Background:This study aimed to establish an immune-glycolysis-related prognostic signature (IGRPS) to predict hepatocellular carcinoma (HCC) outcomes. Additionally, it explored the role of this signature in the tumor immune microenvironment (TIME), glycolytic pathways, and immunotherapy. Methods:We analyzed RNA-seq, single-cell sequencing, and immune- and glycolysis-related gene datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Using weighted gene co-expression network analysis (WGCNA), F-test, and Cox regression, we identified key survival-related immune and glycolytic genes (SRIGRGs) and developed an IGRPS through multivariate Cox regression. The IGRPS's predictive performance was validated in training and validation cohorts using Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, and a prognostic nomogram. Its correlation with TIME and its ability to predict immunotherapy outcomes were also assessed. In vitro experiments were conducted to analyze the expression and function of IGRPS genes in HCC. Results:Thirteen SRIGRGs were identified for constructing the IGRPS. Patients with low-risk scores had significantly longer survival times. The area under the curve (AUC) for ROC curves was over 0.73 for training and 0.7 for validation cohorts, with C-indices of 0.721 and 0.79, respectively. IGRPS was confirmed as an independent prognostic indicator. Patients in the low-risk group showed better responses to combined anti-CTLA4 and anti-PD-1 therapies. In vitro experiments indicated that PRKAG1 and B3GAT3 were upregulated, enhancing glycolysis and promoting HCC cell proliferation and migration. Conclusion:The IGRPS, based on immune- and glycolysis-related genes, effectively predicted prognosis and immunotherapy responses in HCC patients.

Dioscorea opposita Thunb. cv. Tiegun is valued for its medicinal and nutritional benefits, yet the mechanisms underlying its quality changes during storage remain unclear. In this study, a metabolomic approach was utilized to analyze metabolic shifts during 105 days of natural storage (0, 15, 30, 45, 60, 75, 90, and 105 days). Results indicated that 336 metabolites increased while 288 decreased across the storage period. Metabolite set enrichment analysis revealed significant alterations in lipid metabolism, amino acid metabolism, carbohydrate metabolism, and other amino acid pathways. Additionally, characteristic biomarkers associated with specific storage periods were identified, underscoring the critical roles of flavonoids, phenolic acids, lipids, nucleotides, and their derivatives in driving quality changes in Dioscorea opposita Thunb. cv. Tiegun. This study offers significant insights into the metabolic dynamics associated with storage, advancing our understanding of metabolite changes and providing a scientific basis for optimizing storage conditions, extending shelf life, and improving product quality.

Dioscorea opposita Thumb. cv. Tiegun is commonly consumed as both food and traditional Chinese medicine, which has a history of more than two thousand years. Harvest time directly affects its quality, but few studies have focused on metabolic changes during the harvesting process. Here, a comprehensive metabolomics approach was performed to determine the metabolic profiles during six harvest stages. Thirty eight metabolites with significant differences were determined as crucial participants. Related metabolic pathways including phenylalanine, tyrosine and tryptophan biosynthesis, stilbenoid, diarylheptanoid and gingerol biosynthesis, phenylpropanoid biosynthesis, flavonoid biosynthesis and tryptophan metabolism were the most active pathways during harvest. The results revealed that temperature has a significant impact on quality formation, which suggested that Dioscorea opposita thumb. cv. Tiegun harvested after frost had higher potential value of traditional Chinese medicine. This finding not only offered valuable guidance for yam production, but also provided essential information for assessing its quality.

BACKGROUND: Dioscorea opposita Thunb. cv. Tiegun maturity (DM) is an important factor influencing its quality. However, there are few studies on the impact of harvest time on its maturation. In the present study, a NMR-based metabolomics approach was applied to investigate the dynamic metabolic changes of D. opposita Thunb. cv. Tiegun at six different harvest stages: stage 1 (S1), stage 2 (S2), Stage 3 (S3), stage 4 (S4), stage 5 (S5) and stage 6 (S6). RESULTS: Principal component analysis showed distinct segregation of samples obtained from S1, S2 and S3 compared to those derived from S4, S5 and S6. Interestingly, these samples from the two periods were obtained before and after frost, indicating that frost descent might be important for DM. Eight differential metabolites responsible for good separation of different groups were identified by the principal component analysis loading plot and partial least squares-discriminant analysis. In addition, quantitative analysis of these metabolites using liquid chromatography-tandem mass spectrometry determined the effects of harvest time on these metabolite contents, two of which, sucrose and allantoin, were considered as potential biomarkers to determine DM. CONCLUSION: The present study demonstrated that NMR-based metabolomics approach could serve as a powerful tool to identify differential metabolites during harvesting processes, also offering a fresh insight into understanding the DM and the potential mechanism of quality formation. (c) 2024 Society of Chemical Industry. (c) 2024 Society of Chemical Industry.

目的 研究药用植物石菖蒲内生真菌灰黄青霉Penicillium griseofulvum Z005的次级代谢产物.方法 利用包括硅胶、ODS、Sephadex LH-20、半制备HPLC等色谱方法,对目标菌株的大米固体发酵提取物进行系统的分离纯化,并结合理化常数与现代的谱学方法进行化合物的结构鉴定.结果 从石菖蒲内生真菌灰黄青霉Z005固体发酵产物中分离鉴定了 1个新化合物和 12 个已知化合物.分别为灰黄青霉呋喃醇 A(1)、chaetominine(2)、dehydrocyclopeptine(3)、1-methylcyclopenin(4)、4-(2-羟基丁炔氧基)苯甲酸(5)、penipratynolene(6)、hypofuranB(7)、lobechine(8)、4-(2-甲酰基-5-甲氧基甲基-1H-吡咯-1-基)丁酸(9)、2-呋喃甲醇-(5'→11)-1,3-环戊二烯-[5,4-c]-1H-邻二氮杂萘(10)、N-乙酰色胺(11)、1H-吲哚-3-基甲基氨基甲酸甲酯(12)和顺式阿魏酸甲酯(13).结论 灰黄青霉Z005为首次从石菖蒲健康组织中分离获得,化合物1为新的苯并呋喃类化合物,命名为灰黄青霉呋喃醇A(penicifuranol A);化合物2～10和12～13均为首次从该种真菌中分离得到.

Objective: Systematic analysis and identification of chemical constituents of Dioscorea opposita Thunb. cv. Tiegun peel, and exploration of its medicinal and nutritional value. Methods: Ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q/TOF-MS/MS) was performed to analyze the chemical compositions of Dioscorea opposita Thunb. cv. Tiegun peel. The compounds were identified based on their primary and secondary mass spectrometry information and compared with the related references and databases. Further, bioinformatics was applied to predict the targets of potential active ingredients, enrich Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, screen out the important targets, and explore its potential mechanism. Results: 33 compounds were identified such as apigenin, acacetin, liquiritigenin, batatasin I, which were considered to be the potentially vital compounds. Pathway enrichment analysis indicated that Dioscorea opposita Thunb. cv. Tiegun peel exerted medicinal effects by regulating cell signaling pathways, cancer, metabolic and other disease-related pathways. Conclusion: In this study, UPLC-Q/TOF-MS/MS combined with bioinformatics were used, which would provide an important reference for the identification of ingredients, selection of active compounds, discovery of potential medicinal nutritional value, as well as further development and utilization of Dioscorea opposita Thunb. cv. Tiegun peel.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic named coronavirus disease 2019 (COVID-19) that has become the greatest worldwide public health threat of this century. Recent studies have unraveled numerous mysteries of SARS-CoV-2 pathogenesis and thus largely improved the studies of COVID-19 vaccines and therapeutic strategies. However, important questions remain regarding its therapy. In this review, the recent research advances on COVID-19 mechanism are quickly summarized. We mainly discuss current therapy strategies for COVID-19, with an emphasis on antiviral agents, neutralizing antibody therapies, Janus kinase inhibitors, and steroids. When necessary, specific mechanisms and the history of therapy are present, and representative strategies are described in detail. Finally, we discuss key outstanding questions regarding future directions of the development of COVID-19 treatment.

The combination of incretin-based therapies and PYY analogue has shown great potential for the treatment of type 2 diabetes (T2DM) and obesity. In this study we developed the first example of a unimolecular triple agonist peptide to simultaneously target GLP-1, glucagon and Y2 receptors, aiming for superior weight loss and better glycemic control. The strategy for constructing such a unimolecular triple agonist peptide is the conjugation of the GLP-1R/GCGR dual-agonistic moiety and PYY moiety via maleimide-thiol specific reaction. A novel triple agonist peptide, 3b, was identified via stepwise structure optimization, long-acting modification and in vitro receptor screens. Peptide 3b exhibited potent and balanced GCGR and GLP-1R activities as well as potent and highly selective Y2R activity. Peptide 3b potently reduced food intake without triggering nausea associated behavior in kaolin consumption and conditioned taste aversion assays. In diet induced obesity (DIO) mice, a lower dose of 3b achieved significantly better effects on lipid metabolism, body weight, and glycemic control than higher dose of GLP-1R mono-agonist, GLP-1R/GCGR dual agonist and GLP-1R/Y2R dual agonist counterparts. Collectively, these data support the therapeutic potential of our GLP-1R/GCGR/Y2R triple agonist 3b as a novel anti-obesity and anti-diabetic agent. Targeting GLP-1R, GCGR and Y2R with unimolecular triple agonist peptide offers a route to develop new obesity and T2DM treatments.

N6-Methyladenosine (m6A) is the most prevalent mRNA modification in mammalian cells that is mainly catalyzed by the methyltransferase complex of methyltransferase-like 3 and methyltransferase-like 14 (METTL3-METTL14). Many lines of evidence suggest that METTL3 plays important roles in several diseases such as cancers and viral infection. In the present study, 1,042 natural products from commercially available sources were chosen to establish a screening library, and docking-based high-throughput screening was performed to discover potential METTL3 inhibitors. The selected compounds were then further validated by an in vitro methyltransferase inhibition assay in which m6A content was determined by LC-MS/MS. A cellular assay of the inhibition of m6A methylation was performed to determine the METTL3 inhibitory activity of the selected compound. CCK-8 assay was applied to evaluate the effects of the selected compound on tumor cell viability. Additionally, binding mode analysis, molecular dynamics (MD) simulation, and binding free energy analysis were performed to study the process and characteristics of inhibitor binding. Finally, quercetin was identified as a METTL3 inhibitor with an IC50 value of 2.73 μM. The cellular assay of m6A methylation inhibition showed that quercetin decreased m6A level in a dose-dependent manner in MIA PaCa-2 pancreatic cancer cells. CCK-8 assay showed quercetin efficiently inhibited the proliferation of MIA PaCa-2 and Huh7 tumor cells, with IC50 values 73.51 ± 11.22 μM and 99.97 ± 7.03 μM, respectively. Molecular docking studies revealed that quercetin filled the pocket of the adenosine moiety of SAM but not the pocket of the SAM methionine in the METTL3 protein, and hydrogen bonds, hydrophobic interactions, and pi-stacking were formed. The values of the root mean square deviation (RMSD), the root mean square fluctuations (RMSF), and binding free energy suggested that quercetin can efficiently bind to the pocket of the METTL3 protein and form a stable protein-ligand complex. The present study is the first to identify METTL3 inhibitors from natural products, thus providing a basis for subsequent research and facilitating the development of METTL3-targeting drugs for diseases.

目的:建立UPLC-MS/MS法同时测定清热解毒口服液中的栀子苷、绿原酸、新绿原酸、哈巴苷、龙胆苦苷、黄芩苷6个成分含量,并对以上成分展开网络药理学研究,揭示其潜在药理作用机制.方法:色谱柱采用Phenomenex Kinetex C18柱(50 mm×2.1 mm,2.6 μm),流动相采用0.3％甲酸水溶液-0.3％甲酸乙腈梯度洗脱,流速为0.4 mL·min-1,柱温40℃,进样体积为2μL.质谱方法选择电喷雾离子源(ESI),负离子模式,多反应检测模式(MRM);方法学验证包括专属性、精密度、重复性、稳定性、准确度等;网络药理学研究基于Swiss Target Prediction、Drugbank、TTD、KEGG、Cytoscape等数据库或平台,收集成分-靶点-代谢通路-疾病信息,并绘制药理作用网络图.结果:方法学验证均符合方法学要求.栀子苷、绿原酸、新绿原酸、哈巴苷、龙胆苦苷、黄芩苷分别在 0.050～5.000、0.049～4.900、0.050～5.000、0.010～1.020、0.052～5.150、0.052～5.150 μg·mL-1范围内线性关系良好.2个厂家各3个不同批号清热解毒口服液黄芩苷含量均符合药典要求(＞1.0 mg·mL-1),然而栀子苷、绿原酸、新绿原酸、哈巴苷等成分呈现较大含量差异,必要对其进行质量控制.以上成分通过IL-17信号通路、自然杀伤细胞介导的细胞毒性、NF-κB信号通路、抗叶酸耐药通路、TRP通道的炎症介质调节等通路,发挥其抗炎、抗流感、治疗上呼吸道疾病、发热、烦躁口渴等方面的作用.结论:建立的UPLC-MS/MS快速、准确可用于清热解毒口服液质量控制,网络药理学研究工作初步揭示了其潜在作用机制.本研究为清热解毒口服液的质量评价和临床应用提供了参考.

GLP-1 receptor (GLP-1R) and neuropeptide Y2 receptor (Y2R) dual agonists have shown great potential to treat obesity and type 2 diabetes (T2DM). We developed a multitarget strategy to design monomeric agonists based on Xenopus GLP-1 (xGLP-1) and PYY3-36 analogues with dual activation activities on GLP-1R and Y2R. A novel peptide, 6q, was obtained via stepwise structure optimization and in vitro receptor screens. In db/db and diet-induced obesity (DIO) mice, 6q produced greater effects on long-term glycemic control and body weight reduction than GLP-1R and Y2R monoagonist counterparts. Notably, in high-fat diet-induced nonalcoholic steatohepatitis (NASH) mice, 6q treatment significantly reduced hepatic triglyceride and total cholesterol levels and reversed hepatic steatosis compared with GLP-1R monoagonist (liraglutide) treatment. Collectively, these data support the therapeutic potential of our GLP-1R/Y2R dual agonist 6q as a novel antidiabetic, antiobesity, and antisteatotic agent.

目的:通过1H-NMR代谢组学方法探讨雷公藤红素(CEL)对糖脂代谢紊乱模型小鼠的改善作用和潜在机制.方法:选取32只雄性健康C57BL/6J小鼠,随机分对照组(LFD组)、模型组(HFD组)、对照给药组(LFD+CEL组)和模型给药组(HFD+CEL组),建立高脂饮食诱导糖脂代谢紊乱小鼠模型,10周后LFD+CEL组和HFD+CEL组小鼠腹腔注射CEL(100 μg/kg),LFD组和HFD组小鼠腹腔注射等量的溶剂,连续给药6周,检测相关生化指标水平,观察各组小鼠组织病理改变;采用1H-NMR代谢组学方法分析模型小鼠血浆的代谢特征及CEL干预作用.结果:HFD+CEL组小鼠血浆中各生化指标水平与HFD组比较均有显著性差异(P＜0.05,P＜0.01);肝脏脂肪变性显著改善;糖脂代谢紊乱和血浆代谢特征明显好转;CEL改善模型小鼠糖脂紊乱可能与脂质代谢、肌酸代谢、脂肪酸的β-氧化、三羧酸循环、氨基酸代谢、糖异生和糖酵解等多种代谢途径有关.结论:CEL可通过调节脂质代谢、肌酸代谢、脂肪酸的β-氧化、三羧酸循环、氨基酸代谢、糖异生和糖酵解等多种代谢途径改善高脂诱导的糖脂代谢紊乱.

Background and Purpose Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCK2) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP-1/glucagon receptor and GLP-1/CCK2 dual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness. Experimental Approach The in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCK2 tri-agonist (xGLP/GCG/gastrin) against GLP-1, GCG, CCK1 and CCK2 receptors was determined on cells expressing the corresponding receptors by cAMP accumulation or ERK1/2 phosphorylation assays. The in vivo anti-diabetes and anti-obesity effects of this tri-agonist xGLP/GCG/gastrin were studied in both db/db and diet induced obesity (DIO) mice. Key Results xGLP/GCG/gastrin was a potent and selective GLP-1, GCG and CCK2 tri-agonist. In DIO mice, the metabolic benefits of xGLP-1/GCG/gastrin, such as reduction of body weight and hepatic lipid contents were significantly better than those of the peptide ZP3022 (GLP-1/CCK-2 dual agonist) and liraglutide. In a short-term study in db/db mice, xGLP/GCG/gastrin treatment had considerable effects, increasing islet numbers, islet areas and insulin content. In a long-term treatment study using db/db mice, xGLP-1/GCG/gastrin showed a significantly and sustained improvement in glucose tolerance and glucose control compared with that of liraglutide, ZP3022, cotadutide (GLP-1/GCG dual agonist) and xGLP/GCG-15. Conclusions and Implications These results demonstrate the therapeutic potential of xGLP-1/GCG/gastrin for the treatment of obesity and diabetes.

The combined use of gastrointestinal hormones for treating metabolic diseases is gaining increasing attention. It was documented previously that co-administration of a cholecystokinin receptor-1 receptor (CCK-1R) agonist with a glucagon-like peptide-1 receptor (GLP-1R) agonist exerted improved effects on metabolic improvements in obese rodents. Here, we reported a series of novel GLP-1R/CCK-1R co-agonists constructed by linking the C-terminus of a GLP-1R agonist (native GLP-1 or Xenopus GLP-1) to the N-terminus of a CCK-1R selective agonist NN9056. The stability of co-agonists was further enhanced by introducing an albumin binding motif. In vitro functional assays revealed that the co-agonists retained full agonism potency on GLP-1R and CCK-1R. Particularly, 2a and 2c showed higher hypoglycemic and insulinotropic activities than NN9056 and semaglutide. The glucose-lowering durations and PK profiles of 2a and 2c were comparable to those of semaglutide. Desirably, in diet induced obesity (DIO) mice, 2a and 2c exhibited superior metabolic benefits to NN9056 and semaglutide in reducing food intake, inducing body weight loss, and regulating lipid metabolism. In short- and long-term studies in diabetic db/db mice, 2a and 2c showed enhanced effects on HbA1c, glucose tolerance, and pancreas function restoration compared with semaglutide. Importantly, no side effects, toxicities, or pancreatic inflammation were caused by 2a and 2c treatments. These preclinical studies suggest that the pharmacological effects of CCK-1 and GLP-1 pathways can be harnessed in a single fusion peptide, yielding a promising combination therapy strategy for treating metabolic disorders.

BACKGROUND:Currently, there are insufficient indicators for the reliable assessment of treatment response following neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal squamous cell carcinoma (ESCC). Considering the essential role of protein-coding and non-coding RNAs in gene regulation and cellular processes, we systematically explored the molecular features and clinical significance of mRNA and lncRNA in 249 pretreatment biopsies from four hospitals in three districts with a high incidence of ESCC patients in China.METHODS:During the discovery phrase, 13 differentially expressed genes were identified and validated between samples with a complete pathological response (pCR) and those with an incomplete pathological response (<pCR). Subsequently, we constructed a predictive mRNA and lncRNA signature (SERPINE1, LINC00592, and PRKAG2-AS1) using Fisher's linear discriminant analysis (FLDA) with stepwise variant-selection, followed by validation of its predictive ability in both internal and external cohorts.RESULTS:Our signature showed great value in predicting the response to nCRT among ESCC samples and acted as an independent predictive indicator, in addition to demonstrating great potential in estimating patient prognosis. Interestingly, we found that patients with a high signature score had lower PD-L1 and IDO1 expression levels but higher CD8+ T cells infiltration, suggesting that PD-L1 and IDO1 are negatively correlated with a high signature score and further associated with pCR and a better prognosis.CONCLUSION:The present study identified a promising three-gene-based predictive signature that has powerful clinical implications for the identification of pCR and a good prognosis among patients with ESCC. Further immune-related exploration may provide an opportunity for future therapeutic combination.

知母作为传统中药材,具有滋阴润燥、清热泻火等功效,临床应用广泛.知母皂苷B-Ⅱ(TB-Ⅱ)是知母的主要活性成分之一.现代药理研究发现,TB-Ⅱ具有多种药理活性,如抗阿尔茨海默病、抗抑郁、抗糖尿病及其并发症、抗骨质疏松、抗血小板聚集、抗炎、抗肿瘤等.总结近年来TB-Ⅱ药理活性及作用机制的相关研究进展,为TB-Ⅱ的新药开发和临床应用提供参考.

Abstract Background Quality evaluation of multi-species resourced herb medicine (MSRHM) is a main problem for quality control of herb medicine. Current quality evaluation methodology lost consideration of species discrepancy. New quality evaluation strategy for MSRHM is in urgent need. Qinjiao, a representative MSRHM, originated from Gentiana macrophylla Pall., Gentiana straminea Maxim., Gentiana crassicaulis Duthie ex Burk. or Gentiana dahurica Fisch., has been used as an important herb medicine over 2000 years for expelling wind-dampness and relieving impediment pain. However, quality evaluation among species has never been revealed. The current work proposes an integrated quality evaluation strategy for MSRHM of Qinjiao, which may promote innovation of quality control of MSRHM. Methods In this work, 58 batches of Qinjiao covering 4 species were collected. Genetic comparative analysis based on ITS2 sequence was conducted. Metabolomics analysis based on TOF–MS and NMR spectrum were carried out. Compounds underlying species differences were identified and their discrepancies among species were investigated by ANOVA analysis and multivariate analysis. Results Four species of Qinjiao can be authenticated by ITS2 sequence comparation. Metabolomics analysis by TOF/MS and NMR revealed chemical discrepancies among species of Qinjiao. Maximum discrepancy was present between Gentiana crassicaulis Duthie ex Burk. and Gentiana dahurica Fisch. Chemical difference among species were tentative explored. For TOF–MS profiling, 28 constituents were tentative identified, 17 of which were further confirmed by standards. For 1H-NMR profiling, signals from 5 compounds were assigned. Contents discrepancies were investigated by ANOVA analysis. It seems that (seco)iridoids like loganic acid, gentiopicroside or swertiamarin were richer in specie of Gentiana crassicaulis Duthie ex Burk., while flavonoid (morroniside) and triterpenoids (roburic aicd, ursolic acid, oleanolic acid, β-sitosterone) were richer in specie of Gentiana dahurica Fisch. The current research demonstrates that metabolite profiling based on both UPLC/Q-TOF MS and 1H-NMR coupled with ITS2 sequence comparation can be a powerful tool for quality investigation of MSRHM of Qinjiao. Conclusions A comprehensive quality evaluation strategy for MSRHM was proposed by integrating UPLC-Q-TOF–MS, NMR based metabolic analysis and ITS2 sequence genetic comparation. The proposed quality evaluation strategy shall promote innovation of quality control of traditional Chinese medicine.

Hypoxia mediates a metabolic switch from oxidative phosphorylation to glycolysis and increases glycogen synthesis. We previously found that glycogen branching enzyme (GBE1) is downstream of the hypoxia-inducible factor-1 (HIF1) signaling pathway in lung adenocarcinoma (LUAD) cells; however, the molecular mechanism underlying HIF1 regulation of GBE1 expression remains unknown. Herein, the effect of GBE1 on tumor progression via changes in metabolic signaling under hypoxia in vitro and in vivo was evaluated, and GBE1-related genes from human specimens and data sets were analyzed. Hypoxia induced GBE1 upregulation in LUAD cells. GBE1-knockdown A549 cells showed impaired cell proliferation, clone formation, cell migration and invasion, angiogenesis, tumor growth, and metastasis. GBE1 mediated the metabolic reprogramming of LUAD cells. The expression of gluconeogenesis pathway molecules, especially fructose-1,6-bisphosphatase (FBP1), was markedly higher in shGBE1 A549 cells than it was in the control cells. FBP1 inhibited the tumor progression of LUAD. GBE1-mediated FBP1 suppression via promoter methylation enhanced HIF1 α levels through NF-κB signaling. GBE1 may be a negative prognostic biomarker for LUAD patients. Altogether, hypoxia-induced HIF1 α mediated GBE1 upregulation, suppressing FBP1 expression by promoter methylation via NF-κB signaling in LUAD cells. FBP1 blockade upregulated HIF1 α , triggered the switch to anaerobic glycolysis, and enhanced glucose uptake. Therefore, targeting HIF1 α /GBE1/NF-κB/FBP1 signaling may be a potential therapeutic strategy for LUAD.

Bioactive peptides are promising agents for therapeutic applications; however, their small size leads to poor stability, low bioavailability, and rapid renal clearance, so the widespread use is limited. To address these issues, fusing or conjugating peptides to suitable molecular scaffolds is required. Here, human serum albumin (HSA) is used as a delivery carrier for human β‐defensin‐2 peptide (HBD2) in production of HSA‐delivered defensin complex (ADDC) to facilitate its cellular uptake and transport to intracellular targets. Fusion or conjugation can improve the stability of HBD2, as well as extend its circulation time and promote its accumulation in tumors, thereby enhancing the therapeutic efficacy. Herein, ADDC functions as a protective structure against the harsh external environment and serves as a passive tumor‐targeting agent. The data show that the combination of ADDC with clinically relevant drugs, such as Doxorubicin, Gemcitabine, Cisplatin, and Cetuximab, significantly increases the cytotoxicity of ADDC toward human pancreatic cancer cells. Bioinformatics analysis also reveals that ADDC may affect the metabolic processes, gene transcription, and apoptosis of pancreatic cancer cells. Collectively, ADDC exhibits tumor‐specific targeting capability, low systemic toxicity, and enhanced antitumor efficacy in a mouse model of pancreatic cancer.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer death globally. More accurate and reliable diagnostic methods/biomarkers are urgently needed. Joint application of metabolomics and transcriptomics technologies possesses the high efficiency of identifying key metabolic pathways and functional genes in lung cancer patients. In this study, we performed an untargeted metabolomics analysis of 142 NSCLC patients and 159 healthy controls; 35 identified metabolites were significantly different between NSCLC patients and healthy controls, of which 6 metabolites (hypoxanthine, inosine, L-tryptophan, indoleacrylic acid, acyl-carnitine C10:1, and lysoPC(18:2)) were chosen as combinational potential biomarkers for NSCLC. The area under the curve (AUC) value, sensitivity (SE), and specificity (SP) of these six biomarkers were 0.99, 0.98, and 0.99, respectively. Potential diagnostic implications of the metabolic characteristics in NSCLC was studied. The metabolomics results were further verified by transcriptomics analysis of 1027 NSCLC patients and 108 adjacent peritumoral tissues from TCGA database. This analysis identified 2202 genes with significantly different expressions in cancer cells compared to normal controls, which in turn defined pathways implicated in the metabolism of the compounds revealed by metabolomics analysis. We built a fully connected network of metabolites and genes, which shows a good correspondence between the transcriptome analysis and the metabolites selected for diagnosis. In conclusion, this work provides evidence that the metabolic biomarkers identified may be used for NSCLC diagnosis and screening. Comprehensive analysis of metabolomics and transcriptomics data offered a validated and comprehensive understanding of metabolism in NSCLC.