YY1 mediated DCUN1D5 transcriptional activation promotes triple-negative breast cancer progression by targeting FN1/PI3K/AKT pathway.

Triple-negative breast cancer (TNBC) is more aggressive and has a higher metastasis rate compared with other subtypes of breast cancer. Due to the lack of drug-targetable receptors, chemotherapy is now the only available systemic treatment for TNBC. However, some patients might still develop drug resistance and have poor prognosis. Therefore, novel molecular biomarkers and new treatment targets are urgently needed for patients with TNBC. To provide molecular insights into TNBC progression, we investigated the function and the underlying mechanism of Defective in cullin neddylation 1 domain containing 5 (DCUN1D5) in the regulation of TNBC. By TCGA dataset and surgical specimens with immunohistochemical (IHC) staining method, DCUN1D5 was identified to be significantly upregulated in TNBC tumor tissues and negatively associated with prognosis. A series of in vitro and in vivo experiments were performed to confirm the oncogenic role of DCUN1D5 in TNBC. Overexpression of FN1 or PI3K/AKT activator IGF-1 could restore the proliferative and invasive ability induced by DCUN1D5 knockdown and DCUN1D5 could act as a novel transcriptional target of transcription factor Yin Yang 1 (YY1). In conclusion, YY1-enhanced DCUN1D5 expression could promote TNBC progression by FN1/PI3K/AKT pathway and DCUN1D5 might be a potential prognostic biomarker and therapeutic target for TNBC treatment.

Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.

Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.

Well-defined alginate oligosaccharides ameliorate joint pain and inflammation in a mouse model of gouty arthritis.

Background: Gouty arthritis causes severe pain and inflammation. Alginate oligosaccharides (AOSs) are natural products derived from alginate and have anti-inflammatory properties. We explored the potential effects of AOSs with different degrees of polymerization (Dp) on gouty arthritis and associated mechanisms. Methods: We established a mouse model of gouty arthritis by injecting monosodium urate (MSU) into ankle joint. Nocifensive behavior, gait and ankle swelling were used to study AOS's effects. Biochemical assays, in vivo imaging, live cell Ca2+ imaging, electrophysiology, RNA-sequencing, etc. were used for mechanism exploration. Results: AOS2 (Dp=2), AOS3 (Dp=3) and AOS4 (Dp=4) all inhibited ankle swelling, whereas AOS2&3 produced the most obvious analgesia on model mice. AOS3, which was picked for further evaluation, produced dose-dependent ameliorative effects on model mice. AOS3 reversed gait impairments but did not alter locomotor activity. AOS3 inhibited NLRP3 inflammasome activation and inflammatory cytokine up-regulation in ankle joint. AOS3 ameliorated MSU-induced oxidative stress and reactive oxygen species (ROS) production both in vivo and in vitro and reversed the impaired mitochondrial bioenergetics. AOS3 activated the Nrf2 pathway and promoted Nrf2 disassociation from Keap1-bound complex and Nrf2 nuclear translocation, thus facilitating antioxidant gene expression via Nrf2-dependent mechanism. Nrf2 gene deficiency abolished AOS3's ameliorative effects on pain, inflammation and oxidative stress in ankle joints of model mice. AOS3 reduced TRPV1 functional enhancement in DRG neurons and constrained neuroactive peptide release. Conclusions: AOS3 ameliorates gouty arthritis via activating Nrf2-dependent antioxidant signaling, resulting in suppression of ROS-mediated NLRP3 inflammasome activation and TRPV1 enhancement. AOS3 may be novel therapeutics for gouty arthritis.

Urbanization significantly increases greenhouse gas emissions from a subtropical headwater stream in Southeast China.

Streams are disproportionately significant contributors to increases in greenhouse gas (GHG) effluxes in river networks. In the context of global urbanization, a growing number of streams are affected by urbanization, which has been suggested to stimulate the water-air GHG emissions from fluvial systems. This study investigated the seasonal and longitudinal profiles of GHG (N2O, CH4, and CO2) concentrations of Jiuxianghe Stream, a headwater stream undergoing urbanization, and estimated its GHG diffusive fluxes and global warming potentials (GWPs) using the boundary layer method. The results showed that N2O, CH4, and CO2 concentrations in Jiuxianghe Stream were 0.45-7.19 µg L-1, 0.31-586.85 µg L-1, and 0.16-11.60 mg L-1, respectively. N2O, CH4, and CO2 concentrations in the stream showed 4.55-, 23.70-, and 7.68-fold increases from headwaters to downstream, respectively, corresponding to the forest-urban transition within the watershed. Multiple linear regression indicated that NO3--N, NH4+-N, and DOC:NO3--N accurately predicted N2O and CO2 concentrations, indicating that N nutrients were the driving factors. The Jiuxianghe Stream was a source of atmospheric GHGs with a daily GWP of 7.31 g CO2-eq m-2 d-1 on average and was significantly positively correlated with the ratio of construction land and forest in the sub-watershed. This study highlights the critical role of urbanization in amplifying GHG emissions from streams, thereby augmenting our understanding of GHG emissions from river networks. With global urbanization on the rise, streams experiencing urbanization are expected to make an unprecedentedly significant contribution to riverine GHG budgets in the future.

ICP-MS based detection method combined with Au NP and Ag NP labeling for bacteremia diagnosis.

Bacteremia, as a serious infectious disease, has an increasing incidence and a high mortality rate. Early diagnosis and early treatment are crucial for improving the cure rate. In this work, we proposed an inductively coupled plasma mass spectrometry (ICP-MS)-based detection method combined with gold nanoparticle (Au NP) and silver nanoparticle (Ag NP) labeling for the simultaneous detection of Salmonella and Escherichia coli (E. coli O157:H7) in human blood samples. Salmonella and E. coli O157:H7 were captured by magnetic beads coupled with anti-8G3 and anti-7C2, and then specifically labeled by Au NP-anti-5H12 and Ag NP-anti-8B1 respectively, which were used as signal probes for ICP-MS detection. Under the optimal experimental conditions, the limits of detection of 164 CFU mL-1 for Salmonella, 220 CFU mL-1for E. coli O157:H7 and the linear ranges of 400-80,000 CFU mL-1Salmonella, 400-60,000 CFU mL-1 E. coli O157:H7 were obtained. The proposed method can realize the simultaneous detection of two types of pathogenic bacteria in human whole blood in 3.5 h, showing great potential for the rapid diagnosis of bacteremia in clinic.

Improved pregnancy outcome in gestational diabetes mellitus patients treated with insulin aspart and metformin: a comparative study.

OBJECTIVE: To investigate the impact of combining metformin with insulin aspart on blood glucose control, renal injury, and pregnancy outcome in gestational diabetes mellitus (GDM) patients. METHODS: In this retrospective analysis, the clinical data of 140 GDM patients treated at Baoji Maternal and Child Health Hospital between March 2020 and March 2022 were studied. The patients were divided into a control group (insulin aspart alone, n=64) and an observation group (combination of insulin aspart and metformin, n=76) according to their treatment regimen. The blood glucose metabolism, renal injury markers, and pregnancy outcomes between the two groups were assessed and compared. RESULTS: The observation group demonstrated significantly lower levels of blood glucose metabolism markers (fasting plasma glucose [FPG], fasting insulin [FINS], mean amplitude of glycemic excursions [MAGE], and mean of daily differences [MODD]), renal injury indicators (microalbuminuria [mAlb], serum cystatin C [CysC], free fatty acids [FFA], and neutrophil gelatinase-associated lipocalin [NGAL]), and inflammatory markers (interleukin-6 [IL-6], transforming growth factor-ß1 [TGF-ß1], and lipoprotein-associated phospholipase A2 [Lp-PLA2]) compared to the control group (all P<0.05). Additionally, the incidence of adverse pregnancy outcomes in both newborns and mothers was lower in the observation group (P<0.05). Logistic regression analysis identified the treatment regimen, patient age, and pre-pregnancy BMI as independent risk factors for adverse pregnancy outcome. CONCLUSION: The combination of metformin and insulin aspart in treating GDM can effectively reduce blood glucose levels, mitigate renal injury, and improve pregnancy outcome. This treatment approach presents a viable option for optimizing maternal and fetal health in GDM cases.

Protocol for a comprehensive pipeline to study ancient human genomes.

Ancient genomics has revolutionized our understanding of human evolution and migration history in recent years. Here, we present a protocol to prepare samples for ancient genomics research. We describe steps for releasing DNA from human remains, DNA library construction, hybridization capture, quantification, and sequencing. We then detail procedures for mapping sequence reads and population genetics analysis. This protocol also outlines challenges in extracting ancient DNA samples and authenticating ancient DNA to uncover the genetic history and diversity of ancient populations. For complete details on the use and execution of this protocol, please refer to Tao et al.1.

FGF13 enhances the function of TRPV1 by stabilizing microtubules and regulates acute and chronic itch.

Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine-dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule-stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin-binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1-dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome.

Additional prognostic value of polymorphisms within the 3'-untranslated region of programmed cell death pathway genes in early-stage breast cancer.

Introduction: The programmed cell death (PCD) pathway plays an important role in restricting cancer cell survival and proliferation. However, limited studies have investigated the association between genetic variants in the 3'-untranslated region of the PCD pathway genes and breast cancer outcomes. Methods: In this study, we genotyped 28 potentially functional single nucleotide polymorphisms (SNPs) in 23 PCD pathway genes in 1,177 patients with early-stage breast cancer (EBC) from a Han Chinese population. The median follow-up period was 174 months. Results: Among all the candidate SNPs, four independent SNPs (rs4900321 and rs7150025 in ATG2B, rs6753785 in BCL2L11, and rs2213181 in c-Kit) were associated with invasive disease-free survival (iDFS), distant disease-free survival (DDFS), breast cancer-specific survival (BCSS) and overall survival (OS), respectively. Further combined genotypes of these four SNPs revealed that the survival decreased as the number of unfavorable genotypes increased (Ptrend = 1.0 × 10-6, 8.5 × 10-8, 3.6 × 10-4, and 1.3 × 10-4 for iDFS, DDFS, BCSS, and OS, respectively). Receiver operating characteristic curve analysis demonstrated that incorporating unfavorable genotypes and clinicopathological variables improved the ability to predict EBC survival (P = 0.006, 0.004, 0.029, and 0.019 for iDFS, DDFS, BCSS, and OS, respectively). Additionally, rs6753785 and rs2213181 were associated with BCL2L11 and c-Kit mRNA expression, respectively. Conclusions: Our results suggest that these four SNPs may act as novel biomarkers for EBC survival, possibly by modulating the expression of the corresponding genes.

An orally administered bacterial membrane protein nanodrug ameliorates doxorubicin cardiotoxicity through alleviating impaired intestinal barrier.

The cardiotoxicity caused by Dox chemotherapy represents a significant limitation to its clinical application and is a major cause of late death in patients undergoing chemotherapy. Currently, there are no effective treatments available. Our analysis of 295 clinical samples from 132 chemotherapy patients and 163 individuals undergoing physical examination revealed a strong positive correlation between intestinal barrier injury and the development of cardiotoxicity in chemotherapy patients. We developed a novel orally available and intestinal targeting protein nanodrug by assembling membrane protein Amuc_1100 (obtained from intestinal bacteria Akkermansia muciniphila), fluorinated polyetherimide, and hyaluronic acid. The protein nanodrug demonstrated favorable stability against hydrolysis compared with free Amuc_1100. The in vivo results demonstrated that the protein nanodrug can alleviate Dox-induced cardiac toxicity by improving gut microbiota, increasing the proportion of short-chain fatty acid-producing bacteria from the Lachnospiraceae family, and further enhancing the levels of butyrate and pentanoic acids, ultimately regulating the homeostasis repair of lymphocytes in the spleen and heart. Therefore, we believe that the integrity of the intestinal barrier plays an important role in the development of chemotherapy-induced cardiotoxicity. Protective interventions targeting the intestinal barrier may hold promise as a general clinical treatment regimen for reducing Dox-induced cardiotoxicity.

Tracing the fine-scale demographic history and recent admixture in Hmong-Mien speakers.

The linguistic, historical, and subsistent uniqueness of Hmong-Mien (HM) speakers offers a wonderful opportunity to investigate how these factors impact the genetic structure. The genetic differentiation among HM speakers and their population history are not well characterized. Here, we generate genome-wide data from 65 Yao ethnicity samples and analyze them with published data, particularly by leveraging haplotype-based methods. We determined that the fine-scale genetic substructure of HM speakers corresponds better with linguistic classification than with geography. Particularly, parallels between serial founder events and language differentiations can be observed in West Hmongic speakers. Multiple lines of evidence indicate that ~500-year-old GaoHuaHua individuals are most closely related to West Hmongic-speaking Bunu. The strong genetic bottleneck of some HM-speaking groups, especially Bunu, could potentially be associated with their long-term practice of swidden agriculture to some degree. The inferred admixture dates for most of the HM speakers overlap with the reign of the Ming dynasty (1368-1644 CE). Besides a common genetic origin for HM speakers, their genetic ancestry is shared primarily with neighboring Han Chinese and Tai-Kadai speakers in south China. In conclusion, our analyses reveal that recent isolation and admixture events have contributed to the genetic population history of present-day HM speakers.

Interaction between catechol-O-methyltransferase Val/Met polymorphism and cognitive reserve for negative symptoms in schizophrenia.

BACKGROUND: Cognitive reserve (CR) and the catechol-O-methyltransferase (COMT) Val/Met polymorphism are reportedly linked to negative symptoms in schizophrenia. However, the regulatory effect of the COMT genotype on the relationship between CR and negative symptoms is still unexamined. AIM: To investigate whether the relationship between CR and negative symptoms could be regulated by the COMT Val/Met polymorphism. METHODS: In a cross-sectional study, 54 clinically stable patients with schizophrenia underwent assessments for the COMT genotype, CR, and negative symptoms. CR was estimated using scores in the information and similarities subtests of a short form of the Chinese version of the Wechsler Adult Intelligence Scale. RESULTS: COMT Met-carriers exhibited fewer negative symptoms than Val homozygotes. In the total sample, significant negative correlations were found between negative symptoms and information, similarities. Associations between information, similarities and negative symptoms were observed in Val homozygotes only, with information and similarities showing interaction effects with the COMT genotype in relation to negative symptoms (information, ß = -0.282, 95%CI: -0.552 to -0.011, P = 0.042; similarities, ß = -0.250, 95%CI: -0.495 to -0.004, P = 0.046). CONCLUSION: This study provides initial evidence that the association between negative symptoms and CR is under the regulation of the COMT genotype in schizophrenia.

Development and validation of a nomogram model for all-cause mortality risk in patients with chronic heart failure and atrial fibrillation.

BACKGROUND: As the global aging process continues to accelerate, heart failure (HF) has become an important cause of increased morbidity and mortality in elderly patients. Chronic atrial fibrillation (AF) is a major risk factor for HF. Patients with HF combined with AF are more difficult to treat and have a worse prognosis. The aim of this study was to explore the risk factors for 1-year mortality in patients with HF combined with AF and to develop a risk prediction assessment model. METHODS: We recruited hospitalized patients with HF and AF who received standardized care in the Department of Cardiology at Shengjing Hospital of China Medical University from January 2013 to December 2018. The patients were randomly divided into modeling and internal validation groups using a random number generator at a 1:1 ratio. Multivariate Cox regression analysis was used to identify risk factors for all-cause mortality during a one-year follow-up period. Then, a nomogram was constructed based on the weights of each index and validated. Receiver operating characteristic curve, the area under the curve (AUC), decision curve, and calibration curve analyses for survival were used to evaluate the model's predictive and clinical validities and calibration. RESULTS: We included 3,406 patients who met the eligibility criteria; 1,703 cases each were included in the modeling and internal validation groups. Eight statistically significant predictors were identified: age, sex, New York Heart Association cardiac function class III or IV, a history of myocardial infarction, and the albumin, triglycerides, N-terminal pro-b-type natriuretic peptide, and blood urea nitrogen levels. The AUCs were 0.793 (95% confidence interval: 0.763-0.823) and 0.794 (95% confidence interval: 0.763-0.823) in the modeling and validation cohorts, respectively. CONCLUSIONS: We present a predictive model for all-cause mortality in patients with coexisting HF and AF comprising eight key factors. This model gives clinicians a simple assessment tool that may improve the clinical management of these patients.

Inducible Fgf13 ablation alleviates cardiac fibrosis via regulation of microtubule stability.

Fibroblast growth factor (FGF) isoform 13, a distinct type of FGF, boasts significant potential for therapeutic intervention in cardiovascular dysfunctions. However, its impact on regulating fibrosis remains unexplored. This study aims to elucidate the role and mechanism of FGF13 on cardiac fibrosis. Here, we show that following transverse aortic constriction (TAC) surgery, interstitial fibrosis and collagen content increase in mice, along with reduced ejection fraction and fractional shortening, augmented heart mass. However, following Fgf13 deletion, interstitial fibrosis is decreased, ejection fraction and fractional shortening are increased, and heart mass is decreased, compared with those in the TAC group. Mechanistically, incubation of cardiac fibroblasts with transforming growth factor ß (TGFß) increases the expressions of types I and III collagen proteins, as well as α-smooth muscle actin (α-SMA) proteins, and enhances fibroblast proliferation and migration. In the absence of Fgf13, the expressions of these proteins are decreased, and fibroblast proliferation and migration are suppressed, compared with those in the TGFß-stimulated group. Overexpression of FGF13, but not FGF13 mutants defective in microtubule binding and stabilization, rescues the decrease in collagen and α-SMA protein and weakens the proliferation and migration function of the Fgf13 knockdown group. Furthermore, Fgf13 knockdown decreases ROCK protein expression via microtubule disruption. Collectively, cardiac Fgf13 knockdown protects the heart from fibrosis in response to haemodynamic stress by modulating microtubule stabilization and ROCK signaling pathway.

Efficacy and safety of neoadjuvant therapy for HR-positive/HER2-negative early breast cancer: a Bayesian network meta-analysis.

BACKGROUND: Neoadjuvant treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is controversial and requires a comprehensive analysis for optimal therapy assessment. Therefore, a two-step Bayesian network meta-analysis (NMA) was performed to compare the efficacy and safety of different neoadjuvant regimens. RESEARCH DESIGN AND METHODS: Phase II/III randomized clinical trials comparing various neoadjuvant therapies for HR+/HER2- breast cancer were included. NMA and pairwise meta-analyses were conducted using Stata (version 14), R (version 4.2.3), and Review Manager 5.4. RESULTS: Twenty-eight studies (5,625 patients) were eligible. NMA of objective response rate (ORR) indicated the highest SUCRA for chemotherapy (CT) and chemotherapy with anthracycline (CT(A)). Pathologic complete response (PCR) NMA demonstrated significant PCR improvement with chemotherapy regimens containing programmed cell death protein-1 and programmed cell death ligand-1 inhibitors (PD-1i/PD-L1i) and poly ADP-ribose polymerase inhibitors (PARPi). Combined analysis considering both the ORR and safety highlighted CT(A)'s efficacy and toxicity balance. CONCLUSIONS: CT(A) and CT showed improved ORR compared with alternative regimens. CT(A) combined with PD-1/PD-L1 or PARP inhibitors significantly increased PCR rates. Comprehensive assessment of both ORR and safety indicated that CT(A) represents an optimal neoadjuvant therapy for HR+/HER2- breast cancer, whereas AI + CDK4/6 inhibitors rank solely behind chemotherapy. REGISTRATION: PROSPERO Registration: CRD42024538948. International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) registration number INPLASY202440092.

Atmosphere teleconnections from abatement of China aerosol emissions exacerbate Northeast Pacific warm blob events.

During 2010 to 2020, Northeast Pacific (NEP) sea surface temperature (SST) experienced the warmest decade ever recorded, manifested in several extreme marine heatwaves, referred to as "warm blob" events, which severely affect marine ecosystems and extreme weather along the west coast of North America. While year-to-year internal climate variability has been suggested as a cause of individual events, the causes of the continuous dramatic NEP SST warming remain elusive. Here, we show that other than the greenhouse gas (GHG) forcing, rapid aerosol abatement in China over the period likely plays an important role. Anomalous tropospheric warming induced by declining aerosols in China generated atmospheric teleconnections from East Asia to the NEP, featuring an intensified and southward-shifted Aleutian Low. The associated atmospheric circulation anomaly weakens the climatological westerlies in the NEP and warms the SST there by suppressing the evaporative cooling. The aerosol-induced mean warming of the NEP SST, along with internal climate variability and the GHG-induced warming, made the warm blob events more frequent and intense during 2010 to 2020. As anthropogenic aerosol emissions continue to decrease, there is likely to be an increase in NEP warm blob events, disproportionately large beyond the direct radiative effects.

Non-invasive screening and subtyping for breast cancer by serum SERS combined with LGB-DNN algorithms.

Early detection of breast cancer and its molecular subtyping is crucial for guiding clinical treatment and improving survival rate. Current diagnostic methods for breast cancer are invasive, time consuming and complicated. In this work, an optical detection method integrating surface-enhanced Raman spectroscopy (SERS) technology with feature selection and deep learning algorithm was developed for identifying serum components and building diagnostic model, with the aim of efficient and accurate noninvasive screening of breast cancer. First, the high quality of serum SERS spectra from breast cancer (BC), breast benign disease (BBD) patients and healthy controls (HC) were obtained. Chi-square tests were conducted to exclude confounding factors, enhancing the reliability of the study. Then, LightGBM (LGB) algorithm was used as the base model to retain useful features to significantly improve classification performance. The DNN algorithm was trained through backpropagation, adjusting the weights and biases between neurons to improve the network's predictive ability. In comparison to traditional machine learning algorithms, this method provided more accurate information for breast cancer classification, with classification accuracies of 91.38 % for BC and BBD, and 96.40 % for BC, BBD, and HC. Furthermore, the accuracies of 90.11 % for HR+/HR- and 88.89 % for HER2+/HER2- can be reached when evaluating BC patients' molecular subtypes. These results demonstrate that serum SERS combined with powerful LGB-DNN algorithm would provide a supplementary method for clinical breast cancer screening.

FGF13 deficiency ameliorates calcium signaling abnormality in heart failure by regulating microtubule stability.

Calcium signaling abnormality in cardiomyocytes, as a key mechanism, is closely associated with developing heart failure. Fibroblast growth factor 13 (FGF13) demonstrates important regulatory roles in the heart, but its association with cardiac calcium signaling in heart failure remains unknown. This study aimed to investigate the role and mechanism of FGF13 on calcium mishandling in heart failure. Mice underwent transaortic constriction to establish a heart failure model, which showed decreased ejection fraction, fractional shortening, and contractility. FGF13 deficiency alleviated cardiac dysfunction. Heart failure reduces calcium transients in cardiomyocytes, which were alleviated by FGF13 deficiency. Meanwhile, FGF13 deficiency restored decreased Cav1.2 and Serca2α expression and activity in heart failure. Furthermore, FGF13 interacted with microtubules in the heart, and FGF13 deficiency inhibited the increase of microtubule stability during heart failure. Finally, in isoproterenol-stimulated FGF13 knockdown neonatal rat ventricular myocytes (NRVMs), wildtype FGF13 overexpression, but not FGF13 mutant, which lost the binding site of microtubules, promoted calcium transient abnormality aggravation and Cav1.2 downregulation compared with FGF13 knockdown group. Generally, FGF13 deficiency improves abnormal calcium signaling by inhibiting the increased microtubule stability in heart failure, indicating the important role of FGF13 in cardiac calcium homeostasis and providing new avenues for heart failure prevention and treatment.

Oridonin, a small molecule inhibitor of cancer stem cell with potent cytotoxicity and differentiation potential.

Cancer stem cells (CSCs) drive malignant tumor progression, recurrence, and metastasis with unique characteristics, including self-renewal and resistance to conventional treatments. Conventional differentiation inducers, although promising, have limited cytotoxicity and may inadvertently enhance CSC stemness. To address these challenges, ongoing efforts are dedicated to developing strategies that can effectively combine both cytotoxicity and differentiation-inducing effects. In this study, we introduce oridonin (Ori), a small molecule with dual differentiation-inducing and cytotoxicity properties capable of eliminating tumor CSCs. We isolated CSCs in B16F10 cells using the Hoechst side population method and assessed the differentiation effect of Ori. Ori's differentiation-inducing effect was further evaluated using human acute promyelocytic leukemia. The cytotoxic potential of Ori against MCF-7 and B16F10 cell lines was assessed through various methods. In vivo anti-tumor and anti-CSC efficacy of Ori was investigated using mouse melanoma and CSCs melanoma models. Safety evaluation included zebrafish embryotoxicity and mouse acute toxicity experiments. As a result, Ori effectively dismantles tumorspheres, inhibits proliferation, and reduces the expression of CSC-specific markers. It induces significant differentiation, especially in the case of NB4. Additionally, Ori upregulates TP53 expression, mitigates the hypoxic tumor microenvironment, suppresses stemness, and inhibits PD-L1 expression, prompting a robust anti-cancer immune response. Ori demonstrates pronounced cytotoxicity, inducing notable pro-apoptotic effects on B16F10 and MCF-7 cells, with specific triggering of mitochondrial apoptosis. Importantly, Ori maintains a commendable biosafety record. The dual-action prowess of Ori not only induces the differentiation of CSCs but also dispatches differentiated and residual tumor cells, effectively thwarting the relentless march of tumor progression.