Objective This study aimed to investigate the genetic diversity, differentiation, and population structure of Aedes albopictus across different geographical regions in Shandong Province, and to explore the relationship between genetic diversity and geographical distribution. Methods Between July and August 2024, ten Ae. albopictus populations were sampled from seven cities in Shandong Province. Genomic DNA was extracted from individual mosquitoes, and the mitochondrial cytochrome c oxidase subunit I(COⅠ)gene was amplified using PCR and sequenced. The obtained sequences were verified using BLAST and analyzed with MAFFT, MEGA 11, DnaSP v6.12, Arlequin 3.5, PopART 1.7, STRUCTURE 2.3.4 and the R packages adegenet and vegan to assess genetic diversity and population structure. Results A total of 229 COⅠ sequences(662 bp) was obtained, revealing ten variable sites with no insertions or deletions. The overall base composition showed an AT bias of 67.7%. Haplotype analysis identified 11 haplotypes, with Hap2 being the dominant and most widely distributed haplotype across all populations. Neutrality tests showed significant population expansion only in the Rizhao population. Mantel testing result revealed that geographical distance does not significantly impede gene flow. Overall, genetic differentiation among populations was low, indicating frequent gene flow. When combined with additional samples from Shanghai, Fujian, Guangdong, Yunnan, Hainan and Guangxi, STRUCTURE, UPGMA and DAPC analyses revealed two primary genetic clusters of Ae. albopictus. Conclusions Ae. albopictus populations in Shandong Province exhibit frequent gene flow, low genetic differentiation, and relatively low overall genetic diversity. However, the Rizhao population showed signs of recent expansion, highlighting the need for enhanced surveillance and targeted control measures in this area.

ObjectiveMigraine is a leading neurological disorder and the fourth most common cause of years lived with disability worldwide, affecting nearly 116 million individuals. Although pharmacological treatments are available, their efficacy is often limited by side effects and variable response rates. Repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) offers a safe, non-invasive alternative for migraine management. However, the neurophysiological mechanisms, particularly how rTMS modulates local cortical excitability and distributed pain-related circuits, remain poorly understood. Elucidating these mechanisms is essential for optimizing treatment protocols and improving clinical outcomes. MethodsThis study employed concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to investigate neuroplastic and neurocircuitry mechanisms of DLPFC-rTMS in migraine. Study 1 compared 30 migraineurs and 28 healthy controls to identify abnormalities in TMS-evoked potentials (TEPs) and significant current density (SCD) within sensory-discriminative regions including the primary somatosensory cortex (S1) and posterior insula (pINS), cognitive-affective regions including the anterior insula (aINS) and midcingulate cortex (MCC), and a descending modulatory region, the periaqueductal gray (PAG). Study 2 used a single-blind, crossover, sham-controlled design in 34 healthy participants. Each participant received both active (10 Hz, 80% RMT, 1 500 pulses) and sham DLPFC-rTMS in counterbalanced order. TMS-EEG and cold pain tolerance were assessed before and after each session. ResultsIn Study 1, migraineurs showed a significantly less negative N120 amplitude compared to healthy controls (P=0.027, Cohen’s d=0.60), indicating local intracortical disinhibition. No group differences were observed for N40, P60, or P180 components. At the source level, migraineurs exhibited significantly higher SCD in the S1, pINS, aINS, and MCC (allQ<0.05), but not in the ventroposterior thalamus (vpTHAL), mediodorsal thalamus (mdTHAL), or PAG. In Study 2, active rTMS significantly reduced SCD from pre- to post-stimulation in the S1, aINS, and MCC (all Q<0.05). Sham stimulation also reduced SCD in the S1 (Q<0.05) but not in the aINS or MCC. Although no significant group-level analgesic effect was observed between active and sham conditions (P=0.107), correlation analyses revealed that greater SCD reductions in the S1 and MCC were significantly associated with higher post-rTMS pain tolerance (R=-0.487 and -0.495, both Q<0.01) and larger improvements in pain tolerance(R=-0.487 and -0.451, both Q<0.05). No such correlations were found following sham stimulation, suggesting that the behavioural relevance of neural changes is specific to active rTMS. ConclusionThis study provides novel evidence that migraineurs exhibit both local neuroplastic abnormalities (reduced N120 amplitude) and hyperactivity in key pain-processing regions (S1, pINS, aINS, MCC). A single session of DLPFC-rTMS reduced hyperactivity in the aINS, MCC, and S1. Notably, greater reductions in the S1 and MCC were associated with improved pain tolerance. These findings identify distinct cortical circuitries, particularly within the cognitive-affective pain network, that may serve as potential biomarkers for optimizing rTMS treatment in migraine and other chronic pain conditions. Future studies should validate these results in patient populations experiencing spontaneous migraine attacks and explore multi-session or accelerated rTMS protocols.

Aging and cancer share overlapping characteristics, referred to as meta-hallmarks, which elucidate the convergent, antagonistic, or contradictory relationships between aging and cancer. Likewise, as a key characteristic of aging, senescent cells share some meta-hallmarks with tumor cells. These hallmarks include apoptosis resistance, metabolic alterations, secretory phenotypes, epigenetic reprogramming, and immune surveillance, all of which play pivotal roles in both tumorigenesis and senescence. Moreover, senolytic drugs, which are a class of agents selectively designed to eliminate senescent cells, have emerged as promising therapeutic agents in oncology and aging-related diseases. Since the discovery of the first senolytic drug in 2015, a diverse array of such agents has been developed. Notably, most senolytic drugs are repurposed from existing anti-tumor therapies, leveraging their shared mechanisms with senescent cells and tumor cells. Thus, this review examines the similarities between senescent cells and tumor cells, providing a better understanding of the meta-hallmarks. Besides, we categorize existing senolytic drugs based upon meta-hallmarks and elucidate the potential molecular mechanisms underlying their effects. By integrating insights from cancer and senescence research, this work aims to inspire innovative strategies for senolytic drug discovery.

Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

Local anesthetics (LAs), such as articaine (AT), exhibit limited efficacy in inflammatory environments, which constitutes a significant limitation in their clinical application within oral medicine. In our prior research, we developed AT-17, which demonstrated effective properties in chronic inflammatory conditions and appears to function as a novel oral LA that could address this challenge. In the present study, we further elucidated the beneficial effects of AT-17 in acute inflammation, particularly in oral acute inflammation, where mitochondrial-related apoptosis played a crucial role. Our findings indicated that AT-17 effectively inhibited lipopolysaccharide (LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro. This process involved the inhibition of mitochondrial reactive oxygen species (mtROS) production and the subsequent activation of the NRF2 pathway. Most notably, improvements in mitochondria-related apoptosis were key contributors to AT-17's inhibition of voltage-gated sodium channels. Additionally, AT-17 was shown to reduce mtROS production in nerve cells through the Na⁺/NCLX/ETC signaling axis. In conclusion, we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis. This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.

OBJECTIVES: To investigate the mechanism by which circ_EPHB4 regulates temozolomide (TMZ) sensitivity of glioma cells through the miR-424-5p/Wnt3 signal axis. METHODS: We detected the expression levels of circ_EPHB4, miR-424-5p and Wnt3 mRNA in glioma specimens from 25 patients with primary glioma and 25 patients experiencing relapse following temozolomide-based chemotherapy and in TMZ-sensitive and -resistant glioma A172 and SHG44 cells with circ_EPHB4 knockdown using qRT-PCR, and Wnt3 protein expression level was detected with Western blotting. Cell viability, colony-forming ability, and apoptosis of the cells with circ_EPHB4 knockdown were assessed, and the targeted regulation relationship between circ_EPHB4, miR-424-5p, and Wnt3 was verified by dual luciferase reporter assay and RNA immunoprecipitation (RIP) experiments. The effect of circ_EPHB4 knockdown on tumorigenesis of glioma cells was evaluated in subcutaneous tumor-bearing nude mouse models. RESULTS: The expression of circ_EPHB4 was significantly increased in glioma tissues and cells as compared with normal neural tissues and astrocytes (P=0.014). In TMZ-resistant glioma cells, circ_EPHB4 knockdown resulted in an obvious reduction of IC50 value of TMZ, inhibited cell colony formation, and promoted cell apoptosis, and these effects were reversed by miR-424-5p knockdown. The expressions of miR-424-5p and circ_EPHB4 were negatively correlated in glioma tissues (P=0.011). MiR-424-5p knockdown also attenuated the effect of circ_EPHB4 knockdown on expressions of PCNA, P-gp, MRP1 and bax. CONCLUSIONS Circ_EPHB4 regulates Wnt3 expression through "sponge adsorption" of miR-424-5p, thereby modulating TMZ-resistant glioblastoma cell clonogenesis, apoptosis, and TMZ sensitivity, suggesting the potential of circ_EPHB4 as a therapeutic target for reversing drug resistance of gliomas.
MicroRNAs/genetics* ; Humans ; Temozolomide ; Glioma/genetics* ; Animals ; Mice, Nude ; Cell Line, Tumor ; Wnt3 Protein/metabolism* ; Mice ; Apoptosis ; RNA, Circular ; Drug Resistance, Neoplasm ; Brain Neoplasms/pathology* ; Signal Transduction

OBJECTIVES: To explore the molecular mechanism of Jiangzhi Huaban Decoction (JZHBD) for improving atherosclerosis through the "qi meridian-blood channels" pathway. METHODS: ApoE^-/- mouse models of atherosclerosis were established by high-fat diet feeding for 8 weeks, with C57BL/6 mice on a normal diet as the controls. Forty ApoE^-/- mouse models were randomized into model group, low-, medium-, and high-dose JZHBD treatment groups, and atorvastatin treatment group (n=8) for their respective treatments for 8 weeks. The changes in body weight and overall condition of the mice were monitored weekly. After the treatments, serum levels of TC, TG, HDL-C, LDL-C, TBA, ALT, and AST of the mice were measured, pathological changes in the liver and aortic root plaques were examined with HE staining, and lipid accumulation in the liver and aortic wall was assessed using Oil Red O staining. The core molecular mechanism was studied through transcriptomics, and the expressions of the key pathway proteins were confirmed using Western blotting and immunohistochemistry. RESULTS: Treatment with JZHBD significantly reduced blood lipid and total bile acid levels, improved liver function and hepatic steatosis, and decreased aortic lipid deposition and plaque area in the mouse models of atherosclerosis. Transcriptomic analysis suggested that the therapeutic mechanism of JZHBD involved reverse cholesterol transport, PPAR signaling, and the inflammatory pathways. In atherosclerotic mice, JZHBD treatment obviously up-regulated hepatic expressions of PPARγ, LXRα, ABCA1, ABCG1, and CYP7A1, down-regulated hepatic expressions of p-p65/p65, IL-6, IL1β in the liver, increased ABCG5 and ABCG8 expressions in the intestines, and decreased ICAM-1 and VCAM-1 expressions in the aortic plaques. CONCLUSIONS JZHBD improves atherosclerotic vascular damage and plaque formation possibly by regulating hepatic reverse cholesterol transport and inflammation via modulating the hepatic PPARγ/LXRα/NF-κB signaling pathway.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Mice, Inbred C57BL ; Plaque, Atherosclerotic/metabolism* ; Liver/metabolism* ; Mice ; Atherosclerosis/metabolism* ; Cholesterol/metabolism* ; PPAR gamma/metabolism* ; Male ; Diet, High-Fat ; Biological Transport

OBJECTIVES: To investigate the oncogenic role of circular RNA circ_EPHB4 in glioma and its molecular mechanism. METHODS: Microarray analysis was performed to identify the differentially expressed circRNAs in glioma tissues. The effects of circ_EPHB4 on glioma cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and tumorigenicity in vivo were assessed using scratch wound healing assay, Transwell invasion assay and nude mouse models bearing subcutaneous tumors. RNA immunoprecipitation (RIP), RNA stability assays, and gene overexpression and silencing techniques were employed to validate the synergistic regulatory effect of circ_EPHB4 and the N6-methyladenosine (m⁶A) reader protein YTHDF3 on Wnt3 expression. RESULTS: Circ_EPHB4 was significantly overexpressed by 2.3 folds (|log2FC|=1.2, P<0.01) in glioma tissues compared to the adjacent tissues, and by 2.5 folds in glioma cell line U373 compared to normal cells (P<0.001). Overexpression of circ_EPHB4 significantly enhanced migration and invasion of glioma cells, and promoted the expressions of EMT markers N-cadherin and vimentin. In the tumor-bearing mouse models, the tumor volume in circ_EPHB4 overexpression group was significantly greater than that in the control group, and the lung metastatic foci increased by 4.2 folds. Overexpression of circ_EPHB4 promoted oncogenesis by upregulating Wnt3 expression, while YTHDF3 extended the half-life of Wnt3 mRNA in an m⁶A-dependent manner. Simultaneous knockdown of circ_EPHB4 and YTHDF3 resulted in an obvious reduction of Wnt3 mRNA expression by up to 47% compared to its level following knocking down either circ_EPHB4 or YTHDF3 alone. CONCLUSIONS Circ_EPHB4 and YTHDF3 promote glioma progression by jointly targeting the Wnt3 signaling pathway, which may provide a new therapeutic strategy for gliomas.
Glioma/genetics* ; Humans ; Animals ; Cell Line, Tumor ; RNA-Binding Proteins/genetics* ; RNA, Circular ; Epithelial-Mesenchymal Transition ; Mice, Nude ; Cell Movement ; Wnt3 Protein/genetics* ; Mice ; Disease Progression ; Adenosine/metabolism* ; Brain Neoplasms/metabolism* ; Gene Expression Regulation, Neoplastic

BACKGROUND: Pancreatic cancer is a lethal malignancy prone to gemcitabine resistance. The single-strand selective monofunctional uracil DNA glycosylase (SMUG1), which is responsible for initiating base excision repair, has been reported to predict the outcomes of different cancer types. However, the function of SMUG1 in pancreatic cancer is still unclear. METHODS: Gene and protein expression of SMUG1 as well as survival outcomes were assessed by bioinformatic analysis and verified in a cohort from Fudan University Shanghai Cancer Center. Subsequently, the effect of SMUG1 on proliferation, cell cycle, and migration abilities of SMUG1 cells were detected in vitro . DNA damage repair, apoptosis, and gemcitabine resistance were also tested. RNA sequencing was performed to determine the differentially expressed genes and signaling pathways, followed by quantitative real-time polymerase chain reaction and Western blotting verification. The cancer-promoting effect of forkhead box Q1 (FOXQ1) and SMUG1 on the ubiquitylation of myelocytomatosis oncogene (c-Myc) was also evaluated. Finally, a xenograft model was established to verify the results. RESULTS: SMUG1 was highly expressed in pancreatic tumor tissues and cells, which also predicted a poor prognosis. Downregulation of SMUG1 inhibited the proliferation, G1 to S transition, migration, and DNA damage repair ability against gemcitabine in pancreatic cancer cells. SMUG1 exerted its function by binding with FOXQ1 to activate the Protein Kinase B (AKT)/p21 and p27 pathway. Moreover, SMUG1 also stabilized the c-Myc protein via AKT signaling in pancreatic cancer cells. CONCLUSIONS SMUG1 promotes proliferation, migration, gemcitabine resistance, and c-Myc protein stability in pancreatic cancer via protein kinase B signaling through binding with FOXQ1. Furthermore, SMUG1 may be a new potential prognostic and gemcitabine resistance predictor in pancreatic ductal adenocarcinoma.
Humans ; Pancreatic Neoplasms/pathology* ; Forkhead Transcription Factors/genetics* ; Signal Transduction/genetics* ; Animals ; Cell Line, Tumor ; Proto-Oncogene Proteins c-akt/metabolism* ; Cell Proliferation/physiology* ; Mice ; Uracil-DNA Glycosidase/genetics* ; Female ; Male ; Gemcitabine ; Mice, Nude ; Apoptosis/physiology* ; Deoxycytidine/analogs & derivatives* ; Cell Movement/genetics*