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According to this strategic framework, we have put forward a series of five broad recommendations, covering reproductive health, maternal and newborn health, child and adolescent health, the health system, and social contexts. [...]RMNCAH not only plays a pivotal role in guaranteeing the health of each individual woman, child, and adolescent, but is also a cornerstone for the development of the next generation and the sustainable development of the whole society. RMNCAH have direct effects on the majority of family members—women and children—and men play an important role in contributing to RMNCAH. Because of the forecasted trends for population ageing and low fertility, the proportion of the Chinese population covered by RMNCAH (children aged 0–19 years and female individuals aged 20–49 years) will decline from 46·8% in 2015 to 39·9% in 2030 (appendix pp 1–2).2 Improving RMNCAH is vital for China in the context of rapid ageing and decreasing fertility. Following this, the Global Health Strategy for Women, Children and Adolescents (2016–30), which was developed under the framework of the Sustainable Development Goals (SDGs), explicitly recognised the need to extend the focus beyond mortality alone and to promote health across the developmental years: “By 2030, a world in which every woman, child and adolescent in every setting realizes their rights to physical and mental health and wellbeing, has social and economic opportunities, and is able to participate fully in shaping prosperous and sustainable societies”.

Velocardiofacial syndrome (VCFS) is a disease in human with an expansive phenotypic spectrum and diverse genetic mechanisms mainly associated with copy number variations (CNVs) on 22q11.2 or other chromosomes. However, the correlations between CNVs and phenotypes remain ambiguous. This study aims to analyze the types and sizes of CNVs in VCFS patients, to define whether correlations exist between CNVs and clinical manifestations in Chinese VCFS patients. In total, 55 clinically suspected Chinese VCFS patients and 100 normal controls were detected by multiplex ligation-dependent probe amplification (MLPA). The data from MLPA and all the detailed clinical features of the objects were documented and analyzed. A total of 44 patients (80.0%) were diagnosed with CNVs on 22q11.2. Among them, 43 (78.2%) presented with 22q11.2 heterozygous deletions, of whom 40 (93.0%) had typical 3-Mb deletion, and 3 (7.0%) exhibited proximal 1.5-Mb deletion; no patient was found with atypical deletion on 22q11.2. One patient (1.8%) presented with a 3-Mb duplication mapping to the typical 3-Mb region on 22q11.2, while none of the chromosomal abnormalities in the MLPA kit were found in the other 11 patients and 100 normal controls. All the 43 patients with 22q11.2 deletions displayed characteristic face and palatal anomalies; 37 of them (86.0%) had cognitive or behavioral disorders, and 23 (53.5%) suffered from immune deficiencies; 10 patients (23.3%) manifested congenital heart diseases. Interestingly, all patients with the characteristic face had 22q11.2 heterozygous deletions, but no difference in phenotypic spectrum was observed between 3-Mb and 1.5-Mb deletions. Our data suggest that the characteristic face can be used as a key indicator for direct diagnosis of 22q11.2 deletions in Chinese VCFS patients.

Neutrophil extracellular traps (NETs) seriously impede diabetic wound healing. The disruption or scavenging of NETs using deoxyribonuclease (DNase) or cationic nanoparticles has been limited by liberating trapped bacteria, short half‐life, or potential cytotoxicity. In this study, a positive correlation between the NETs level in diabetic wound exudation and the severity of wound inflammation in diabetic patients is established. Novel NETs scavenging bio‐based hydrogel microspheres ‘micro‐cage’, termed mPDA‐PEI@GelMA, is engineered by integrating methylacrylyl gelatin (GelMA) hydrogel microspheres with cationic polyethyleneimine (PEI)‐functionalized mesoporous polydopamine (mPDA). This unique ‘micro‐cage’ construct is designed to non‐contact scavenge of NETs between nanoparticles and the diabetic wound surface, minimizing biological toxicity and ensuring high biosafety. NETs are introduced into ‘micro‐cage’ along with wound exudation, and cationic mPDA‐PEI immobilizes them inside the ‘micro‐cage’ through a strong binding affinity to the cfDNA web structure. The findings demonstrate that mPDA‐PEI@GelMA effectively mitigates pro‐inflammatory responses associated with diabetic wounds by scavenging NETs both in vivo and in vitro. This work introduces a novel nanoparticle non‐contact NETs scavenging strategy to enhance diabetic wound healing processes, with potential benefits in clinical applications. This study documents the higher NETs levels in the wound exudation of diabetic patients and their correlation with the the severity of wound inflammation in diabetic patients. A novel NETs scavenging bio‐based hydrogel microsphere ‘micro‐cage’, termed mPDA‐PEI@GelMA, is developed and effectively mitigated pro‐inflammatory responses associated with diabetic wounds by scavenging NETs both in vivo and in vitro.

Osteoporosis is a common form of metabolic bone disease that is costly to treat and is primarily diagnosed on the basis of bone mineral density. As the influences of genetic lesions and environmental factors are increasingly studied in the pathological development of osteoporosis, regulated epigenetics are emerging as the important pathogenesis mechanisms in osteoporosis. Recently, osteoporosis genome-wide association studies and multi-omics technologies have revealed that susceptibility loci and the misregulation of epigenetic modifiers are key factors in osteoporosis. Over the past decade, extensive studies have demonstrated epigenetic mechanisms, such as DNA methylation, histone/chromatin modifications, and non-coding RNAs, as potential contributing factors in osteoporosis that affect disease initiation and progression. Herein, we review recent advances in epigenetics in osteoporosis, with a focus on exploring the underlying mechanisms and potential diagnostic/prognostic biomarker applications for osteoporosis.

Nimodipine has shown neuroprotective effects in several studies; however, the specific targets and mechanisms remain unclear. This study aims to explore the potential targets and mechanisms of nimodipine in the treatment of neurodegenerative diseases (NDDs), providing a theoretical foundation for repurposing nimodipine for NDDs. Drug-related targets were predicted using SwissTargetPrediction and integrated with results from CTD, GeneCards, and DrugBank. These targets were then cross-referenced with disease-related targets retrieved from CTD to identify overlapping targets. The intersecting targets were imported into STRING to construct a protein-protein interaction (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R package ClusterProfiler. Molecular docking was carried out using AutoDock Vina, and the ligand-receptor complexes with the highest binding affinities were further simulated using GROMACS to assess the dynamic structural stability and interactions between the ligand and receptor in the dynamic system. A total of 33 intersecting drug-disease targets were identified. After constructing the PPI network and removing isolated targets, the network contained 28 nodes and 69 edges. Network degree analysis combined with enrichment analysis highlighted 12 key targets: CASP3, TNF, BAX, BCL2, IL1B, GSK3B, IL1A, MAOB, MAOA, BDNF, APP, and GFAP. Molecular docking analysis revealed binding energies greater than -6 kcal/mol for MAOA, GSK3B, MAOB, CASP3, BCL2, IL1B and APP. MAOA, with the highest binding energy of -7.343 kcal/mol, demonstrated a stable structure in a 100ns dynamic simulation with nimodipine, exhibiting an average dynamic binding energy of -52.39 ± 3.05 kcal/mol. The dynamic cross-correlation matrix (DCCM) of nimodipine resembled that of harmine, reducing the interactions between protein residues compared to the apo state (regardless of positive or negative correlations). Furthermore, nimodipine induced new negative correlations in residues 100-200 and 300-400. Nimodipine binds to the internal pocket of MAOA and shows potential inhibitory effects. Given its brain-enrichment characteristics and proven neuroprotective effects, it is hypothesized that nimodipine may exert therapeutic effects on NDDs by inhibiting MAOA activity and modulating cerebral oxidative stress. Thus, MAOA emerges as a promising new target for nimodipine in the treatment of NDDs.

Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.

Neuroblastoma (NB), an embryonic tumour originating from sympathetic crest cells, is the most common extracranial solid tumour type in children with poor overall prognosis. Accumulating evidence has demonstrated the involvement of long non‐coding RNA (lncRNA) in numerous biological processes and their associations with embryonic development and multiple diseases. Ectopic lncRNA expression is linked to malignant tumours. Previous studies by our team indicate that MEG3 attenuates NB autophagy through inhibition of FOXO1 and epithelial‐mesenchymal transition via the mTOR pathway in vitro. Moreover, MEG3 and EZH2 negatively regulate each other. In present study, we first collected 60 NB tissues and 20 adjacent tissues for Quantitative real‐time polymerase chain reaction (Q‐PCR) experiments and performed clinical correlation analysis of the results. At the same time, nude mice were used for subcutaneous tumour formation to detect the effect of MEG3 in vivo. Two NB cell lines, SK‐N‐AS and SK‐N‐BE(2)C, were overexpressed MEG3 and rescued with EZH2 and then were subjected to proliferation, migration, invasion, apoptosis and autophagy experiments. RNA‐binding protein immunoprecipitation (RIP) and Co‐Immunoprecipitation (Co‐IP) experiments were performed to explore the molecular mechanism of MEG3 and EZH2 interaction. Q‐PCR revealed that MEG3 expression was negatively correlated with INSS stage and risk grade of NB. Moreover, MEG3 overexpression was associated with inhibition of NB growth in vivo. MEG3 exerted an anti‐cancer effect via stimulatory effects on EZH2 ubiquitination leading to its degradation. Conversely, EZH2 interacted with DNMT1 and HDAC1 to induce silencing of MEG3. The EZH2 inhibitor, DZNep, and HDAC inhibitor, SAHA, displayed synergistic activity against NB. Combined treatment with DZNep and SAHA inhibited proliferation, migration and invasion of NB through suppression of the PI3K/AKT/mTOR/FOXO1 pathway. In conclusion, downregulation of MEG3 and upregulation of EZH2 forms a feedback loop that concertedly promotes the development of NB. Combined blockage of EZH2 and HDAC1 with the appropriate inhibitors may therefore present an effective treatment strategy for NB cases with low MEG3 and high EZH2 expression.

Mitochondrial dysfunction induces insulin resistance in myocytes via a reduction of insulin receptor substrate-1 (IRS-1) expression. However, the effect of mitochondrial dysfunction on insulin sensitivity is not understood well in hepatocytes. Although research has implicated the translational repression of target genes by endogenous non-coding microRNAs (miRNA) in the pathogenesis of various diseases, the identity and role of the miRNAs that are involved in the development of insulin resistance also remain largely unknown. To determine whether mitochondrial dysfunction induced by genetic or metabolic inhibition causes insulin resistance in hepatocytes, we analyzed the expression and insulin-stimulated phosphorylation of insulin signaling intermediates in SK-Hep1 hepatocytes. We used qRT-PCR to measure cellular levels of selected miRNAs that are thought to target IRS-1 3' untranslated regions (3'UTR). Using overexpression of miR-126, we determined whether IRS-1-targeting miRNA causes insulin resistance in hepatocytes. Mitochondrial dysfunction resulting from genetic (mitochondrial DNA depletion) or metabolic inhibition (Rotenone or Antimycin A) induced insulin resistance in hepatocytes via a reduction in the expression of IRS-1 protein. In addition, we observed a significant up-regulation of several miRNAs presumed to target IRS-1 3'UTR in hepatocytes with mitochondrial dysfunction. Using reporter gene assay we confirmed that miR-126 directly targeted to IRS-1 3'UTR. Furthermore, the overexpression of miR-126 in hepatocytes caused a substantial reduction in IRS-1 protein expression, and a consequent impairment in insulin signaling. We demonstrated that miR-126 was actively involved in the development of insulin resistance induced by mitochondrial dysfunction. These data provide novel insights into the molecular basis of insulin resistance, and implicate miRNA in the development of metabolic disease.

Excessive subchondral angiogenesis is a key pathological feature of osteoarthritis (OA), as it alters the balance of subchondral bone remodeling and causes progressive cartilage degradation. We previously found that miR-210-3p correlates negatively with angiogenesis, though the specific mechanism of miR-210-3p-related angiogenesis in subchondral bone during OA progression remains unclear. This study was conducted to identify the miR-210-3p-modulating subchondral angiogenesis mechanism in OA and investigate its therapeutic effect. We found that miR-210-3p expression correlated negatively with subchondral endomucin positive (Emcn + ) vasculature in the knee joints of OA mice. miR-210-3p overexpression regulated the angiogenic ability of endothelial cells (ECs) under hypoxic conditions in vitro . Mechanistically, miR-210-3p inhibited ECs angiogenesis by suppressing transforming growth factor beta receptor 1 (TGFBR1) mRNA translation and degrading DNA-binding inhibitor 4 (ID4) mRNA. In addition, TGFBR1 downregulated the expression of ID4. Reduced ID4 levels led to a negative feedback regulation of TGFBR1, enhancing the inhibitory effect of miR-210-3p on angiogenesis. In OA mice, miR-210-3p overexpression in ECs via adeno-associated virus (AAV) alleviated cartilage degradation, suppressed the type 17 immune response and relieved symptoms by attenuating subchondral Emcn + vasculature and subchondral bone remodeling. In conclusion, we identified a miR-210-3p/TGFBR1/ID4 axis in subchondral ECs that modulates OA progression via subchondral angiogenesis, representing a potential OA therapy target.

Abnormal cardiac development has been observed in individuals with Cornelia de Lange syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. However, the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed that CdLS patients with SMC3 mutations have high rates of congenital heart disease (CHD). We utilized heart-specific Smc3 -knockout (SMC3-cKO) mice, which exhibit varying degrees of outflow tract (OFT) abnormalities, to further explore this relationship. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. By employing single-nucleus RNA sequencing and chromosome conformation capture high-throughput genome-wide translocation sequencing, we revealed that Smc3 deletion downregulates the expression of key genes, including Ets2 , in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SEs) and promoters. Notably, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research revealed a novel role for SMC3 in heart development via the regulation of SE-associated genes, suggesting its potential relevance as a CHD-related gene and providing crucial insights into the molecular basis of cardiac development. Cohesin Complex: SMC3’s Crucial Role in Congenital Heart Disease Understanding heart development is vital as defects in this process are a major cause of birth abnormalities. This study focuses on a protein, SMC3, and its role in heart development. Experiments were conducted on mice genetically altered to lack SMC3 in heart cells. Researchers found that mice without SMC3 had various heart defects, like those seen in humans with congenital heart disease. They also found mutations in the SMC3 gene in patients with congenital heart disease, suggesting a link between SMC3 and heart development in humans. The findings reveal that SMC3 plays a crucial role in heart development, with its absence leading to significant heart defects in mice. These results suggest a potential genetic cause for some forms of congenital heart disease in humans. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. Introduction