Current gene therapy最新文献

Neurodegenerative disorders pose significant challenges in the realm of healthcare, as these conditions manifest in complex, multifaceted ways, often attributed to genetic anomalies. With the emergence of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, a new frontier has been unveiled in the quest for targeted, precise genetic manipulation. This abstract explores the recent advancements and potential applications of CRISPR-based therapies in addressing genetic components contributing to various neurodegenerative disorders. The review delves into the foundational principles of CRISPR technology, highlighting its unparalleled ability to edit genetic sequences with unprecedented precision. In addition, it talks about the latest progress in using CRISPR to target specific genetic mutations linked to neurodegenerative diseases like Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. It talks about the most important studies and trials that show how well and safely CRISPR-based therapies work. This shows how this technology can change genetic variants that cause diseases. Notably, the discussion emphasizes the challenges and ethical considerations associated with the implementation of CRISPR in clinical settings, including off-target effects, delivery methods, and long-term implications. Furthermore, the article explores the prospects and potential hurdles in the widespread application of CRISPR technology for treating neurodegenerative disorders. It touches upon the need for continued research, improved delivery mechanisms, and ethical frameworks to ensure responsible and equitable access to these groundbreaking therapies.

Tumor cells achieve their adaptability through various metabolic reprogramming processes. Among them, ammonia, as a traditional metabolic waste, plays an increasingly important role in the tumor microenvironment along with its associated metabolites. Other cells in the microenvironment can also reshape the immune status of the microenvironment by regulating ammonia- related metabolism, and targeting this metabolic aspect has emerged as a potential strategy for tumor treatment. In this study, we have systematically reviewed the source and destination of ammonia in tumor cells, as well as the links between ammonia and other biological processes. We have also analyzed the ammonia-related metabolic regulation of other cells (including T cells, macrophages, dendritic cells, natural killer cells, myeloid-derived suppressor cells, and stromal cells) in the tumor microenvironment, and summarized the tumor treatment methods that target this metabolism. Through ammonia-related metabolic reprogramming, tumor cells obtain the energy they need for rapid growth and proliferation. Multiple immune cells and stromal cells in the microenvironment also interact with each other through this metabolic regulation, ultimately leading to immune suppression. Despite the heterogeneity of tumors and the complexity of cellular functions, further research into therapeutic interventions targeting ammonia-related metabolism is warranted. This review has focused on the role and regulation of ammonia-related metabolism in tumor cells and other cells in the microenvironment, and highlighted the efficacy and prospects of targeted ammonia- related metabolism therapy.

Background: Cancer-Associated Fibroblasts (CAFs) constitute a heterogeneous group of cells critical for the remodeling of the tumor microenvironment (TME). Given their significant impact on tumor progression, particularly in skin cancers, a deeper understanding of their characteristics and functions is essential.

Methods: This study employed a single-cell transcriptomic analysis to explore the diversity of CAFs within three major types of skin cancer: basal cell carcinoma, melanoma, and head and neck squamous cell carcinoma. We applied analytical techniques, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), pseudotime tracking, metabolic profiling, and stemness assessment to delineate and define the functional attributes of identified CAF subgroups.

Results: Our analysis successfully delineated nine distinct CAF subgroups across the studied tumor types. Of particular interest, we identified a novel CAF subtype, designated as C0, exclusive to basal cell carcinoma. This subtype exhibits phenotypic traits associated with invasive and destructive capabilities, significantly correlating with the progression of basal cell carcinoma. The identification of this subgroup provides new insights into the role of CAFs in cancer biology and opens avenues for targeted therapeutic strategies.

Conclusion: A pan-cancer analysis was performed on three cancers, BCC, MA, and HNSCC, focusing on tumor fibroblasts in TME. Unsupervised clustering categorized CAF into nine subpopulations, among which the C0 subpopulation had a strong correspondence with BCC-CAF and an invasive- destructive-related phenotype.

Background: Significant variations in immune profiles across different age groups manifest distinct clinical symptoms and prognoses in Coronavirus Disease 2019 (COVID-19) patients. Predominantly, severe COVID-19 cases that require hospitalization occur in the elderly, with the risk of severe illness escalating with age among young adults, children, and adolescents.

Objective: This study aimed to delineate the unique immune characteristics of COVID-19 across various age groups and evaluate the feasibility of detecting COVID-19-induced immune alterations through peripheral blood analysis.

Methods: By employing a machine learning approach, we analyzed gene expression data from nasopharyngeal and peripheral blood samples of COVID-19 patients across different age brackets. Nasopharyngeal data reflected the immune response to COVID-19 in the upper respiratory tract, while peripheral blood samples provided insights into the overall immune system status. Both datasets encompassed COVID-19 patients and healthy controls, with patients divided into children, adolescents, and adult age groups. The analysis included the expression levels of 62,703 genes per patient. Then, 9 feature-sequencing methods (least absolute shrinkage and selection operator, light gradient boosting machine, Monte Carlo feature selection, random forest, ridge regression, adaptive boosting, categorical boosting, extremely randomized trees, and extreme gradient boosting) were employed to evaluate the association of the genes with COVID-19. Key genes were then utilized to develop efficient classification models.

Results: The findings identified specific markers: insulin-like growth factor binding protein 3 (downregulated in the peripheral blood of COVID-19 patients), interferon alpha-inducible protein 27 (upregulated), and SERPING1 (upregulated in nasopharyngeal tissues). In addition, fibulin-2 was downregulated in adolescent patients, but upregulated in the other groups, while epoxide hydrolase 3 was upregulated in healthy controls, but downregulated in children and adolescents.

Conclusion: This study offers valuable insights into the local and systemic immune responses of COVID-19 patients across age groups, aiding in identifying potential therapeutic targets and formulating personalized treatment strategies.

Background: Plasmalogens, the primary phospholipids in the brain, possess intrinsic antioxidant properties and are crucial components of the myelin sheath surrounding neuronal axons. While their neuroprotective effects have been demonstrated in Alzheimer's disease, their potential benefits in spinal cord injury remain unexplored. This study investigates the reparative effects of plasmalogens on spinal cord injury and the underlying mechanisms.

Methods: In vitro, we developed dorsal root ganglion (DRG) and RAW 264.7 cell models under high-reactive oxygen species (ROS) conditions to assess ROS levels, neuronal damage, and inflammatory microenvironment changes before and after plasmalogen application. In vivo, we used a complete mouse spinal cord transection model to evaluate changes in ROS levels, neuronal demyelination, and apoptosis following plasmalogen treatment. Additionally, we assessed sensory and motor function recovery and investigated the regulatory effects of plasmalogens on the AKT/mTOR signaling pathway.

Results: In high-ROS cell models, plasmalogens protected DRG neurons (TUJ-1) from axonal damage and modulated the proinflammatory/anti-inflammatory balance in RAW 264.7 cells. In vivo, plasmalogens significantly reduced ROS levels, improved the immune microenvironment, decreased the proinflammatory (iNOS)/anti-inflammatory (ARG-1) ratio, lowered neuronal (TUJ-1) apoptosis (Caspase-3, BAX), and reduced axonal degeneration while promoting myelin (MBP) regeneration, indicating a neuroprotective effect. These findings are linked to the activation of the AKT/mTOR signaling pathway.

Conclusion: Plasmalogens reduce ROS levels and regulate inflammation-induced damage, contributing to neuroprotection. This study reveals that plasmalogens promote remyelination, reduce axonal degeneration and neuronal apoptosis, and-used here for the first time in spinal cord injury repair- may protect neurons by reducing ROS levels and activating the AKT/mTOR signaling pathway.

Introduction: Tumor immunity has garnered increasing attention in cancer treatment and progression. However, there is still a challenge in understanding the mechanisms of specific molecules affecting the clinical prognosis and tumor microenvironment (TME).

Methods: Here, we applied the ESTIMATE algorithm to calculate the immune and stromal scores in 504 HNSC cases from TCGA. Patients were grouped according to the median value of the immune and stromal. Clinicopathological characteristics and differentially expressed genes (DEG) were analyzed. Subsequently, LASSO, COX regression, survival analysis, and clinicopathological characteristics were conducted. Subsequently, SLC2A3 was determined as a predictive factor that high expression of SLC2A3 at the mRNA and protein levels predicted a worse clinical prognosis. GSEA25099 was utilized for external validation of immune infiltration, while tissue PCR, IHC, and Western Blot were used to confirm the expression levels of SLC2A3.

Results: A series of immune-infiltration analyses showed that SLC2A3 expression was negatively correlated with CD8+ T cells, significantly affecting the survival prognosis of HNSC. In the GSEA analysis, the high expression of SLC2A3 was mainly enriched for immune-related biological processes. Meanwhile, high expression of SLC2A3 possessed higher TIDE scores and was also strongly positively correlated with a series of immune checkpoints affecting survival prognosis, thus causing greater susceptibility to immune escape.

Conclusion: Conclusively, SLC2A3 is a potential oncogene and factor of HNSC development, notably by an altered state of the immune microenvironment, immune-suppressive regulation, and immune escape.

Alternative splicing (AS) of pre-mRNA occurs widely in human genes to produce multiple isoforms with different or even opposite functions. Aberrant AS is often associated with gene mutations and can be corrected by gene therapy. Oral diseases are important public health problems worldwide. Accumulated pieces of evidence demonstrate that AS of pathogenic genes plays key roles in some oral diseases. However, considering the extensiveness and complexity of AS, it may affect the initiation and development of oral diseases deeply and widely. This review describes the diversity of AS and resulting isoforms in genetic, infectious, and malignant oral diseases and highlights the key roles of AS in determining the function of isoforms and the occurrence and progression of these diseases. The studies of alternative splicing may provide great opportunities for the understanding and treatment of oral diseases.

Background: The role of HEPACAM family member 2 (HEPACAM2) is unclear in colorectal cancer (CRC).

Objective: The objective of this study was to perform an extensive examination of HEPACAM2 and validate it experimentally in CRC.

Methods: This study investigated the significance of HEPACAM2 in CRC and its potential diagnostic utility utilizing data from the Cancer Genome Atlas (TCGA) database. Additionally, the study examined potential regulatory networks involving HEPACAM2, including its associations with immune infiltration, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), mRNA expression-based stemness index (mRNAsi), and drug sensitivity in CRC. The expression of HEPACAM2 was further validated using the GSE89076 dataset, and quantitative reverse transcription PCR (qRT-PCR) was employed to confirm HEPACAM2 expression levels in six pairs of CRC tissue samples.

Results: HEPACAM2 exhibited abnormal expression patterns in various types of cancer, including CRC. A decrease in HEPACAM2 expression levels in CRC was found to be significantly correlated with the T stage (p < 0.001). Reduced HEPACAM2 expression in CRC patients was also linked to poorer overall survival (OS) (p = 0.007). The expression levels of HEPACAM2 in CRC patients were identified as an independent prognostic factor (p = 0.016). Furthermore, HEPACAM2 was associated with TCF-dependent signaling in response to WNT, G2/M checkpoints, and other pathways. The expression of HEPACAM2 in CRC was found to be associated with immune infiltration, immune checkpoint genes, TMB / MSI, and mRNAsi. Additionally, the expression of HEPACAM2 in CRC was significantly and inversely correlated with the drug sensitivities to gw772405x and 6-phenyl-6h-indeno[1,2-c]isoquinoline-5,11-dione. qRT-PCR confirmed that the expression level of HEPACAM2 was found to be lowly expressed in CRC tissues.

Conclusion: These findings suggest that HEPACAM2 may serve as a potential prognostic biomarker and immunotherapeutic target for CRC patients.

Colorectal cancer (CRC) has become a significant threat in recent decades, and its incidence is predicted to continue rising. Despite notable advancements in therapeutic strategies, managing CRC poses complex challenges, primarily due to the lack of clinically feasible therapeutic targets. Among the myriad molecules implicated in CRC, the signal transducer and activator of transcription 3 (STAT3) stands out as a promising target tightly regulated by various genes. This intracellular transcription factor, spanning 750-795 amino acids and weighing approximately 92 kDa, is crucial in key cellular activities such as growth, migration, invasion, inflammation, and angiogenesis. Aberrant activation of STAT3 signaling has been linked to various cancers, including CRC. Therefore, targeting this signaling pathway holds significance for potential CRC treatment strategies. STAT3, as a central intracellular transcription factor, is implicated in colorectal cancer development by activating aberrant signaling pathways. Numerous studies have demonstrated that the abnormal hyperactivation of STAT3 in CRC tissues enhances cell proliferation, suppresses apoptosis, promotes angiogenesis, and facilitates tumor invasion and metastasis. As a focal point in colorectal cancer research, STAT3 emerges as a promising candidate for detecting and treating CRC. This review aims to present recent data on STAT3, emphasizing the activation and functions of STAT3 inhibitors in CRC. Indeed, STAT3 inhibitors have been identified to have therapeutic potential in CRC, especially inhibitors targeting the DNA-binding domain (DBD). Indeed, STAT3 inhibitors have been identified to have a therapeutic potential in CRC, especially the inhibitors targeting the DNA binding domain (DBD). For example, imatinib acts by targeting cell surface receptors, and these inhibitors have shown potential for the control and treatment of tumor growth, angiogenesis, and metastasis. Imatinib, for example acts by targeting cell surface receptors, and these inhibitors have shown the future direction toward the control and treatment of tumor growth, angiogenesis, and metastasis.

Dementia is a comprehensive term that refers to illnesses characterized by a decline in cognitive memory and other cognitive functions, affecting a person's overall ability to operate. The exact causes of dementia are unknown to this day. The heterogeneity of Alzheimer's indicates the contribution of genetic polymorphism to this disease. This disease is the most prevalent and damaging illness. Studies indicate that the global prevalence of Alzheimer's disease (AD) exceeds 26 million individuals. Investigation of variations in many genes indicates that these variations may be linked to the susceptibility to AD. Additional genetic factors could potentially influence AD. Analysis of several single-nucleotide polymorphisms in this context reveals a correlation between certain variants and AD. Regardless, Alzheimer's disease is always influenced by a particular APOE gene allele. The study's findings indicate that risk of Alzheimer's disease (AD) is linked to polymorphisms in the following genes: BDNF, presenilin-1 (PS-1), presenilin-2 (PS-2), LRP, APP, CTSD,5-6HT, TREM2, TNF-α, LPL, Clusterin (CLU), SORL1 (Sortilin-Related Receptor), PICALM, Complement Receptor 1 (CR1), and APOE genes.