Alternative pre-mRNA splicing in stem cell function and therapeutic potential: A critical review of current evidence.

Alternative splicing is a crucial regulator in stem cell biology, intricately influencing the functions of various biological macromolecules, particularly pre-mRNAs and the resultant protein isoforms. This regulatory mechanism is vital in determining stem cell pluripotency, differentiation, and proliferation. Alternative splicing's role in allowing single genes to produce multiple protein isoforms facilitates the proteomic diversity that is essential for stem cells' functional complexity. This review delves into the critical impact of alternative splicing on cellular functions, focusing on its interaction with key macromolecules and how this affects cellular behavior. We critically examine how alternative splicing modulates the function and stability of pre-mRNAs, leading to diverse protein expressions that govern stem cell characteristics, including pluripotency, self-renewal, survival, proliferation, differentiation, aging, migration, somatic reprogramming, and genomic stability. Furthermore, the review discusses the therapeutic potential of targeting alternative splicing-related pathways in disease treatment, particularly focusing on the modulation of RNA and protein interactions. We address the challenges and future prospects in this field, underscoring the need for further exploration to unravel the complex interplay between alternative splicing, RNA, proteins, and stem cell behaviors, which is crucial for advancing our understanding and therapeutic approaches in regenerative medicine and disease treatment.

New frontiers in salivary extracellular vesicles: transforming diagnostics, monitoring, and therapeutics in oral and systemic diseases.

Salivary extracellular vesicles (EVs) have emerged as key tools for non-invasive diagnostics, playing a crucial role in the early detection and monitoring of diseases. These EVs surpass whole saliva in biomarker detection due to their enhanced stability, which minimizes contamination and enzymatic degradation. The review comprehensively discusses methods for isolating, enriching, quantifying, and characterizing salivary EVs. It highlights their importance as biomarkers in oral diseases like periodontitis and oral cancer, and underscores their potential in monitoring systemic conditions. Furthermore, the review explores the therapeutic possibilities of salivary EVs, particularly in personalized medicine through engineered EVs for targeted drug delivery. The discussion also covers the current challenges and future prospects in the field, emphasizing the potential of salivary EVs in advancing clinical practice and disease management.

Epitranscriptomic modifications in mesenchymal stem cell differentiation: advances, mechanistic insights, and beyond.

RNA modifications, known as the "epitranscriptome", represent a key layer of regulation that influences a wide array of biological processes in mesenchymal stem cells (MSCs). These modifications, catalyzed by specific enzymes, often termed "writers", "readers", and "erasers", can dynamically alter the MSCs' transcriptomic landscape, thereby modulating cell differentiation, proliferation, and responses to environmental cues. These enzymes include members of the classes METTL, IGF2BP, WTAP, YTHD, FTO, NAT, and others. Many of these RNA-modifying agents are active during MSC lineage differentiation. This review provides a comprehensive overview of the current understanding of different RNA modifications in MSCs, their roles in regulating stem cell behavior, and their implications in MSC-based therapies. It delves into how RNA modifications impact MSC biology, the functional significance of individual modifications, and the complex interplay among these modifications. We further discuss how these intricate regulatory mechanisms contribute to the functional diversity of MSCs, and how they might be harnessed for therapeutic applications. The review also highlights current challenges and potential future directions in the study of RNA modifications in MSCs, emphasizing the need for innovative tools to precisely map these modifications and decipher their context-specific effects. Collectively, this work paves the way for a deeper understanding of the role of the epitranscriptome in MSC biology, potentially advancing therapeutic strategies in regenerative medicine and MSC-based therapies.

Constructing a T-Cell Receptor-Related Gene Signature for Prognostic Stratification and Therapeutic Guidance in Head and Neck Squamous Cell Carcinoma.

BACKGROUD: The stratification of head and neck squamous cell carcinoma (HNSCC) patients based on prognostic differences is critical for therapeutic guidance. This study was designed to construct a predictive signature derived from T-cell receptor-related genes (TCRRGs) to forecast the clinical outcomes in HNSCC. METHODS: We sourced gene expression profiles from The Cancer Genome Atlas (TCGA) HNSCC dataset, GSE41613, and GSE65858 datasets. Utilizing consensus clustering analysis, we identified two distinct HNSCC clusters according to TCRRG expression. A TCRRG-based signature was subsequently developed and validated across diverse independent HNSCC cohorts. Moreover, we established a nomogram model based on TCRRGs. We further explored differences in immune landscapes between high- and low-risk groups. RESULTS: The TCGA HNSCC dataset was stratified into two clusters, displaying marked variations in both overall survival (OS) and immune cell infiltration. Furthermore, we developed a robust prognostic signature based on TCRRG utilizing the TCGA HNSCC train cohort, and its prognostic efficacy was validated in the TCGA HNSCC test cohort, GSE41613, and GSE65858. Importantly, the high-risk group was characterized by a suppressive immune microenvironment, in contrast to the low-risk group. Our study successfully developed a robust TCRRG-based signature that accurately predicts clinical outcomes in HNSCC, offering valuable strategies for improved treatments.

ACTN1 promotes HNSCC tumorigenesis and cisplatin resistance by enhancing MYH9-dependent degradation of GSK-3ß and integrin ß1-mediated phosphorylation of FAK.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors globally. Understanding the molecular basis of tumor progression and drug resistance can offer innovative strategies to enhance clinical outcomes for HNSCC patients. METHODS: The cytoskeletal remodeling genes associated with cisplatin resistance were screened using a PCR array. The role of alpha-actinin 1 (ACTN1) in modulating cisplatin resistance and tumorigenesis in HNSCC was evaluated both in vitro and in vivo. Co-immunoprecipitation (Co-IP), IP-mass spectrometry (MS), western blotting, dual-luciferase assay, and bioinformatics analysis were performed to elucidate the underlying mechanisms involved. RESULTS: Our study identifies ACTN1 as a crucial contributor to cisplatin resistance and tumorigenesis in HNSCC, as evidenced across cellular, animal, and patient-derived xenograft models. From a clinical perspective, overexpression of ACTN1 significantly correlates with a suboptimal response to neoadjuvant chemotherapy and reduced overall survival in HNSCC patients. Mechanistically, ACTN1 predominantly activates ß-catenin-mediated signaling by promoting the interaction between myosin heavy chain 9 (MYH9) and GSK-3ß, leading to the ubiquitin-dependent degradation of GSK-3ß. ACTN1 also interacts with integrin ß1, subsequently activating the FAK/PI3K/AKT pathway, providing an additional avenue for the activation of ß-catenin signaling. Our study also unveils that the ß-catenin/c-Myc axis transcriptionally regulates ACTN1, thereby creating a positive feedback loop promoting HNSCC tumorigenesis and drug resistance. CONCLUSIONS: These insights underscore the novel mechanisms that highlight ACTN1's pivotal role in driving HNSCC progression and resistance to chemotherapy, suggesting ACTN1 as a promising therapeutic target in HNSCC management.

The oral microbiome in autoimmune diseases: friend or foe?

The human body is colonized by abundant and diverse microorganisms, collectively known as the microbiome. The oral cavity has more than 700 species of bacteria and consists of unique microbiome niches on mucosal surfaces, on tooth hard tissue, and in saliva. The homeostatic balance between the oral microbiota and the immune system plays an indispensable role in maintaining the well-being and health status of the human host. Growing evidence has demonstrated that oral microbiota dysbiosis is actively involved in regulating the initiation and progression of an array of autoimmune diseases.Oral microbiota dysbiosis is driven by multiple factors, such as host genetic factors, dietary habits, stress, smoking, administration of antibiotics, tissue injury and infection. The dysregulation in the oral microbiome plays a crucial role in triggering and promoting autoimmune diseases via several mechanisms, including microbial translocation, molecular mimicry, autoantigen overproduction, and amplification of autoimmune responses by cytokines. Good oral hygiene behaviors, low carbohydrate diets, healthy lifestyles, usage of prebiotics, probiotics or synbiotics, oral microbiota transplantation and nanomedicine-based therapeutics are promising avenues for maintaining a balanced oral microbiome and treating oral microbiota-mediated autoimmune diseases. Thus, a comprehensive understanding of the relationship between oral microbiota dysbiosis and autoimmune diseases is critical for providing novel insights into the development of oral microbiota-based therapeutic approaches for combating these refractory diseases.

Diverse Pathways of Engineered Nanoparticle-Induced NLRP3 Inflammasome Activation.

With the rapid development of engineered nanomaterials (ENMs) in biomedical applications, their biocompatibility and cytotoxicity need to be evaluated properly. Recently, it has been demonstrated that inflammasome activation may be a vital contributing factor for the development of biological responses induced by ENMs. Among the inflammasome family, NLRP3 inflammasome has received the most attention because it directly interacts with ENMs to cause the inflammatory effects. However, the pathways that link ENMs to NLRP3 inflammasome have not been thoroughly summarized. Thus, we reviewed recent findings on the role of major ENMs properties in modulating NLRP3 inflammasome activation, both in vitro and in vivo, to provide a better understanding of the underlying mechanisms. In addition, the interactions between ENMs and NLRP3 inflammasome activation are summarized, which may advance our understanding of safer designs of nanomaterials and ENM-induced adverse health effects.

Bone marrow­derived mesenchymal stem cell­conditioned medium attenuates tubulointerstitial fibrosis by inhibiting monocyte mobilization in an irreversible model of unilateral ureteral obstruction.

Mesenchymal stem cell­conditioned medium (MSC­CM) contains various cytokines (osteopontin and macrophage colony stimulating factor 1) secreted by MSCs and may modulate the immune response in tubulointerstitial fibrosis. The aim of the present study was to investigate whether MSC­CM treatment may affect B cell­dependent immune responses, which have previously been reported to facilitate the renal fibrotic processes following unilateral ureteral obstruction (UUO). In the present study, histological analysis, flow cytometry, western blotting and reverse transcription­quantitative polymerase chain reaction were performed. MSC­CM treatment was observed to impede renal infiltration of B lymphocytes and the expression of CC chemokine ligand­2. Additionally, UUO suppressed the subsequent recruitment of monocytes/macrophages to the kidney, limited local inflammation and attenuated renal fibrosis. The findings of the present study identified a potential mechanism of MSC­CM in ameliorating the UUO­kidney.

[Autologous mesenchymal stem cell implantation promotes myocardial expressions of growth factors and improves cardiac function in failing rat hearts].

OBJECTIVE: To explore the underlying mechanism of mesenchymal stem cells (MSCs) transfer induced cardiac function improvement in failing hearts. METHODS: Congestive heart failure (CHF) was induced in rats by cauterization of the heart wall. MSCs were cultured from autologous bone marrow and injected into the border zone and the remote myocardium 5 days after cauterization. RESULTS: Ten weeks later, cardiomyocyte nucleus mitotic index, capillary density and expression of insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) were significantly increased in the border zone and significantly reduced in the remote myocardium in CHF rats (all P<0.05 vs. sham). Besides cardiac function improvement and left ventricular remodeling attenuation evidenced by hemodynamic and echocardiographic examinations, expressions of IGF-1, HGF and VEGF in the remote myocardium and in the border zone were also significantly upregulated (P<0.05 or P<0.01 vs. CHF), and cardiomyocyte nucleus mitotic index as well as capillary density were significantly increased in CHF rats with MSCs (P<0.05 or P<0.01 vs. CHF). Moreover, collagen area was significantly reduced and myocardial area was significantly increased in the border zone in these rats too. CONCLUSION: Autologous MSC implantation upregulated expressions of growth factors enhanced cardioangiogenesis which might be the underlying mechanisms for improved cardiac function and attenuated left ventricular remodeling induced by MSCs transplantation in failing rat myocardium.