METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2.

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-d-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment.

Transcriptome Profiling of miRNA-mRNA Interactions and Associated Mechanisms in Chemotherapy-Induced Neuropathic Pain.

Chemotherapy-induced neuropathic pain (CINP) is a dose-limiting adverse event affecting 40% of chemotherapy patients. MiRNA-mRNA interaction plays an important role in various processes. However, detailed profiling of miRNA-mRNA interactions in CINP remains unclear. Here, a rat-based CINP model was established using paclitaxel, followed by nociceptive behavioral tests related to mechanical allodynia, thermal hyperalgesia, and cold allodynia. The landscape of miRNA-mRNA interaction in the spinal dorsal horn was investigated through mRNA transcriptomics and small RNA sequencing. Under CINP condition, 86 differentially expressed mRNAs and 56 miRNAs were identified. Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated the activity of Odorant binding, postsynaptic specialization and synaptic density, extracellular matrix, mitochondrial matrix, retrograde endocannabinoid signaling, and GTPase activity. Protein-protein interaction (PPI), networks of circRNA-miRNA-mRNA, lncRNA-miRNA-mRNA, and TF-genes were demonstrated. We next explored the immune infiltration microenvironment and found a higher infiltration abundance of Th17 and a lower abundance of MDSC in CINP. RT-qPCR and dual-luciferase assays were used to verify the sequencing results, and single-cell analysis based on the SekSeeq database was conducted. Combined with bioinformatics analyses and experimental validations, Mpz, a protein-coding gene specifically expressed in Schwann cells, was found critical in maintaining CINP under miRNA regulation. Therefore, these data highlight the expression patterns of miRNA-mRNA, and the underlying mechanism in the spinal dorsal horn under CINP condition, and Mpz may serve as a promising therapeutic target for patients with CINP.

Homologous post-treatment strategy enabling phase-pureα-FAPbI3films.

Formamidinium lead triiodide (FAPbI3) is considered as the prospective light-absorbing layer on account of the close-to-ideal bandgap of theα-phase, wide optical absorption spectrum and good thermal stability. Therefore, how to realizeδtoα-phase transition to obtain phase-pureα-FAPbI3without additives is important for FAPbI3perovskite films. Herein, a homologous post-treatment strategy (HPTS) without additives is proposed to prepare FAPbI3films with pureα-phase. The strategy is processed along with dissolution and reconstruction process during the annealing. The FAPbI3film has tensile strain with the substrate, and the lattice keeps tensile, and the film maintains in anα/δhybrid phase. The HPTS process releases the tensile strain between the lattice and the substrate. The process of strain release realizes the phase transition fromδtoα-phase during this process. This strategy can accelerate the transformation from hexagonalδ-FAPbI3to cubicα-FAPbI3at 120 °C. As a result, the acquiredα-FAPbI3films exhibit better film quality in optical and electrical properties, accordingly achieving device efficiency of 19.34% and enhanced stability. This work explores an effective approach to obtain additive-free and phase-pureα-FAPbI3films through a HPTS to fabricate uniform high-performanceα-FAPbI3perovskite solar cells.

Identification of a novel cuproptosis-related gene signature and integrative analyses in patients with lower-grade gliomas.

Background: Cuproptosis is a newly discovered unique non-apoptotic programmed cell death distinguished from known death mechanisms like ferroptosis, pyroptosis, and necroptosis. However, the prognostic value of cuproptosis and the correlation between cuproptosis and the tumor microenvironment (TME) in lower-grade gliomas (LGGs) remain unknown. Methods: In this study, we systematically investigated the genetic and transcriptional variation, prognostic value, and expression patterns of cuproptosis-related genes (CRGs). The CRG score was applied to quantify the cuproptosis subtypes. We then evaluated their values in the TME, prognostic prediction, and therapeutic responses in LGG. Lastly, we collected five paired LGG and matched normal adjacent tissue samples from Sun Yat-sen University Cancer Center (SYSUCC) to verify the expression of signature genes by quantitative real-time PCR (qRT-PCR) and Western blotting (WB). Results: Two distinct cuproptosis-related clusters were identified using consensus unsupervised clustering analysis. The correlation between multilayer CRG alterations with clinical characteristics, prognosis, and TME cell infiltration were observed. Then, a well-performed cuproptosis-related risk model (CRG score) was developed to predict LGG patients' prognosis, which was evaluated and validated in two external cohorts. We classified patients into high- and low-risk groups according to the CRG score and found that patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (P<0.001). A high CRG score implies higher TME scores, more significant TME cell infiltration, and increased mutation burden. Meanwhile, the CRG score was significantly correlated with the cancer stem cell index, chemoradiotherapy sensitivity-related genes and immune checkpoint genes, and chemotherapeutic sensitivity, indicating the association with CRGs and treatment responses. Univariate and multivariate Cox regression analyses revealed that the CRG score was an independent prognostic predictor for LGG patients. Subsequently, a highly accurate predictive model was established for facilitating the clinical application of the CRG score, showing good predictive ability and calibration. Additionally, crucial CRGs were further validated by qRT-PCR and WB. Conclusion: Collectively, we demonstrated a comprehensive overview of CRG profiles in LGG and established a novel risk model for LGG patients' therapy status and prognosis. Our findings highlight the potential clinical implications of CRGs, suggesting that cuproptosis may be the potential therapeutic target for patients with LGG.

Autologous activated platelet-rich plasma in hair growth: A pilot study in male androgenetic alopecia with in vitro bioactivity investigation.

BACKGROUND: Platelet-rich plasma (PRP) is effective in the treatment of androgenetic alopecia (AGA). AIMS: The purpose of this study is to assess the effect of PRP on the proliferation of human follicle dermal papilla cells (HFDPCs), to observe the effect of PRP on the growth of hair follicles and hair shaft in vitro, to measure growth factors, and to evaluate the efficacy and safety of PRP injection. PATIENTS/METHODS: The effect of PRP on the proliferation of HFDPCs was observed. The length of hair follicle and hair shaft in vitro was measured. Then, the concentration of growth factors (EGF, FGF-2, FGF-7, IGF-1, HGF, PDGF-BB, and VEGF-A) was evaluated. Half-head injection of PRP was conducted to 10 males. Three treatments were conducted at 30-day intervals. Digital photographs were taken; hair diameter, hair density, unit density of hair follicles, and terminal hair/ vellus hair were analyzed. RESULTS: Platelet-rich plasma significantly promoted the proliferation of HFDPCs. Under the PRP culture, the hair follicle and hair shaft were grown, and the hair growth length on the 3rd and 6th days was greater than that of the control. PRP contained growth factors such as EGF, FGF-2, FGF-7, IGF-1, HGF, PDGF-B, and VEGF-A. Hair diameter, hair density, and unit hair follicle density on the PRP injection side peaked in the 6th month. The terminal hair/ vellus hair of the PRP injection side reached a peak in the 4th month. The average patient satisfaction during the entire treatment was 5.4 points (0-10 points). CONCLUSION: Platelet-rich plasma can promote hair growth. PRP injection is safe and effective for the treatment of AGA.

Integration of protein interaction and gene co-expression information for identification of melanoma candidate genes.

Cutaneous melanoma is an aggressive form of skin cancer that causes death worldwide. Although much has been learned about the molecular basis of melanoma genesis and progression, there is also increasing appreciation for the continuing discovery of melanoma genes to improve the genetic understanding of this malignancy. In the present study, melanoma candidate genes were identified by analysis of the common network from cancer type-specific RNA-Seq co-expression data and protein-protein interaction profiles. Then, an integrated network containing the known melanoma-related genes represented as seed genes and the putative genes represented as linker genes was generated using the subnetwork extraction algorithm. According to the network topology property of the putative genes, we selected seven key genes (CREB1, XPO1, SP3, TNFRSF1B, CD40LG, UBR1, and ZNF484) as candidate genes of melanoma. Subsequent analysis showed that six of these genes are melanoma-associated genes and one (ZNF484) is a cancer-associated gene on the basis of the existing literature. A signature comprising these seven key genes was developed and an overall survival analysis of 461 cutaneous melanoma cases was carried out. This seven-gene signature can accurately determine the risk profile for cutaneous melanoma tumors (log-rank P=3.27E-05) and be validated on an independent clinical cohort (log-rank P=0.028). The presented seven genes might serve as candidates for studying the molecular mechanisms and help improve the prognostic risk assessment, which have clinical implications for melanoma patients.