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Background Familial hypercholesterolemia (FH) is characterized by lifelong elevated LDL-C levels and increased cardiovascular risk. PCSK9 inhibitors (PCSK9i) reduce LDL-C and Lp(a), however, the effect of dual lipid reduction on mechanical vascular function remains unclear. The aim of this study was to evaluate the efficacy of PCSK9i in reducing LDL-C and Lp(a) and to assess the relationship between the dual lipid reduction and the mechanical vascular profile improvement in FH subjects. Methods This prospective observational study included 301 genetically confirmed FH subjects treated with PCSK9i added to high-intensity statins and ezetimibe. Biochemical and PWV measurements were performed at baseline and after six months. Subjects were stratified into four groups based on median values of ΔLDL-C and ΔLp(a). Results After six months of add-on PCSK9i, 44.9% of FH subjects achieved their LDL-C targets. Reductions were observed in LDL-C (− 49.8%, p  < 0.001), Lp(a) (− 21.4%, p  < 0.001), and PWV (Δ − 22.7%, p  < 0.001). PWV improvement increased across groups with greater lipid reductions ( p for trend < 0.01); Group 3 and Group 4 exhibited a similar mechanical vascular benefit. Logistic regression showed that subjects with the greatest combined lipid reduction (ΔLDL-C ≤ − 45.22% and ΔLp(a) ≤ − 11.49%) had the strongest association with PWV improvement (OR: 5.12; 95% CI: 2.08–11.02). Conclusions Dual lipid reduction with PCSK9i was associated with a pronounced mechanical vascular profile improvement in FH subjects; however, an intensive Lp(a) reduction may be needed to achieve a greater mechanical vascular benefit.

Background Glioblastoma (GBM), the most aggressive primary brain tumor, has a dismal prognosis largely due to therapy-resistant stem-like cells that drive recurrence. While N6-methyladenosine modifications in GBM are well-studied, the role of 5-methylcytosine (m 5 C) modifications specifically in circular RNAs (circRNAs) remains poorly understood. Methods Bioinformatic analysis, qRT-PCR and Western blot assays were used to investigate the expression of NSUN7, circNTRK2, YBX3, STK31, IKZF1 in GBM tissues and cell lines. m 5 C dot blot assays, m 5 C-bisulfite sequence assays, Sanger’s sequencing, RNA pull down and RIP assays, in vitro kinase assays, chromatin immunoprecipitation and luciferase reporter gene assays are used to clarify the interaction between factors above. Colony formation assays, sphere formation assays, and stemness marker (OCT4, DCLK1) analysis were utilized to assess the impact of the factors above on GBM stemness. Subcutaneous heterotopic and orthotopic xenograft are utilized to demonstrate the function of YBX3/circNTRK2/STK31/IKZF1 axis in GBM in vivo. Results NSUN7 and YBX3 are both upregulated in GBM tissues and cell lines. NSUN7 catalyzes m 5 C modification of circNTRK2. YBX3 decreasing circNTRK2 stability and function via binding m 5 C of circNTRK2. CircNTRK2 binds to and activates STK31, leading to phosphorylation of IKZF1 at S 63 , which decreases the O -GlcNAc levels and transcriptional activity of IKZF1, thereby promoting the stem cell characteristics of GBM cells. Conclusions This study unveils that NSUN7-mediated m 5 C modification of circNTRK2 fuels GBM stemness via circNTRK2-dependent STK31 activation, thus identifying potential biomarkers for targeted molecular therapy of GBM and providing novel therapeutic targets for GBM treatment.

In recent years, 5-methylcytosine (m 5 C) RNA modification has emerged as a key player in regulating RNA metabolism and function through coding as well as non-coding RNAs. Accumulating evidence has shown that m 5 C modulates the stability, translation, transcription, nuclear export, and cleavage of RNAs to mediate cell proliferation, differentiation, apoptosis, stress responses, and other biological functions. In humans, m 5 C RNA modification is catalyzed by the NOL1/NOP2/sun (NSUN) family and DNA methyltransferase 2 (DNMT2). These RNA modifiers regulate the expression of multiple oncogenes such as fizzy-related-1, forkhead box protein C2, Grb associated-binding protein 2, and TEA domain transcription factor 1, facilitating the pathogenesis and progression of cancers. Furthermore, the aberrant expression of methyltransferases have been identified in various cancers and used to predict the prognosis of patients. In this review, we present a comprehensive overview of m 5 C RNA methyltransferases. We specifically highlight the potential mechanism of action of m 5 C in cancer. Finally, we discuss the prospect of m 5 C-relative studies.

Background Lactylation, a novel contributor to post-translational protein modifications, exhibits dysregulation across various tumors. Nevertheless, its intricate involvement in colorectal carcinoma, particularly for non-histone lactylation and its intersection with metabolism and immune evasion, remains enigmatic. Methods Employing immunohistochemistry on tissue microarray with clinical information and immunofluorescence on colorectal cell lines, we investigated the presence of global lactylation and its association with development and progression in colorectal cancer as well as its functional location. Leveraging the AUCell algorithm alongside correlation analysis in single-cell RNA sequencing data, as well as cox-regression and lasso-regression analysis in TCGA dataset and confirmed in GEO dataset, we identified a 23-gene signature predicting colorectal cancer prognosis. Subsequently, we analyzed the associations between the lactylation related gene risk and clinical characteristics, mutation landscapes, biological functions, immune cell infiltration, immunotherapy responses, and drug sensitivity. Core genes were further explored for deep biological insights through bioinformatics and in vitro experiments. Results Our study innovatively reveals a significant elevation of global lactylation in colorectal cancer, particularly in malignant tumors, confirming it as an independent prognostic factor for CRC. Through a comprehensive analysis integrating tumor tissue arrays, TCGA dataset, GEO dataset, combining in silico investigations and in vitro experiments, we identified a 23-gene Lactylation-Related Gene risk model capable of predicting the prognosis of colorectal cancer patients. Noteworthy variations were observed in clinical characteristics, biological functions, immune cell infiltration, immune checkpoint expression, immunotherapy responses and drug sensitivity among distinct risk groups. Conclusions The Lactylation-Related Gene risk model exhibits significant potential for improving the management of colorectal cancer patients and enhancing therapeutic outcomes, particularly at the intersection of metabolism and immune evasion. This finding underscores the clinical relevance of global lactylation in CRC and lays the groundwork for mechanism investigation and targeted therapeutic strategies given the high lactate concentration in CRC.

Targeting non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), has recently emerged as a promising strategy for treating malignancies and other diseases. In recent years, the development of ncRNA-based therapeutics for targeting protein-coding and non-coding genes has also gained momentum. This review systematically examines ongoing and completed clinical trials to provide a comprehensive overview of the emerging landscape of ncRNA-based therapeutics. Significant efforts have been made to advance ncRNA therapeutics to early clinical studies. The most advanced trials have been conducted with small interfering RNAs (siRNAs), miRNA replacement using nanovector-entrapped miRNA mimics, or miRNA silencing by antisense oligonucleotides. While siRNA-based therapeutics have already received FDA approval, miRNA mimics, inhibitors, and lncRNA-based therapeutics are still under evaluation in preclinical and early clinical studies. We critically discuss the rationale and methodologies of ncRNA targeting strategies to illustrate this rapidly evolving field.

Gastric cancer remains a significant health burden globally, especially prevalent in Asian and European regions. Despite a notable decline in incidence in the United States and Western Europe over recent decades, the disease’s persistence underscores the urgency for advanced research in its pathogenesis and treatment strategies. Central to this pursuit is the exploration of the mitogen-activated protein kinase (MAPK) pathway, a pivotal cellular mechanism implicated in the complex processes of gastric cancer development, including cellular proliferation, invasion, migration, and metastasis. The MAPK or extracellular signal-regulated kinase pathway serves as a crucial conduit for transmitting extracellular signals to elicit intracellular responses, with its signaling cascades subject to alterations due to genetic and epigenetic variations across various diseases, prominently cancer. This review delves into the intricate role of the MAPK signaling pathway in the pathogenesis of gastric cancer, drawing upon the most recent and critical studies that shed light on MAPK pathway alterations as a gateway to the disease. It highlights the pathway’s involvement in Helicobacter pylori -mediated gastric carcinogenesis and the tumorigenic processes induced by the Epstein-Barr virus, showcasing the substantial influence of miRNAs and lncRNAs in modulating gastric cancer’s biological properties through their interaction with the MAPK pathway. Furthermore, the review extends into the therapeutic arena, discussing the promising impacts of herbal medicines, MAPK pathway inhibitors, and immunosuppressants on mitigating gastric cancer’s progression. Through an exhaustive examination of the MAPK pathway’s multifaceted role in gastric cancer, from molecular crosstalks to therapeutic prospects, this review aspires to contribute to the ongoing efforts in understanding and combating this global health challenge, paving the way for novel therapeutic interventions and improved patient outcomes.

Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs characterized by their lack of 5′ caps and 3′ poly(A) tails. These molecules have garnered substantial attention from the scientific community. A wide range of circRNA types has been found to be expressed in various tissues of the human body, exhibiting unique characteristics such as high abundance, remarkable stability, and tissue-specific expression patterns. These attributes, along with their detectability in liquid biopsy samples such as plasma, position circRNAs an ideal choice as cancer diagnostic and prognostic biomarkers. Additionally, several studies have reported that the functions of circRNAs are associated with tumor proliferation, metastasis, and drug resistance. They achieve this through various mechanisms, including modulation of parental gene expression, regulation of gene transcription, acting as microRNA (miRNA) sponges, and encoding functional proteins. In recent years, a large number of studies have focused on synthesizing circRNAs in vitro and delivering them to tumor tissue to exert its effects in inhibit tumor progression. Herein, we briefly discuss the biogenesis, characteristics, functions, and detection of circRNAs, emphasizing their clinical potential as biomarkers for cancer diagnosis and prognosis. We also provide an overview the recent techniques for synthesizing circRNAs and delivery strategies, and outline the application of engineered circRNAs in clinical cancer therapy.

Integrins, which consist of two non-covalently linked α and β subunits, play a crucial role in cell–cell adhesion and cell-extracellular matrix (ECM) interactions. Among them, integrin β1 is the most common subunit and has emerged as a key mediator in cancer, influencing various aspects of cancer progression, including cell motility, adhesion, migration, proliferation, differentiation and chemotherapy resistance. However, given the complexity and sometimes contradictory characteristics, targeting integrin β1 for therapeutics has been a challenge. The emerging understanding of the mechanisms regulating by integrin β1 may guide the development of new strategies for anti-cancer therapy. In this review, we summarize the multiple functions of integrin β1 and signaling pathways which underlie the involvement of integrin β1 in several malignant cancers. Our review suggests the possibility of using integrin β1 as a therapeutic target and highlights the need for patient stratification based on expression of different integrin receptors in future clinical studies.

Background Gut microbiota modulation has been demonstrated to be effective in protecting patients against detrimental effects of anti-cancer therapies, as well as to improve the efficacy of certain anti-cancer treatments. Among the most characterized probiotics, Lactobacillus   rhamnosus GG (LGG) is currently utilized in clinics to alleviate diarrhea, mucositis or intestinal damage which might be associated with several triggers, including Clostridium difficile infections, inflammatory gut diseases, antibiotic consumption, chemotherapy or radiation therapy. Here, we investigate whether LGG cell-free supernatant (LGG-SN) might exert anti-proliferative activity toward colon cancer and metastatic melanoma cells. Moreover, we assess the potential adjuvant effect of LGG-SN in combination with anti-cancer drugs. Methods LGG-SN alone or in combination with either 5-Fuorouracil and Irinotecan was used to treat human colon and human melanoma cancer cell lines. Dimethylimidazol-diphenyl tetrazolium bromide assay was employed to detect cellular viability. Trypan blue staining, anti-cleaved caspase-3 and anti-total versus anti-cleaved PARP western blots, and annexin V/propidium iodide flow cytometry analyses were used to assess cell death. Flow cytometry measurement of cellular DNA content (with propidium iodide staining) together with qPCR analysis of cyclins expression were used to assess cell cycle. Results We demonstrate that LGG-SN is able to selectively reduce the viability of cancer cells in a concentration-dependent way. While LGG-SN does not exert any anti-proliferative activity on control fibroblasts. In cancer cells, the reduction in viability is not associated with apoptosis induction, but with a mitotic arrest in the G2/M phase of cell cycle. Additionally, LGG-SN sensitizes cancer cells to both 5-Fluorouracil and Irinotecan, thereby showing a positive synergistic action. Conclusion Overall, our results suggest that LGG-SN may contain one or more bioactive molecules with anti-cancer activity which sensitize cancer cells to chemotherapeutic drugs. Thus, LGG could be proposed as an ideal candidate for ground-breaking integrated approaches to be employed in oncology, to reduce chemotherapy-related side effects and overcome resistance or relapse issues, thus ameliorating the therapeutic response in cancer patients.

Background Long noncoding RNA NEAT1 has been implicated in glioma progression. However, the effect of NEAT1 on glycolysis of glioma cell and the potential mechanism remain unclear. Methods In vitro experiments, including CCK-8, colony formation, ECAR, and lactate detection assays were performed to evaluate the effect of NEAT1 on proliferation and glycolysis of glioma cell. RNA pulldown and RIP assays were performed to identify the interaction between NEAT1 and PGK1. Truncated mutation of NEAT1 and PGK1 was used to confirm the specific interactive domains between NEAT1 and PGK1. Animal studies were performed to analyze the effect of NEAT1/PGK1 on glioma progression. Results NEAT1 knockdown significantly suppressed the proliferation and glycolysis of glioma cells. NEAT1 could specifically interact with PGK1, which promotes PGK1 stability. Hairpin A of NEAT1 is essential for interaction with M1 domain of PGK1. Depletion of NEAT1 markedly inhibited tumor growth in mice, while PGK1 could reverse this effect. Higher expression of NEAT1 was associated with poor overall survival of GBM patients. Conclusions NEAT1 over expression promotes glioma progression through stabilizing PGK1. NEAT1/PGK1 axis is a candidate therapeutic target for glioma treatment.