciferase reporter assays confirm the role of these HREs in transcriptional activation. Chromatin immunoprecipitation (ChIP)–qPCR assays demonstrate that IFI16 is not recruited to HREs, and IFI16 deletion reduces HIF-1α binding to APOL1 HREs. RT-qPCR analysis indicates that IFI16 selectively affects APOL1 expression, with a negligible impact on other hypoxia-responsive genes in podocytes. These findings highlight the unique contribution of IFI16 to hypoxia-driven APOL1 gene expression and suggest alternative IFI16-dependent mechanisms regulating APOL1 gene expression under hypoxic conditions.
The DUX4–HIF1α Axis in Murine and Human Muscle Cells: A Link More Complex Than Expected
Authors: Nguyen Thuy-Hang , Limpens Maelle , Bouhmidi Sihame , Paprzycki Lise , Legrand Alexandre , Declèves Anne-Emilie , Heher Philipp , Belayew Alexandra , Banerji Christopher R. S. , Zammit Peter S. , Tassin Alexandra
Published: March 2024

FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent inherited muscle disorders and is linked to the inappropriate expression of the DUX4 transcription factor in skeletal muscles. The deregulated molecular network causing FSHD muscle dysfunction and pathology is not well understood. It has been shown that the hypoxia response factor HIF1α is critically disturbed in FSHD and has a major role in DUX4-induced cell death. In this study, we further explored the relationship between DUX4 and HIF1α. We found that the DUX4 and HIF1α link differed according to the stage of myogenic differentiation and was conserved between human and mouse muscle. Furthermore, we found that HIF1α knockdown in a mouse model of DUX4 local expression exacerbated DUX4-mediated muscle fibrosis. Our data indicate that the suggested role of HIF1α in DUX4 toxicity is complex and that targeting HIF1α might be challenging in the context of FSHD therapeutic approaches.
Treatment with Rasburicase in Hospitalized Patients with Cardiorenal Syndrome: Old Treatment, New Scenario
Authors: Melero Rosa , Torroba-Sanz Beatriz , Goicoechea Marian , Sousa-Casasnovas Iago , Barrio Jose María , García-Prieto Ana María , Rodriguez-Benitez Patrocinio , García-González Xandra , Sanjurjo-Sáez María
Published: March 2024

Cardiorenal syndrome (CRS) involves joint dysfunction of the heart and kidney. Acute forms share biochemical alterations like hyperuricaemia (HU) with tumour lysis syndrome (TLS). The mainstay treatment of acute CRS with systemic overload is diuretics, but rasburicase is used in TLS to prevent and treat hyperuricaemia. An observational, retrospective study was performed to assess the effectiveness and safety of a single dose of rasburicase in hospitalized patients with cardiorenal syndrome, worsening renal function and uric acid levels above 9 mg/dL. Rasburicase improved diuresis and systemic congestion in the 35 patients included. A total of 86% of patients did not need to undergo RRT, and early withdrawal was possible in the remaining five. Creatinine (Cr) decreased after treatment with rasburicase from a peak of 3.6 ± 1.27 to 1.79 ± 0.83 mg/dL, and the estimated glomerular filtration rate (eGFR) improved from 17 ± 8 to 41 ± 20 mL/min/1.73 m2 (p = 0.0001). The levels of N-terminal type B Brain Natriuretic Peptide (Nt-ProBNP) and C-reactive protein (CRP) were also significantly reduced. No relevant adverse events were detected. Our results show that early treatment with a dose of rasburicase in patients with CRS and severe HU is effective to improve renal function and systemic congestion, avoiding the need for sustained extrarenal clearance, regardless of comorbidities and ventricular function.
Enhancing Clinical Utility: Utilization of International Standards and Guidelines for Metagenomic Sequencing in Infectious Disease Diagnosis
Authors: Kan Chau-Ming , Tsang Hin Fung , Pei Xiao Meng , Ng Simon Siu Man , Yim Aldrin Kay-Yuen , Yu Allen Chi-Shing , Wong Sze Chuen Cesar
Published: March 2024

Metagenomic sequencing has emerged as a transformative tool in infectious disease diagnosis, offering a comprehensive and unbiased approach to pathogen detection. Leveraging international standards and guidelines is essential for ensuring the quality and reliability of metagenomic sequencing in clinical practice. This review explores the implications of international standards and guidelines for the application of metagenomic sequencing in infectious disease diagnosis. By adhering to established standards, such as those outlined by regulatory bodies and expert consensus, healthcare providers can enhance the accuracy and clinical utility of metagenomic sequencing. The integration of international standards and guidelines into metagenomic sequencing workflows can streamline diagnostic processes, improve pathogen identification, and optimize patient care. Strategies in implementing these standards for infectious disease diagnosis using metagenomic sequencing are discussed, highlighting the importance of standardized approaches in advancing precision infectious disease diagnosis initiatives.
New Hybrid Ethylenediurea (EDU) Derivatives and Their Phytoactivity
Authors: Oshchepkov Maxim S. , Kovalenko Leonid V. , Kalistratova Antonida V. , Tkachenko Sergey V. , Gorunova Olga N. , Bystrova Nataliya A. , Kochetkov Konstantin A.
Published: March 2024

Natural and synthetic phytohormones are widely used in agriculture. The synthetic cytokinin ethylenediurea (EDU) induces protection in plants against ozone phytotoxicity. In our study, new hybrid derivatives of EDU were synthesized and tested for phytoactivity. The germination potential (Gp), germination of seeds (G), and relative water content in leaves (RWC), characterizing the drought resistance of plants, were determined. The results of laboratory studies showed that EDU and its hybrid derivatives have a positive effect on root length, the growth and development of shoots, as well as the ability of plants to tolerate stress caused by a lack of water.
The Metabolic Impact of Nonalcoholic Fatty Liver Disease on Cognitive Dysfunction: A Comprehensive Clinical and Pathophysiological Review
Authors: Giuffrè Mauro , Merli Nicola , Pugliatti Maura , Moretti Rita
Published: March 2024

Nonalcoholic fatty liver disease (NAFLD) exponentially affects the global healthcare burden, and it is currently gaining increasing interest in relation to its potential impact on central nervous system (CNS) diseases, especially concerning cognitive deterioration and dementias. Overall, scientific research nowadays extends to different levels, exploring NAFLD’s putative proinflammatory mechanism of such dysmetabolic conditions, spreading out from the liver to a multisystemic involvement. The aim of this review is to analyze the most recent scientific literature on cognitive involvement in NAFLD, as well as understand its underlying potential background processes, i.e., neuroinflammation, the role of microbiota in the brain–liver–gut axis, hyperammonemia neurotoxicity, insulin resistance, free fatty acids, and vitamins.
Acute Impacts of Ionizing Radiation Exposure on the Gastrointestinal Tract and Gut Microbiome in Mice
Authors: Jameus Alexandra , Dougherty Jessica , Narendrula Ramya , Levert Daniela , Valiquette Manon , Pirkkanen Jake , Lalonde Christine , Bonin Patrice , Gagnon Jeffrey D. , Appanna Vasu D. , Tharmalingam Sujeenthar , Thome Christopher
Published: March 2024

Radiation therapy for abdominopelvic malignancies often results in damage to the gastrointestinal tract (GIT) and permanent changes in bowel function. An overlooked component of the pathophysiology of radiation-induced bowel injury is the role of the gut microbiome. The goal of this research was to identify the impacts of acute radiation exposure on the GIT and gut microbiome. C57BL/6 mice exposed to whole-body X-rays (0.1–3 Gy) were assessed for histological and microbiome changes 48 h post-radiation exposure. Within the ileum, a dose of 3 Gy significantly decreased crypt depth as well as the number of goblet cells, but increased overall goblet cell size. Overall, radiation altered the microbial distribution within each of the main phyla in a dose- and tissue-dependent manner. Within the Firmicutes phylum, high dose irradiation resulted in significant alterations in bacteria from the class Bacilli within the small bowels, and from the class Clostridia in the large bowels. The 3 Gy radiation also significantly increased the abundance of bacterial families from the Bacteroidetes phylum in the colon and feces. Overall, we identified various alterations in microbiome composition following acute radiation exposure, which could potentially lead to novel biomarkers for tracking patient toxicities or could be used as targets for mitigation strategies against radiation damage.
Mind, Mood and Microbiota—Gut–Brain Axis in Psychiatric Disorders
Authors: Toader Corneliu , Dobrin Nicolaie , Costea Daniel , Glavan Luca-Andrei , Covache-Busuioc Razvan-Adrian , Dumitrascu David-Ioan , Bratu Bogdan-Gabriel , Costin Horia-Petre , Ciurea Alexandru Vlad
Published: March 2024

Psychiatric disorders represent a primary source of disability worldwide, manifesting as disturbances in individuals’ cognitive processes, emotional regulation, and behavioral patterns. In the quest to discover novel therapies and expand the boundaries of neuropharmacology, studies from the field have highlighted the gut microbiota’s role in modulating these disorders. These alterations may influence the brain’s processes through the brain–gut axis, a multifaceted bidirectional system that establishes a connection between the enteric and central nervous systems. Thus, probiotic and prebiotic supplements that are meant to influence overall gut health may play an insightful role in alleviating psychiatric symptoms, such as the cognitive templates of major depressive disorder, anxiety, or schizophrenia. Moreover, the administration of psychotropic drugs has been revealed to induce specific changes in a microbiome’s diversity, suggesting their potential utility in combating bacterial infections. This review emphasizes the intricate correlations between psychiatric disorders and the gut microbiota, mentioning the promising approaches in regard to the modulation of probiotic and prebiotic treatments, as well as the antimicrobial effects of psychotropic medication.
Cognitive Impairment in Nonagenarians: Potential Metabolic Mechanisms Revealed by the Synergy of In Silico Gene Expression Modeling and Pathway Enrichment Analysis
Authors: Mamchur Aleksandra , Zelenova Elena , Dzhumaniiazova Irina , Erema Veronika , Kashtanova Daria , Ivanov Mikhail , Bruttan Maria , Gusakova Mariia , Terekhov Mikhail , Yudin Vladimir , Rumyantseva Antonina , Matkava Lorena , Strazhesko Irina , Isaev Ruslan , Kruglikova Anna , Maytesyan Lilit , Tarasova Irina , Beloshevskaya Olga , Mkhitaryan Elen , Kraevoy Sergey , Tkacheva Olga , Yudin Sergey
Published: March 2024

Previous studies examining the molecular and genetic basis of cognitive impairment, particularly in cohorts of long-living adults, have mainly focused on associations at the genome or transcriptome level. Dozens of significant dementia-associated genes have been identified, including APOE, APOC1, and TOMM40. However, most of these studies did not consider the intergenic interactions and functional gene modules involved in cognitive function, nor did they assess the metabolic changes in individual brain regions. By combining functional analysis with a transcriptome-wide association study, we aimed to address this gap and examine metabolic pathways in different areas of the brain of older adults. The findings from our previous genome-wide association study in 1155 older adults, 179 of whom had cognitive impairment, were used as input for the PrediXcan gene prediction algorithm. Based on the predicted changes in gene expression levels, we conducted a transcriptome-wide association study and functional analysis using the KEGG and HALLMARK databases. For a subsample of long-living adults, we used logistic regression to examine the associations between blood biochemical markers and cognitive impairment. The functional analysis revealed a significant association between cognitive impairment and the expression of NADH oxidoreductase in the cerebral cortex. Significant associations were also detected between cognitive impairment and signaling pathways involved in peroxisome function, apoptosis, and the degradation of lysine and glycan in other brain regions. Our approach combined the strengths of a transcriptome-wide association study with the advantages of functional analysis. It demonstrated that apoptosis and oxidative stress play important roles in cognitive impairment.
Prostaglandin Transporter and Dipeptidyl Peptidase-4 as New Pharmacological Targets in the Prevention of Acute Kidney Injury in Diabetes: An In Vitro Study
Authors: Gallego-Tamayo Beatriz , Santos-Aparicio Ángela , Yago-Ibáñez Julia , Muñoz-Moreno Laura , Lucio-Cazaña Francisco Javier , Fernández-Martínez Ana B.
Published: March 2024

The probability of acute kidney injury (AKI) is higher in septic diabetic patients, which is associated with, among other factors, proximal tubular cell (PTC) injury induced by the hypoxic/hyperglycemic/inflammatory microenvironment that surrounds PTCs in these patients. Here, we exposed human PTCs (HK-2 cells) to 1% O2/25 mM glucose/inflammatory cytokines with the aim of studying the role of prostaglandin uptake transporter (PGT) and dipeptidyl peptidase-4 (DPP-4, a target of anti-hyperglycemic agents) as pharmacological targets to prevent AKI in septic diabetic patients. Our model reproduced two pathologically relevant mechanisms: (i) pro-inflammatory PTC activation, as demonstrated by the increased secretion of chemokines IL-8 and MCP-1 and the enhanced expression of DPP-4, intercellular leukocyte adhesion molecule-1 and cyclo-oxygenase-2 (COX-2), the latter resulting in a PGT-dependent increase in intracellular prostaglandin E2 (iPGE2); and (ii) epithelial monolayer injury and the consequent disturbance of paracellular permeability, which was related to cell detachment from collagen IV and the alteration of the cell cytoskeleton. Most of these changes were prevented by the antagonism of PGE2 receptors or the inhibition of COX-2, PGT or DPP-4, and further studies suggested that a COX-2/iPGE2/DPP-4 pathway mediates the pathogenic effects of the hypoxic/hyperglycemic/inflammatory conditions on PTCs. Therefore, inhibitors of PGT or DPP-4 ought to undergo testing as a novel therapeutic avenue to prevent proximal tubular damage in diabetic patients at risk of AKI.
Topical Neuropeptide Y for Ischemic Skin Wounds
Authors: Stangerup Tais , Gjerdrum Lise Mette Rahbek , Bzorek Michael , Andersen Line , Heegaard Anne-Marie , Jorgensen Lars N. , Ågren Magnus S.
Published: March 2024

Our objective was to investigate the effects of topically applied neuropeptide Y (NPY) on ischemic wounds. Initially, the animal model for ischemic wound healing was validated using 16 male Sprague Dawley albino rats. In the intervention study, an additional 28 rats were divided into three groups: NPY (0.025%), the positive control insulin-like growth factor-I (IGF-I, 0.0025%), and the hydrogel carrier alone (control). The hydrogel was selected due to its capacity to prolong NPY release (p < 0.001), as demonstrated in a Franz diffusion cell. In the animals, an 8 mm full-thickness wound was made in a pedunculated dorsal ischemic skin flap. Wounds were then treated and assessed for 14 days and collected at the end of the experiment for in situ hybridization analysis (RNAscope®) targeting NPY receptor Y2R and for meticulous histologic examination. Wound healing rates, specifically the percentage changes in wound area, did not show an increase with NPY (p = 0.907), but there was an increase with rhIGF-I (p = 0.039) compared to the control. Y2R mRNA was not detected in the wounds or adjacent skin but was identified in the rat brain (used as a positive control). Light microscopic examination revealed trends of increased angiogenesis and enhanced inflammatory cell infiltration with NPY compared to control. An interesting secondary discovery was the presence of melanophages in the wounds. Our findings suggest the potential of NPY to enhance neovascularization under ischemic wound healing conditions, but further optimization of the carrier and dosage is necessary. The mechanism remains elusive but likely involves NPY receptor subtypes other than Y2R.
Novel Anthraquinone-Based Benzenesulfonamide Derivatives and Their Analogues as Potent Human Carbonic Anhydrase Inhibitors with Antitumor Activity: Synthesis, Biological Evaluation, and In Silico Analysis
Authors: Wu Shanshan , Zhou Xiaoping , Li Fei , Sun Wei , Zheng Qingchuan , Liang Di
Published: March 2024

In this study, we designed two series of novel anthraquinone-based benzenesulfonamide derivatives and their analogues as potential carbonic anhydrase inhibitors (CAIs) and evaluated their inhibitory activities against off-target human carbonic anhydrase II (hCA II) isoform and tumor-associated human carbonic anhydrase IX (hCA IX) isoform. Most of these compounds exhibited good inhibitory activities against hCA II and IX. The compounds that exhibited the best hCA inhibition were further studied against the MDA-MB-231, MCF-7, and HepG2 cell lines under hypoxic and normoxic conditions. Additionally, the compounds exhibiting the best antitumor activity were subjected to apoptosis and mitochondrial membrane potential assays, which revealed a significant increase in the percentage of apoptotic cells and a notable decrease in cell viability. Molecular docking studies were performed to demonstrate the presence of numerous hydrogen bonds and hydrophobic interactions between the compounds and the active site of hCA. Absorption, distribution, metabolism, excretion (ADME) predictions showed that all of the compounds had good pharmacokinetic and physicochemical properties.
Cooperativity of ESPT and Aggregation-Induced Emission Effects—An Experimental and Theoretical Analysis of a 1,3,4-Thiadiazole Derivative
Authors: Budziak-Wieczorek Iwona , Kaczmarczyk Dominika , Rząd Klaudia , Gagoś Mariusz , Stepulak Andrzej , Myśliwa-Kurdziel Beata , Karcz Dariusz , Starzak Karolina , Burdziński Gotard , Srebro-Hooper Monika , Matwijczuk Arkadiusz
Published: March 2024

4-[5-(Naphthalen-1-ylmethyl)-1,3,4-thiadiazol-2-yl]benzene-1,3-diol (NTBD) was extensively studied through stationary UV–vis absorption and fluorescence measurements in various solvents and solvent mixtures and by first-principles quantum chemical calculations. It was observed that while in polar solvents (e.g., methanol) only a single emission band emerged; the analyzed 1,3,4-thiadiazole derivative was capable of producing dual fluorescence signals in low polarity solvents (e.g., n-hexane) and certain solvent mixtures (e.g., methanol/water). As clearly follows from the experimental spectroscopic studies and theoretical modeling, the specific emission characteristic of NTBD is triggered by the effect of enol → keto excited-state intramolecular proton transfer (ESIPT) that in the case of solvent mixture is reinforced by aggregation of thiadiazole molecules. Specifically, the restriction of intramolecular rotation (RIR) due to environmental hindrance suppresses the formation of non-emissive twisted intramolecular charge transfer (TICT) excited keto* states. As a result, this particular thiadiazole derivative is capable of simultaneously producing both ESIPT and aggregation-induced emission (AIE).
Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure
Authors: Oizumi Takashi , Suzuki Tomoya , Kobayashi Junya , Nakamura Asako J.
Published: March 2024

DNA damage is induced by both endogenous and exogenous factors. Repair of DNA double-strand break (DSB), a serious damage that threatens genome stability, decreases with senescence. However, the molecular mechanisms underlying the decline in DNA repair capacity during senescence remain unclear. We performed immunofluorescence staining for phosphorylated histone H2AX (γ-H2AX) in normal human fetal lung fibroblasts and human skin fibroblasts of different ages after chronic irradiation (total dose, 1 Gy; dose rate, 1 Gy/day) to investigate the effect of cellular senescence and organismal aging on DSB repair. Accumulation of DSBs was observed with cellular senescence and organismal aging, probably caused by delayed DSB repair. Importantly, the formation of γ-H2AX foci, an early event in DSB repair, is delayed with cellular senescence and organismal aging. These results suggest that the delay in γ-H2AX focus formation might delay the overall DSB repair. Interestingly, immediate γ-H2AX foci formation was suppressed in cells with senescence-associated heterochromatin foci (SAHF). To investigate the relationship between the γ-H2AX focus formation and SAHF, we used LiCl to relax the SAHFs, followed by irradiation. We demonstrated that LiCl rescued the delayed γ-H2AX foci formation associated with cellular senescence. This indicates that SAHF interferes with γ-H2AX focus formation and inhibits DSB repair in radiation-induced DSB. Our results suggest that therapeutic targeting of SAHFs have potential to resolve DSB repair dysfunction associated with cellular senescence.
ZmSMR10 Increases the Level of Endoreplication of Plants through Its Interactions with ZmPCNA2 and ZmCSN5B
Authors: Bao Lulu , Si Jihao , Zhai Mingming , Liu Na , Qu Haoran , Capulong Christian , Li Jinyuan , Liu Qianqian , Liu Yilin , Huang Chenggang , Zhang Maoxi , Ao Zhengxiong , Yang Aojun , Qin Chao , Guo Dongwei
Published: March 2024

As a plant-specific endoreplication regulator, the SIAMESE-RELATED (SMR) family (a cyclin-dependent kinase inhibitor) plays an important role in plant growth and development and resistance to stress. Although the genes of the maize (Zea mays) SMR family have been studied extensively, the ZmSMR10 (Zm00001eb231280) gene has not been reported. In this study, the function of this gene was characterized by overexpression and silencing. Compared with the control, the transgenic plants exhibited the phenotypes of early maturation, dwarfing, and drought resistance. Expression of the protein in prokaryotes demonstrates that ZmSMR10 is a small protein, and the results of subcellular localization suggest that it travels functionally in the nucleus. Unlike ZmSMR4, yeast two-hybrid experiments demonstrated that ZmSMR10 does not interact strongly with with some cell cycle protein-dependent protein kinase (CDK) family members ZmCDKA;1/ZmCDKA;3/ZmCDKB1;1. Instead, it interacts strongly with ZmPCNA2 and ZmCSN5B. Based on these results, we concluded that ZmSMR10 is involved in the regulation of endoreplication through the interaction of ZmPCNA2 and ZmCSN5B. These findings provide a theoretical basis to understand the mechanism of the regulation of endoreplication and improve the yield of maize through the use of molecular techniques.
Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications
Authors: Cao Qing , Tian Ye , Deng Zhiyi , Yang Fangfang , Chen Erfei
Published: March 2024

Colorectal cancer (CRC), a prevalent malignant tumor of the digestive system, ranks as the third and second in global incidence and mortality, respectively, in 2020, with 1.93 million new cases (≈10% of all cancers). There are 940,000 deaths (≈9.4% of all cancers), and the incidence of CRC in younger patients (under 50 years of age) has become a new trend. The pathogenesis of CRC is primarily attributed to a series of genetic and epigenetic abnormalities within normal colonic epithelial cells, coupled with the reshaping of the tumor microenvironment in the surrounding stroma. This process leads to the transformation of colorectal adenomas into invasive adenocarcinomas. Although genetic changes are known to be the primary driving force in the occurrence and progression of CRC, recent research indicates that epigenetic regulation serves as a crucial molecular marker in cancer, playing a significant role in the pathological and physiological control of interactions between genetics and the environment. This review discusses the current global epidemiology of CRC, its risk factors, and preventive treatment strategies. The current study explores the latest advancements in the epigenetic regulation of CRC, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These developments hold potential as screening tools, prognostic biomarkers, and therapeutic targets for CRC.
Multi-Level Attention Split Network: A Novel Malaria Cell Detection Algorithm
Authors: Xiong Zhao , Wu Jiang
Published: March 2024

Malaria is one of the major global health threats. Microscopic examination has been designated as the “gold standard” for malaria detection by the World Health Organization. However, it heavily relies on the experience of doctors, resulting in long diagnosis time, low efficiency, and a high risk of missed or misdiagnosed cases. To alleviate the pressure on healthcare workers and achieve automated malaria detection, numerous target detection models have been applied to the blood smear examination for malaria cells. This paper introduces the multi-level attention split network (MAS-Net) that improves the overall detection performance by addressing the issues of information loss for small targets and mismatch between the detection receptive field and target size. Therefore, we propose the split contextual attention structure (SPCot), which fully utilizes contextual information and avoids excessive channel compression operations, reducing information loss and improving the overall detection performance of malaria cells. In the shallow detection layer, we introduce the multi-scale receptive field detection head (MRFH), which better matches targets of different scales and provides a better detection receptive field, thus enhancing the performance of malaria cell detection. On the NLM—Malaria Dataset provided by the National Institutes of Health, the improved model achieves an average accuracy of 75.9% in the public dataset of Plasmodium vivax (malaria)-infected human blood smear. Considering the practical application of the model, we introduce the Performance-aware Approximation of Global Channel Pruning (PAGCP) to compress the model size while sacrificing a small amount of accuracy. Compared to other state-of-the-art (SOTA) methods, the proposed MAS-Net achieves competitive results.
A Comparison of β–Phenyl Elimination in Nickel and Palladium Alkyl Complexes: A Potentially Relevant Process in the Mizoroki–Heck Reaction
Authors: López Jorge A. , Cabo Diego A. , Palma Pilar , Cámpora Juan
Published: March 2024

There is currently much interest in avoiding precious metals in catalysis. The development of nickel catalysts to replace palladium in the Mizoroki–Heck reaction is a relevant case in this line of research, since both elements share many chemical features. This contribution focuses on β–phenyl (β–Ph) elimination in alkyl—nickel complexes. This is the microscopic reverse of olefin insertion (or carbometallation), a fundamental step in the Heck cycle that is usually considered irreversible and selectivity-determining. However, the potential reversibility of carbometallation is generally concealed by the facile β–hydrogen (β–H) elimination that follows. Where β–hydrogen elimination is hindered, β–aryl elimination may ensue. We have previously shown that cationic 2–methyl–2–phenylpropyl (neophyl) palladium complexes supported by bidentate ligands experience β–Ph elimination, which can be seen as an example of olefin de-insertion. In this contribution, we report that β–Ph elimination can also occur in their nickel analogs, in which case fast hydrolyses of the resulting phenyl product can follow the reaction. We investigated the mechanism of these processes and compared their feasibility for nickel and palladium catalysts using DFT calculations. These results are relevant information for the design of nickel-based catalysts for the Heck reaction.