Molecular Mechanisms Research Articles

Mechanism of vitamin D deficiency involvement in the development of pulmonary arterial hypertension related to monocrotaline-induced connective tissue disease in rats

Objective: To investigating the impact of vitamin D (VitD) deficiency on the jagged 1 protein (Jagged1)/Notch3 signaling pathway in the pulmonary arteries of rats with monocrotaline (MCT)-induced connective tissue disease (CTD)-related pulmonary arterial hypertension (PAH) and to explore the pathological and molecular mechanisms of VitD involvement in the development of CTD-PAH. Methods: Twenty-four 7-week-old male Wistar rats were divided into a normal diet group and a VitD-free diet group using random number table, with 12 rats in each group. After 5 weeks of feeding, the rats were further randomly divided into saline and MCT groups, forming group A (normal diet+saline), group B (normal diet+MCT), group C (VitD-free+saline), and group D (VitD-free+MCT), with 6 rats in each group, and the rats were continued to be fed for another 4 weeks. The MCT group was injected with MCT solution subcutaneously on the back of the neck to construct the CTD-PAH model, and the saline group was injected with an equal amount of saline as a control. At the end of the experiment, blood samples were collected from all rats, and the serum 1, 25-dihydroxy vitamin D levels were determined by enzyme-linked immunosorbent assay. Hemodynamic measurements were performed on all rats, recording and calculating the mean values of right ventricular pressure and pulmonary artery pressure. Lung tissues and pulmonary arteries of all rats were stained with hematoxylin-eosin staining, the inner and outer diameters of pulmonary vessels were measured, and the percentage of pulmonary artery medial layer thickness was calculated. The right ventricular hypertrophy index was determined by weighing the parts of the heart and calculating the ratio. The apoptosis of pulmonary artery smooth muscle cells was assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. The expression levels of Jagged1, Notch3, and hairy and enhancer of split-1 (Hes1) mRNA and protein in the pulmonary arteries were analyzed by reverse transcription quantitative polymerase chain reaction and Western blotting. Results: The serum 1, 25-dihydroxy vitamin D levels in group D were significantly lower than those in groups A, B, and C [(51.01±0.96) μg/L, (65.15±1.83), (57.49±0.28), (54.52±2.87) μg/L, respectively, all P<0.05]. The right ventricular pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, and mean pulmonary artery pressure in Group D rats were significantly higher than those in groups A, B and C (all P<0.05). The percentage of pulmonary artery medial layer thickness in group D (56.28%±9.51%) was significantly higher than that in Groups A (21.28%±1.89%), B [22.72% (22.16%, 30.10%)], and C (38.73%±7.34%) (all P<0.05); the right ventricular hypertrophy index in group D (45.74%±12.68%) was significantly higher than that in groups A (21.78%±2.80%), B (40.93%±9.10%), and C (23.71%±1.22%) (all P<0.05). The apoptosis of pulmonary artery smooth muscle cells in group D (0.07±0.01) was significantly lower than that in groups A (1.00±0.08), B (0.17±0.02), and C (0.49±0.07) (all P<0.05). The levels of Jagged1, Notch3, and Hes1 mRNA and protein in Group D were all significantly higher than those in Groups A, B, and C (all P<0.05). Conclusions: VitD deficiency is involved in the pathophysiological mechanisms of CTD-PAH development. This occurs by upregulating the expression of the Jagged1/Notch3/Hes1 pathway in the pulmonary arteries of rats with MCT-induced PAH. The consequences include pulmonary artery thickening, increased pulmonary artery pressure, increased right ventricular pressure, right ventricular hypertrophy, and decreased apoptosis of pulmonary artery cells.

Study the role of xanthine oxidase inhibitor, allopurinol in experimentally induced steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease which can lead to cirrhosis and hepatic failure. It is observed in patients with both type 1 and type 2 diabetes mellitus (T1DM, T2DM). Allopurinol, a xanthine oxidase inhibitor that is widely used in clinical practice, has been demonstrated to reduce hepatic oxidative stress and attenuate acute liver injury which may be through activation of antioxidant pathways. This work aimed at investigating the role of Allopurinol (ALP) in attenuation of type 1 diabetes associated with Nonalcoholic fatty liver disease (NAFLD) and exploring the possible molecular mechanism by which ALP attenuates NASH in type 1 diabetes. Forty-five adult male albino rats were included in the study. They were randomly allocated to 3 equal groups: group I (control), Group II (diabetic animals), Group III (diabetic animals with allopurinol treatment). At the end of this experimental study measurements of serum glucose, ALT, AST, cholesterol, triglyceride, serum levels of uric acid, malondialdehyde (MDA), serum superoxide dismutase (SOD) were done. Histological analysis of liver tissue to diagnose steatohepatitis and gene expression of nuclear factor-erythroid-2- related factor-2 (Nrf2) &amp; TNFα were done. Diabetic rates treated with allopurinol (group III) showed decrease in serum levels of ALT, AST, cholesterol, uric acid and MDA compared to diabetic rat group. As regards TNF, gene expression was significantly decreased in group III compared to group II. This study also demonstrated that Nrf2α was significantly increased in group III compared to group II. Allopurinol also, ameliorated the histopathological changes observed in group II. In conclusion, allopurinol treatment increases the Nrf2 gene expression in the liver of STZ-induced diabetic rats and ameliorates steatohepatitis through modulation of TNF-α gene expression. Allopurinol could be a candidate for prevention or treatment of NAFLD.

Reported race-associated differences in control and schizophrenia post-mortem brain transcriptomes implicate stress-related and neuroimmune pathways

BackgroundThe molecular mechanisms underlying racial disparities in schizophrenia (SCZ) illness courses and outcomes are poorly understood. While these differences are thought to arise partly through stressful social gradients, little is known about how these differences are reflected in the brain, nor how they might underlie disparate psychiatric outcomes.MethodsTo better understand the neuro-molecular correlates of social gradients, SCZ, and their overlap, we analyzed post-mortem dorsolateral prefrontal cortex (DLPFC) RNAseq data from two racially diverse cohorts in the CommonMind Consortium (235 reported Black and 546 White, 322 SCZ cases and 459 controls) using differential expression and gene set variation analyses.ResultsWe observed differences in brain gene expression that were consistent across cohorts and reported race. A combined mega-analysis identified 1,514 genes with differential expression (DE) between reported race groups after accounting for diagnosis and other covariates. Functional enrichment analyses identified upregulation of genes involved in stress and immune response, highlighting the potential role of environmental differences between reported race groups. In a race-by-diagnosis interaction analysis, no individual genes passed statistical significance. However, 109 gene sets showed statistically significant differences, implicating metabolic and immune pathways.ConclusionOur results suggest molecular mechanisms uniquely perturbed across reported race groups and identify several candidate pathways associated with SCZ in a reported race-dependent manner. Our results underscore the importance of diverse cohort ascertainment to better capture population-level differences in SCZ pathogenesis.

The wheat CC-NBS-LRR protein TaRGA3 confers resistance to stripe rust by suppressing Ascorbate peroxidase 6 activity

Abstract Nucleotide-binding leucine-rich repeat (NLR) proteins are intracellular immune receptors that activate innate immune responses upon sensing pathogen attack. However, the molecular mechanisms by which NLR proteins initiate downstream signal transduction pathways to counteract pathogen invasion remain poorly understood. In this study, we identified the wheat (Triticum aestivum) NLR protein Resistance Gene Analogs3 (TaRGA3), which was significantly up-regulated during Puccinia striiformis f. sp. tritici (Pst) infection. TaRGA3 and its coiled-coil (CC) domain, localized to the cytoplasm and nucleus, can induce cell death in Nicotiana benthamiana. Virus-induced gene silencing (VIGS) and overexpression suggested that TaRGA3 contributed to wheat resistance to stripe rust by facilitating reactive oxygen species (ROS) accumulation. Yeast two-hybrid, luciferase complementation imaging, and co-immunoprecipitation assays revealed that TaRGA3 interacted with wheat protein Ascorbate Peroxidase 6 (TaAPX6). Further analysis showed that TaAPX6 specifically targeted the CC domain of TaRGA3. The TaRGA3-TaAPX6 interplay led to reduced enzyme activity of TaAPX6. Notably, TaAPX6 negatively regulated wheat resistance to Pst by removing excessive ROS accompanying Pst-induced hypersensitive responses. Our findings reveal that TaRGA3 responding to Pst infection confers enhanced wheat resistance to stripe rust, possibly by suppressing TaAPX6-modulated ROS scavenging, and demonstrate that TaRGA3 can be used to engineer stripe rust resistance in wheat.

Transcriptomic and Metabolomics Joint Analyses Reveal the Influence of Gene and Metabolite Expression in Blood on the Lactation Performance of Dual-Purpose Cattle (Bos taurus)

Blood is an important component for maintaining animal lives and synthesizing sugars, lipids, and proteins in organs. Revealing the relationship between genes and metabolite expression and milk somatic cell count (SCC), milk fat percentage, milk protein percentage, and lactose percentage in blood is helpful for understanding the molecular regulation mechanism of milk formation. Therefore, we separated the buffy coat and plasma from the blood of Xinjiang Brown cattle (XJBC) and Chinese Simmental cattle (CSC), which exhibit high and low SCC/milk fat percentage/milk protein percentage/lactose percentages, respectively. The expression of genes in blood and the metabolites in plasma was detected via RNA-Seq and LC-MS/MS, respectively. Based on the weighted gene coexpression network analysis (WGCNA) and functional enrichment analysis of differentially expressed genes (DEGs), we further found that the expression of genes in the blood mainly affected the SCC and milk fat percentage. Immune or inflammatory-response-related pathways were involved in the regulation of SCC, milk fat percentage, milk protein percentage, and lactose percentage. The joint analysis of the metabolome and transcriptome further indicated that, in blood, the metabolism pathways of purine, glutathione, glycerophospholipid, glycine, arginine, and proline are also associated with SCC, while lipid metabolism and amino-acid-related metabolism pathways are associated with milk fat percentage and milk protein percentage, respectively. Finally, related SCC, milk fat percentage, and milk protein percentage DEGs and DEMs were mainly identified in the blood.

Adipose tissue retains an epigenetic memory of obesity after weight loss

AbstractReducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.

FGF8 protects against polymicrobial sepsis by enhancing the host's anti-infective immunity

Abstract Background Sepsis is characterized by a life-threatening syndrome caused by an unbalanced host response to infection. Fibroblast Growth Factor 8 (FGF8) has been newly identified to play important roles in inflammation and innate immunity, but its role in host response to sepsis is undefined. Methods A cecal ligation and puncture (CLP) -induced mouse sepsis model was established to evaluate the immunomodulatory function of FGF8 during sepsis. The underlying molecular mechanisms were elucidated by cell models using relevant molecular biology experiments. The clinical value of FGF8 in the adjuvant diagnosis of sepsis was evaluated using clinical samples. Results FGF8 protein concentrations were elevated in CLP-induced septic mice compared to controls. In vivo, FGF8 blockade using anti-FGF8 antibody significantly increased mortality and bacterial burden and was paralleled by significantly aggravated tissue injury after CLP. Therapeutic administration of recombinant FGF8 (rFGF8) improved the bacterial clearance and mortality of septic mice in a FGFR1-dependent manner. In vitro, FGF8 directly enhanced bacterial phagocytosis and killing of macrophages by enhancing the phosphorylation of the ERK1/2 signaling pathway, which could be abrogated with the ERK1/2 pathway inhibitor U0126. Clinically, serum FGF8 levels in both adult and pediatric patients with sepsis from ICU were significantly higher than those in healthy controls. Conclusions These results present a previously unrecognized role of FGF8 in improving survival of sepsis by enhancing host immune defense. Therefore, targeting FGF8 may provide new strategies for the diagnosis and immunotherapy of sepsis.

Bibliometric analysis of microphthalmos and anophthalmos over 20 years: from 2004 to 2023

AIM: To conduct a bibliometric analysis of studies on microphthalmos and anophthalmos (M/A), explore research hotspots, and provide information on future research interests in this field to benefit clinicians and researchers. METHODS: Totally 751 publications related to M/A from the year 2004 to 2023 were collected from the Web of Science Core Collection database. These publications consist of both original and review articles, that are composed in English. The contributions of different countries, institutions, journals, and authors were analyzed, and network analysis was conducted by using Microsoft Excel 2021, VOSviewer, and R Studio to visualize research hotspots. RESULTS: Among all publications included, the highest number of publications came from USA (218, 29.03%). China followed with 99 publications (13.18%), and England with 86 publications (11.45%). The publications from the USA had the highest frequency of citations, with 16 699 citations, and the highest H-index of 49. The American Journal of Medical Genetics Part A (43, 5.73%) published the largest number of papers, and the University of London had the most publications (41, 5.46%). The genetic and molecular mechanisms of M/A were still unclear and the clinical intervention for M/A had gained a lot of attention as an emerging area of interest. CONCLUSION: Data have been gathered on the yearly count of published materials and citations, as well as the rise in publication trends, the efficiency of regions or countries, authors, journals, and organizations, along with the high-cited publications in M/A. The recent trend of research has shifted from genetic mechanisms to different clinical phenotypes and corresponding clinical interventions, which can give direction to future research.

Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases

Pathological aggregation of a specific protein into insoluble aggregates is a common hallmark of various neurodegenerative diseases (NDDs). In the earlier literature, each NDD is characterized by the aggregation of one or two pathogenic proteins, which can serve as disease-specific biomarkers. The aggregation of these specific proteins is thought to be a major cause of or deleterious result in most NDDs. However, accumulating evidence shows that a pathogenic protein can interact and co-aggregate with other pathogenic proteins in different NDDs, thereby contributing to disease onset and progression synergistically. During the past years, more than one type of NDD has been found to co-exist in some individuals, which may increase the complexity and pathogenicity of these diseases. This article reviews and discusses the biochemical characteristics and molecular mechanisms underlying the co-aggregation and co-pathologies associated with TDP-43 pathology. The TDP-43 aggregates, as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), can often be detected in other NDDs, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and spinocerebellar ataxia type 2 (SCA2). In many cases, TDP-43 is shown to interact and co-aggregate with multiple pathogenic proteins in vitro and in vivo. Furthermore, the co-occurrence and co-aggregation of TDP-43 with other pathogenic proteins have important consequences that may aggravate the diseases. Thus, the current viewpoint that the co-aggregation of TDP-43 with other pathogenic proteins in NDDs and their relevance to disease progression may gain insights into the patho-mechanisms and therapeutic potential of various NDDs.

NOTCH3 promotes malignant progression of bladder cancer by directly regulating SPP1 and activating PI3K/AKT pathway

AbstractThe biological role and precise molecular mechanisms of Notch receptor 3 (NOTCH3) in the malignant progression of bladder cancer (BLCA) remain unclear. In this study, we found that NOTCH3 was significantly upregulated and associated with poor prognosis in BLCA patients. Functional experiments demonstrated that NOTCH3 knockdown inhibited BLCA cell proliferation, migration, invasion and significantly suppressed tumor growth and metastasis in vivo as well. Mechanically, chromatin immunoprecipitation and dual-luciferase reporter assays confirmed that NOTCH3 could promote the transcription of secreted phosphoprotein 1 (SPP1), a potential downstream target gene of NOTCH3, by binding to the CSL elements in the SPP1 promoter. Moreover, we also found that targeting NOTCH3 inhibited BLCA growth and metastasis by suppressing the SPP1-PI3K/AKT axis. Our study highlights the critical role of NOTCH3-SPP1-PI3K/AKT axis in the malignant progression of BLCA, suggesting that NOTCH3 may be a potential therapeutic target for BLCA.

EphrinB2-mediated CDK5/ISL1 pathway enhances cardiac lymphangiogenesis and alleviates ischemic injury by resolving post-MI inflammation

AbstractEphrinB2 (erythropoietin-producing hepatoma interactor B2) is a key Eph/ephrin family member, promoting angiogenesis, vasculogenesis, and lymphangiogenesis during embryonic development. However, the role of EphrinB2 in cardiac lymphangiogenesis following myocardial infarction (MI) and the potential molecular mechanism remains to be demonstrated. This study revealed that EphrinB2 prevented ischemic heart post-MI from remodeling and dysfunction by activating the cardiac lymphangiogenesis signaling pathway. Deletion of EphrinB2 impaired cardiac lymphangiogenesis and aggravated adverse cardiac remodeling and ventricular dysfunction post-MI. At the same time, overexpression of EphrinB2 stimulated cardiac lymphangiogenesis which facilitated cardiac infiltrating macrophage drainage and reduced inflammation in the ischemic heart. The beneficial effects of EphrinB2 on improving clearance of inflammatory response and cardiac function were abolished in Lyve1 knockout mice. Mechanistically, EphrinB2 accelerated cell cycling and lymphatic endothelial cell proliferation and migration by activating CDK5 and CDK5-dependent ISL1 nuclear translocation. EphrinB2 enhanced the transcriptional activity of ISL1 at the VEGFR3 (FLT4) promoter, and VEGFR3 inhibitor MAZ51 significantly diminished the EphrinB2-mediated lymphangiogenesis and deteriorated the ischemic cardiac function. We uncovered a novel mechanism of EphrinB2-driven cardiac lymphangiogenesis in improving myocardial remodeling and function after MI.

CGAS/STING in skin melanoma: from molecular mechanisms to therapeutics

cGAS/STING in skin melanoma: from molecular mechanisms to therapeutics

LcASR enhances tolerance to abiotic stress in Leymus chinensis and Arabidopsis thaliana by improving photosynthetic performance

SUMMARYAs a crucial forage grass, Leymus chinensis plays significant roles in soil and water conservation owing to its robust stress resistance. However, the underlying molecular mechanisms of its stress tolerance remain unclear. In this study, a novel gene, designated as LcASR (Abiotic Stress Resistance in Leymus chinensis), imparting resilience to both high light and drought, was identified. Under normal growth conditions, heterologous overexpression of LcASR in Arabidopsis (HO lines) showed no significant difference in appearance compared to wild‐type. Nevertheless, HO lines accumulate significantly higher chlorophyll content during the dark‐to‐light transition compared to the wild‐type, indicating that the LcASR protein participates in chlorophyll synthesis during chloroplast development. Meanwhile, transgenic Arabidopsis and L. chinensis plants exhibited resistance to abiotic stresses such as high light and drought. Photosystem complexes analysis revealed that LHCII proteins remained stable within their respective complexes during high light stress. We hypothesize that LcASR may play a role in fine tuning of chlorophyll synthesis to enable plant adaptation to diverse stress conditions. Moreover, overexpression of LcASR in L. chinensis led to agronomically valuable traits such as deeper green color, higher biomass accumulation, prolonged withering period, and extended grazing durations. This study uncovers a novel gene in L. chinensis that enhances forage yield and provides valuable genetic resources for sheepgrass breeding.

A dynamical systems model for the total fission rate in Drp1-dependent mitochondrial fission

Mitochondrial hyperfission in response to cellular insult is associated with reduced energy production and programmed cell death. Thus, there is a critical need to understand the molecular mechanisms coordinating and regulating the complex process of mitochondrial fission. We develop a nonlinear dynamical systems model of dynamin related protein one (Drp1)-dependent mitochondrial fission and use it to identify parameters which can regulate the total fission rate (TFR) as a function of time. The TFR defined from a nondimensionalization of the model undergoes a Hopf bifurcation with bifurcation parameter μ = k + M k - where M is the total concentration of mitochondrial fission factor (Mff) and k+ and k− are the association and dissociation rate constants between oligomers on the outer mitochondrial membrane. The variable μ can be thought of as the maximum build rate over the disassembling rate of oligomers. Though the nondimensionalization of the system results in four dimensionless parameters, we found the TFR and the cumulative total fission (TF) depend strongly on only one, μ. Interestingly, the cumulative TF does not monotonically increase as μ increases. Instead it increases with μ to a certain point and then begins to decrease as μ continues to increase. This non-monotone dependence on μ suggests interventions targeting k+, k−, or M may have a non-intuitive impact on the fission mechanism. Thus understanding the impact of regulatory parameters, such as μ, may assist future therapeutic target selection.

Deficiency of FABP7 Triggers Premature Neural Differentiation in Idiopathic Normocephalic Autism Organoids

AbstractAutism spectrum disorder (ASD), which is caused by heterogeneous genetic and environmental factors, is characterized by diverse clinical phenotypes linked to distinct pathological mechanisms. ASD individuals with a shared clinical phenotype might contribute to revealing the molecular mechanism underlying ASD progression. Here, it is generated induced pluripotent stem cell (iPSC)‐derived cerebral organoids from normocephalic individuals with ASD in a prospective birth cohort with a shared clinical diagnosis. Multiple cell lines and time series scRNA‐seq combined with a histomorphological analysis revealed premature neural differentiation of neural stem cells (NSCs) and decreased expression of Fatty acid binding protein 7 (FABP7) in ASD organoids. It is subsequently revealed alterations in the phosphorylation levels of Mitogen‐Activated Protein Kinase Kinase 1/2 (MEK1/2), which are downstream of FABP7, and the regulation of the FABP7/MEK pathway reversed improper neural differentiation in the ASD organoids. Moreover, both Fabp7‐knockdown and MEK2‐overexpressing mice exhibited repetitive stereotyped behaviors and social defects relevant to autism. This study reveals the role of the FABP7/MEK pathway in abnormal NSC differentiation in normocephalic individuals with ASD, which might provide a promising therapeutic target for ASD treatment.

A Critical Review of Recent Advances in Maize Stress Molecular Biology

With the intensification of global climate change and environmental stress, research on abiotic and biotic stress resistance in maize is particularly important. High temperatures and drought, low temperatures, heavy metals, salinization, and diseases are widespread stress factors that can reduce maize yields and are a focus of maize-breeding research. Molecular biology provides new opportunities for the study of maize and other plants. This article reviews the physiological and biochemical responses of maize to high temperatures and drought, low temperatures, heavy metals, salinization, and diseases, as well as the molecular mechanisms associated with them. Special attention is given to key transcription factors in signal transduction pathways and their roles in regulating maize stress adaptability. In addition, the application of transcriptomics, genome-wide association studies (GWAS), and QTL technology provides new strategies for the identification of molecular markers and genes for maize-stress-resistance traits. Crop genetic improvements through gene editing technologies such as the CRISPR/Cas system provide a new avenue for the development of new stress-resistant varieties. These studies not only help to understand the molecular basis of maize stress responses but also provide important scientific evidence for improving crop tolerance through molecular biological methods.

Aflatoxin Exposure-Caused Male Reproductive Toxicity: Molecular Mechanisms, Detoxification, and Future Directions

Widespread endocrine disorders and infertility caused by environmental and food pollutants have drawn considerable global attention. Aflatoxins (AFTs), a prominent class of mycotoxins, are recognized as one of the key contributors to environmental and food contamination. Aflatoxin B1 (AFB1) is the most potent and toxic pollutant among them and is known to cause multiple toxic effects, including neuro-, nephro-, hepato-, immune-, and genotoxicity. Recently, concerns have been raised regarding AFB1-induced infertility in both animals and humans. Exposure to AFB1 can disrupt the structure and functionality of reproductive organs, leading to gametogenesis impairment in males, subsequently reducing fertility. The potential molecular mechanisms have been demonstrated to involve oxidative stress, cell cycle arrest, apoptosis, inflammatory responses, and autophagy. Furthermore, several signaling pathways, including nuclear factor erythroid 2-related factor 2; NOD-, LRR-, and pyrin domain-containing protein 3; nuclear factor kappa-B; p53; p21; phosphoinositide 3-kinase/protein kinase B; the mammalian target of rapamycin; adenosine 5′-monophosphate-activated protein kinase; and mitochondrial apoptotic pathways, are implicated in these processes. Various interventions, including the use of small molecules, Chinese herbal extracts, probiotic supplementation, and camel milk, have shown efficacy in ameliorating AFB1-induced male reproductive toxicity, by targeting these signaling pathways. This review provides a comprehensive summary of the harmful impacts of AFB1 exposure on male reproductive organs in mammals, highlighting the potential molecular mechanisms and protective agents.

Molecular Mechanisms of Heterosis and Its Applications in Tree Breeding: Progress and Perspectives

Heterosis, or hybrid vigor, refers to the phenomenon where hybrid progenies outperform their parents in traits such as yield and resistance. This phenomenon has been widely applied in plant breeding. Recent advances in high-throughput genomics have significantly advanced our understanding of heterosis. This review systematically summarizes the genetic, molecular, and epigenetic mechanisms underlying heterosis. Furthermore, we discuss recent advances in predictive methods for heterosis and their applications in improving growth rate, resistance to abiotic stresses, and wood yield in tree species. We also explore the role of tree genomics in unraveling the mechanisms underlying heterosis, emphasizing the potential of integrating high-resolution genomics, single-cell sequencing, and spatial transcriptomics to achieve a comprehensive understanding of heterosis from the molecular to spatial levels. Building on this, CRISPR-based gene-editing technologies can be employed to precisely edit heterotic loci, enabling the study of allele function. Additionally, molecular marker-assisted selection (MAS) can be utilized to identify heterotic loci in parental lines, facilitating the selection of optimal hybrid combinations and significantly reducing the labor and time costs of hybrid breeding. Finally, we review the utilization of heterosis in tree breeding and provide a forward-looking perspective on future research directions, highlighting the potential of integrating multi-omics approaches and emerging gene-editing tools to revolutionize tree hybrid breeding.

Abstract C046: PARP inhibitors as immune modulators in metastatic ovarian cancer treatment

Abstract Epithelial ovarian carcinoma (EOC) is one of the top five causes of cancer-related death in women. Most patients with EOC achieve initial remission after primary or interval cytoreductive surgery combined with platinum-taxane chemotherapy. However, mutations in BRCA1 or BRCA2 genes, which lead to homologous recombination (HR) defects, play a crucial role in platinum sensitivity and justify the use of poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy, commonly linked to extended progression-free survival (PFS). Besides their direct cytotoxic and cytostatic effects, PARP inhibitors (PARPi) have shown significant immunostimulatory properties by disrupting DNA repair in cancer cells, and opening possibilities for synergy with immune checkpoint inhibitors (ICIs). In this study, we investigate the immunomodulatory effects of PARPi using multiparametric flow cytometry, multiplexed immunolabeling, single-cell transcriptomics, and functional assays in an experimental BR5Brca1-/- syngeneic mouse model and human EOC tumor samples. We examine the molecular and cellular mechanisms that can be exploited to develop more effective combination therapies. PARPi may increase the mutational burden in EOCs due to unresolved DNA damage and the release of damage-associated molecular patterns (DAMPs), thereby increasing T-cell infiltration. In addition, PARPi appear to promote potent type I interferon (IFN) secretion through the activation of cGAMP synthase and the stimulator of the interferon genes (STING) pathway. In combination with ICIs, PARPi showed a beneficial effect on the balance between adaptive anti-tumor immunity and innate myeloid components, leading to an improved cytotoxic T-cell response, as observed in mouse models and HGSOC tumor samples. These observations emphasize the role of strategically designed combinations of PARPi and immunotherapeutic agents, which could be the key to overcoming immunosuppression in the EOC microenvironment, thereby improving clinical outcomes. Citation Format: Sarka Vosahlikova, Peter Holicek, Irena Moserova, Michal Hensler, Romana Mikyskova, Lenka Kasikova, Josef Pasuvka, Jana Drozenova, Katerina Mojzisova, Marek Kovar, Iain McNiesh, Michael Halaska, Lukas Rob, Sandra Orsulic, Milan Reinis, Lorenzo Galluzzi, Radek Spisek, Jitka Palich Fucikova. PARP inhibitors as immune modulators in metastatic ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C046.

Impact of Hyaluronic Acid and Other Re-Epithelializing Agents in Periodontal Regeneration: A Molecular Perspective

This narrative review delves into the molecular mechanisms of hyaluronic acid (HA) and re-epithelializing agents in the context of periodontal regeneration. Periodontitis, characterized by chronic inflammation and the destruction of tooth-supporting tissues, presents a significant challenge in restorative dentistry. Traditional non-surgical therapies (NSPTs) sometimes fail to fully manage subgingival biofilms and could benefit from adjunctive treatments. HA, with its antibacterial, antifungal, anti-inflammatory, angiogenic, and osteoinductive properties, offers promising therapeutic potential. This review synthesizes the current literature on the bioactive effects of HA and re-epithelializing agents, such as growth factors and biomaterials, in promoting cell migration, proliferation, and extracellular matrix (ECM) synthesis. By modulating signaling pathways like the Wnt/β-catenin, TGF-β, and CD44 interaction pathways, HA enhances wound healing processes and tissue regeneration. Additionally, the role of HA in facilitating cellular crosstalk between epithelial and connective tissues is highlighted, as it impacts the inflammatory response and ECM remodeling. This review also explores the combined use of HA with growth factors and cytokines in wound healing, revealing how these agents interact synergistically to optimize periodontal regeneration. Future perspectives emphasize the need for further clinical trials to evaluate the long-term outcomes of these therapies and their potential integration into periodontal treatment paradigms.