Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has garnered attention for its cardiovascular benefits beyond glycemic control. Ferroptosis, a novel form of regulated cell death, contributes to the pathogenesis of diabetic cardiomyopathy (DCM). However, whether EMPA mitigates DCM by suppressing ferroptosis remains unclear. Here, Type 2 diabetic db/db mice were used to establish a DCM model and treated with EMPA (10 mg/kg/day) for 12 weeks. EMPA significantly improved cardiac function, reduced myocardial fibrosis, and attenuated ferroptosis, concomitant with upregulated silent information regulator 3 (SIRT3) expression. In the rat cardiomyocytes (H9c2 cells) exposed to high glucose and palmitic acid, EMPA treatment or SIRT3 overexpression alleviated oxidative stress, mitochondrial dysfunction, and ferroptosis. Mechanistically, molecular docking, molecular dynamics simulation, cellular thermal shift assay and drug affinity responsive target stability assay confirmed that SIRT3 is the drug target of EMPA, stabilizing its protein levels and reducing acetylated p53 expression. Notably, SIRT3 silencing abolished EMPA's beneficial effects on oxidative stress and ferroptosis. Our findings demonstrate that EMPA exerts cardioprotective effects by inhibiting oxidative stress and ferroptosis in cardiomyocytes, which is mediated by SIRT3. This study provides novel insights into the mechanisms underlying EMPA's therapeutic effects in DCM.

Quality of life (QOL) research in diabetes has long been a concern with many specific instruments being developed, but no scale for diabetes has been developed based on the modular approach. This study aimed to develop and validate the Diabetes Mellitus Scale of the System of Quality of Life Instruments for Chronic Diseases QLICD-DM (V2.0) by a modular approach and mixed methods. The Scale was developed based on procedural decision-making methods and by combining the general module and the specific module. The instrument was used to assess the quality of life of 242 diabetic patients both before and after treatments. Under Classical Test Theory (CTT), the psychometric properties of the scale were assessed with regard to validity, reliability and responsiveness by correlation analyses, structural equation modeling, as well as t-tests. In addition, G-study and D-study in Generalizability Theory (GT) were used to validate the scale further. The QLICD-DM (V2.0) was developed with a 14-item specific module and a 28-item general module in the final scale. For all domains, Cronbach’s α values were greater than 0.70 with the exception of physical function (0.68), the test-retest reliability correlations r and ICCs were greater than 0.80 with the exception of physical and social function (0.65,0.64). The theoretical construct was supported by correlation analyses and confirmatory factor analysis using structural equation modeling, which demonstrated good construct validity. There were significant differences (P < 0.05) in the domains of physical function, specific module and the total scale before and after treatments. The standardized response means (SRMs) of the physical, psychological, social, and the specific module were 0.36, 0.14, 0.11 and 0.28 respectively. All G-coefficients were all greater than 0.70 with the exception of the physical domain (0.683), further confirming the reliability of the scale further. The overall error was found to be small in the G-study and in the D-study, indicating a high level of accuracy. The QLICD-DM (V2.0) not only integrated characteristics of generic and disease-specific instruments but also demonstrated good reliability, validity, and moderate responsiveness, and it could serve as a quality of life assessment tool for diabetes patients.

BackgroundHereditary spherocytosis (HS) is an inherited form of hemolytic anemia resulting from defects in the red blood cell membrane skeleton. Its classic clinical presentation includes anemia, jaundice, and splenomegaly. Key laboratory findings that support the diagnosis are the presence of spherocytes and an elevated reticulocyte count on peripheral blood smear.Case presentationAn 8-year-old girl presented with a longstanding history of jaundice—noted for four years—affecting both her skin and sclera. She also reported intermittent episodes of tea-colored urine. Physical examination revealed hepatosplenomegaly. Laboratory investigations demonstrated normocytic anemia, a positive osmotic fragility test, and the presence of spherocytes on peripheral blood smear, which was subsequently confirmed by electron microscopy. Whole-exome sequencing identified a novel heterozygous pathogenic mutation (c.2388 + 2T > A) in the ANK1 gene (NM_000037.4, Intron). This splice-site mutation leads to aberrant splicing, causing a frameshift and introduction of a premature termination codon (PTC), likely triggering nonsense-mediated mRNA decay (NMD) and resulting in a truncated, dysfunctional Ankyrin-1 protein.ConclusionThis study reports a novel ANK1 mutation (c.2388 + 2T > A) identified in a Chinese patient with hereditary spherocytosis. Located at a critical splice donor site, this previously unreported variant is predicted to cause disease through the inclusion of a cryptic exon. The finding provides new insight into the genetic basis of HS in the Chinese population.

Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory disorders with distinct pathological mechanisms. Even advancements in conventional therapies, the treatment of these diseases remains challenging due to their complex pathophysiology and limited efficacy of current anti-inflammatory treatments. SIRT1, an NAD+-dependent deacetylase, exerting protective effects by inhibiting NF-κB and STAT3, activating Nrf2 and FOXO3, and suppressing TGF-β/Smad. In asthma, SIRT1 attenuates Th2 inflammation, mucus hypersecretion, and airway smooth muscle proliferation; in COPD, it reduces neutrophilic inflammation, alveolar senescence, and protease/antiprotease imbalance. Shared benefits include mitigation of oxidative stress, mitochondrial dysfunction, and extracellular matrix remodeling. However, clinical translation faces critical barriers: cell type-specific SIRT1 effects, pharmacokinetic limitations of current activators, and lack of biomarker-guided strategies. This review examines challenges, compares SIRT1's divergent roles, and evaluates chronotherapy, biomarker-guided selection, and SIRT1 activators. Integration of current evidence and knowledge gaps reveals pathways to personalized SIRT1-targeted therapies for obstructive airway diseases.

Williams syndrome (WS) is a multisystem disorder caused by a 1.5–1.8 Mb heterozygous microdeletion at chromosome 7q11.23. Lynch syndrome (LS) is a cancer predisposition syndrome resulting from germline mutations in DNA mismatch repair genes. Co-occurrence of both conditions in a single pediatric patient has not been reported to date. A 20-month-old male presented with an 8-month history of motor developmental delay. Clinical examination revealed global developmental delay, characteristic facial dysmorphisms, knee hyperextension on assisted standing, generalized hypotonia, and asymmetric dermatoglyphs of the lower extremities. Diagnostic workup identified left hip dysplasia, visual and auditory abnormalities, and proteinuria. Whole-exome sequencing revealed a heterozygous 1.48 Mb de novo deletion at 7q11.23, classified as pathogenic, alongside a heterozygous frameshift variant in MSH2 (c.1457_1460del, p.Asn486Thrfs*10), also designated as pathogenic and identified as an American College of Medical Genetics and Genomics (ACMG) secondary finding. To our knowledge, this represents the first pediatric case of coexisting WS and LS, providing critical insights into the individualized clinical management and genetic counseling of patients with dual Mendelian disorder diagnoses.

Alzheimer's disease (AD) is a neurodegenerative disorder driven by amyloid-β accumulation, tau pathology, and synaptic dysfunction. Recent studies highlight miR-137, a brain-enriched microRNA, as a pivotal regulator of AD pathogenesis. This review synthesizes evidence that miR-137 modulates amyloid-β production, tau phosphorylation, synaptic plasticity, and neuroinflammation, while also preserving mitochondrial function and mitigating oxidative stress. Notably, circulating miR-137 levels correlate with AD progression, offering promise as a non-invasive diagnostic biomarker. Beyond diagnostics, miR-137's ability to target multiple AD-related pathways positions it as a novel therapeutic candidate for neuroprotection. Hence, miR-137 serves as both a biomarker and therapeutic target, offering promising strategies to slow AD progression and improve outcomes. Our bioinformatic analyses further identify miR-137-regulated genes and disrupted networks, underscoring its central role in AD. By bridging molecular mechanisms and clinical potential, miR-137-based strategies could transform AD management, addressing both pathological hallmarks and cognitive decline. Hence, this review article consolidates evidence of miR-137's multifaceted functions in AD, encouraging further investigation into its molecular mechanisms and translational potential to address this pathogenic condition.

Genetic screening for the CAP+40-+43 (-AAAC) mutation within the 5' untranslated region of the Hemoglobin Subunit Beta(HBB) gene is a typical component of (3-thalassemia prevention and diagnosis. This mutation is known for its unpredictable phenotypic expression and controversial pathogenicity. This review comprehensively synthesizes decades of research, analyzing the genetic and clinical implications of the CAP+40-+43 (-AAAC) mutation and elucidating its underlying molecular mechanisms. We conducted an extensive literature review from 1980 to 2024, using PubMed and Chinese databases, focusing on all studies related to this specific mutation, including epidemiological surveys, case studies, and recent genetic findings. The results from populations in mainland China and Taiwan suggest that the CAP+40-+43 (-AAAC) mutation should not be considered inherently pathogenic but may contribute to variability in disease phenotype among individuals. Further detailed research is needed to better understand its role in (3-thalassemia. Future studies should aim to identify the exact molecular pathways influenced by this mutation and develop intervention strategies that could alleviate its clinical impact, thus enhancing our comprehensive understanding of its biological significance.

In children,autism spectrum disorder(ASD)is primarily characterized by social(communication)impairments and repetitive,stereotyped behaviors and restricted interests,affecting children's social interaction,communication abilities,and behavioral patterns.In recent years,with technological advancements,digital therapeutics has played a significant role in managing ASD.For instance,multimodal data integration and machine learning algorithms have been used for the early identification of ASD,while virtual reality,augmented reality,and gamified learning platforms have been widely applied to enhance the social skills and cognitive functions of children with ASD.Although digital therapy has shown great potential and benefits in the field of autism,it also faces challenges,including individual differences in treatment response,uncertainty of long-term effectiveness,and data privacy protection.Overall,digital therapeutics has opened up a new path for the management of autism,and also points out important directions for future research and applications.

Genetic screening for the CAP+40-+43 (-AAAC) mutation within the 5' untranslated region of the Hemoglobin Subunit Beta(HBB) gene is a typical component of β-thalassemia prevention and diagnosis. This mutation is known for its unpredictable phenotypic expression and controversial pathogenicity. This review comprehensively synthesizes decades of research, analyzing the genetic and clinical implications of the CAP+40-+43 (-AAAC) mutation and elucidating its underlying molecular mechanisms. We conducted an extensive literature review from 1980 to 2024, using PubMed and Chinese databases, focusing on all studies related to this specific mutation, including epidemiological surveys, case studies, and recent genetic findings. The results from populations in mainland China and Taiwan suggest that the CAP+40-+43 (-AAAC) mutation should not be considered inherently pathogenic but may contribute to variability in disease phenotype among individuals. Further detailed research is needed to better understand its role in β-thalassemia. Future studies should aim to identify the exact molecular pathways influenced by this mutation and develop intervention strategies that could alleviate its clinical impact, thus enhancing our comprehensive understanding of its biological significance.

Background:Acute lymphoblastic leukemia (ALL) is a rapidly progressive hematological malignancy caused by the dysregulated proliferation and abnormal differentiation or differentiation block of lymphoid precursors. The sirtuin family, as a highly conserved class of protein deacetylases dependent on NAD+, has been widely reported in leukemia. However, there has been no research on the prognostic value and molecular functions of the sirtuin protein family in pediatric ALL. Methods:In this study, we employed the Therapeutically Applicable Research to Generate Effective Treatments (TARGET), Genotype-Tissue Expression (GTEx), Encyclopedia of RNA Interactomes (ENCORI), Cancer Therapeutics Response Portal (CTRP), and STRING databases as well as R language to explore and visualize the role of the sirtuin family in childhood ALL. The receiver operating characteristic (ROC) curve was performed to investigate their diagnostic value, while the Kaplan-Meier survival curve and Cox regression analysis were utilized to test their prognostic value. Additionally, we conducted Pearson correlation analysis to explore the association between sirtuin family mRNA expression and DNA methylation. Results:Our results indicate that sirtuin family mRNA expression is dysregulated in pediatric ALL. The ROC curve revealed that SIRT1 and SIRT4 expression is highly sensitive and specific in diagnosing childhood ALL (AUC > 85.0%, p < 0.001). While higher SIRT1, SIRT4, SIRT5, and SIRT7 expression was related to higher event-free survival rate and overall survival (OS) rate, higher SIRT2 expression was associated with lower event-free survival rate and rate in childhood ALL (p < 0.05). Moreover, Cox regression and nomogram analyses suggested that SIRT1 mRNA expression is an independent factor for pediatric ALL. Subtype analysis revealed that SIRT1 primarily functions in B-cell precursor ALL (B-ALL). Furthermore, SIRT1 is involved in various RNA splicing and acetyltransferase complex in B-ALL. The data from the CTRP database and the Cell Counting Kit-8 (CCK-8) experiment suggested that SIRT1 increased the sensitivity of B-ALL cell lines to vincristine. In vitro experiments demonstrated that SIRT1 inhibits invasion activity in B-ALL cell lines (NALM6 and REH). Conclusions:SIRT1 represents a potential prognostic biomarker and therapeutic target in childhood B-ALL.

Tumor-associated macrophages (TAMs) are the main tumor infiltrating immune cell types in tumor microenvironment (TME) that have related to tumor progression. However, crosstalk between TAMs and colorectal cancer (CRC) cells remains poorly understood. In this study, conditioned media (CM) was harvested from CRC cells or activated TAMs. Immunofluorescence assay and real-time quantitative PCR were used to detect phenotypic alteration of macrophages. Scratch test, colony-formation assay, and transwell invasion assay were performed to measure the migration and invasion of CRC. Enzyme-linked immunosorbent assay, and bioinformatics analysis were used to investigate the underlying mechanisms. Moreover, an in vivo model was applied to validate the effects of TAMs on CRC progression. Our findings showed that THP-1-derived macrophages exhibited an M1-like TAMs characteristics after culturing with CM from CRC cells. CM from activated M1-like TAMs promoted the colony forming, invasion, and migration abilities of CRC cells by secreting IL1β. TAMs-derived IL1β promoted CRC progression via activating the NF-κB signaling pathway, which in turn increased the production of CCL2 that induced macrophage recruitment. Neutralization of IL1β or CCL2 disrupted this loop and inhibited TAMs-mediated tumor progression and macrophage migration. In summary, our data indicates that CM from CRC could polarize macrophages into M1-like TAMs. And these TAMs promoted CRC migration and invasion through activating IL1β/NF-κB signaling, which in turn enhanced to the secretion of CCL2 that promoted macrophage recruitment, indicating a crosstalk between TAMs and tumor cells in CRC microenvironment.

Aims Doxorubicin (DOX), a highly effective anthracycline chemotherapeutic agent, is limited by its dose-dependent cardiotoxicity. This study investigates the cardioprotective mechanisms of cardiac adriamycin responsive protein (CARP) and its underlying mechanisms in DOX-induced cardiotoxicity (DIC). Methods and results Cardiac-specific CARP transgenic and wild-type mice were subjected to a DIC model. Cardiac function was assessed via echocardiography, histopathology, and transmission electron microscopy (TEM). In vitro , DOX-treated cardiomyocytes overexpressing CARP were analyzed for oxidative stress (ROS levels), mitochondrial function (mt DNA copy number etc.), and mitochondrial-related proteins (Western blot). CARP-NRF1 interaction was validated by co-immunoprecipitation (Co-IP), and NRF1 siRNA knockdown was performed to assess the role of CARP in mitochondrial homeostasis. CARP overexpression markedly alleviated DOX-induced cardiac dysfunction and mitochondrial damage, restoring mitochondrial dynamics and mitophagy. Mechanistically, CARP directly interacted with NRF1, and NRF1 knockdown ameliorated CARP-mediated cardioprotection in DIC. Conclusion CARP safeguards against DIC by maintaining mitochondrial homeostasis via NRF1 signaling, positioning it as a promising therapeutic target for DOX-induced cardiomyopathy. ### Competing Interest Statement The authors have declared no competing interest. National Natural Science Foundation, 81670252 Guangdong Basic and Applied Basic Foundation, 2019A1515011306

Congenital disorder of glycosylation type Ia (CDG-Ia) is an autosomal recessive genetic disease caused by a mutation in the phosphomannomutase 2 (PMM2) gene. We have identified a 13-month-old boy who has been diagnosed with CDG-Ia. He displays several characteristic symptoms, including cerebellar hypoplasia, severe developmental retardation, hypothyroidism, impaired liver function, and abnormal serum ferritin levels. Through whole-exome sequencing, we discovered novel complex heterozygous mutations in the PMM2 gene, specifically the c.663C > G (p.F221L) mutation and loss of exon 2. Further analysis revealed that the enzymatic activity of the mutant PMM2 protein was significantly reduced by 44.97% (p < 0.05) compared to the wild-type protein.

Ankyrin repeat domain 1 (Ankrd1) is an acute response protein that belongs to the muscle ankyrin repeat protein (MARP) family. Accumulating evidence has revealed that Ankrd1 plays a crucial role in a wide range of biological processes and diseases. This review consolidates current knowledge on Ankrd1’s functions in myocardium and skeletal muscle development, neurogenesis, cancer, bone formation, angiogenesis, wound healing, fibrosis, apoptosis, inflammation, and infection. The comprehensive profile of Ankrd1 in cardiovascular diseases, myopathy, and its potential as a candidate prognostic and diagnostic biomarker are also discussed. In the future, more studies of Ankrd1 are warranted to clarify its role in diseases and assess its potential as a therapeutic target.

There is substantial evidence demonstrating the crucial role of inflammation in oncogenesis. ANKRD1 has been identified as an anti-inflammatory factor and is related to tumor drug resistance. However, there have been no studies investigating the prognostic value and molecular function of ANKRD1 in pan-cancer. In this study, we utilized the TCGA, GTEx, GSCALite, ENCORI, CTRP, DAVID, AmiGO 2, and KEGG databases as well as R language, to explore and visualize the role of ANKRD1 in tumors. We employed the ROC curve to explore its diagnostic significance, while the Kaplan–Meier survival curve and Cox regression analysis were used to investigate its prognostic value. Additionally, we performed Pearson correlation analysis to evaluate the association between ANKRD1 expression and DNA methylation, immune cell infiltration, immune checkpoints, TMB, MSI, MMR, and GSVA. Our findings indicate that ANKRD1 expression is dysregulated in pan-cancer. The ROC curve revealed that ANKRD1 expression is highly sensitive and specific in diagnosing CHOL, LUAD, LUSC, PAAD, SKCM, and UCS (AUC > 85.0%, P < 0.001). Higher ANKRD1 expression was related to higher overall survival (OS) in LGG, but with lower OS in COAD and STAD (P < 0.001). Moreover, Cox regression and nomogram analyzes suggested that ANKRD1 is an independent factor for COAD, GBM, HNSC, and LUSC. Dysregulation of ANKRD1 expression in pan-cancer involves DNA methylation and microRNA regulation. Using the CTRP database, we discovered that ANKRD1 may influence the half-maximal inhibitory concentration (IC50) of several anti-tumor drugs. ANKRD1 expression showed significant correlations with immune cell infiltration (including cancer-associated fibroblast and M2 macrophages), immune checkpoints, TMB, MSI, and MMR. Furthermore, ANKRD1 is involved in various inflammatory and immune pathways in COAD, GBM, and LUSC, as well as cardiac functions in HNSC. In vitro experiments demonstrated that ANKRD1 promotes migration, and invasion activity, while inhibiting apoptosis in colorectal cancer cell lines (Caco2, SW480). In summary, ANKRD1 represents a potential prognostic biomarker and therapeutic target in human cancers, particularly in COAD.

目的 探讨广东顺德地区地中海贫血(简称地贫)患儿酰基肉碱、氨基酸代谢特点.方法 回顾性收集2021 年 7-12 月于广东医科大学顺德妇女儿童医院新生儿疾病筛查中心进行新生儿血红蛋白电泳筛查阳性且同时进行遗传代谢病筛查的 349 例新生儿的临床资料,地贫基因检测发现地贫基因阳性 207 例,其中α地贫组 163 例、β地贫组 44 例,另外 142 例地贫基因阴性新生儿为对照组.串联质谱法检测新生儿干血斑中11种氨基酸和12种肉碱水平,分析其在各组中的水平差异.结果 α地贫组丙氨酸、甘氨酸、缬氨酸、苯丙氨酸、酪氨酸水平低于对照组;β地贫组甘氨酸、苯丙氨酸水平低于对照组,而瓜氨酸水平高于对照组,差异均有统计学意义(P<0.05).α地贫组游离肉碱、乙酰肉碱、丁酰肉碱、异戊酰肉碱、辛酰肉碱、肉豆蔻酰肉碱、棕榈酰肉碱、十八碳酰肉碱水平高于对照组;β地贫组丁酰肉碱、异戊酰肉碱水平高于对照组,月桂酰肉碱水平低于对照组,差异均有统计学意义(P<0.05).此外,丙氨酸、甘氨酸、蛋氨酸、缬氨酸、瓜氨酸、精氨酸、苯丙氨酸、脯氨酸与胎龄、出生体重、母妊娠期、围生期疾病、手术史及新生儿期疾病史具有相关性,肉豆蔻酰肉碱、棕榈酰肉碱、十八碳酰肉碱与胎龄有关.结论 佛山市顺德区地贫患儿体内氨基酸、肉碱水平与对照组相比呈现不同的代谢差异,孕期芳香族氨基酸和支链氨基酸的补充及生后动态监测氨基酸代谢水平是改善地贫患儿生长发育的有利措施.

Ferroptosis represents a novel non-apoptotic form of regulated cell death that is driven by iron-dependent lipid peroxidation and plays vital roles in various diseases including cardiovascular diseases, neurodegenerative disorders and cancers. Plenty of iron metabolism-related proteins, regulators of lipid peroxidation, and oxidative stress-related molecules are engaged in ferroptosis and can regulate this complex biological process. Sirtuins have broad functional significance and are targets of many drugs in the clinic. Recently, a growing number of studies have revealed that sirtuins can participate in the occurrence of ferroptosis by affecting many aspects such as redox balance, iron metabolism, and lipid metabolism. This article reviewed the studies on the roles of sirtuins in ferroptosis and the related molecular mechanisms, highlighting valuable targets for the prevention and treatment of ferroptosis-associated diseases.

Asthma is a complex and heterogeneous disease characterized by chronic airway inflammation, airway hyperresponsiveness, and airway remodeling. Most asthmatic patients are well-established using standard treatment strategies and advanced biologicals. However, a small group of patients who do not respond to biological treatments or are not effectively controlled by available treatment strategies remain a clinical challenge. Therefore, new therapies are urgently needed for poorly controlled asthma. Mesenchymal stem/stromal cells (MSCs) have shown therapeutic potential in relieving airway inflammation and repairing impaired immune balance in preclinical trials owing to their immunomodulatory abilities. Noteworthy, MSCs exerted a therapeutic effect on steroid-resistant asthma with rare side effects in asthmatic models. Nevertheless, adverse factors such as limited obtained number, nutrient and oxygen deprivation in vitro, and cell senescence or apoptosis affected the survival rate and homing efficiency of MSCs, thus limiting the efficacy of MSCs in asthma. In this review, we elaborate on the roles and underlying mechanisms of MSCs in the treatment of asthma from the perspective of their source, immunogenicity, homing, differentiation, and immunomodulatory capacity and summarize strategies to improve their therapeutic effect.