Current Issues in Molecular Biology最新文献

Cyanobacteria harbor sophisticated molecular defense systems that have evolved over billions of years to protect against viral invasion and foreign genetic elements. These ancient photosynthetic organisms possess a diverse array of restriction-modification (R-M) systems and CRISPR-Cas arrays that present challenges for genetic engineering, but also offer unique opportunities for cancer-targeted biotechnological applications. These systems exist in prokaryotes mainly as defense mechanisms but they are currently used in molecular applications as gene editing tools. Moreover, latest developments in nucleases such as zinc finger nucleases (ZFNs), TALENs (transcription-activator-like effector nucleases) are discussed. A comprehensive genomic analysis of 126 cyanobacterial species found 89% encode multiple R-M systems, averaging 3.2 systems per genome, creating formidable barriers to transformation but also providing molecular machinery that could be harnessed for precise recognition and targeting of cancer cells. This review critically examines the dual nature of these defense systems, their ecological functions, and the emerging strategies to translate their molecular precision into advanced anticancer therapeutics. Hence, the review main objectives are to explore the recent understanding of these mechanisms and to exploit the knowledge gained in opening new avenues for cancer-focused targeted interventions, while acknowledging the significant challenges to translate these systems from laboratory curiosities to practical applications.

Alopecia profoundly impacts psychological well-being and quality of life, yet current therapeutic options such as minoxidil and finasteride exhibit limited efficacy. Fibroblast growth factor 7 (FGF-7), also known as keratinocyte growth factor (KGF), is a paracrine growth factor secreted by dermal papilla cells that specifically activates the epithelial receptor FGFR2b. Receptor engagement triggers multiple downstream signaling cascades, including the MAPK/ERK, PI3K/Akt, and Wnt/β-catenin pathways, promoting keratinocyte proliferation, stem cell activation, and the transition of hair follicles into the anagen phase. Both in vitro and in vivo animal studies consistently demonstrate that FGF-7 accelerates telogen-to-anagen transition and enhances follicular regeneration. FGF-7 acts synergistically with insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) to sustain nutrient delivery and cell proliferation. Human scalp studies further reveal a strong association between the FGF-7/FGFR2b signaling and follicular activity; however, clinical trials remain scarce. Topical application of FGF-7 has demonstrated an excellent safety profile, whereas systemic administration necessitates careful monitoring. Future directions include the development of engineering to extend the systemic half-life, advanced delivery systems, and gene or mRNA-based therapeutic approaches. Thus, the FGF-7/FGFR2b axis is a highly compelling molecular target for next-generation hair regeneration therapies.

Objective: To investigate the mechanism by which sphingosine-1-phosphatase 2 (SGPP2) modulates endoplasmic reticulum stress (ERS) through the SIRT1/AMPK pathway to improve ischemic cardiomyopathy-induced chronic heart failure (IHF). Methods: Key genes of IHF and ERS were identified through bioinformatics analysis, and significantly associated pathways of the key genes were obtained via single-gene enrichment analysis. In vivo, IHF was induced in Sprague-Dawley (male) rats via ligation of the left anterior descending coronary artery, with cardiac function examined through echocardiography. Myocardial tissue injury and fibrosis were evaluated utilizing hematoxylin-eosin, Masson, and TUNEL staining. Serum levels of NT-proBNP and cTnT were measured via ELISA. SGPP2 protein expression was assessed via immunohistochemistry and Western blotting (WB). In vitro, neonatal rat cardiomyocytes (NRCMs) were isolated and underwent oxygen-glucose deprivation (OGD) to establish an IHF model. SGPP2-overexpressing NRCMs were constructed and treated with the ERS inducer tunicamycin (Tu) or the SIRT1 inhibitor EX527. Cell injury was evaluated using Cell Counting Kit-8 and lactate dehydrogenase release assays, as well as flow cytometry. Endoplasmic reticulum structure was examined by transmission electron microscopy. The endoplasmic reticulum was labeled with the ER-Tracker Red molecular probe. WB was utilized to detect the expression of apoptosis- and ERS-linked proteins, and the activity of the SIRT1/AMPK signaling pathway. Results: Six key genes (CTSK, FURIN, SLC2A1, RSAD2, SGPP2, and STAT3) were identified through bioinformatics analysis, with SGPP2 showing the most significant differential expression. Additionally, SGPP2 was found to be downregulated in IHF. Single-gene enrichment analysis showed that SGPP2 exhibited a significant association with the AMPK signaling pathway. Animal experiments demonstrated that rats with IHF exhibited significantly impaired cardiac function, marked myocardial tissue injury and fibrosis, ERS in myocardial tissue, lowered SGPP2 expression, and decreased SIRT1/AMPK signaling pathway activity. In vitro experiments confirmed that SGPP2 overexpression alleviated OGD-induced cardiomyocyte injury by inhibiting ERS and simultaneously activating the SIRT1/AMPK signaling pathway. Rescue experiments further demonstrated that both Tu and EX527 significantly promoted ERS and cellular injury, thereby counteracting the protective effects of SGPP2. Conclusions: SGPP2 alleviates IHF by inhibiting ERS modulated by the SIRT1/AMPK pathway.

Neonatal Diabetes Mellitus (NDM) is a rare, heterogeneous monogenic disorder typically presenting within the first six months of life. Unlike type 1 or type 2 diabetes, NDM is caused by single-gene mutations that disrupt pancreatic β-cell function or development. With the advent of next-generation sequencing, the genetic spectrum of NDM has expanded significantly, necessitating a shift from symptomatic management to precision medicine. This narrative review summarizes the genetic basis and pathogenic mechanisms of NDM, categorizing them into three major pathways: (1) ATP-sensitive potassium (K_ATP) channelopathies (e.g., ABCC8, KCNJ11), where gain-of-function mutations inhibit insulin secretion; (2) Transcription factor defects (e.g., GLIS3, PAX6, GATA6), which impair pancreatic development and often present with syndromic features; and (3) Endoplasmic reticulum (ER) stress-mediated β-cell apoptosis, exemplified by WFS1 mutations. Furthermore, we highlight the clinical complexity of these mutations, including the "biphasic phenotype" observed in ABCC8 and HNF1A variants. Understanding these molecular mechanisms is critical for clinical decision-making. We discuss the transformative impact of genetic diagnosis in treatment, particularly the successful transition from insulin to oral sulfonylureas in patients with K_ATP channel mutations, and emphasize the importance of early genetic testing to optimize glycemic control and prevent complications.

Glioblastoma multiforme (GBM) is the most aggressive primary brain cancer (with a median survival time of 14.5 months), characterized by heterogeneity. Identifying prognostic molecular subtypes could provide a deeper exposition of GBM biology with potential therapeutic implications. In this study, we classified GBM into two prognostic subtypes, C1-GBM (n = 57; OS: 313 days) and C2-GBM (n = 109; OS: 452 days), using pathway-based signatures derived from RNA-seq data. Unsupervised consensus clustering revealed that only binary classification (cluster number, CN = 2; mean cluster consensus score = 0.84) demonstrated statistically prognostic differences. We characterized C1 and C2 based on oncogenic pathway and immune signatures. Specifically, C1-GBM was categorized as an immune-infiltrated "hot" tumor, with high infiltration of immune cells, particularly macrophages and CD4⁺ T cells, while C2-GBM as an "inherent driving" subtype, showing elevated activity in G2/M checkpoint genes. To predict the C1 or C2 classification and explore therapeutic interventions, we developed a neural network model. By using Weighted Correlation Network Analysis (WGCNA), we obtained the gene co-expression module based on both gene expression pattern and distribution among patients in TCGA dataset (n = 166) and identified nine hub genes as potentially prognostic biomarkers for the neural network. The model showed strong accuracy in predicting C1/C2 classification and prognosis, validated by the external CGGA-GBM dataset (n = 85). Based on the classification of the BP neural network model, we constructed a Cox nomogram prognostic prediction model for the TCGA-GBM dataset. We predicted potential therapeutic small molecular drugs by targeting subtype-specific oncogenic pathways and validated drug sensitivity (C1-GBM: Methotrexate and Cisplatin; C2-GBM: Cytarabine) by assessing IC₅₀ values against GBM cell lines (divided into C1/C2 subtypes based on the nine hub genes) from the Genomics of Drug Sensitivity in Cancer database. This study introduces a pathway-based prognostic molecular classification of GBM with "hot" (C1-GBM) and "inherent driving" (C2-GBM) tumor subtypes, providing a prediction model based on hub biomarkers and potential therapeutic targets for treatments.

Systemic sclerosis (SSc) is a rare multisystemic autoimmune disease associated with progressive fibrosis, vasculopathy, and immune dysregulation. Despite advances in its management, the disease remains associated with substantial morbidity and mortality, with limited therapeutic options. This systematic review aimed to identify phytocompounds and medicinal plants that had demonstrated efficacy in SSc. A comprehensive literature search was performed in PubMed and ScienceDirect, yielding 7797 records, of which 32 studies met the inclusion criteria. A second search was performed using the SwissTargetPrediction tool to identify new putative molecular targets for these phytocompounds, whose relevance for SSc pathogenesis was verified by a third search in PubMed and ScienceDirect databases. Our search found 24 phytocompouds (e.g., halofunginone, crocetin, and tanshinone IIA) and 5 plant extracts (e.g., caper bush and ciplukan) reported to modulate key pathogenic processes in SSc. These phytochemicals were mainly associated with effects on endothelial to mesenchymal transition, oxidative stress, inflammation, and profibrotic signaling pathways, particularly TGF-β/Smad. The SwissTargetPrediction tool indicated 93 new potential molecular targets of the selected phytochemicals, among which only 41 showed relevance to SSc pathogenesis. In conclusion, available evidence is scarce but promising. Further studies, especially human investigations, are required to clarify clinical efficacy, safety, and potential interactions with drugs used in SSc.

The hypoxic microenvironment within breast cancer tumors leads to the sustained activation of hypoxia-inducible factors (HIFs), notably HIF-1α, which, in turn, triggers adaptive responses such as angiogenesis and metabolic reprogramming. These processes contribute to tumor invasion, progression, metastasis, and therapy resistance. Although a substantial portion of the human genome is transcribed into non-coding RNAs (ncRNAs), which have been shown to play key regulatory roles in the development and progression of breast cancer, the interplay between HIFs and ncRNAs-and how such crosstalk influences breast cancer pathogenesis-remains poorly understood. This review aims to systematically outline the mechanisms of hypoxia-related signaling and ncRNA function in breast cancer, with a focus on their molecular interactions in disease progression and their potential clinical implications.

Background: Peanut is susceptible to iron (Fe) deficiency, particularly in calcareous soils. However, comparative studies on the adaptive mechanisms of different peanut cultivars to Fe deficiency remain limited. This study aimed to investigate the physiological and molecular responses of two distinct peanut cultivars to Fe deprivation and to identify the key traits contributing to differential Fe efficiency. Methods: Two peanut cultivars, LH11 and YZ9102, were cultivated under Fe-sufficient and Fe-deficient conditions, using both hydroponic and pot-based soil culture systems. Multiple parameters were assessed, including visual symptomology, biomass, tissue Fe concentration, active Fe in leaves, chlorophyll (Chl) content (SPAD value), net photosynthetic rate (Pn), Chl fluorescence (Fv/Fm), rhizosphere pH, root ferric chelate reductase (FCR) activity, and the relative expression of two Fe-acquisition-related genes (AhIRT1 and AhFRO1) via qRT-PCR. Results: Cultivar YZ9102 exhibited more severe Fe deficiency chlorosis symptoms, which also appeared earlier than in LH11, under both cultivation systems. Under Fe deficiency, YZ9102 showed significantly lower Chl content, Pn, and Fv/Fm compared to LH11. In contrast, LH11 demonstrated a greater capacity for rhizosphere acidification and maintained significantly higher root FCR activity under Fe-limited conditions. Gene expression analysis revealed that Fe deficiency induced the up-regulation of AhIRT1 and AhFRO1 in the roots of LH11, while their transcript levels were suppressed or unchanged in YZ9102. Conclusions: The peanut cultivar LH11 possesses superior tolerance to Fe deficiency compared to YZ9102. This enhanced tolerance is attributed to a synergistic combination of traits: the maintenance of photosynthetic performance, efficient rhizosphere acidification, heightened root Fe³⁺ reduction capacity, and the positive transcriptional regulation of key Fe uptake genes. These findings provide crucial insights for the selection and breeding of Fe-efficient peanut varieties for cultivation in Fe-deficient environments.

Cisplatin (CDDP) is a cornerstone chemotherapeutic drug, yet its efficacy is frequently compromised by renal toxicity, primarily manifesting as acute kidney injury (AKI). Magnolol (MG) is a polyphenol from Magnolia officinalis and has been widely documented for its pronounced antioxidant and anti-inflammatory properties. This study evaluated the renoprotective effects of MG in a murine model of CDDP-induced AKI. Male C57BL/6 mice received MG (20 mg/kg) via daily intraperitoneal injection for four consecutive days, starting one day before a single CDDP injection. MG significantly reduced the serum concentrations of blood urea nitrogen and creatinine. Histopathological assessment revealed attenuated tubular damage and reduced expression of tubular injury markers. MG inhibited pro-inflammatory cytokines at both systemic and renal levels, alleviated endoplasmic reticulum stress, and suppressed activation of mitogen-activated protein kinase signaling pathways. Apoptotic damage was mitigated, as shown by the fewer TUNEL-positive cells and lowered expression of pro-apoptotic markers. In parallel, ferroptotic processes were alleviated through downregulation of pro-ferroptotic proteins and preservation of key antioxidant regulators. Importantly, MG restored nuclear factor erythroid 2-related factor 2 activity and upregulated downstream antioxidant effectors. These findings highlight the multi-targeted renoprotective actions of MG and support its possible utility as a therapeutic agent to prevent CDDP-induced renal injury.

Oncological safety is essential for autologous reconstruction after resection of cartilage-infiltrating head and neck tumors. High hydrostatic pressure (HHP) enables complete devitalization of tumor-infiltrated tissue while preserving extracellular matrix integrity. However, residual soluble tumor-derived products may influence infiltrating stromal cells. This study examined whether conditioned media (CM) from HHP-treated head and neck squamous cell carcinoma (HNSCC) cells induce cancer-associated fibroblast (CAF)-like transdifferentiation of human adipose stromal cells (hASCs). HASCs were exposed to CM from untreated or HHP-treated (300 MPa) HNSCC cells, tumor-CM (TCM), or TGF-β1. Morphological changes in hASCs were evaluated, and CAF marker expression was analyzed by qRT-PCR, immunofluorescence, Western blot, and ELISA. Cytokines were quantified via multiplex analysis. TGF-β1 induced a CAF-like phenotype with α-SMA upregulation, whereas TCM and 0 MPa-CM caused only modest increases in selected markers. Although 300 MPa-CM did not induce CAF-associated molecular signatures, hASCs exhibited morphological alterations, underscoring that morphology alone is insufficient to define CAF transdifferentiation. Cytokine secretion was elevated in response to all CM conditions. These findings indicate that HHP treatment at 300 MPa abolishes the paracrine CAF-inducing potential of tumor-derived mediators in vitro, supporting the oncological safety of HHP-treated tissues under these experimental condition, although further in vivo validation is warranted.