Frontiers in bioscience (Landmark edition)最新文献

Background: Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insufficiently understood.

Methods: We developed a single-cell transcriptomic profile of peripheral blood mononuclear cells (PBMCs) from 11 newly-diagnosed pMN patients and 5 healthy donors. Through correlation analysis, we identified potential biomarkers for disease stratification and poor prognosis.

Results: Expression levels of several proinflammatory factors were significantly increased in patients compared to healthy donors, such as interleukins (IL1B, IL8, and IL15) and interferon G (IFNG). Multiple pattern recognition receptors involved in proinflammatory signaling were also upregulated in patients, including NOD-like receptors (NLRs) (NLRP1, NLRP3, and NLRC5), RNA helicases (DDX58, IFIH1, DHX9, and DHX36), cGAS (cyclic GMP-AMP synthase) and IFI16 (interferon gamma inducible protein 16). Additionally, human leukocyte antigen molecules HLA-DQA1 and HLA-DRB1 enriched in memory B cells were upregulated in patients. More importantly, we found that the genes for antiviral defense response were significantly elevated in high-risk patients relative to the low-risk group. More than twenty genes were negatively correlated with estimated glomerular filtration rate (eGFR), such as BST2 (bone marrow stromal cell antigen 2) and SLC35F1 (solute carrier family 35 member F1). Their predicted values were confirmed in a larger population with nephrotic syndrome or other chronic kidney diseases from a public database. Furthermore, we developed a series of scoring systems for distinguishing high-risk patients from low- and moderate-risk individuals.

Conclusions: Our study provides insight into the immunological mechanism of pMN and identifies numerous biomarkers and signaling pathways as potential therapeutic targets for managing the progression of high-risk pMN.

Over the past decade, new technologies have emerged to increase intrinsic potency, enhance bioavailability, and improve targeted delivery of drugs. Most pharmaceutical formulations require multiple dosing due to their fast release and short elimination kinetics, increasing the risk of adverse events and patient non-compliance. Due to these limitations, enormous efforts have focused on developing drug delivery systems (DDSs) for sustained release and targeted delivery. Sustained release strategies began with pioneering research using silicone rubber embedding for small molecules and non-inflammatory polymer encapsulation for proteins or DNA. Subsequently, numerous DDSs have been developed as controlled-release formulations to deliver systemic or local therapeutics, such as small molecules, biologics, or live cells. In this review, we discuss the latest developments of DDSs, specifically nanoparticles, hydrogels, and microgrippers for the delivery of systemic or localized drugs to the gastrointestinal (GI) tract. We examine innovative DDS design and delivery strategies tailored to the GI tract's unique characteristics, such as its extensive length and anatomical complexity, varying pH levels and enzymatic activity across different sections, and intrinsic peristalsis. We particularly emphasize those designed for the treatment of inflammatory bowel disease (IBD) with in vivo preclinical studies.

This review presents a comprehensive overview of single-cell RNA sequencing (scRNA-seq) analyses used to study tooth and periodontal tissues. The intricate cellular composition of both teeth and periodontium are revealed, leading to the identification of new cell types and tracing lineage profiles for each cell type. Herein, we summarize the progression of dental and periodontal tissue formation, tooth homeostasis, and regenerative mechanisms. scRNA-seq analyses have demonstrated that the cellular constituent ratio of dental and periodontal tissues transforms homeostasis or injury repair. Importantly, single-cell data in the diseased tissue demonstrated a change in both cell types and intercellular communication patterns compared to the normal state. These findings provide valuable insights into the underlying disease mechanisms at the cellular level in the context of single-cell vision, thereby facilitating the investigation of potential therapeutic interventions.

Background: Psoriasis is an enduring inflammatory skin disorder defined by recurring attacks, distinguished primarily by red patches and scaly skin. Quercetin, a kind of natural flavonoid compound, is widely found in various vegetables, fruits, and Chinese herbs. Quercetin is a multifaceted compound with a wide range of potential health benefits. In addition to antioxidant, cardiovascular protection, and anti-tumor effects, quercetin has shown potential in regulating immune and inflammation effects. In the initial stages, in vivo studies have demonstrated that quercetin positively affects psoriasis and is connected with the phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (AKT)/glucose transporter 1 (GLUT1) signaling. Nevertheless, the precise mechanism by which quercetin influences the PI3K/AKT/GLUT1 signaling cascade in the context of psoriasis remains uncertain.

Objective: The aim of this study was to investigate the potential therapeutic influence of quercetin on psoriasis and the relationship with the PI3K/AKT/GLUT1 signaling pathway.

Methods: A mouse model for psoriasis induced by imiquimod was employed to assess alterations in the morphology of skin lesions and their histopathological characteristics. Cell Counting kit-8 (CCK-8) assay was used to assess the impact of proliferation of HaCaT human keratinocyte cells. HaCaT cells were examined using flow cytometry for the influence of quercetin on apoptosis. Additionally, Western blot analysis was used to evaluate the protein expression levels in the PI3K/AKT/GLUT1 signaling pathway.

Results: concerning pathological alterations, the mice in the model group exhibited characteristic alterations associated with psoriasis. The extent of excessive keratinization in the epidermis and hypertrophy of the spinous layer observed in each quercetin dosage group was less pronounced compared to the model group. The CCK-8 assay laid out that quercetin can suppress the proliferation of HaCaT cells. Furthermore, it was found that quercetin facilitates the apoptosis of these cells. Analysis of immunoblotting demonstrated that the intervention of quercetin in HaCaT cells led to modifications in the proteins related to the PI3K/AKT/GLUT1 signaling pathway.

Conclusion: Through in vivo and in vitro experiments, this study shows that quercetin may play a therapeutic role in psoriasis and inhibit the PI3K/AKT/GLUT1 signaling pathway.

Background: Metastasis is a major cause of prostate cancer (PCa)-related deaths in men. Recent studies have indicated that VGF nerve growth factor inducible (VGF) affects tumor invasion and metastasis. The present study investigated whether VGF is abnormally expressed in PCa and affects PCa progression and investigated the specific regulatory mechanisms by which VGF affects PCa invasion and metastasis.

Methods: The sh- hypoxia-inducible factor1 alpha (HIF-1α) plasmid was transfected into human cell lines 22Rv1 and C4-2 to create cell lines with stable low expression and overexpression of VGF. Quantitative PCR (qPCR) was performed to detect VGF mRNA. Western blot was performed to detect invasive migration-related proteins. Akt activator SC79 (4 μg/mL) was added. After adding docetaxel (4 nM) to cells transfected with sh-NC and sh-VGF, the capacity of the cells to migrate invasively was assessed using the Transwell and scratch assays. Nude mice were injected with cells stably transfected with sh-NC or sh-VGF and the metastasis of the cancer cells was detected by live imaging and HE staining after the injection of docetaxel (10 mg/kg).

Results: Abnormal levels of VGF in PCa tissue and plasma samples were detected, and VGF knockdown suppressed PCa metastasis. VGF was also shown to affect the invasion and metastasis of PCa cells via PI3K/Akt signaling. VGF knockdown limited PCa metastasis and the inhibitory impact was higher when paired with docetaxel (p < 0.001). After hypoxia induction, both the mRNA and protein levels of VGF and HIF-1α increased, which is associated with a poor prognosis for PCa.

Conclusion: By stimulating the PI3K/Akt pathway, VGF encourages the invasive metastasis of PCa. As a result, targeting VGF may be a potential treatment approach for metastatic PCa therapy.

Background: Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene, resulting in progressive motor neuron loss and muscle atrophy. The urotensin 2 (UTS2) gene, located on chromosome 9q34.2, plays a significant role in cellular activities such as proliferation, apoptosis, and inflammatory responses. Notably, elevated expression levels of UTS2 have been observed in SMA patients. However, its precise contribution to disease pathogenesis remains unclear. This study aimed to investigate the effects of UTS2, which is overexpressed in SMA patients, in SMA cell models using a UTS2 inhibitor.

Methods: We conducted genomic sequencing and bioinformatics analysis on clinical samples to identify proteins highly expressed in association with SMA. Using RNA interference technology, we suppressed SMN1 gene expression in bone marrow mesenchymal stem cells (MSCs) to establish an in vitro cellular model of SMA. To assess the biological consequences of SMN1 gene knockdown, we employed molecular biological techniques such as immunofluorescence, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting. Furthermore, we treated the SMA cellular model with the urantide UTS2 receptor inhibitor and examined its effects on cell proliferation, apoptosis, and the expression of relevant proteins.

Results: UTS2 was successfully identified as a highly expressed protein associated with SMA. A stable MSC model with SMN1 gene knockdown was established. RNA interference (RNAi) technology effectively suppressed SMN1 gene expression, leading to changes in cellular morphology and neuron-specific marker expression. Urantide intervention significantly affected both proliferation and apoptosis in the SMA cell model in a dose-dependent manner. Techniques such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, TUNEL fluorescence staining, and flow cytometry analysis revealed that uride decreased cell viability while increasing the proportion of apoptotic cells. Following urantide intervention, there was a notable increase in caspase-3 messenger ribonucleic acid (mRNA) levels, as well as an increase in caspase-3 protein expression, as demonstrated by immunofluorescence analysis.

Conclusion: We elucidated the role of the UTS2 gene in an SMA cell model, emphasizing its dysregulation and identifying potential therapeutic targets. Urantide, a UTS2 inhibitor, had significant biological effects on the SMA cell model, indicating that it is a promising therapeutic strategy for SMA. These findings provide valuable insights for advancing drug development and clinical treatment of SMA.

Introduction: N-acetyltransferase 10 (NAT10) mediates N4-acetylcytidine (ac4C) mRNA modification and promotes malignant tumor progression. However, there has been limited research on its role in cervical cancer. This study aimed to decipher the role of NAT10 in cervical cancer.

Methods: The prognostic value of NAT10 was explored using the cancer genome atlas (TCGA) database and immunohistochemistry of cervical cancer tissue. The biological actions of NAT10 in cervical cancer were investigated by cell proliferation, transwell, wound healing, and chicken chorioallantoic membrane assays. The therapeutic action of remodelin (a NAT10 inhibitor) was verified in a nude mouse model. Mechanistic analyses were conducted by RNA sequencing, ac4C dot blotting, acetylated RNA immunoprecipitation, quantitative PCR, and RNA stability experiments.

Results: NAT10 was overexpressed in cervical carcinoma and its overexpression was associated with poor prognosis. NAT10 knockout impaired proliferative and metastatic potentials of cervical cancer cells, while its overexpression had the opposite effects. Remodelin impaired cervical cancer proliferation in vivo and in vitro. NAT10 acetylated solute carrier family 7 member 5 (SLC7A5) enhanced mRNA stability to regulate SLC7A5 expression.

Conclusions: NAT10 exerts a critical role in cervical cancer progression via acetylating SLC7A5 mRNA and could represent a key prognostic and therapeutic target in cervical cancer.

Background: The neuropeptide B/W signalling system (NPB/W) has been identified in multiple body regions and is integral to several physiological processes, including the regulation of food intake and energy homeostasis. Recently, it has also been detected in human skin; however, its specific functions in this context remain to be thoroughly investigated. This study aims to identify the expression of neuropeptides B/W receptor 1 (NPBWR1) and neuropeptides B/W receptor 2 (NPBWR2) in human dermal fibroblasts of mesenchymal origin using genomic and proteomic techniques. We will also investigate the role of these receptors in cell proliferation and calcium signalling.

Methods: The mRNAs for NPBWR1 and NPBWR2 were detected using quantitative PCR (qPCR) analysis and further validated by western blot and immunofluorescence analyses. Additionally, we synthesised ligands for these receptors, specifically hNPB (25-53) and hNPW (33-62), to investigate their effects on cell proliferation and intracellular calcium levels in human fibroblasts.

Results: Our results demonstrated that hNPW (33-62) has anti-proliferative effect on human dermal fibroblasts and concentration of 0.1-μmol/L can significantly decrease intracellular calcium levels (p < 0.05).

Conclusion: This finding suggests a potential role for the NPB/W signalling system in pathologies associated with impaired calcium handling, such as fibrosis. Furthermore, we observed that the proliferation of human fibroblasts was not affected by hNPB (25-53). Our findings could lead to the development of new therapeutic strategies for various skin conditions and improved wound healing.