Origin and evolution of a new tetraploid mangrove species in an intertidal zone.

Polyploidy is a major factor in the evolution of plants, yet we know little about the origin and evolution of polyploidy in intertidal species. This study aimed to identify the evolutionary transitions in three true-mangrove species of the genus Acanthus distributed in the Indo-West Pacific region. For this purpose, we took an integrative approach that combined data on morphology, cytology, climatic niche, phylogeny, and biogeography of 493 samples from 42 geographic sites. Our results show that the Acanthus ilicifolius lineage distributed east of the Thai-Malay Peninsula possesses a tetraploid karyotype, which is morphologically distinct from that of the lineage on the west side. The haplotype networks and phylogenetic trees for the chloroplast genome and eight nuclear genes reveal that the tetraploid species has two sub-genomes, one each from A. ilicifolius and A . ebracteatus, the paternal and maternal parents, respectively. Population structure analysis also supports the hybrid speciation history of the new tetraploid species. The two sub-genomes of the tetraploid species diverged from their diploid progenitors during the Pleistocene. Environmental niche models revealed that the tetraploid species not only occupied the near-entire niche space of the diploids, but also expanded into novel environments. Our findings suggest that A. ilicifolius species distributed on the east side of the Thai-Malay Peninsula should be regarded as a new species, A. tetraploideus, which originated from hybridization between A. ilicifolius and A. ebracteatus, followed by chromosome doubling. This is the first report of a true-mangrove allopolyploid species that can reproduce sexually and clonally reproduction, which explains the long-term adaptive potential of the species.

Identification of differentially expressed tumour-related genes regulated by UHRF1-driven DNA methylation.

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an epigenetic regulator that plays critical roles in tumours. However, the DNA methylation alteration patterns driven by UHRF1 and the related differentially expressed tumour-related genes remain unclear. In this study, a UHRF1-shRNA MCF-7 cell line was constructed, and whole-genome bisulfite sequencing and RNA sequencing were performed. The DNA methylation alteration landscape was elucidated, and DNA methylation-altered regions (DMRs) were found to be distributed in both gene bodies and adjacent regions. The DMRs were annotated and categorized into 488 hypermethylated/1696 hypomethylated promoters and 1149 hypermethylated/5501 hypomethylated gene bodies. Through an integrated analysis with the RNA sequencing data, 217 methylation-regulated upregulated genes and 288 downregulated genes were identified, and these genes were primarily enriched in nervous system development and cancer signalling pathways. Further analysis revealed 21 downregulated oncogenes and 15 upregulated TSGs. We also showed that UHRF1 silencing inhibited cell proliferation and migration and suppressed tumour growth in vivo. Our study suggested that UHRF1 and the oncogenes or TSGs it regulates might serve as biomarkers and targets for breast cancer treatment.

Colchicine-mediated selective autophagic degradation of HBV core proteins inhibits HBV replication and HBV-related hepatocellular carcinoma progression.

The HBV core protein (HBc) is an important viral protein of HBV that plays an indispensable role in the lifecycle of HBV, including capsid assembly and transport, reverse transcription and virus release. In recent years, evidence has shown that HBc may be involved in the malignant progression of HCC. Thus, HBc is an attractive target for antiviral agents and provides a new strategy for the treatment of HBV-related HCC. Here, we identified a novel anti-HBc compound-colchicine, an alkaloid compound-that promoted selective autophagic degradation of HBc through the AMPK/mTOR/ULK1 signalling pathway. We further confirmed that colchicine promoted the selective autophagy of HBc by enhancing the binding of HBc to the autophagy receptor p62. Finally, we evaluated the effects of colchicine on HBV replication and HBc-mediated HCC metastasis in vitro and in vivo. Our research indicated that the inhibitory effects of colchicine on HBV and HBV-related HCC depend on the selective autophagic degradation of HBc. Thus, colchicine is not only a promising therapeutic strategy for chronic hepatitis B but also a new treatment for HBV-related HCC.

Enhanced desmosome assembly driven by acquired high-level desmoglein-2 promotes phenotypic plasticity and endocrine resistance in ER+ breast cancer.

Acquired resistance to endocrine treatments remains a major clinical challenge. In this study, we found that desmoglein-2 (DSG2) plays a major role in acquired endocrine resistance and cellular plasticity in ER+ breast cancer (BC). By analysing the well-established fulvestrant-resistant ER+ BC model using single-cell RNA-seq, we revealed that ER inhibition leads to a specific increase in DSG2 in cancer cell populations, which in turn enhances desmosome formation in vitro and in vivo and cell phenotypic plasticity that promotes resistance to treatment. DSG2 depletion reduced tumorigenesis and metastasis in fulvestrant-resistant xenograft models and promoted fulvestrant efficiency. Mechanistically, DSG2 forms a desmosome complex with JUP and Vimentin and triggers Wnt/PCP signalling. We showed that elevated DSG2 levels, along with reduced ER levels and an activated Wnt/PCP pathway, predicted poor survival, suggesting that a DSG2high signature could be exploited for therapeutic interventions. Our analysis highlighted the critical role of DSG2-mediated desmosomal junctions following antiestrogen treatment.

Assessment of myocardial microvascular dysfunction in patients with different stages of diabetes mellitus: An adenosine stress perfusion cardiac magnetic resonance study.

PURPOSE: To examine myocardial perfusion and T1 mapping indicesin individuals with type 2 diabetes mellitus (T2DM) at various stages of glycemic control and whether uncontrolled glycemic levels would worsen myocardial microvascular function. METHOD: Cardiac magnetic resonance examinations were performed on 114 T2DM patients without obstructive coronary artery disease and 55 matched controls. Participants were further divided into four subgroups: Q1 (control); Q2 (prediabetes); Q3 (controlled T2DM) and Q4 (uncontrolled T2DM). The correlation between glycosylated hemoglobin (HbA1c) levels and myocardial perfusion parameters was evaluated. RESULTS: Global myocardial perfusion reserve index (MPRI) was significantly reduced in the Q3 and Q4 subgroups compared to the Q1 or Q2 subgroup (all P<0.001). Compared with the Q1 subgroup, global stress T1 reactivity (stress ΔT1) was significantly reduced in the Q3 and Q4 subgroups (P=0.004 and < 0.001, respectively), but elevated in the Q2 subgroup (P=0.018). Global extracellular volume (ECV) was considerably higher in the Q2 subgroup and gradually rose in the Q3 and Q4 subgroups compared to the Q1 subgroup (P=0.011, 0.001, and 0.007, respectively). HbA1c levels correlated negatively with global MPRI and stress ΔT1, but positively with global ECV (ß = -1.993, P<0.001; ß = -0.180, P<0.001; and ß = 0.127, P<0.001, respectively). CONCLUSIONS: Global stress ΔT1 reduced in T2DM patients but rose in prediabetes patients. Compared to MPRI, the ECV parameter can indicate diabetes-induced coronary microvascular dysfunction earlier and persists throughout the disorder. Myocardial perfusion and T1 mapping at stress can be used to detect early signs of microvascular dysfunction and subclinical risk factors in patients with T2DM.

Long-term trends in lifestyle factors among respondents with dyslipidemia in the United States.

OBJECTIVES: To explore the long-term trends in unhealthy lifestyle factors and the risk sociodemographic subgroups among people with dyslipidemia. METHODS: Data extracted from the 1999 to 2018 National Health and Nutrition Examination Survey (NHANES). Lifestyle factors were smoking status, alcohol drinking, obesity, dietary quality, depression, physical activity, and sedentary behavior. A Joinpoint regression model was used to estimate trends in the log-transformed age-standardized prevalence. Multinomial logistic regression models adjusted for age, sex, and race/ethnicity were used to analyze subgroups by sociodemographic factors. RESULTS: Data for 33,680 respondents were extracted between 1999 and 2018. The prevalence of smoking and poor-quality diet decreased from 1999 to 2018 (P<0.001), while obesity significantly increased (P<0.001). The prevalence of depression marginally increased from 2005 to 2018 (P=0.074). We observed that non-Hispanic Black individuals, Hispanics, males, as well as those with lower family income-to-poverty ratios and education levels, unemployed individuals, or those lacking a spouse/live-in partner, were at elevated risk of unhealthy lifestyle factors when compared to the reference groups. CONCLUSIONS: Among NHANES respondents from 1999 to 2018 with dyslipidemia, significant reductions in the prevalence of current smoking and poor diet were observed, while the prevalence of obesity was markedly increased. There were sociodemographic differences in the management of lifestyle factors. Further initiatives to encourage people with dyslipidemia are required to reduce potential adverse outcomes.

The molecular mechanism underlying KRAS regulation on STK31 expression in pancreatic ductal adenocarcinoma.

KRAS gene mutations are common in pancreatic ductal adenocarcinoma (PDAC), but targeting mutant KRAS is still challenging. Here, an endoribonuclease-prepared small interfering RNA (esiRNA) library was used to screen new kinases that play critical roles in PDAC driven by KRAS gene mutations, and serine/threonine kinase 31 (STK31) was identified and characterized as a potential therapeutic target for KRAS-mutant PDAC. Our results showed that STK31 was upregulated in KRAS-mutant PDAC patients with poor survival and highly expressed in PDAC cell lines with KRASG12D mutation. Inhibition of STK31 in KRAS-mutant cell lines significantly reduced PDAC cell growth in vitro and hindered tumor growth in vivo. Gain and loss of function experiments revealed that STK31 is a downstream target of KRAS in PDAC. A pharmacological inhibition assay showed MAPK/ERK signaling involved in STK31 regulation. The further mechanistic study validated that c-Jun, regulated by KRAS/MAPK signaling, directly modulates the transcription level of STK31 by binding to its promoter region. Through RNA sequencing, we found that the cell cycle regulators CCNB1 and CDC25C are downstream targets of STK31. Taken together, our results indicate that STK31, which is the downstream target of the KRAS/MAPK/ERK/c-Jun signaling pathway in KRAS-mutant PDAC, promotes PDAC cell growth by modulating the expression of the cell cycle regulators CCNB1 and CDC25C.

Achieving Digestive Autonomy and Gastrointestinal Continuity in a Patient with Short Bowel Syndrome Secondary to Concomitant Jejunal Atresia and Small Intestinal Hirschsprung's Disease.

Concomitant presentation of jejunal atresia and Hirschsprung's disease is rare and places children at high risk for developing short bowel syndrome and parenteral nutrition dependence, which can affect the feasibility/timing of pull-through. A patient was born with jejunal atresia with a delayed diagnosis of Hirschsprung's disease. After several procedures and bowel resections, the patient was ultimately left with an end jejunostomy and long Hartman's pouch with short bowel syndrome, dependent on parenteral nutrition. The patient initially presented to our institution at age 2 with failure to thrive secondary to an obstructed/dilated jejunostomy and mild enterocolitis of their defunctionalized segment. The patient subsequently underwent completion of subtotal colectomy and revision of jejunostomy utilizing a serial transverse enteroplasty to manage the dilated bowel and gain length. The patient was able to wean off parenteral nutrition and achieve nutritional autonomy by age 5. Following this, the patient was able to undergo an ileoanal pull-through. After the pull-through, the patient was able to pass stool independently and suffered no major complications to date. Serial transverse enteroplasty can be successfully utilized in patients with a history of Hirschsprung's disease and jejunal atresia to achieve nutritional autonomy and ultimately reestablish gastrointestinal continuity with pull-through.

Speciation, phytoavailability, and accumulation of toxic elements and sulfur by humic acid-fertilized lemongrass and common sage in a sandy soil treated with heavy oil fly ash: A trial for management of power stations wastes.

Globally, power stations generate huge amounts of the hazardous waste heavy oil fly ash (HOFA), which is rich in Ni, V, Fe, S, and dumped into landfills. Thus, exploring new approaches for a safe recycling and sustainable management of HOFA is needed and of great environmental interest. The potential application of HOFA as an amendment to sandy soils has not been studied yet. This is the first research investigating the potentiality of using HOFA as a soil conditioner. To this end, we conducted a greenhouse experiment in order to investigate the impacts of HOFA addition (1.2, 2.4, 3.6 t ha-1) to sandy soil on the total and available content of nutrients (e.g., S, Fe, Mn, Cu, Zn) and toxic elements (TEs; e.g., Cd, Co, Cr, Ni, Pb, V) in the soil and their phytoextraction and translocation by lemongrass (Cymbopogon citratus) and common sage (Salvia officinalis). We also assessed the impact of humic acid (HA) foliar application (50 and 100 l ha-1) on the growth and elements accumulation by the two plants. The studied HOFA was acidic and highly enriched in S (43,268.0), V (3,527.0), Ni (1774.0), and Fe (15,159.0) (units in mg kg-1). The X-ray absorption near edge structure (XANES) data showed that V in HOFA was composed primarily of V(IV) sorbed onto goethite, V(V) sorbed onto humic substances, in the forms of V2O3, and VCl4. Addition of the lower doses of HOFA (1.2 and 2.4 t ha-1) did not change significantly soil pH, salinity, and the total and available elements content compared to the unamended soil. Although the elements content in the 3.6 t ha-1 HOFA-treated soil was significantly higher than the untreated, the total content of all elements (except for Ni) was lower than the maximum allowable concentrations in soils. HOFA addition, particularly in the highest dose (3.6 t ha-1), decreased significantly the growth and biomass of both plants. Common sage accumulated more elements than lemongrass; however, the elements content in the plants was lower than the critical concentrations for sensitive plants. The foliar application of humic acid enhanced significantly the plant growth and increased their tolerance to the HOFA-induced stress. We conclude that the addition of HOFA up to 2.4 t ha-1 in a single application as amendment to sandy soils is not likely to create any TE toxicity problems to plants, particularly if combined with a foliar application of humic acid; however, repeated additions of HOFA may induce toxicity. These findings should be verified under field conditions.

Dearomative Intramolecular meta-Thermocycloadditions of Benzene Rings via Wheland Intermediates.

Dearomative cycloadditions are powerful synthetic transformations utilizing aromatic compounds for cycloaddition reactions. They have been extensively applied to the synthesis of biologically relevant compounds not only because of the complexity generated from simplicity but also the atom- and step-economy. For the most studied yet challenging benzene ring systems, ortho- and para-cycloadditions have been realized both photochemically and thermally, while the meta-cycloadditions are still limited to the photochemical processes tracing back to the 1960s. Herein, we for the first time realized the thermal cycloadditions of benzene rings with alkenes in a meta fashion via Wheland intermediates. A broad spectrum of readily available C(sp2)-rich aniline-tethered enynes were transformed into C(sp3)-rich 3D complex polycyclic architectures simply by stirring in TFA. Moreover, the reaction could be performed in gram-scales and the products could be diversely elaborated.

Idebenone alleviates doxorubicin-induced cardiotoxicity by stabilizing FSP1 to inhibit ferroptosis.

Doxorubicin (DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients, but related pharmacotherapeutic measures are relatively limited. Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity. Idebenone, a novel ferroptosis inhibitor, is a well-described clinical drug widely used. However, its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear. In this study, we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism. A single intraperitoneal injection of DOX (15 mg/kg) was administrated to establish DOX-induced cardiotoxicity. The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe2+ and ROS overload, which resulted in ferroptosis. CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1. Interestingly, idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX. Idebenone could form stable hydrogen bonds with FSP1 protein at K355, which may influence its association with ubiquitin. The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation. In conclusion, this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1, making it a potential clinical drug for patients receiving DOX treatment.

Accumulation and bio-oxidation of arsenite mediated by thermoacidophilic Cyanidiales: innate potential biomaterials toward arsenic remediation.

Addressing geogenic and anthropogenic arsenic (As) pollution is critical for environmental health. This study explored arsenite [As(III)] removal using Cyanidiales, particularly Cyanidium caldarium (Cc) and Galdieria partita (Gp), under acidic to neutral pH, and determined As(III) detoxification mechanisms in relation to As speciation and protein secondary structure in Cyanidiales. Regarding As(III) sorption amounts, Cc outperformed Gp, reaching 83.2 mg g-1 of removal at pH 5.0. Wherein, 23.5 % of sorbed As on Cc presented as arsenate [As(V)] complexation with polysaccharides, alongside other predominant species including As(III)-cysteine (41.2 %) and As(III)-polysaccharides (35.3 %) complexes. This suggested that As(III) was directly transported into cells, rather than As(V). Coupled with the formation of As(III)-cysteine complexes within cells, these mechanisms may be key to efficiently accumulating As(III) in Cyanidiales during the 6-h incubation. These results highlight the potential of Cyanidiales for sustainable As(III) remediation and provide new insights into managing As(III) toxicity.

Development of composite functional tissue sheets using hiPSC-CMs and hADSCs to improve the cardiac function after myocardial infarction.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in therapy of ischemic heart disease. However, there are still remaining issues that limit the therapeutic efficacy, such as immune rejection and low retention of hiPSC-CMs. Human adipose mesenchymal stromal cells (hADSCs) have been reported to be able to regulate the immune response, promote angiogenesis and promote the maturation of hiPSC-CMs. In this study, we co-cultured these two types of cells on fiber scaffold made of biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer for several days to develop a composited 3D cardiac tissue sheet. As expected, the cells formed 231.00 ± 15.14 µm thickness tissue, with improved organization, alignment, ECM condition, contractile ability, and paracrine function compared to culture hiPSC-CMs only on PLGA fiber. Furthermore, the composited 3D cardiac tissue sheet significantly promoted the engraftment and survival after transplantation. The composited 3D cardiac tissue sheet also increased cardiac function, attenuated ventricular remodeling, decreased fibrosis, and enhanced angiogenesis in rat myocardial infarction model, indicating that this strategy wound be a promising therapeutic option in the clinical scenario.

Associations between chronic obstructive pulmonary disease and ten common cancers: novel insights from Mendelian randomization analyses.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a significant global health issue, suspected to elevate the risk for various cancers. This study sought to discern whether COPD serves as a risk marker or a causative factor for prevalent cancers. METHODS: We employed univariable MR (UVMR) analyses to investigate the causal relationship between COPD and the top ten common cancers. Sensitivity analyses were performed to validate the main findings. Multivariable MR (MVMR) and two-step MR analyses were also conducted. False-discovery-rate (FDR) was used to correct multiple testing bias. RESULTS: The UVMR analysis demonstrated notable associations between COPD and lung cancer (odds ratio [OR] = 1.42, 95%CI 1.15-1.77, FDR = 6.37 × 10-3). This relationship extends to lung cancer subtypes such as squamous cell carcinoma (LUSC), adenocarcinoma (LUAD), and small cell lung cancer (SCLC). A tentative link was also identified between COPD and bladder cancer (OR = 1.53, 95%CI 1.03-2.28, FDR = 0.125). No significant associations were found between COPD and other types of cancer. The MVMR analysis that adjusted for smoking, alcohol drinking, and body mass index did not identify any significant causal relationships between COPD and either lung or bladder cancer. However, the two-step MR analysis indicates that COPD mediated 19.2% (95% CI 12.7-26.1%), 36.1% (24.9-33.2%), 35.9% (25.7-34.9%), and 35.5% (26.2-34.8%) of the association between smoking and overall lung cancer, as well as LUAD, LUSC, and SCLC, respectively. CONCLUSIONS: COPD appears to act more as a risk marker than a direct cause of prevalent cancers. Importantly, it partially mediates the connection between smoking and lung cancer, underscoring its role in lung cancer prevention strategies.

Comparative efficacy and safety of targeted therapy and immunotherapy for HER2-positive breast cancer: a systematic review and network meta-analyses.

Background: In recent years, novel therapies targeting specific molecular pathways and immunotherapies have exhibited promising outcomes for treating human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Our work aimed to assess the effectiveness and safety of these emerging treatment regimens for this disease. Material and methods: We systematically searched databases including PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials their inception to August 2023 to identify relevant randomized controlled trials (RCTs). The quality of eligible RCTs was evaluated with the Cochrane risk-of-bias tool, version 2 (RoB2). Investigated outcomes encompassed progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), pathologic complete remission (pCR), and adverse events (AEs). They were expressed as hazard ratio (HR) with 95% conference intervals (CI) or risk ratio (RR) with 95% CI. Results: Our analysis identified a total of 28 RCTs suitable for inclusion in the NMA. Regarding the PFS, all these treatment regimens exhibited comparable effectiveness. In terms of OS, Capecitabine+Trastuzumab, Lapatinib+Trastuzumab and Pyrotinib+Capecitabine exhibited better effect compared to other treatments. Regarding pCR and AEs, all these treatment regimens exhibited comparable effectiveness, especially Lapatinib+Trastuzumab and Pyrotinib+Capecitabine. Conclusion: Our study highlights the prominent role of targeted therapies and immunotherapies in treating HER2-positive breast cancer. The efficacy of trastuzumab-containing regimens was superior to other treatment options, while maintaining a comparable safety profile. Based on these findings, trastuzumab-containing regimens emerge as a preferable and recommended choice in clinical practice for managing HER2-positive breast cancer. Systematic Review Registration: PROSPERO, identifier CRD42023414348.

Exploring new frontiers: cell surface vimentin as an emerging marker for circulating tumor cells and a promising therapeutic target in advanced gastric Cancer.

BACKGROUND: Circulating tumor cells (CTCs) hold immense promise in guiding treatment strategies for advanced gastric cancer (GC). However, their clinical impact has been limited due to challenges in identifying epithelial-mesenchymal transition (EMT)-CTCs using conventional methods. METHODS: To bridge this knowledge gap, we established a detection platform for CTCs based on the distinctive biomarker cell surface vimentin (CSV). A prospective study involving 127 GC patients was conducted, comparing CTCs enumeration using both EpCAM and CSV. This approach enabled the detection of both regular and EMT-CTCs, providing a comprehensive analysis. Spiking assays and WES were employed to verify the reliability of this marker and technique. To explore the potential inducer of CSV+CTCs formation, a combination of Tandem Mass Tag (TMT) quantitative proteomics, m6A RNA immunoprecipitation-qPCR (MeRIP-qPCR), single-base elongation- and ligation-based qPCR amplification method (SELECT) and RNA sequencing (RNA-seq) were utilized to screen and confirm the potential target gene. Both in vitro and in vivo experiments were performed to explore the molecular mechanism of CSV expression regulation and its role in GC metastasis. RESULTS: Our findings revealed the potential of CSV in predicting therapeutic responses and long-term prognosis for advanced GC patients. Additionally, compared to the conventional EpCAM-based CTCs detection method, the CSV-specific positive selection CTCs assay was significantly better for evaluating the therapeutic response and prognosis in advanced GC patients and successfully predicted disease progression 14.25 months earlier than radiology evaluation. Apart from its excellent role as a detection marker, CSV emerges as a promising therapeutic target for attenuating GC metastasis. It was found that fat mass and obesity associated protein (FTO) could act as a potential catalyst for CSV+CTCs formation, and its impact on the insulin-like growth factor-I receptor (IGF-IR) mRNA decay through m6A modification. The activation of IGF-I/IGF-IR signaling enhanced the translocation of vimentin from the cytoplasm to the cell surface through phosphorylation of vimentin at serine 39 (S39). In a GC mouse model, the simultaneous inhibition of CSV and blockade of the IGF-IR pathway yielded promising outcomes. CONCLUSION: In summary, leveraging CSV as a universal CTCs marker represents a significant breakthrough in advancing personalized medicine for patients with advanced GC. This research not only paves the way for tailored therapeutic strategies but also underscores the pivotal role of CSV in enhancing GC management, opening new frontiers for precision medicine.

Lapatinib combined with doxorubicin causes dose-dependent cardiotoxicity partially through activating the p38MAPK signaling pathway in zebrafish embryos.

Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies.

Deep sequencing identified miR-193b-3p as a positive regulator of autophagy targeting Akt3 in Ctenopharyngodon idella CIK cells during GCRV infection.

Recent research has highlighted complex and close interaction between miRNAs, autophagy, and viral infection. In this study, we observed the autophagy status in CIK cells infected with GCRV at various time points. We found that GCRV consistently induced cellar autophagy from 0 h to 12 h post infection. Subsequently, we performed deep sequencing on CIK cells infected with GCRV at 0 h and 12 h respectively, identifying 38 DEMs and predicting 9581 target genes. With the functional enrichment analyses of GO and KEGG, we identified 35 autophagy-related target genes of these DEMs, among which akt3 was pinpointed as the most central hub gene using module assay of the PPI network. Then employing the miRanda and Targetscan programs for prediction, and verification through a double fluorescent enzyme system and qPCR method, we confirmed that miR-193 b-3p could target the 3'-UTR of grass carp akt3, reducing its gene expression. Ultimately, we illustrated that grass carp miR-193 b-3p could promote autophagy in CIK cells. Above results collectively indicated that miRNAs might play a critical role in autophagy of grass carp during GCRV infection and contributed significantly to antiviral immunity by targeting autophagy-related genes. This study may provide new insights into the intricate mechanisms involved in virus, autophagy, and miRNAs.

Surfactant-assisted molecular-level tunning of phenol-formaldehyde-based hard carbon microspheres for high-performance sodium-ion batteries.

The phenol-formaldehyde (PF) resin is an economical precursor for spherical hard carbon (HC) anodes for sodium-ion batteries (SIBs). However, achieving precise molecular-level control of PF-based HC microspheres, particularly for optimizing ion transport microstructure, is challenging. Here, a sodium linoleate (SL)-assisted strategy is proposed to enable molecular-level engineering of PF-based HC microspheres. PF microspheres are synthesized through the polymerization of 3-aminophenol and formaldehyde, initially forming oxazine rings and then undergoing ring-opening polymerization to create a macromolecular network. SL functions as both a surfactant to control microsphere size and a catalyst to enhance ring-opening polymerization and increase polymerization of PF resin. These modifications lead to reduced microsphere diameter, increased interlayer spacing, enhanced graphitization, and significantly improved electron and ion transfer. The synthesized HC microspheres exhibit a remarkable reversible capacity of 337 mAh/g, maintaining 96.9 mAh/g even at a high current density of 5.0 A/g. Furthermore, the full cell demonstrates a high capacity of 150 mAh/g, an energy density of 125.3 Wh kg-1, an impressive initial coulombic efficiency (ICE) of 930.3% at 1 A/g, and remarkable long-term stability over 3000 cycles. This study highlights the potential of surfactant-assisted molecular-level engineering in customizing HC microspheres for advanced SIBs.