Exploring the Two-Way Link between Migraines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

BACKGROUND: The objective of this study is to utilize Mendelian randomization to scrutinize the mutual causality between migraine and venous thromboembolism (VTE) thereby addressing the heterogeneity and inconsistency that were observed in prior observational studies concerning the potential interrelation of the two conditions. METHODS: Employing a bidirectional Mendelian randomization approach, the study explored the link between migraine and VTE, incorporating participants of European descent from a large-scale meta-analysis. An inverse-variance weighted (IVW) regression model, with random-effects, leveraging single nucleotide polymorphisms (SNPs) as instrumental variables was utilized to endorse the mutual causality between migraine and VTE. SNP heterogeneity was evaluated using Cochran's Q-test and to account for multiple testing, correction was implemented using the intercept of the MR-Egger method, and a leave-one-out analysis. RESULTS: The IVW model unveiled a statistically considerable causal link between migraine and the development of VTE (odds ratio [OR] = 96.155, 95% confidence interval [CI]: 4.342-2129.458, p = 0.004), implying that migraine poses a strong risk factor for VTE development. Conversely, both IVW and simple model outcomes indicated that VTE poses as a weaker risk factor for migraine (IVW OR = 1.002, 95% CI: 1.000-1.004, p = 0.016). The MR-Egger regression analysis denoted absence of evidence for genetic pleiotropy among the SNPs while the durability of our Mendelian randomization results was vouched by the leave-one-out sensitivity analysis. CONCLUSION: The findings of this Mendelian randomization assessment provide substantiation for a reciprocal causative association between migraine and VTE within the European population.

Emerging role of extracellular vesicles in veterinary practice: novel opportunities and potential challenges.

Extracellular vesicles are nanoscale vesicles that transport signals between cells, mediating both physiological and pathological processes. EVs facilitate conserved intercellular communication. By transferring bioactive molecules between cells, EVs coordinate systemic responses, regulating homeostasis, immunity, and disease progression. Given their biological importance and involvement in pathogenesis, EVs show promise as biomarkers for veterinary diagnosis, and candidates for vaccine production, and treatment agents. Additionally, different treatment or engineering methods could be used to boost the capability of extracellular vesicles. Despite the emerging veterinary interest, EV research has been predominantly human-based. Critical knowledge gaps remain regarding isolation protocols, cargo loading mechanisms, in vivo biodistribution, and species-specific functions. Standardized methods for veterinary EV characterization and validation are lacking. Regulatory uncertainties impede veterinary clinical translation. Advances in fundamental EV biology and technology are needed to propel the veterinary field forward. This review introduces EVs from a veterinary perspective by introducing the latest studies, highlighting their potential while analyzing challenges to motivate expanded veterinary investigation and translation.

Nutrient availability regulates the secretion and function of immune cell-derived extracellular vesicles through metabolic rewiring.

Extracellular vesicle (EV)-based immunotherapeutics have emerged as promising strategy for treating diseases, and thus, a better understanding of the factors that regulate EV secretion and function can provide insights into developing advanced therapies. Here, we report that nutrient availability, even changes in individual nutrient components, may affect EV biogenesis and composition of immune cells [e.g., macrophages (Mφs)]. As a proof of concept, EVs from M1-Mφ under glutamine-depleted conditions (EVGLN-) had higher yields, functional compositions, and immunostimulatory potential than EVs from conventional GLN-present medium (EVGLN+). Mechanistically, the systemic metabolic rewiring (e.g., altered energy and redox metabolism) induced by GLN depletion resulted in up-regulated pathways related to EV biogenesis/cargo sorting (e.g., ESCRT) and immunostimulatory molecule production (e.g., NF-κB and STAT) in Mφs. This study highlights the importance of nutrient status in EV secretion and function, and optimizing metabolic states and/or integrating them with other engineering methods may advance the development of EV therapeutics.

The mitochondria‒paraspeckle axis regulates the survival of transplanted stem cells under oxidative stress conditions.

Rationale: Stem cell-based therapies have emerged as promising tools for tissue engineering and regenerative medicine, but their therapeutic efficacy is largely limited by the oxidative stress-induced loss of transplanted cells at injured tissue sites. To address this issue, we aimed to explore the underlying mechanism and protective strategy of ROS-induced MSC loss. Methods: Changes in TFAM (mitochondrial transcription factor A) signaling, mitochondrial function, DNA damage, apoptosis and senescence in MSCs under oxidative stress conditions were assessed using real-time PCR, western blotting and RNA sequencing, etc. The impact of TFAM or lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) knockdown or overexpression on mitochondrial function, DNA damage repair, apoptosis and senescence in MSCs was also analyzed. The effect of mitochondrion-targeted antioxidant (Mito-TEMPO) on the survival of transplanted MSCs was evaluated in a mouse model of renal ischemia/reperfusion (I/R) injury. Results: Mitochondrial ROS (mtROS) bursts caused defects in TFAM signaling and overall mitochondrial function, which further impaired NEAT1 expression and its mediated paraspeckle formation and DNA repair pathways in MSCs, thereby jointly promoting MSC senescence and death under oxidative stress. In contrast, targeted inhibition of the mtROS bursts is a sufficient strategy for attenuating early transplanted MSC loss at injured tissue sites, and coadministration of Mito-TEMPO improved the local retention of transplanted MSCs and reduced oxidative injury in ischemic kidneys. Conclusions: This study identified the critical role of the mitochondria‒paraspeckle axis in regulating cell survival and may provide insights into developing advanced stem cell therapies for tissue engineering and regenerative medicine.

Noval ceRNA axis-mediated high expression of TOP2A correlates with poor prognosis and tumor immune infiltration of hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a highly malignant tumor with limited treatment options, suboptimal efficacy, and poor prognosis, resulting in an economic burden to countries worldwide. TOP2A is a mammalian protein that plays a vital role in DNA replication. Previous studies have shown that upregulation of TOP2A expression is associated with tumorigenesis and progression in various cancers, but the exact mechanism of upregulation remains unclear. Methods: We first conducted a pan-cancer analysis using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases to study the oncogenicity of TOP2A through the cBioPortal database. Next, using The Encyclopedia of RNA Interactomes (ENCORI) database, we identified microRNAs (miRNAs) that are associated with the downregulation of TOP2A and investigated potential long non-coding RNAs (lncRNAs) that may act as competing endogenous RNAs (ceRNAs) by binding to candidate miRNAs. We then analyzed immune cell infiltration and immune checkpoints using the TIMER database. Finally, we performed a multivariate regression analysis using lncRNAs and clinical pathological characteristics, constructed a nomogram to predict the prognosis of HCC based on the analysis results, and evaluated its diagnostic efficiency. Results: TOP2A was highly expressed in HCC and was associated with poor patient prognosis. TOP2A was subject to post-transcriptional regulation in HCC, with the ceRNA mechanism being a significant pathway. miR-139-5p was an important miRNA that suppressed the upregulation of TOP2A in HCC, and patients with low expression of miR-139-5p had worse overall survival (OS). After screening and analysis, three lncRNAs, AC078846.1, AC124798.1 and SNHG3, were found to inhibit the activity of miR-139-5p through the ceRNA mechanism, and patients with high expression of these three lncRNAs had worse prognosis. In addition, TOP2A was found to be closely related to tumor-infiltrating immune cells (TIICs) and immune checkpoints. A nomogram constructed using the three lncRNAs and selected clinicopathological features showed good predictive value for the prognosis of liver cancer. Conclusions: The TOP2A-miR-139-5p-AC078846.1/AC124798.1/SNHG3 axis plays a significant role in the progression of HCC and leads to poor patient outcomes. Additionally, TOP2A influences the development of HCC by affecting TIICs and immune checkpoints. A nomogram constructed using the three lncRNAs and clinicopathological features has good clinical utility.