Functional identification of DNA demethylase gene CaROS1 in pepper (Capsicum annuum L.) involved in salt stress.

Pepper, which is a widely cultivated important vegetable, is sensitive to salt stress, and the continuous intensification of soil salinization has affected pepper production worldwide. However, genes confer to salt tolerance are rarely been cloned in pepper. Since the REPRESSOR OF SILENCING 1 (ROS1) is a DNA demethylase that plays a crucial regulatory role in plants in response to various abiotic stresses, including salt stress. We cloned a ROS1 gene in pepper, named CaROS1 (LOC107843637). Bioinformatic analysis showed that the CaROS1 protein contains the HhH-GPD glycosylase and RRM_DME domains. qRT-PCR analyses showed that the CaROS1 was highly expressed in young and mature fruits of pepper and rapidly induced by salt stress. Functional characterization of the CaROS1 was performed by gene silencing in pepper and overexpressing in tobacco, revealed that the CaROS1 positively regulates salt tolerance ability. More detailly, CaROS1-silenced pepper were more sensitive to salt stress, and their ROS levels, relative conductivity, and malondialdehyde content were significantly higher in leaves than those of the control plants. Besides, CaROS1-overexpressing tobacco plants were more tolerant to salt stress, with a higher relative water content, total chlorophyll content, and antioxidant enzyme activity in leaves compared to those of WT plants during salt stress. These results revealed the CaROS1 dose play a role in salt stress response, providing the theoretical basis for salt tolerance genetic engineering breeding in pepper.

Causal relationship between inflammatory proteins and glioblastoma: a two-sample bi­directional mendelian randomization study.

Background: Observational studies have indicated a potential correlation between glioblastoma and circulating inflammatory proteins. Further investigation is required to establish a causal relationship between these two factors. Methods: We performed a Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on glioblastoma. The GWAS summary data for glioblastoma included 243 cases and 287,137 controls. The inverse variance weighted (IVW) method was used as the primary analytical method to assess causality. Four additional MR methods [simple mode, MR-Egger, weighted median, and weighted mode] were used to supplement the IVW results. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Reverse MR analysis was also performed. glioblastoma transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to validate the findings obtained through MR, while pathway and functional enrichment analyses were conducted to predict the potential underlying mechanisms. Results: Our findings from employing the inverse variance weighted method in our forward MR analysis provide robust evidence supporting a potential association between glioblastoma and elevated levels of Cystatin D, as well as decreased levels of fibroblast growth factor 21 (FGF21) in the circulation. Moreover, our reverse MR analysis revealed that glioblastoma may contribute to increased concentrations of C-X-C motif chemokine 9 (CXCL9) and Interleukin-33 (IL-33) in the bloodstream. Transcriptomic analysis showed that FGF21 expression was inversely associated with the risk of developing glioblastoma, whereas an increased risk was linked to elevated levels of CXCL9 and IL-33. Pathway and functional enrichment analyses suggested that Cystatin D might exert its effects on glioblastoma through intracellular protein transport, whereas FGF21 might affect glioblastoma via glucose response mechanisms. Conclusion: These results indicate that FGF21 is a significant factor in glioblastoma susceptibility. Glioblastoma also affects the expression of inflammatory proteins such as C-X-C motif chemokine 9 and Interleukin-33, providing new insights into the mechanisms of glioblastoma genesis and clinical research.

Integrated single-cell and spatial transcriptomic analysis reveals YBX1 drives immune regulation in GBM progression.

The RNA modification 5-methylcytosine (m5C) is widespread across various RNA types, significantly impacting RNA stability and translational efficiency. Accumulating evidence highlights its significant role within the tumorigenesis and progression of multiple malignancies. Nevertheless, the specific process through m5C is implicated in Glioblastoma (GBM) remains unclear. We conducted acomprehensive analysis of m5C expression distribution in single-cell GBM data. Our findings revealed elevated m5C scores in GBM single-cell data compared to the normal group. Additionally, multiple tumors exhibited significantly higher m5C scores than the normal group. Moreover, there was a positive correlation observed between the m5C score and inflammation score. m5C regulatory factor YBX1 exhibited a heightened expression in GBM, correlating closely with metastatic tendencies and an unfavorable prognosis across various cancer types. YBX1 has different biological functions in myeloid cells 1 and myeloid cells 2. YBX1 may act as immunosuppressive regulator by inhibiting the NF-κB pathway and inflammatory response in myeloid cells 1. YBX1 is essential for immune infiltrates, which creates a highly immunosuppressive tumor microenvironment by TNF signaling pathway in myeloid cells 2. YBX1+ neoplastic cells promote cell proliferation by NF-κB pathway. APOE mediates the interaction of YBX1+ myeloid cells and neoplastic cells by NF-κB.

Hot-water soluble fraction of starch as particle-stabilizers of oil-in-water emulsions: Effect of dry heat modification.

Dry heat treatment (DHT) ranging from 130 to 190 °C was employed to modify corn starch. The hot-water soluble fraction (HWS) of the DHT-modified starch was isolated, and its capacity and mechanism for stabilizing O/W emulsions were investigated. Corn starch underwent a significant structural transformation by DHT at 190 °C, characterized by a 7.3 % reduction in relative crystallinity, a tenfold decrease in weight-average molecular weight from 95.21 to 8.11 × 106 g/mol, and a degradation of over one-third of the extra-long chains of amylopectin (DP > 36) into short chains (DP 6-12). These structural modifications resulted in a substantial formation of soluble amylopectin, leading to a sharp increase in the HWS content of corn starch from 3.16 % to 85.06 %. This augmented HWS content surpassed the critical macromolecule concentration, prompting the formation of HWS nanoaggregates. These nanoaggregates, with an average particle size of 33 nm, functioned as particle stabilizers, ensuring the stability of the O/W emulsion through the Pickering mechanism. The O/W emulsion stabilized by HWS nanoaggregates exhibited noteworthy centrifugal and storage stability, with rheological properties remaining nearly unchanged over a storage period of 180 days. Given its straightforward preparation process, the HWS of DHT-modified starch could be a promising natural emulsifier.

ScRNA-seq reveals novel immune-suppressive T cells and investigates CMV-TCR-T cells cytotoxicity against GBM.

BACKGROUND: Glioblastoma (GBM) is a fatal primary brain malignancy in adults. Previous studies have shown that cytomegalovirus (CMV) is a risk factor for tumorigenesis and aggressiveness for glioblastoma. However, little is known about how CMV infection affects immune cells in the tumor microenvironment of GBM. Furthermore, there has been almost no engineered T-cell receptor (TCR)-T targeting CMV for GBM research to date. METHODS: We evaluated the CMV infection status of patients with GBM's tumor tissue by immune electron microscopy, immunofluorescence, and droplet digital PCR. We performed single-cell RNA sequencing for CMV-infected GBM to investigate the effects of CMV on the GBM immune microenvironment. CellChat was applied to analyze the interaction between cells in the GBM tumor microenvironment. Additionally, we conducted single-cell TCR/B cell receptor (BCR) sequencing and Grouping of Lymphocyte Interactions with Paratope Hotspots 2 algorithms to acquire specific CMV-TCR sequences. Genetic engineering was used to introduce CMV-TCR into primary T cells derived from patients with CMV-infected GBM. Flow cytometry was used to measure the proportion and cytotoxicity status of T cells in vitro. RESULTS: We identified two novel immune cell subpopulations in CMV-infected GBM, which were bipositive CD68+SOX2+ tumor-associated macrophages and FXYD6+ T cells. We highlighted that the interaction between bipositive TAMs or cancer cells and T cells was predominantly focused on FXYD6+ T cells rather than regulatory T cells (Tregs), whereas, FXYD6+ T cells were further identified as a group of novel immunosuppressive T cells. CMV-TCR-T cells showed significant therapeutic effects on the human-derived orthotopic GBM mice model. CONCLUSIONS: These findings provided an insight into the underlying mechanism of CMV infection promoting the GBM immunosuppression, and provided a novel potential immunotherapy strategy for patients with GBM.

Electronic structure modulation of iron sites with fluorine coordination enables ultra-effective H2O2 activation.

Electronic structure modulation of active sites is critical important in Fenton catalysis as it offers a promising strategy for boosting H2O2 activation. However, efficient generation of hydroxyl radicals (•OH) is often limited to the unoptimized coordination environment of active sites. Herein, we report the rational design and synthesis of iron oxyfluoride (FeOF), whose iron sites strongly coordinate with the most electronegative fluorine atoms in a characteristic moiety of F-(Fe(III)O3)-F, for effective H2O2 activation with potent •OH generation. Results demonstrate that the fluorine coordination plays a pivotal role in lowering the local electron density and optimizing the electronic structures of iron sites, thus facilitating the rate-limiting H2O2 adsorption and subsequent peroxyl bond cleavage reactions. Consequently, FeOF exhibits a significant and pH-adaptive •OH yield (~450 µM) with high selectivity, which is 1 ~ 3 orders of magnitude higher than the state-of-the-art iron-based catalysts, leading to excellent degradation activities against various organic pollutants at neutral condition. This work provides fundamental insights into the function of fluorine coordination in boosting Fenton catalysis at atomic level, which may inspire the design of efficient active sites for sustainable environmental remediation.

Global research trends on innate lymphoid cells in the brain, gut and lung field: a bibliometric and visualized analysis.

Background: ILCs play important roles in the brain, gut, and lungs. Researchers are attempting to establish a research framework on the brain-gut-lung axis using ILCs. However, no one has yet conducted a bibliometric analysis to summarize the findings. In this study, we utilized bibliometrics to analyze the emerging trends and focal areas of ILCs in the brain, intestine, and lung. We aim to provide references for future research on the brain-gut-lung axis. Methods: To conduct a comprehensive bibliometric analysis on ILCs in the fields of brain, intestine, and lung, we utilized software such as HistCite, VOSviewer, and CiteSpace. Our analysis focused on various aspects, including the number of publications, countries, authors, journals, co-cited documents, and keywords. This approach allowed us to gain valuable insights into the research landscape surrounding ILCs in these specific fields. Results: A total of 8411 articles or reviews on ILCs in the fields of brain, intestine, and lung were included. The number of published articles has shown a consistent upward trend since 2003. A total of 45279 authors from 99 countries have contributed to these articles. The United States has the highest number of publications (n=3044) and the most cited articles (TGCS=210776). The top three published authors in this field are David Artis, Marco Colonna and Andrew NJ McKenzie. The journal Immunity is the most authoritative choice for researchers. The main research focuses in this field include NK cell, ILC2, tumor immunity, multiple sclerosis, inflammatory bowel disease, airway inflammation, RORγT, and immunotherapy. In recent years, cancer and tumor microenvironment have emerged as hot keywords, particularly immunotherapy, PD-1 related directions, indicating a potential shift in research focus. Conclusion: European and American countries have been pivotal in conducting research on ILCs, while China has produced a significant number of publications, its impact is still limited. Tumors are likely to emerge as the next focal points in this field. The connection and regulation between the brain and the lung are not yet fully understood, and further investigation is necessary to explore the role of ILCs in the brain-lung axis.

Insight into deep learning for glioma IDH medical image analysis: A systematic review.

BACKGROUND: Deep learning techniques explain the enormous potential of medical image analysis, particularly in digital pathology. Concurrently, molecular markers have gained increasing significance over the past decade in the context of glioma patients, providing novel insights into diagnosis and more personalized treatment options. Deep learning combined with imaging and molecular analysis enables more accurate prognostication of patients, more accurate treatment plan proposals, and accurate biomarker (IDH) prediction for gliomas. This systematic study examines the development of deep learning techniques for IDH prediction using histopathology images, spanning the period from 2019 to 2023. METHOD: The study adhered to the PRISMA reporting requirements, and databases including PubMed, Google Scholar, Google Search, and preprint repositories (such as arXiv) were systematically queried for pertinent literature spanning the period from 2019 to the 30th of 2023. Search phrases related to deep learning, digital pathology, glioma, and IDH were collaboratively utilized. RESULTS: Fifteen papers meeting the inclusion criteria were included in the analysis. These criteria specifically encompassed studies utilizing deep learning for the analysis of hematoxylin and eosin images to determine the IDH status in patients with gliomas. CONCLUSIONS: When predicting the status of IDH, the classifier built on digital pathological images demonstrates exceptional performance. The study's predictive effectiveness is enhanced with the utilization of the appropriate deep learning model. However, external verification is necessary to showcase their resilience and universality. Larger sample sizes and multicenter samples are necessary for more comprehensive research to evaluate performance and confirm clinical advantages.

Predictive Panel for Immunotherapy in Low-Grade Glioma.

BACKGROUND: The main treatment of low-grade glioma (LGG) is still surgical resection followed by radiotherapy and/or chemotherapy, which has certain limitations, including side effects and drug resistance. Immunotherapy is a promising treatment for LGG, but it is generally hindered by the tumor microenvironment with the limited expression of tumor antigens. METHODS: We integrated RNA sequencing data sets and clinical information and conducted consistent cluster analysis to explore the most suitable patients for immune checkpoint therapy. Gene set enrichment analysis, UMAP analysis, mutation correlation analysis, TIMER analysis, and TIDE analysis were used to identify the immune characteristics of 3 immune subtypes and the feasibility of 5 antigens as immune checkpoint markers. RESULTS: We analyzed the isolation and mutation of homologous recombination repair genes (HRR) of the 3 immune subtypes, and the HRR genes of the 3 subtypes were obviously segregated. Among them, the IS2 subtype has a large number of HRR gene mutations, which increases the immunogenicity of tumors-this is consistent with the results of tumor mutation load analysis of 3 immune subtypes. Then we evaluated the immune cell infiltration of immune subtypes and found that IS2 and IS3 subtypes were rich in immune cells. It is worth noting that there are many Treg cells and NK cells in the IS1 subtype. In addition, when analyzing the immune checkpoint gene expression of the 3 subtypes, we found that they were upregulated most in IS2 subtypes compared with other subtypes. Then when we further confirmed the role of immune-related genes in LGG; through TIDE analysis and TISIDB analysis, we obtained 5 markers that can predict the efficacy of ICB in patients with LGG. In addition, we confirmed that they were associated with poor prognosis through survival analysis. CONCLUSIONS: We obtained 3 reliable immune subtypes, and patients with the IS2 subtype are suitable for immunotherapy, in which NAMPT, SLC11A1, TNC, VIM, and SPP1 are predictive panel markers for ICB in the LGG group. Our findings provide a rationale for immunotherapy selection and prediction of patient prognosis in LGG patients.

Chronic stress as an emerging risk factor for the development and progression of glioma.

ABSTRACT: Gliomas tend to have a poor prognosis and are the most common primary malignant tumors of the central nervous system. Compared with patients with other cancers, glioma patients often suffer from increased levels of psychological stress, such as anxiety and fear. Chronic stress (CS) is thought to impact glioma profoundly. However, because of the complex mechanisms underlying CS and variability in individual tolerance, the role of CS in glioma remains unclear. This review suggests a new proposal to redivide the stress system into two parts. Neuronal activity is dominant upstream. Stress-signaling molecules produced by the neuroendocrine system are dominant downstream. We discuss the underlying molecular mechanisms by which CS impacts glioma. Potential pharmacological treatments are also summarized from the therapeutic perspective of CS.

[Effect and mechanism of Zuogui Pills on neural function recovery in ischemic stroke mice based on OPN/IGF-1/mTOR].

To explore the effect and mechanism of Zuogui Pills in promoting neural tissue recovery and functional recovery in mice with ischemic stroke. Male C57BL/6J mice were randomly divided into a sham group, a model group, and low-, medium, and high-dose Zuogui Pills groups(3.5, 7, and 14 g·kg~(-1)), with 15 mice in each group. The ischemic stroke model was established using photochemical embolization. Stiker remove and irregular ladder walking behavioral tests were conducted before modeling and on days 7, 14, 21, and 28 after medication. Triphenyl tetrazolium chloride(TTC) staining was performed on day 3 after modeling, and T2-weighted imaging(T2WI) and diffusion-weighted imaging(DWI) were performed on day 28 after medication to evaluate the extent of brain injury. Hematoxylin-eosin(HE) staining was performed to observe the histology of the cerebral cortex. Axonal marker proteins myelin basic protein(MBP), growth-associated protein 43(GAP43), mammalian target of rapamycin(mTOR), and its downstream phosphorylated s6 ribosomal protein(p-S6), as well as mechanism-related proteins osteopontin(OPN) and insulin-like growth factor 1(IGF-1), were detected using immunofluorescence and Western blot. Zuogui Pills had a certain restorative effect on the neural function impairment caused by ischemic stroke in mice. TTC staining showed white infarct foci in the sensory-motor cortex area, and T2WI imaging revealed cystic necrosis in the sensory-motor cortex area. The Zuogui Pills groups showed less brain tissue damage, fewer scars, and more capillaries. The number of neuronal axons in those groups was higher than that in the model group, and neuronal activity was stronger. The expression of GAP43, OPN, IGF-1, and mTOR proteins in the Zuogui Pills groups was higher than that in the model group. In summary, Zuogui Pills can promote the recovery of neural function and axonal growth in mice with ischemic stroke, and its mechanism may be related to the activation of the OPN/IGF-1/mTOR signaling pathway.

Deep learning in precision medicine and focus on glioma.

Deep learning (DL) has been successfully applied to different fields for a range of tasks. In medicine, DL methods have been also used to improve the efficiency of disease diagnosis. In this review, we first summarize the history of the development of artificial intelligence models, demonstrate the features of the subtypes of machine learning and different DL networks, and then explore their application in the different fields of precision medicine, such as cardiology, gastroenterology, ophthalmology, dermatology, and oncology. By digging more information and extracting multilevel features from medical data, we found that DL helps doctors assess diseases automatically and monitor patients' physical health. In gliomas, research regarding application prospect of DL was mainly shown through magnetic resonance imaging and then by pathological slides. However, multi-omics data, such as whole exome sequence, RNA sequence, proteomics, and epigenomics, have not been covered thus far. In general, the quality and quantity of DL datasets still need further improvements, and more fruitful multi-omics characteristics will bring more comprehensive and accurate diagnosis in precision medicine and glioma.

Membrane-bound transcription factor LRRC4 inhibits glioblastoma cell motility.

Membrane-bound transcription factors (MTFs) have been observed in many types of organisms, such as plants, animals and microorganisms. However, the routes of MTF nuclear translocation are not well understood. Here, we reported that LRRC4 is a novel MTF that translocates to the nucleus as a full-length protein via endoplasmic reticulum-Golgi transport, which is different from the previously described nuclear entry mechanism. A ChIP-seq assay showed that LRRC4 target genes were mainly involved in cell motility. We confirmed that LRRC4 bound to the enhancer element of the RAP1GAP gene to activate its transcription and inhibited glioblastoma cell movement by affecting cell contraction and polarization. Furthermore, atomic force microscopy (AFM) confirmed that LRRC4 or RAP1GAP altered cellular biophysical properties, such as the surface morphology, adhesion force and cell stiffness. Thus, we propose that LRRC4 is an MTF with a novel route of nuclear translocation. Our observations demonstrate that LRRC4-null glioblastoma led to disordered RAP1GAP gene expression, which increased cellular movement. Re-expression of LRRC4 enabled it to suppress tumors, and this is a potential for targeted treatment in glioblastoma.

Exploration of lung mycobiome in the patients with non-small-cell lung cancer.

As the Human Microbiome Project (HMP) progresses, the relationship between microbes and human health has been receiving increasing attention. A growing number of reports support the correlation between cancer and microbes. However, most studies have focused on bacteria, rather than fungal communities. In this study, we studied the alteration in lung mycobiome in patients with non-small-cell lung cancer (NSCLC) using metagenomic sequencing and qPCR. The higher fungal diversity and more complex network were observed in the patients with NSCLC. In addition, Alternaria arborescens was found as the most relevant fungus to NSCLC, and the enrichment of it in cancerous tissue was also detected. This study proposes that the changes in fungal communities may be closely related to lung cancer, and provides insights into further exploration the relationship between lung cancer and fungi.

Leucine-rich repeats containing 4 protein (LRRC4) in memory, psychoneurosis, and glioblastoma.

ABSTRACT: Leucine-rich repeats containing 4 ( LRRC4 , also named netrin-G ligand 2 [NGL-2]) is a member of the NetrinGs ligands (NGLs) family. As a gene with relatively high and specific expression in brain, it is a member of the leucine-rich repeat superfamily and has been proven to be a suppressor gene for gliomas, thus being involved in gliomagenesis. LRRC4 is the core of microRNA-dependent multi-phase regulatory loops that inhibit the proliferation and invasion of glioblastoma (GB) cells, including LRRC4/NGL2-activator protein 2 (AP2)-microRNA (miR) 182-LRRC4 and LRRC4-miR185-DNA methyltransferase 1 (DNMT1)-LRRC4/specific protein 1 (SP1)-DNMT1-LRRC4. In this review, we demonstrated LRRC4 as a new member of the partitioning-defective protein (PAR) polarity complex that promotes axon differentiation, mediates the formation and plasticity of synapses, and assists information input to the hippocampus and storage of memory. As an important synapse regulator, aberrant expression of LRRC4 has been detected in autism, spinal injury and GBs. LRRC4 is a candidate susceptibility gene for autism and a neuro-protective factor in spinal nerve damage. In GBs, LRRC4 is a novel inhibitor of autophagy, and an inhibitor of protein-protein interactions involving in temozolomide resistance, tumor immune microenvironment, and formation of circular RNA.

Schaftoside improves cerebral ischemia-reperfusion injury by enhancing autophagy and reducing apoptosis and inflammation through the AMPK/mTOR pathway.

BACKGROUND: As a flavonoid compound, schaftoside (SS) possesses a wide range of pharmaceutical activities. Nonetheless, it is unclear whether SS has a neuroprotective effect in cerebral ischemia-reperfusion injury (CI/RI). OBJECTIVES: To examine the neuroprotective effect of SS in CI/RI and explore the underlying mechanism. MATERIAL AND METHODS: An in vivo middle cerebral artery occlusion (MCAO) was used to simulate CI/RI in rats. Oxygen glucose deprivation/reperfusion (OGD/R) of HT22 cells was used to establish a cellular model of CI/RI in vitro. Pathological changes were evaluated with hematoxylin and eosin (H&E) staining, apoptosis was measured using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and flow cytometry, and inflammatory factors were assessed using enzyme-linked immunosorbent assay (ELISA). Protein expression was detected using western blot or immunofluorescence. RESULTS: Our results indicated that SS attenuated CI/RI by improving neurologic deficits and reducing brain edema. Moreover, SS treatment blocked apoptosis and inflammation and enhanced autophagy in MCAO rats. Schaftoside was found to amplify the activation of adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway induced by MCAO. Similarly, SS pretreatment increased cell viability and autophagy, and reduced apoptosis and inflammation in OGD/R-induced HT22 cells. The OGD/R enlarges the p-AMPK/AMPK ratio while restricting the p-mTOR/mTOR ratio, and it was found that SS further enhanced the effect of OGD/R on the AMPK/mTOR pathway. Rapamycin promoted the effect of SS on OGD/R-induced HT22 cells, while compound C produced the opposite results. Mechanistically, SS promoted autophagy and reduced apoptosis and inflammation through the regulation of the AMPK/mTOR signaling pathway. CONCLUSIONS: The obtained results showed that SS protected against CI/RI through an autophagy-mediated AMPK/mTOR pathway when accessed in vitro and in vivo.

Novel insights into noncanonical open reading frames in cancer.

With technological advances, previously neglected noncanonical open reading frames (nORFs) are drawing ever-increasing attention. However, the translation potential of numerous putative nORFs remains elusive, and the functions of noncanonical peptides have not been systemically summarized. Moreover, the relationship between noncanonical peptides and their counterpart protein or RNA products remains elusive and the clinical implementation of noncanonical peptides has not been explored. In this review, we highlight how recent technological advances such as ribosome profiling, bioinformatics approaches and CRISPR/Cas9 facilitate the research of noncanonical peptides. We delineate the features of each nORF category and the evolutionary process underneath the nORFs. Most importantly, we summarize the diversified functions of noncanonical peptides in cancer based on their subcellular location, which reflect their extensive participation in key pathways and essential cellular activities in cancer cells. Meanwhile, the equilibrium between noncanonical peptides and their corresponding transcripts or counterpart products may be dysregulated under pathological states, which is essential for their roles in cancer. Lastly, we explore their underestimated potential in clinical application as diagnostic biomarkers and treatment targets against cancer.

Blocking glycine utilization inhibits multiple myeloma progression by disrupting glutathione balance.

Metabolites in the tumor microenvironment are a critical factor for tumor progression. However, the lack of knowledge about the metabolic profile in the bone marrow (BM) microenvironment of multiple myeloma (MM) limits our understanding of MM progression. Here, we show that the glycine concentration in the BM microenvironment is elevated due to bone collagen degradation mediated by MM cell-secreted matrix metallopeptidase 13 (MMP13), while the elevated glycine level is linked to MM progression. MM cells utilize the channel protein solute carrier family 6 member 9 (SLC6A9) to absorb extrinsic glycine subsequently involved in the synthesis of glutathione (GSH) and purines. Inhibiting glycine utilization via SLC6A9 knockdown or the treatment with betaine suppresses MM cell proliferation and enhances the effects of bortezomib on MM cells. Together, we identify glycine as a key metabolic regulator of MM, unveil molecular mechanisms governing MM progression, and provide a promising therapeutic strategy for MM treatment.

LncRNA PELATON, a Ferroptosis Suppressor and Prognositic Signature for GBM.

PELATON is a long noncoding RNA also known as long intergenic nonprotein coding RNA 1272 (LINC01272). The known reports showed that PELATON functions as an onco-lncRNA or a suppressor lncRNA by suppressing miRNA in colorectal cancer, gastric cancer and lung cancer. In this study, we first found that PELATON, as an onco-lncRNA, alleviates the ferroptosis driven by mutant p53 and promotes mutant p53-mediated GBM proliferation. We also first confirmed that PELATON is a new ferroptosis suppressor lncRNA that functions as a ferroptosis inhibitor mainly by mutant P53 mediating the ROS ferroptosis pathway, which inhibits the production of ROS, reduces the levels of divalent iron ions, promotes the expression of SLC7A11, and inhibits the expression of ACSL4 and COX2.PELATON can inhibit the expression of p53 in p53 wild-type GBM cells and regulate the expression of BACH1 and CD44, but it has no effect on p53, BACH1 and CD44 in p53 mutant GBM cells. PELATON and p53 can form a complex through the RNA binding protein EIF4A3. Knockdown of PELATON resulted in smaller mitochondria, increased mitochondrial membrane density, and enhanced sensitivity to ferroptosis inducers to inhibit GBM cell proliferation and invasion. In addition, we established a favourite prognostic model with NCOA4 and PELATON. PELATON is a promising target for the prognosis and treatment of GBM.

Administration of growth hormone improves endometrial function in women undergoing in vitro fertilization: a systematic review and meta-analysis.

BACKGROUND: The positive effects of growth hormone (GH) on IVF are often attributed to improvements in oocyte and embryo quality. While emerging evidence emphasizes GH-induced improvements in the endometrium, these results are controversial. OBJECTIVE AND RATIONALE: This meta-analysis aimed to evaluate whether GH administration improved endometrial function and reproductive outcomes during IVF cycles and to thus guide clinical practice. SEARCH METHODS: A literature search in the Cochrane Central Register of Controlled Trials, PubMed and Embase was performed through to 30 November 2021, without language restrictions. Randomized controlled trials (RCTs) evaluating the effects of GH on IVF outcomes were included. Risk of bias and quality of evidence (QoE) were assessed according to the Cochrane Collaboration's tool and the Grading of Recommendations Assessment, Development and Evaluation system. Odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs) were assessed by random-effects models. OUTCOMES: A total of 25 trials with 2424 women were included. Seventeen RCTs with poor responders (n = 1723) showed that GH administration significantly increased endometrial thickness (EMT) (MD = 0.38, 95% CI: 0.18-0.59; moderate QoE), which contributed to an improved live birth rate (OR = 1.67, 95% CI: 1.13-2.49; very low QoE) and clinical pregnancy rate (CPR) (OR = 1.97, 95% CI: 1.43-2.72; low QoE). Subgroup analyses showed a dose- and time-dependent relationship between GH cotreatment and IVF outcomes; the optimal recommendation for improving CPR was consistent with that for EMT, rather than for oocytes and embryos. Hence, GH might improve fertility via effects on the endometrium. Administration of GH daily from the follicular phase of previous cycle until the hCG trigger with < 5 IU/day led to a thicker endometrium and a greater chance of becoming pregnant, while 5-10 IU/day or administration from the luteal phase of the previous cycle until the hCG trigger resulted in higher oocyte and embryo quality. Poor responders might benefit from cotreatment with the GnRH agonist long protocol more than other stimulation protocols. Pooled data from four trials (n = 354) on women with a thin endometrium indicated that improved endometrial function might be critical for improving reproductive outcomes during GH treatment, as no improvements in embryo quality were found. GH administration not only increased EMT (MD = 1.48, 95% CI: 1.21-1.75; moderate QoE) but also promoted endometrial morphology (OR = 2.67, 95% CI: 1.36-5.23; low QoE) and perfusion (OR = 5.84, 95% CI: 1.30-26.17; low QoE), thereby improving the CPR (OR = 2.71, 95% CI: 1.69-4.34; P < 0.0001; low QoE). There was insufficient evidence to reach a conclusion regarding the effects of GH in normal responders (n = 80). Due to obvious improvements in the CPR, women with a thin endometrium might be the most appropriate population to benefit from GH administration. WIDER IMPLICATIONS: Improving endometrial function might be another vital mechanism by which GH improves IVF outcomes. Optimal treatment should be offered to the target population according to their personal conditions and needs. The QoE was moderate to very low, due to limited sample sizes and methodological problems; thus, the results should be interpreted with caution. More rigorous RCTs with large sample sizes are needed to confirm the effects and determine optimal GH protocols.