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Journal of Applied Toxicology : JAT Jun 2024Doxorubicin-based chemotherapy is a widely used first-line treatment for breast cancer, yet it is associated with various side effects, including splenic atrophy....
Doxorubicin-based chemotherapy is a widely used first-line treatment for breast cancer, yet it is associated with various side effects, including splenic atrophy. However, the pathogenic mechanisms underlying doxorubicin-induced atrophy of the spleen remain unclear. This study investigates that doxorubicin treatment leads to splenic atrophy through several interconnected pathways involving histological changes, an inflammatory response, and apoptosis. Immunohistochemical and western blot analyses revealed reduced size of white and red pulp, decreased cellularity, amyloidosis, and fibrotic remodeling in the spleen following doxorubicin treatment. Additionally, increased secretion of pro-inflammatory cytokines was detected using an antibody array and enzyme-linked immunosorbent assay (ELISA), which triggers inflammation through the regulation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-κB) signaling pathways. Further analysis revealed that the loss of regulators and effectors of the oxidative defense system, including sirtuin (Sirt)3, Sirt5, superoxide dismutase (SOD)1, and SOD2, was implicated in the upstream regulation of caspase-dependent cellular apoptosis. These findings provide insights on the pathogenic mechanisms underlying doxorubicin-induced splenic atrophy and suggest that further investigation may be warranted to explore strategies for managing potential side effects in breast cancer patients treated with doxorubicin.
PubMed: 38943348
DOI: 10.1002/jat.4666 -
Nucleic Acids Research Jun 2024BRCA1/2 proteins function in genome stability by promoting repair of double-stranded DNA breaks through homologous recombination and by protecting stalled replication...
BRCA1/2 proteins function in genome stability by promoting repair of double-stranded DNA breaks through homologous recombination and by protecting stalled replication forks from nucleolytic degradation. In BRCA1/2-deficient cancer cells, extensively degraded replication forks can be rescued through distinct fork recovery mechanisms that also promote cell survival. Here, we identified a novel pathway mediated by the E3 ubiquitin ligase RAD18, the E2-conjugating enzyme UBC13, the recombination factor PALB2, the E3 ubiquitin ligase RNF168 and PCNA ubiquitination that promotes fork recovery in BRCA1- but not BRCA2-deficient cells. We show that this pathway does not promote fork recovery by preventing replication fork reversal and degradation in BRCA1-deficient cells. We propose a mechanism whereby the RAD18-UBC13-PALB2-RNF168 axis facilitates resumption of DNA synthesis by promoting re-annealing of the complementary single-stranded template strands of the extensively degraded forks, thereby allowing re-establishment of a functional replication fork. We also provide preliminary evidence for the potential clinical relevance of this novel fork recovery pathway in BRCA1-mutated cancers, as RAD18 is over-expressed in BRCA1-deficient cancers, and RAD18 loss compromises cell viability in BRCA1-deficient cancer cells.
PubMed: 38943334
DOI: 10.1093/nar/gkae563 -
BMC Psychology Jun 2024This study explores the intricate web of symptoms experienced by academically gifted high school students, focusing on procrastination, rumination, perfectionism, and...
BACKGROUND
This study explores the intricate web of symptoms experienced by academically gifted high school students, focusing on procrastination, rumination, perfectionism, and cognitive flexibility. The well-being of these gifted adolescents remains a pivotal concern, and understanding the dynamics of these symptoms is vital.
METHODS
A diverse sample of 207 academically gifted high school students from Mashhad, Iran, participated in this study. Using convenience sampling, participants from grades 10, 11, and 12 were included, with detailed assessments conducted through questionnaires measuring the mentioned symptoms.
RESULTS
Our network analysis uncovers compelling insights into the interplay of these symptoms: Procrastination, though moderately central, exerts significant influence within the network, underscoring its relevance. Cognitive flexibility, while centrally positioned, curiously exhibits a negative influence, potentially serving as a protective factor. Negative perfectionism emerges as the keystone symptom, with both high centrality and a positive influence. Rumination displays substantial centrality and a positive influence, indicating its role in symptom exacerbation. Positive perfectionism, moderately central, lacks direct influence on other symptoms.
CONCLUSION
This network analysis provides a nuanced understanding of the relationships among procrastination, rumination, perfectionism, and cognitive flexibility in academically gifted adolescents. Negative perfectionism and cognitive flexibility emerge as critical factors deserving attention in interventions aimed at enhancing the well-being of this unique group. Further research should explore causal relationships to refine targeted interventions.
Topics: Humans; Adolescent; Procrastination; Male; Female; Students; Perfectionism; Child, Gifted; Rumination, Cognitive; Iran; Surveys and Questionnaires; Adolescent Behavior
PubMed: 38943210
DOI: 10.1186/s40359-024-01868-6 -
Fish & Shellfish Immunology Jun 2024Takifugu rubripes is a highly valued cultured fish in Asia, while pathogen infections can result in severe diseases and lead to substantial economic losses. Toll-like...
Takifugu rubripes is a highly valued cultured fish in Asia, while pathogen infections can result in severe diseases and lead to substantial economic losses. Toll-like receptors (TLRs), as pattern recognition receptors, play a crucial role on recognition pathogens and initiation innate immune response. However, the immunological properties of teleost-specific TLR23 remain largely unknown. In this study, we investigated the biological functions of TLR23 (TrTLR23) from T. rubripes, found that TrTLR23 existed in various organs. Following bacterial pathogen challenge, the expression levels of TrTLR23 were significantly increased in immune related organs. TrTLR23 located on the cellular membrane and specifically recognized pathogenic microorganism. Co-immunoprecipitation and antibody blocking analysis revealed that TrTLR23 recruited myeloid differentiation primary response protein (MyD88), thereby mediating the activation of the ERK signaling pathway. Furthermore, in vivo showed that, when TrTLR23 is overexpressed in T. rubripes, bacterial replication in fish tissues is significantly inhibited. Consistently, when TrTLR23 expression in T. rubripes is knocked down, bacterial replication is significantly enhanced. In conclusion, these findings suggested that TrTLR23 played a critical role on mediation TLR23-MyD88-ERK axis against bacterial infection. This study revealed that TLR23 involved in the innate immune mechanism, and provided the foundation for development disease control strategies in teleost.
PubMed: 38942251
DOI: 10.1016/j.fsi.2024.109724 -
Journal of Hazardous Materials Jun 2024The hydrogen molecule can effectively regulate plant growth and development, improving plant resistance to abiotic stresses. However, studies regarding the optimal...
The hydrogen molecule can effectively regulate plant growth and development, improving plant resistance to abiotic stresses. However, studies regarding the optimal concentration of hydrogen and the associated mechanisms of action in organisms are lacking. This study showed that the maximum germination rate of radish seeds decreased from 90 % to 50 % under the stress of cadmium ions (Cd), and hydrogen nanobubble (NB) water significantly alleviated the stress effect of Cd on radish seed germination. A hydrogen concentration of 0.8 ppm had the best effect, reducing Cd accumulation in radish seeds by 63.23 % and increasing the maximum germination rate from 50 % to 65 %. At concentrations exceeding 1.2 ppm, the beneficial effect of hydrogen was weakened or even reversed. Consequently, we integrated the concept of the oxidative window into a REDOX balance model and demonstrated that an appropriate hydrogen concentration can effectively maintain the REDOX state within organisms. Transcriptome sequencing analysis revealed that hydrogen NB water modulated Cd absorption and accumulation in seeds by regulating cell wall components, alleviating oxidative stress through oxidoreductase activity, and enhancing nutrient synthesis and metabolism. This collectively alleviated the inhibitory effect of Cd on seed germination. This study is helpful for further understanding the effect of hydrogen concentration on the REDOX balance of seed germination, providing a theoretical basis for selecting hydrogen concentration to improve its effectiveness in agricultural fields.
PubMed: 38941838
DOI: 10.1016/j.jhazmat.2024.135035 -
Veterinary Microbiology Jun 2024Rabies, caused by lyssavirus rabies (Rabies lyssavirus, RABV), is a fatal disease among humans and almost all warm-blooded animals. In this study, we found that RABV...
Rabies, caused by lyssavirus rabies (Rabies lyssavirus, RABV), is a fatal disease among humans and almost all warm-blooded animals. In this study, we found that RABV infection induces the up-regulation of receptor transporter protein 4 (RTP4) in mouse brains and different cells of nervous tissue. Over-expression of RTP4 reduces the viral titer of RABV in different neuronal cells. Furthermore, a recombinant RABV expressing RTP4, named rRABV-RTP4, was constructed and displayed a lower viral titer in different neuronal cells due to the expression of RTP4. Moreover, the survival rates of mice infected with rRABV-RTP4 were significantly higher than those of mice infected with parent virus rRABV or control virus rRABV-RTP4(-). In terms of mechanism, RTP4 could bind viral genomic RNA (vRNA) of RABV, and suppress the whole viral genome amplification. In addition, we found that the zinc finger domain (ZFD) of RTP4 exerts the antiviral function by truncation analysis, and an important amino acids site (C95) in the RTP4 3CxxC motif which is essential for its antiviral function was identified by mutation analysis. This study contributes to our understanding of how RTP4 or other RTP proteins play a role in defense against the invasion of RABV or other viruses.
PubMed: 38941768
DOI: 10.1016/j.vetmic.2024.110159 -
Water Research Jun 2024Metals in the drinking water distribution system (DWDS) play an important role on the fate of disinfection by-products (DBPs). They can increase the formation of DBPs... (Review)
Review
Metals in the drinking water distribution system (DWDS) play an important role on the fate of disinfection by-products (DBPs). They can increase the formation of DBPs through several mechanisms, such as enhancing the proportion of reactive halogen species (RHS), catalysing the reaction between natural organic matter (NOM) and RHS through complexation, or by increasing the conversion of NOM into DBP precursors. This review comprehensively summarizes these complex processes, focusing on the most important metals (copper, iron, manganese) in DWDS and their impact on various DBPs. It organizes the dispersed 'metals-DBPs' experimental results into an easily accessible content structure and presents their underlying common or unique mechanisms. Furthermore, the practically valuable application directions of these research findings were analysed, including the toxicity changes of DBPs in DWDS under the influence of metals and the potential enhancement of generalization in DBP model research by the introduction of metals. Overall, this review revealed that the metal environment within DWDS is a crucial factor influencing DBP levels in tap water.
PubMed: 38941679
DOI: 10.1016/j.watres.2024.121991 -
Annual Review of Immunology Jun 2024The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities... (Review)
Review
The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.
Topics: Humans; Immunity, Innate; COVID-19; SARS-CoV-2; Cytokine Release Syndrome; Cytokines; Animals; Coronavirus Infections; Immune Evasion
PubMed: 38941608
DOI: 10.1146/annurev-immunol-083122-043545 -
Annual Review of Immunology Jun 2024Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (T) cells are strategically... (Review)
Review
Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (T) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating T cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of T cell heterogeneity and function across tissues and disease states. We discuss mechanisms of T cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how T cell responses might be durably boosted or dampened for therapeutic gain.
Topics: Humans; Animals; Immunologic Memory; Memory T Cells; Autoimmune Diseases; Organ Specificity; T-Lymphocyte Subsets; Immunologic Surveillance
PubMed: 38941605
DOI: 10.1146/annurev-immunol-101320-020220 -
The endosymbiont increases resistance to pathogens by enhancing iron sequestration and melanization.MBio Jun 2024Facultative endosymbiotic bacteria, such as and species, are commonly found in association with insects and can dramatically alter their host physiology. Many...
UNLABELLED
Facultative endosymbiotic bacteria, such as and species, are commonly found in association with insects and can dramatically alter their host physiology. Many endosymbionts are defensive and protect their hosts against parasites or pathogens. Despite the widespread nature of defensive insect symbioses and their importance for the ecology and evolution of insects, the mechanisms of symbiont-mediated host protection remain poorly characterized. Here, we utilized the fruit fly and its facultative endosymbiont to characterize the mechanisms underlying symbiont-mediated host protection against bacterial and fungal pathogens. Our results indicate a variable effect of on infection outcome, with endosymbiont-harboring flies being more resistant to , and but more sensitive or as sensitive as endosymbiont-free flies to the infections with species. Further focusing on the protective effect, we identified Transferrin-mediated iron sequestration induced by as being crucial for the defense against and . In the case of , enhanced melanization in -harboring flies plays a major role in protection. Both iron sequestration and melanization induced by require the host immune sensor protease Persephone, suggesting a role of proteases secreted by the symbiont in the activation of host defense reactions. Hence, our work reveals a broader defensive range of than previously appreciated and adds nutritional immunity and melanization to the defensive arsenal of symbionts.
IMPORTANCE
Defensive endosymbiotic bacteria conferring protection to their hosts against parasites and pathogens are widespread in insect populations. However, the mechanisms by which most symbionts confer protection are not fully understood. Here, we studied the mechanisms of protection against bacterial and fungal pathogens mediated by the endosymbiont . We demonstrate that besides the previously described protection against wasps and nematodes, also confers increased resistance to pathogenic bacteria and fungi. We identified -induced iron sequestration and melanization as key defense mechanisms. Our work broadens the known defense spectrum of and reveals a previously unappreciated role of melanization and iron sequestration in endosymbiont-mediated host protection. We propose that the mechanisms we have identified here may be of broader significance and could apply to other endosymbionts, particularly to , and potentially explain their protective properties.
PubMed: 38940615
DOI: 10.1128/mbio.00936-24