Volume 13, Issue 3

Small extracellular vesicles (sEVs), also referred as exosomes, have emerged as valuable indicators of cancer progression and response to treatment. They offer prospective targets for therapeutic interventions as well as insightful information about the fundamental mechanisms underlying the development of cancer. sEVs have garnered significant attention as a useful tool for liquid biopsies used in non-invasive cancer diagnosis. We discussed their potential in predicting treatment outcomes, monitoring disease progression, and classifying cancer stages and subtypes. sEVs can also shed light on how resistance to several cancer treatments, such as drug resistance, radiation resistance, chemotherapy resistance, and immunotherapy resistance develops. sEV-based cancer diagnostics have initiated clinical trials, underscoring their potential clinical value. Additionally, significant progress has been made in the development of techniques for isolating and enriching sEVs, enabling the sensitive and efficient detection of sEV proteins and nucleic acids. These advancements have resulted in enhanced sensitivity and specificity, facilitating the identification of biomarkers with low expression levels. In conclusion, sEV biomarkers offer significant potential for the diagnosis and monitoring of cancer. The utilization of sEVs in liquid biopsies presents a non-invasive method for acquiring tumour-specific information. Ongoing research and advancements in sEV-based diagnostics and therapeutics are crucial for unlocking the complete potential of sEV biomarkers in clinical settings.

For more than two decades, peripheral administration of GLP-1 or GLP-1 receptor (GLP-1R) agonist (GLP-1RA) curbs appetite and reduce body weight gain in animal models. More importantly, the body weight lowering effect has been effectively observed in clinical practice. There is no doubt that the target sites for GLP-1 or GLP-1RAs to exert those functions are located in the brain. It, however, remains controversy on exactly how these drugs access their targets in the brain. Here, we have discussed literatures on whether peripheral GLP-1 or GLP-1RAs enters the brain via crossing the blood-brain barrier, or the blood cerebrospinal fluid barrier, or given circumventricular organs. We have then commented the view or opinion that peripheral GLP-1RAs may exert their brain functions via organ-organ communications without entering the brain.

Mitochondrial dysfunction is increasingly recognized as a critical driver in the pathogenesis of cardiovascular diseases. Mitochondrial quality control (MQC) is an ensemble of adaptive mechanisms aimed at maintaining mitochondrial integrity and functionality and is essential for cardiomyocyte viability and optimal cardiac performance under the stress of cardiovascular pathology. The key MQC components include mitochondrial fission, fusion, mitophagy, and mitochondria-dependent cell death, each contributing uniquely to cellular homeostasis. The dynamic interplay among these processes is intricately linked to pathological phenomena, such as redox imbalance, calcium overload, dysregulated energy metabolism, impaired signal transduction, mitochondrial unfolded protein response, and endoplasmic reticulum stress. Aberrant mitochondrial fission is an early marker of mitochondrial injury and cardiomyocyte apoptosis, whereas reduced mitochondrial fusion is frequently observed in stressed cardiomyocytes and is associated with mitochondrial dysfunction and cardiac impairment. Mitophagy is a protective, selective autophagic degradation process that eliminates structurally compromised mitochondria, preserving mitochondrial network integrity. However, dysregulated mitophagy can exacerbate cellular injury, promoting cell death. Beyond their role as the primary energy source of the cell, mitochondria are also central regulators of cardiomyocyte survival, mediating apoptosis and necroptosis in reperfused myocardium. Consequently, MQC impairment may be a determining factor in cardiomyocyte fate. This review consolidates current insights into the regulatory mechanisms and pathological significance of MQC across diverse cardiovascular conditions, highlighting potential therapeutic avenues for the clinical management of heart diseases. Graphical Abstract Healthy cardiomyocytes feature a precise balance between mitochondrial fusion (mediated by MFN1/2 and Opa1) and division (mediated by Drp1). Fusion contributes to mitochondrial network stability and functional restoration, while division ensures mitochondrial renewal and the removal of damaged parts. PGC-1α, NRF1/2 and TFAM regulate mitochondrial biogenesis to ensure mtDNA transcription and replication and maintain mitochondrial quantity and quality. Mitochondrial autophagy selectively removes damaged mitochondria through LC3II, FUNDC1, PINK1-Parkin, and other molecular pathways to prevent the accumulation of cell damage. The cell begins to undergo a series of stress responses when the balance between mitochondrial fusion and division is disrupted or biogenesis and autophagy are impaired. Initially, BAX activates caspase-9, initiating the apoptosis pathway, leading to the activation of caspase-3 and cell death. If mitochondrial damage is aggravated, RIPK3 activates MLKL, which triggers necroptosis through CAMKII mediation, leading to cell structure destruction and loss of function. The interactions between mitochondrial fusion and division, biogenesis and autophagy were demonstrated, and the specific mechanisms of how these processes progressively affect cardiomyocyte survival are described. MFN1/2: mitofusin 1 and 2; Opa1: optic atrophy protein 1; Drp1: dynamin related protein 1; FUNDC1: Fun14 domain-containing protein 1; PINK1: PTEN induced putative kinase 1; RIPK3: receptor-interacting protein kinase 3; MLKL: mixed lineage kinase domain-like protein; CAMKII: Ca2+-calmodulin-dependent protein kinase II.

Background and Objectives Considerable evidence has shown that alterations in gut microbiota composition are associated with atrial fibrillation (AF). However, the causal associations remain largely unresolved. This study aims to reveal the causality between gut microbiota and AF. Methods We incorporated data from the largest genome-wide association studies (GWASs) of gut microbiota composition (involving 18,304 individuals) and GWASs of AF (comprising 60,620 cases and 970,216 controls) in European individuals. A two-sample Mendelian randomization framework was designed to investigate the role of gut microbiota in the development of AF. The inverse variance weighted method was applied for the main causal estimate. Complementary sensitivity analyses were utilized to confirm the robustness of the results. Finally, gene ontology enrichment analyses and Kyoto Encyclopedia of genes and genomes pathway analysis are used to investigate the bio-function. Results Among all gut microbiota, five microbial taxa, namely Lachnospiraceae FCS020 , Rikenellaceae RC9 gut group , Catenibacterium , Victivallis , and Erysipelatoclostridium were identified to be causally associated with the higher risk of AF. Besides, genetically predicted eight microbial taxa, namely Lachnospiraceae NK4A136 group , Howardella , Intestinibacter bartlettii , Alloprevotella , Anaerostipes , Odoribacter , Ruminococcus (gnavus group) , and Ruminiclostridium 5 can prevent AF. Conclusion Our study provides evidence of the causal effect of the gut microbiota on AF, highlighting causal microbial taxa. Our results may offer novel insights into gut microbiota-mediated mechanisms and interventions of AF.

Background and Objectives Relapse is one of the most critical causes of transplant failure in patients with acute myeloid leukemia (AML) receiving haploidentical-related donor (HID) hematopoietic stem cell transplantation (HSCT). We aimed to develop an artificial intelligence (AI)-based predictive model for post-transplant relapse in patients with AML receiving HID HSCT. Methods This study included patients with consecutive AML (aged ≥ 12 years) receiving HID HSCT in complete remission (CR). We randomly selected 70% of the entire population ( n = 665) as the training cohort for developing the model and nomogram, which were both evaluated using data from the remaining 30% of the patients (validation cohort, n = 286). Furthermore, the model was validated in an independent cohort ( n = 213) and in the clinical practice of five experienced clinicians. Results Five variables (AML risk category, number of courses of induction chemotherapy for first CR, disease status, measurable residual disease before HSCT, and blood group disparity) were included in the final model ( i.e ., PKU-AML model). The concordance index of the nomogram was 0.707. The Hosmer−Lemeshow test showed a good fit for this model ( P = 0.205). The calibration curve was close to the ideal diagonal line, and decision curve analysis showed a significantly better net benefit for this model. The reliability of our prediction nomogram was demonstrated in a validation cohort, an independent cohort, and in clinical practice. Conclusions Our PKU-AML model can predict the relapse of patients with AML receiving HID HSCT in CR, providing an effective tool for the early prediction and timely management of post-transplant relapse.

Background and Objectives Circular RNAs play a vital role in developing triple-negative breast cancer (TNBC). Likewise, the function of circRNAs in TNBC resistance to chemotherapy remains largely unknown. Here, we aimed to investigate whether circPLK1 has a biological efect on anthracycline resistance in TNBC. Methods We identified circPLK1—a circRNA—using a circRNA microarray in TNBC cells and paired TNBC samples. We assessed the role of circPLK1 in anthracycline resistance in TNBC. Cytotoxicity assay, colony formation assay, and flow cytometry were performed as functional experiments. Western blot analysis, qRT-PCR, in situ hybridization, and immunohistochemistry were used to evaluate the expression of circPLK1, miR-940, and ETS1. RNA immunoprecipitation and luciferase reporter assay were conducted to evaluate the interaction among circPLK1, miR-940, and ETS1. We evaluated the prognosis value of circPLK1 and ETS1 in 240 TNBC patients. Results The upregulation of circPLK1 in non-pCR TNBC patients receiving anthracyclines-based neoadjuvant chemotherapy was significantly associated with aggressive characteristics. Colony formation and doxorubicin resistance of TNBC cells were promoted by circPLK1 overexpression but inhibited by circPLK1 knockdown in vitro . circPLK1 overexpression facilitated doxorubicin resistance of TNBC in the nude mouse xenograft model. We found that circPLK1 could promote ETS1 expression by sponging miR-940. High circPLK1 and ETS1 expression were significantly associated with reduced survival in TNBC. Conclusion circPLK1 plays a vital role in the resistance of TNBC to anthracycline and is associated with poor prognosis. The inhibition of circPLK1 may be a practical therapeutic approach to modulate anthracycline resistance in TNBC.

Background and Objectives N-glycosylation, a crucial post-translational modification, is well-recognized for its pivotal role in cardiovascular functions. N-acetylglucosaminyltransferase V (GnT-V) is one of the major glycosyltransferases that determine the complexity of N-glycans in N-glycosylation modification. This study aimed to explore the role of GnT-V in myocardial infarction (MI). Methods Proteomics and N-glycoproteomic analysis were performed on myocardial tissues for the N-glycosylation profile after MI. Adeno-associated virus (AAV) with a mouse cTnT promoter was utilized to induce overexpression of GnT-V in the heart for the role of GnT-V in MI. Echocardiography and histological analysis were used to evaluate the effect of GnT-V on MI. For the potential mechanisms of GnT-V, proteomic analysis was performed on cardiomyocytes that were subjected to GnT-V overexpression and hypoxic stress. The results were validated by western blot, lectin blot and immunoprecipitation assays, and confirmed with PNGase F and tunicamycin treatment. Results N-glycosylation of protein was significantly reduced after MI, which could be related to a decrease in the expression levels of GnT-V and its target glycans. Targeted GnT-V overexpression in the heart by using AAV improved cardiac function and reduced the infarct size after MI. Further, proteomics analysis of cardiomyocytes revealed that insulin-like growth factor-binding protein 3 (IGFBP3) was targeted by GnT-V and induced degradation through the lysosome pathway. Consequently, the insulin-like growth factor 1 receptor (IGF1R) signaling pathway was activated through overexpression of GnT-V. Conclusion Our findings suggest that promoting the IGF1R signaling cascades by regulating the N-glycosylation of certain proteins in the signaling pathway, especially through GnT-V, may act as a promising strategy for treating MI.

Background and Objectives Hemostasis factors affecting clot patterns, particularly fibrinogen, may influence the effectiveness of intravenous thrombolysis (IVT). We aimed to investigate the impact of differences in fibrinogen plasma levels on the efficacy and safety of tenecteplase versus alteplase in an acute ischemic cerebrovascular events-II (TRACE-II) trial. Methods In a multi-center, prospective, open-label, end-point blinded, randomized, controlled trial. Adults with acute ischemic stroke (AIS) were enrolled. Patients received intravenous tenecteplase (0–25 mg/kg) or alteplase (0–9 mg/kg) within 4–5 h. Patients were divided into three groups according to their plasma fibrinogen level: low fibrinogen level (< 2 g/L), normal fibrinogen level (2–4 g/L), and high fibrinogen level (> 4 g/L). The Modified Rankin Score (mRS) from 2 to 6 was used to define the efficacy outcome. The safety outcomes were the occurrence of symptomatic intracranial hemorrhage (sICH) within 36 h and 90 days, parenchymal hematoma 2 (PH 2 ) within 36 h, any intracranial hemorrhage (ICH), other significant hemorrhagic events, and death at 3 months. SAS software version 9.4 was used for statistical analysis. Binary logistic regression was used to evaluate the efficacy and safety outcomes differences between tenecteplase and alteplase in the three fibrinogen groups. The interaction between treatment and fibrinogen subgroups was used to assess the effect of fibrinogen levels on the efficacy and safety of different treatments. All P -values are two-tailed and significance was defined as P < 0.05. Results The trial enrolled 1409 patients with AIS. Among them, 705 patients received tenecteplase treatment and 704 patients received alteplase treatment. Six percent of all patients had a low plasma fibrinogen level ( < 2 g/L), 81% had a normal fibrinogen level (2–4 g/L), and 13% had a high plasma fibrinogen level ( > 4 g/L). The efficacy of tenecteplase compared to alteplase remained consistent across varying fibrinogen levels (interaction P = 0.30). Additionally, the safety outcomes were comparable between the two treatments across all fibrinogen levels [sICH at 36 h (interaction P = 0.94); sICH at 90 days (interaction P = 0.77); PH 2 ICH at 36 h (interaction P = 0.84); Other symptomatic hemorrhagic events within 90 days (interaction P = 0.54)]. Similarly, there was no significant difference in mortality rates between patients treated with tenecteplase and alteplase across different plasma fibrinogen levels (interaction P = 0.58). Conclusion The results of the study suggest that the efficacy and safety of tenecteplase in treated AIS patients within 4.5 h are comparable to those of alteplase, regardless of plasma fibrinogen levels.