Current molecular medicine最新文献

Cancer is a major health concern worldwide, and there have been numerous efforts to fully understand the mechanism of cancer pathogenesis and develop effective treatments. In this context, exosomes play a crucial role in the detection and management of cancer. Exosomes are extracellular vesicles that share components with their parent cells and mediate intercellular communication, especially in cancer patients. Exosomal cargo, which includes proteins, lipids, and RNAs, has been extensively investigated due to its potential significance in cancer. Exosomes play a crucial role in cancer biology, as they have been demonstrated to alter the tumor microenvironment and facilitate communication between the tumor and its host. Exosomal composition is influenced by packaging and secretion processes, which can affect the function, distribution, and uptake of cargo in target cells. Exosome-mediated communication within the tumor microenvironment suggests that variations in endocytosis and plasma membrane remodeling, which are specific to cancer, are partly responsible for the abnormal exosomal process in cancer. Numerous processes, including the modification of the tumor microenvironment, the promotion of angiogenesis, metastasis, and invasion, as well as the regulation of tumor cells' immune escape, are thought to be facilitated by exosomes in the development and progression of cancers originating from various tissues. Exosomal components have the ability to mediate immune responses against cancer and aid in the development of cancer cell resistance to treatments and medications. This study aims to provide a concise review of exosome composition, the processes involved in their synthesis, their roles in cancer development, progression, and metastasis, as well as their ability to evade immune surveillance and contribute to resistance against cancer-related drugs and therapies. Therefore, we conducted an extensive search across numerous academic databases, including Scopus, PubMed, ScienceDirect, Crossref, and Google Scholar, using the keywords "cancer," "exosomes," "progression," "metastasis," "therapy resistance," etc. The retrieved literature was critically analyzed. This knowledge may contribute to more effective cancer treatment in the future by informing potential therapeutic applications.

Introduction: Mutations in Chromodomain Helicase DNA Binding Protein 7 (CHD7) and Paired Box Gene 4 (PAX4) are critical for normal cartilage development and are implicated through their impact on chondrocyte functions. This study examines how these genetic alterations specifically modulate Tumor protein p53 (p53) expression to affect cellular proliferation and apoptosis, shedding light on potential therapeutic targets for mitigating developmental anomalies in cartilage.

Method: Using Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- associated protein 9 (Cas9), specific mutations were introduced into CHD7 and PAX4 in chondrocytes. Subsequent analyses included 5-ethynyl-2'-deoxyuridine (EdU) assay for proliferation, Terminal deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) staining for apoptosis, quantitative real-time polymerase chain reaction (qRTPCR), and Western blot alongside co-immunoprecipitation (Co-IP) to evaluate expression levels and protein interactions.

Result: Mutations in CHD7 and PAX4 resulted in decreased proliferation and increased apoptosis in chondrocytes. Notably, these mutations disrupted the interaction between the mutant proteins and p53, leading to altered expression of apoptotic regulators such as Bcl2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), indicating activation of p53-dependent apoptotic pathways.

Discussion: This study elucidates the core molecular mechanism by which mutations in the CHD7 and PAX4 genes disrupt their interaction with p53, leading to aberrant activation of the p53-dependent apoptotic pathway. These findings provide a new theoretical basis and potential intervention strategies for developing p53 pathwaytargeted therapies to treat related cartilage developmental disorders. Future research should focus on in vivo validation and mechanistic refinement.

Conclusion: The study reveals that CHD7 and PAX4 mutations exacerbate the apoptotic pathways in chondrocytes by enhancing the activity of p53, leading to decreased cell proliferation and increased apoptosis. These findings underscore the mutations' profound impact on cartilage cell dynamics and highlight the therapeutic potential of targeting p53 to correct the cellular imbalances caused by these genetic changes in cartilage-related developmental disorders.

Introduction: Sepsis-induced acute lung injury (ALI) is closely related to the dysfunction of mitochondria. Sirtuin 6 (SIRT6), as a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylase, is involved in several cellular processes. However, research has shown that the interaction of SIRT6 and mitochondrial function plays a role in acute lung injury. The objective of this research study was to explore the effect of SIRT6 on mitochondrial function during septic lung injury.

Methods: Lipopolysaccharide (LPS) was used to establish ALI models in C57BL/6J, SIRT6fl/fl/CAG-CreERT2 mice and in MLE12 cells. Hematoxylin and eosin staining, cell counting kit-8 (CCK-8), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate lung injury, cell viability, and inflammation. Western blot (WB) was used to measure the protein expression of SIRT6 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). The function and integrity of mitochondria were detected by transmission electron microscopy (TEM), etc. Results: In this study, LPS stimulation reduced the protein expression levels of SIRT6 and PGC-1α. Furthermore, it inhibited mitochondrial DNA (mtDNA), mitochondrial membrane potential, and mitochondrial oxygen consumption rate, while promoting mitochondrial swelling in vivo in a model of acute lung injury. Adenovirus-mediated SIRT6 overexpression alleviated acute lung injury, simultaneously enhancing the protein levels of PGC-1α, mtDNA content, mitochondrial membrane potential, and mitochondrial oxygen consumption rate, and inhibiting mitochondrial swelling in vivo. Conversely, the deletion or knockout of SIRT6 diminished PGC-1α protein expression levels, enhanced mitochondrial dysfunction, and further aggravated acute lung injury.

Conclusion: SIRT6 protected against LPS-induced acute lung injury by promoting PGC-1α expression and improving mitochondrial function both in vivo and in vitro.

The abnormal expansion of trinucleotide cytosine-adenine-guanine [CAG] repeats within disease-associated genes is the primary cause of polyglutamine [polyQ] diseases. This study aims to evaluate the pathological threshold at which the polyglutamine [polyQ] tract, following mutation, leads to neurotoxic effects and to explore emerging therapeutic strategies targeting these mechanisms. The formation of protein aggregates comprising pathogenic polyQ proteins, which induce cellular cytotoxicity, is a key hallmark of polyQ diseases. Despite extensive research, the molecular pathways responsible for the cellular toxicity caused by mutant polyQ proteins remain untreatable. However, strategies to reduce the abnormal expansion of CAG repeats, inhibit the accumulation and aggregation of toxic polyQ-expanded proteins, and promote protein refolding, degradation, or prevention of proteolytic cleavage have shown promise. Additionally, therapeutic approaches such as induced autophagy and stem cell therapies represent promising avenues for intervention. Current treatment modalities for polyQ diseases primarily focus on temporarily alleviating symptoms and slowing disease progression. Continued research into targeted therapeutic strategies is essential to address the underlying pathophysiology of these disorders effectively.

Introduction: In the field of interventional cardiology, coronary in-stent restenosis (ISR) continues to present a clinical hurdle, even with the progress made in stent design and pharmacological interventions. While drug-eluting stents (DESs) and drug-eluting balloons (DEBs) have markedly decreased the occurrence of ISR when compared to bare-metal stents, the condition persists as a complication in revascularization, contributing to increased patient morbidity and challenging long-term treatment outcomes. Thus, a deeper understanding of ISR mechanisms and the development of novel therapeutic approaches are crucial for improving patient outcomes.

Methods: In this study, we utilized the A10 cell as an in vitro model and induced common carotid artery balloon dilation injury in Sprague-Dawley rats as an animal model to explore the potential clinical applications of SCH79797, particularly in the treatment of ISR.

Results: SCH79797, a protease-activated receptor-1 antagonist, induced apoptosis of smooth muscle cells through various pathways. SCH79797 promoted apoptosis via JNK/c-Jun and p53 upregulation in the cytosol. We also observed an increased Bax/Bcl-2 ratio in mitochondria, p53 translocation to mitochondria, and changes in the mitochondrial membrane potential to mitochondrial membrane permeabilization. Our comparative analysis with vorapaxar revealed the apoptotic effects of SCH79797 to be independent of its PAR-1 antagonist activity. Furthermore, SCH79797 administration significantly reduced common carotid artery restenosis and thrombosis following balloon injury in vivo.

Discussion: Our study has been the first to demonstrate SCH79797 to directly induce VSMC apoptosis via the p53-mediated mitochondrial pathway, providing a novel mechanistic insight into ISR treatment. Unlike traditional anti-proliferative agents used in DESs, SCH79797 uniquely combines apoptotic induction with antithrombotic effects, making it a dual-action therapeutic candidate. This research study has laid the groundwork for localized drug-eluting strategies that can leverage SCH79797's properties to prevent ISR more effectively while minimizing systemic side effects.

Conclusion: Our findings have established SCH79797 as a promising candidate for reducing ISR through apoptosis modulation. By leveraging the p53-mediated mitochondrial apoptotic pathway, SCH79797 may provide a groundbreaking approach to reducing restenosis. These findings could offer significant implications for the future development of targeted drug-eluting strategies by locally delivering SCH79797 in a controlled manner using DES or DEB, presenting SCH79797 as a transformative candidate in interventional cardiology.

Background: Gastric cancer (GC) remains a major health burden with poor prognosis, highlighting the need for reliable prognostic biomarkers and therapeutic targets. ELOVL4 (Elongation of Very Long Chain Fatty Acids Protein 4) is an enzyme involved in lipid metabolism, which has been implicated in various cancers, but its role in GC remains largely unexplored.

Methods: We evaluated the prognostic value of ELOVL4 expression in GC based on samples from The Cancer Genome Atlas (TCGA) database. Subsequently, we investigated the associations between ELOVL4 expression and tumor immune microenvironment features, including tumor microenvironment (TME) scores, immune cell infiltration, and immune checkpoint gene expression. Moreover, we assessed the correlation between ELOVL4 expression and tumor mutational burden (TMB) as well as drug sensitivity profiles. Functional and pathway enrichment analyses were performed to gain mechanistic insights.

Results: High ELOVL4 expression was significantly associated with adverse clinical outcomes. A nomogram incorporating ELOVL4 expression was developed for individualized prognosis evaluation. Patients with high ELOVL4 expression exhibited an activated TME, with distinct immune cell infiltration patterns and correlations with immune checkpoint gene expression. Additionally, ELOVL4 expression was negatively correlated with TMB. Differential drug sensitivity profiles were identified between the high and low ELOVL4 expression groups. Enrichment analyses revealed the involvement of ELOVL4 in various biological processes and signaling pathways.

Conclusion: Our findings establish ELOVL4 as a biomarker for poor prognosis and therapeutic target in GC, with implications for prognosis evaluation, immune microenvironment modulation, and chemotherapeutic response.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options. Astragalus mongholicus (AM), a cornerstone herb in traditional Chinese medicine (TCM), demonstrates significant therapeutic potential for IPF due to its multi-target mechanisms. This review synthesizes evidence on AM and its bioactive components; astragalus polysaccharide (APS), astragaloside IV (AS IV), and calycosin (CAL) in targeting key IPF pathological processes. These include suppression of inflammatory responses (via TLR4/NF-κB inhibition), inhibition of extracellular matrix deposition (via MMP/TIMP modulation), attenuation of oxidative stress, regulation of autophagy, and blockade of epithelial-mesenchymal transition (via lncRNA-ATB/miR-200c/ZEB1 axis). We further highlight the integration of molecularlevel mechanisms with systems pharmacology to elucidate AM's holistic actions. Clinical studies support AM-containing TCM prescriptions in improving lung function with fewer adverse effects. This synthesis underscores AM's promise as a multi-target therapeutic agent and advocates for systematic pharmacology approaches in future IPF drug development.

Hemophilia, a rare inherited bleeding illness that needs to be managed throughout one's life to stop bleeding episodes and lessen complications. Although the genetic foundation of hemophilia is well documented, recent research has demonstrated that epigenetic pathways can influence the severity of the disease, the effectiveness of treatment, and the occurrence of complications. Advances in epigenetic research have made it possible to better understand the complexities of hemophilia and design suitable and targeted treatments. Emerging advancements as well as challenges are explored within many countries around the globe. Several epigenetic factors influence how the disorder manifests and its severity. Therapeutic interventions are the cornerstone for treating the disorder. The epigenetic regulation of the principal hemophilia genes (F8/F9) is still not fully understood. With the right treatment, preventative strategies, and better healthcare protocols, hemophilia cases in a confined area can be decreased. We explore the intricate blood clotting processes, inheritance patterns, and genetic changes that contribute to hemophilia's pathophysiology. The current understanding of epigenetics in hemophilia is examined in this review, with particular attention paid to non-coding RNAs, histone changes, and DNA methylation.

Introduction: This study assessed the effects of the synthesized ACE inhibitory peptide LAP (Leu-Arg-Pro-Val-Ala-Ala) on cognitive impairment in hypertensive rats.

Methods: Rho-associated coiled-coil containing protein kinase (ROCK) activity in peripheral blood mononuclear cells (PBMCs) was initially measured in elderly patients with hypertension and cognitive impairment using western blot analysis. The effect of LAP on the ROCK pathway was studied in a human cell line with ROCK1. Fifteenweek- old male spontaneously hypertensive rats (SHR) received intragastric LAP (500 μg/week) for eight weeks. Cognitive function was assessed using the Morris water maze test, and thoracic aorta remodeling was evaluated by determining the media/lumen ratio through immunohistochemistry. Amyloid beta (Aβ), phosphorylated tau (p-tau), and apoptotic neurons in the hippocampus were examined by western blot analysis and immunohistochemistry. Protein expression and activation related to the ROCK pathway, including moesin, myosin light chain (MLC), and myosin phosphatase target subunit (MYPT), were analyzed in the aorta and hippocampus using western blot and immunohistochemistry.

Results: Hypertensive patients with cognitive impairment showed increased phosphorylated/total myosin-binding subunit ratios in PBMCs, indicating higher ROCK pathway activity. In vitro, LAP reduced p-moesin levels, confirming ROCK inhibition. In vivo, oral LAP lowered blood pressure and heart rate in SHR models and improved cognitive function. LAP also reduced aortic remodeling, decreased hippocampal Aβ and p-tau deposition, reduced neuronal apoptosis, and increased neuronal survival. Mechanistically, LAP inhibited ROCK pathway activation in the aorta and hippocampus, similar to the ROCK inhibitor fasudil.

Discussion: Hypertension contributes to neurodegenerative changes through the activation of the ROCK signaling pathway. The study found that the ACE inhibitory peptide LAP not only sustainably lowered blood pressure, but also inhibited the ROCK pathway, reducing hippocampal Aβ and p-tau deposition, thereby offering a dual therapeutic approach for hypertension-related cognitive impairment.

Conclusion: LAP alleviated hypertension-related cognitive impairment in SHR by inhibiting the hippocampal ROCK pathway, showing therapeutic potential.

Introduction: This study aimed to explore the mechanism of semaphorin 3F- (Sema3F) induced hippocampal axonal growth cone collapse by studying the effect of Sema3F on vascular endothelial growth factor (VEGF) in vitro primary rat hippocampal neuron culture system.

Methods: Hippocampal neurons were taken from Wistar rats within 24 hours after birth for primary culture in vitro. On the third day, Sema3F was added to the experimental group, and fetal bovine serum at the same concentration was added to the control group. The cells were collected at 0, 5, 15, and 30 min. The expression of VEGF messenger ribonucleic acid (mRNA) in the hippocampal neurons was detected by real-time polymerase chain reaction (PCR), while VEGF expression was detected by Western blot. The level of VEGF expression in the hippocampal neuron culture medium was detected by enzyme-linked immunosorbent assay.

Results: The expression of both VEGF mRNA and VEGF protein in the rats' hippocampal neurons decreased at different times. The VEGF concentration in the culture medium initially increased before decreasing over time.

Discussion: Sema3F is known to induce growth cone collapse in hippocampal neurons, and this study provides evidence that this effect may be mediated by downregulating VEGF expression and secretion. The initial increase in VEGF concentration in the culture medium could be a compensatory response to the collapse of growth cones, while the subsequent decrease suggests a sustained effect of Sema3F on VEGF regulation. The findings highlight the complex interplay between Sema3F and VEGF in neuronal development and repair. Future research should explore the underlying signaling pathways and potential therapeutic applications of these interactions.

Conclusion: Sema3F inhibited the synthesis of VEGF in hippocampal neurons at transcription and translation levels in a time-dependent manner. Sema3F may also affect the secretion level of VEGF, initially increasing its extracellular expression before decreasing it over time.