WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis.

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear. METHODS: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes. RESULTS: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis. CONCLUSION: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.

Multi-Omics Analysis and Verification of the Oncogenic Value of CCT8 in Pan-Cancers.

Background: Chaperonin-containing TCP1 subunit 8 (CCT8) has been proved to be involved in the occurrence and development of some cancers. However, no study has reported the potential role of CCT8 in a pan-cancer manner. Methods: TIMER2.0, GEPIA2, UALCAN and Sangerbox were used to explore the expression, prognosis and methylation of CCT8. We used cBioPortal, TISIDB, SangerBox, TIMER2.0 and TISMO to investigate the genetic alteration of CCT8 and the relationship of CCT8 with molecular subtype, immune subtype, immune infiltration and immunotherapy response. CCT8-related genes were screened out through GEPIA and STRING for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. CCK-8, the colony formation assay, the wound healing assay and the Transwell assay were performed to explore the influence of CCT8 on proliferation and migration. Results: CCT8 was highly expressed in most cancers with a poor prognosis. The expression level of CCT8, which was affected by the promoter region methylation and genetic alteration, was related to the molecular and immune subtype of cancers. Interestingly, CCT8 was positively associated with the activated CD4 T cells and type 2 T-helper cells. CCT8 played a vital role in the cell cycle and RNA transport of cancers, and it significantly inhibited the proliferation and migration of lung adenocarcinoma cells when it was knocked down. Conclusion: CCT8 plays an indispensable role in promoting the proliferation and migration of many cancers. CCT8 might be a biomarker of T-helper type 2 (Th2) cell infiltration and a promising therapeutic target for T-helper type 1(Th1)/Th2 imbalance.

Molecular subtypes based on centrosome-related genes can predict prognosis and therapeutic responsiveness in patients with low-grade gliomas.

Background: Abnormalities in centrosome regulatory genes can induce chromosome instability, cell differentiation errors, and tumorigenesis. However, a limited number of comprehensive analyses of centrosome-related genes have been performed in low-grade gliomas (LGG). Methods: LGG data were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The ConsensusClusterPlus" R package was used for unsupervised clustering. We constructed a centrosome-related genes (CRGs) signature using a random forest model, lasso Cox model, and multivariate Cox model, and quantified the centrosome-related risk score (centS). The prognostic prediction efficacy of centS was evaluated using a Receiver Operating Characteristic (ROC) curve. Immune cell infiltration and genomic mutational landscapes were evaluated using the ESTIMATE algorithm, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm, and "maftools" R package, respectively. Differences in clinical features, isocitrate dehydrogenase (IDH) mutation, 1p19q codeletion, O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation, and response to antitumor therapy between the high- and low-centS groups were explored. "pRRophetic" R packages were used for temozolomide (TMZ) sensitivity analysis. qRT-PCR verified the differential expression of the centrosomal gene team, the core of which is CEP135, between LGG cells and normal cells. Results: Two distinct CRG-based clusters were identified using consensus unsupervised clustering analysis. The prognosis, biological characteristics, and immune cell infiltration of the two clusters differed significantly. A well-performing centS signature was developed to predict the prognosis of patients with LGG based on 12 potential CRGs. We found that patients in the high-centS group showed poorer prognosis and lower proportion of IDH mutation and 1p19q codeletion compared to those in the low-centS group. Furthermore, patients in the high-centS group showed higher sensitivity to TMZ, higher tumor mutation burden, and immune cell infiltration. Finally, we identified a centrosomal gene team whose core was CEP135, and verified their differential expression between LGG cells and normal glial cells. Conclusion: Our findings reveal a novel centrosome-related signature for predicting the prognosis and therapeutic responsiveness of patients with LGG. This may be helpful for the accurate clinical treatment of LGG.

Construction of a novel molecular typing and scoring system for anoikis distinguishes between different prognostic risks and treatment responsiveness in low-grade glioma.

Background: The main factors responsible for low-grade glioma (LGG)s' poor prognosis and treatment effectiveness include recurrence and malignant progression. A specific type of programmed cell death, known as anoikis, which is crucial for tumor invasion and metastasis, however, has not yet been investigated in LGGs. Methods: We downloaded data of 509 samples from the TCGA-LGG cohort, carried out cluster analysis for typing twice on the basis of 19 anoikis-associated genes, and the subtypes were evaluated the differences in clinicopathological and biological features. ESTIMATE and single-sample gene set enrichment analysis were employed to examine the immunological milieu of LGGs, and enrichment analysis was used to look into the underlying biological mechanisms in LGGs. Cox regression analysis and the Least Absolute Shrinkage and Selection Operator regression algorithm were used to create a prediction scoring system. The scoring system was used for classifying LGG into high- and low- anoikis riskscore (anoiS) groups. The impact of the anoiS on the prognosis, standard treatment, and immunotherapy of patients with LGG was assessed using survival analysis and drug sensitivity analysis. Cell experiments were employed for the verification of the differential expression between LGG cells and normal cells of the anoikis gene team that regard CCT5 as the core. Results: Based on the expression profiles of the 19 anoikis-associated genes, all individuals with LGG were classified into four subtypes and two macrosubtypes. The different macrosubtypes had significantly different biological characteristics, and the anoirgclusterBD subtype manifested a significantly bad prognosis and a high immune level of infiltration. And subsequent secondary genotyping also showed good prognostic discrimination. We further constructed an anoikis scoring system, anoiS. LGG patients having a high anoiS had a worse prognosis in comparison to those having a low anoiS. The high anoiS group exhibited larger levels of immune infiltration and superior immunotherapy efficacy than the low anoiS group. The high anoiS group was also more susceptible to temozolomide (TMZ) than the low anoiS group, according to a drug sensitivity analysis of TMZ. Conclusion: This study constructed a scoring system for predicting the prognosis of patients with LGG and their responsive to TMZ and immunotherapy.

Multi-omics analysis of the oncogenic value of copper Metabolism-Related protein COMMD2 in human cancers.

BACKGROUND: The copper metabolism MURR1 domain (COMMD) protein family is involved in tumorigenicity of malignant tumors. However, as the member of COMMD, the role of COMMD2 in human tumors remains unknown. METHODS: We used The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Human Protein Atlas (HPA) database, Cancer Cell Line Encyclopedia (CCLE) platform, univariate Cox regression analysis, Kaplan-Meier curve, cBioPortal, UALCAN database, Sangerbox online platform, GSCA database gene set enrichment analysis (GSEA), and GeneMANIA to analyze the expression of COMMD2, its prognostic values, genomic alteration patterns, and the correlation with tumor stemness, tumor mutational burden (TMB), microsatellite instability (MSI), and immune infiltrates, drug sensitivity, and gene function enrichment in pan-cancer. qRT-PCR, CCK-8, EdU, wound healing, and transwell migration assays were performed to confirm the function of COMMD2. RESULTS: COMMD2 was strongly expressed in most cancer types. Elevated COMMD2 expression affects the prognosis, clinicopathological stage, and molecular or immune subtypes of various tumors. Moreover, promoter hypomethylation and mutations in the COMMD2 gene may be associated with its high expression and poor survival. Additionally, we discovered that COMMD2 expression was linked to tumor stemness, TMB, MSI, immune cell infiltration, immune-checkpoint inhibitors, and drug sensitivity in pan-cancer. Furthermore, the COMMD2 gene co-expression network is constructed with GSEA analysis, displaying significant interaction of COMMD2 with E2F targets, G2-M checkpoint, and mitotic spindle in bladder cancer (BLCA). Finally, RNA interference data showed suppression of COMMD2 prevented proliferation and migration of BLCA and uterine corpus endometrial carcinoma (UCEC) cells. CONCLUSION: Our findings shed light on the COMMD2 functions in human cancers and demonstrate that it is a promising prognostic biomarker and therapeutic target in pan-cancer.

Cuproptosis status affects treatment options about immunotherapy and targeted therapy for patients with kidney renal clear cell carcinoma.

The development of immunotherapy has changed the treatment landscape of advanced kidney renal clear cell carcinoma (KIRC), offering patients more treatment options. Cuproptosis, a novel cell death mode dependent on copper ions and mitochondrial respiration has not yet been studied in KIRC. We assembled a comprehensive cohort of The Cancer Genome Atlas (TCGA)-KIRC and GSE29609, performed cluster analysis for typing twice using seven cuproptosis-promoting genes (CPGs) as a starting point, and assessed the differences in biological and clinicopathological characteristics between different subtypes. Furthermore, we explored the tumor immune infiltration landscape in KIRC using ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) and the potential molecular mechanisms of cuproptosis in KIRC using enrichment analysis. We constructed a cuproptosis score (CUS) using the Boruta algorithm combined with principal component analysis. We evaluated the impact of CUS on prognosis, targeted therapy, and immunotherapy in patients with KIRC using survival analysis, the predictions from the Cancer Immunome Atlas database, and targeted drug susceptibility analysis. We found that patients with high CUS levels show poor prognosis and efficacy against all four immune checkpoint inhibitors, and their immunosuppression may depend on TGFB1. However, the high-CUS group showed higher sensitivity to sunitinib, axitinib, and elesclomol. Sunitinib monotherapy may reverse the poor prognosis and result in higher progression free survival. Then, we identified two potential CPGs and verified their differential expression between the KIRC and the normal samples. Finally, we explored the effect of the key gene FDX1 on the proliferation of KIRC cells and confirmed the presence of cuproptosis in KIRC cells. We developed a targeted therapy and immunotherapy strategy for advanced KIRC based on CUS. Our findings provide new insights into the relationship among cuproptosis, metabolism, and immunity in KIRC.

Heat Stress Tolerance 2 confers basal heat stress tolerance in allohexaploid wheat (Triticum aestivum L.).

Heat stress substantially reduces the yield potential of wheat (Triticum aestivum L.), one of the most widely cultivated staple crops, and greatly threatens global food security in the context of global warming. However, few studies have explored the heat stress tolerance (HST)-related genetic resources in wheat. Here, we identified and fine-mapped a wheat HST locus, TaHST2, which is indispensable for HST in both the vegetative and reproductive stages of the wheat life cycle. The studied pair of near isogenic lines (NILs) exhibited diverse morphologies under heat stress, based on which we mapped TaHST2 to a 485 kb interval on chromosome arm 4DS. Under heat stress, TaHST2 confers a superior conversion rate from soluble sugars to starch in wheat grains, resulting in faster grain filling and a higher yield potential. A further exploration of genetic resources indicated that TaHST2 underwent strong artificial selection during wheat domestication, suggesting it is an essential locus for basal HST in wheat. Our findings provide deeper insights into the genetic basis of wheat HST and might be useful for global efforts to breed heat-stress-tolerant cultivars.

Genome-wide association study of six quality-related traits in common wheat (Triticum aestivum L.) under two sowing conditions.

KEY MESSAGE: We identified genomic regions associated with six quality-related traits in wheat under two sowing conditions and analyzed the effects of multienvironment-significant SNPs on the stability of these traits. Grain quality affects the nutritional and commercial value of wheat (Triticum aestivum L.) and is a critical factor influencing consumer preferences for specific wheat varieties. Climate change is predicted to increase environmental stress and thereby reduce wheat quality. Here, we performed a genotyping assay involving the use of the wheat 90 K array in a genome-wide association study of six quality-related traits in 486 wheat accessions under two sowing conditions (normal and late sowing) over 4 years. We identified 64 stable quantitative trait loci (QTL), including 10 for grain protein content, 9 for wet gluten content, 4 for grain starch content, 14 for water absorption, 15 for dough stability time and 12 for grain hardness in wheat under two sowing conditions. These QTL harbored 175 single nucleotide polymorphisms (SNPs), explaining approximately 3-13% of the phenotypic variation in multiple environments. Some QTL on chromosomes 6A and 5D were associated with multiple traits simultaneously, and two (QNGPC.cau-6A, QNGH.cau-5D) harbored known genes, such as NAM-A1 for grain protein content and Pinb for grain hardness, whereas other QTL could facilitate gene discovery. Forty-three SNPs that were detected under late or both normal and late sowing conditions appear to be related to phenotypic stability. The effects of these SNP alleles were confirmed in the association population. The results of this study will be useful for further dissecting the genetic basis of quality-related traits in wheat and developing new wheat cultivars with desirable alleles to improve the stability of grain quality.

Phosphate adsorption from sewage sludge filtrate using zinc-aluminum layered double hydroxides.

A series of layered double hydroxides (LDHs) with different metal cations were synthesized to remove phosphate in waste sludge filtrate from a municipal wastewater treatment plant for phosphorus recovery and to help control eutrophication. The highest phosphate adsorption capacity was obtained by using Zn-Al-2-300, that is LDHs with Zn/Al molar ratio of 2 and calcined at 300 degrees C for 4h. Circumneutral and mildly alkaline waters appeared suitable for the possible application of Zn-Al LDHs due to the amphoteric nature of aluminum hydroxide. Phosphate adsorption from the sludge filtrate by the LDHs followed pseudo-second-order kinetics, and the adsorption capacity at equilibrium was determined to be approximately 50 mg P/g. Adsorption isotherms showed that phosphate uptake in this study was an endothermic process and had a good fit with a Langmuir-type model. The absorbed phosphate can be effectively desorbed (more than 80%) from LDHs particles by a 5 wt% NaOH solution. The regeneration rate of used LDHs was approximately 60% after six cycles of adsorption-desorption-regeneration.