UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.

BACKGROUND: The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. METHOD: Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. RESULT: We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. CONCLUSION: These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

Comprehensive analysis of RNA-binding protein SRSF2-dependent alternative splicing signature in malignant proliferation of colorectal carcinoma.

Aberrant expression of serine/arginine-rich splicing factor 2 (SRSF2) can lead to tumorigenesis, but its molecular mechanism in colorectal cancer is currently unknown. Herein, we found SRSF2 to be highly expressed in human colorectal cancer (CRC) samples compared with normal tissues. Both in vitro and in vivo, SRSF2 significantly accelerated the proliferation of colon cancer cells. Using RNA-seq, we screened and identified 33 alternative splicing events regulated by SRSF2. Knockdown of SLMAP-L or CETN3-S splice isoform could suppress the growth of colon cancer cells, predicting their role in malignant proliferation of colon cancer cells. Mechanistically, the in vivo crosslinking immunoprecipitation assay demonstrated the direct binding of the RNA recognition motif of SRSF2 protein to SLMAP and CETN3 pre-mRNAs. SRSF2 activated the inclusion of SLMAP alternative exon 24 by binding to constitutive exon 25, while SRSF2 facilitated the exclusion of CETN3 alternative exon 5 by binding to neighboring exon 6. Knockdown of SRSF2, its splicing targets SLMAP-L, or CETN3-S caused colon cancer cells to arrest in G1 phase of the cell cycle. Rescue of SLMAP-L or CETN3-S splice isoform in SRSF2 knockdown colon cancer cells could effectively reverse the inhibition of cell proliferation by SRSF2 knockdown through mediating cell cycle progression. Importantly, the percentage of SLMAP exon 24 inclusion increased and CETN3 exon 5 inclusion decreased in CRC samples compared to paired normal samples. Collectively, our findings identify that SRSF2 dysregulates colorectal carcinoma proliferation at the molecular level of splicing regulation and reveal potential splicing targets in CRC patients.

Marine algae-derived characterized bioactive compounds as therapy for cancer: A review on their classification, mechanism of action, and future perspectives.

In 2022, there were around 20 million new cases and over 9.7 million cancer-related deaths worldwide. An increasing number of metabolites with anticancer activity in algae had been isolated and identified, which were promising candidates for cancer therapy. Red algae are well-known for the production of brominated metabolites, including terpenoids and phenols, which have the capacity to induce cell toxicity. Some non-toxic biological macromolecules, including polysaccharides, are distinct secondary metabolites found in many algae, particularly green algae. They possess anticancer activities by inhibiting tumor angiogenesis, stimulating the immune response, and inducing apoptosis. However, the structure-activity relationship between these components and antitumor activity, as well as certain taxa within the algae, remains relatively unstudied. This work is based on the reports published from 2003 to 2024 in PubMed and ISI Web of Science databases. A comprehensive review of the characterized algal anticancer active compounds, together with their structure and mechanism of action was performed. Also, their structure-activity relationship was preliminarily summarized to better assess their potential properties as a natural, safe bioactive product to be used as an alternative for the treatment of cancers, leading to new opportunities for drug discovery.

Anti-Inflammatory Effects of Two-Week Sacral Nerve Stimulation Therapy in Patients With Ulcerative Colitis.

BACKGROUND AND AIMS: Sacral nerve stimulation (SNS) showed anti-inflammatory properties in animal models of inflammatory bowel disease. We aimed to evaluate the effectiveness and safety of SNS in patients with ulcerative colitis (UC). MATERIALS AND METHODS: Twenty-six patients with mild and moderate disease were randomized into two groups: SNS (delivered at S3 and S4 sacral foramina) and sham-SNS (delivered 8-10 mm away from sacral foramina), with the therapy applied once daily for one hour, for two weeks. We evaluated the Mayo score and several exploratory biomarkers, including C-reactive protein in the plasma, pro-inflammatory cytokines and norepinephrine in the serum, assessment of autonomic activity, and diversity and abundance of fecal microbiota species. RESULTS: After two weeks, 73% of the subjects in the SNS group achieved clinical response, compared with 27% in the sham-SNS group. Levels of C-reactive protein, pro-inflammatory cytokines in the serum, and autonomic activity were significantly improved toward a healthy profile in the SNS group but not in the sham-SNS group. Absolute abundance of fecal microbiota species and one of the metabolic pathways were changed in the SNS group but not in the sham-SNS group. Significant correlations were observed between pro-inflammatory cytokines and norepinephrine in the serum on the one side and fecal microbiota phyla on the other side. CONCLUSIONS: Patients with mild and moderate UC were responsive to a two-week SNS therapy. After performing further studies to evaluate its efficacy and safety, temporary SNS delivered through acupuncture needles may become a useful screening tool for identifying SNS therapy responders before considering long-term implantation of the implantable pulse generator and SNS leads for performing long-term SNS therapy.

Liquid-liquid phase separation-related gene in gliomas: FABP5 is a potential prognostic marker.

BACKGROUND: The glioma is the most malignant human brain tumor. Early glioma detection and treatment are still difficult. New biomarkers are desperately required to aid in the evaluation of diagnosis and prognosis. METHODS: The single cell sequencing dataset scRNA-6148 for glioblastoma was obtained from the Chinese Glioma Genome Atlas database. Data were gathered for the transcriptome sequencing project. Genes involved in liquid-liquid phase separation (LLPS) were taken out of the DrLLPS database. To find the modules connected to LLPS, the weighted co-expression network was analyzed. Differential expression analysis was used to identify the differentially expressed genes (DEGs) in gliomas. Pseudo-time series analysis, gene set enrichment analysis (GSEA) and immune cell infiltration analysis were used to investigate the role of important genes in the immunological microenvironment. We examined the function of key glioma genes using polymerase chain reaction (PCR) testing, CCK-8 assays, clone generation assays, transwell assays and wound healing assays. RESULTS: FABP5 was identified as a key gene in glioblastoma by multiomics research. Pseudo-time series analysis showed that FABP5 was highly linked with the differentiation of many different types of cells. GSEA revealed that FABP5 was strongly linked to several hallmark pathways in glioblastoma. We looked at immune cell infiltration and discovered a significant link between FABP5, macrophages and T cell follicular helpers. The PCR experiment results demonstrated that FABP5 expression was elevated in glioma samples. Cell experiments showed that FABP5 knockdown dramatically decreased the viability, proliferation, invasion and migration of the LN229 and U87 glioma cell lines. CONCLUSIONS: Our study provides a new biomarker, FABP5, for glioma diagnosis and treatment.

Synthesis of bioactive oligosaccharides and their potential health benefits.

Oligosaccharides, a low polymerization degree of carbohydrate, possess various physiological activities, such as anti-diabetes, anti-obesity, anti-aging, anti-viral, and gut microbiota regulation, having a widely used in food and medical fields. However, due to the limited natural oligosaccharides, many un-natural oligosaccharides from complex polysaccharides are being studied for amplifying the available pool of oligosaccharides. More recently, various oligosaccharides were developed by using several artificial strategies, such as chemical degradation, enzyme catalysis, and biosynthesis, then they can be applied in various sectors. Moreover, it has gradually become a trend to use biosynthesis to realize the synthesis of oligosaccharides with clear structure. Emerging research has found that un-natural oligosaccharides exert more comprehensive effects against various human diseases through multiple mechanisms. However, these oligosaccharides from various routes have not been critical reviewed and summarized. Therefore, the purpose of this review is to present the various routes of oligosaccharides preparations and healthy effects, with a focus on diabetes, obesity, aging, virus, and gut microbiota. Additionally, the application of multi-omics for these natural and un-natural oligosaccharides has also been discussed. Especially, the multi-omics are needed to apply in various disease models to find out various biomarkers to respond to the dynamic change process of oligosaccharides.

FOSL1 promotes proneural-to-mesenchymal transition of glioblastoma stem cells via UBC9/CYLD/NF-κB axis.

Proneural (PN) to mesenchymal (MES) transition (PMT) is a crucial phenotypic shift in glioblastoma stem cells (GSCs). However, the mechanisms driving this process remain poorly understood. Here, we report that Fos-like antigen 1 (FOSL1), a component of AP1 transcription factor complexes, is a key player in regulating PMT. FOSL1 is predominantly expressed in the MES subtype, but not PN subtype, of GSCs. Knocking down FOSL1 expression in MES GSCs leads to the loss of MES features and tumor-initiating ability, whereas ectopic expression of FOSL1 in PN GSCs is able to induce PMT and maintain MES features. Moreover, FOSL1 facilitates ionizing radiation (IR)-induced PMT and radioresistance of PN GSCs. Inhibition of FOSL1 enhances the anti-tumor effects of IR by preventing IR-induced PMT. Mechanistically, we find that FOSL1 promotes UBC9-dependent CYLD SUMOylation, thereby inducing K63-linked polyubiquitination of major nuclear factor κB (NF-κB) intermediaries and subsequent NF-κB activation, which results in PMT induction in GSCs. Our study underscores the importance of FOSL1 in the regulation of PMT and suggests that therapeutic targeting of FOSL1 holds promise to attenuate molecular subtype switching in patients with glioblastomas.

Identification of 3 subpopulations of tumor-infiltrating immune cells for malignant transformation of low-grade glioma.

BACKGROUND: Tumor-infiltrating immune cells (TIICs) are highly relevant to clinical outcome of glioma. However, previous studies cannot account for the diverse functions that make up the immune response in malignant transformation (MT) from low-grade glioma (LGG) to high-grade glioma (HGG). METHODS: Transcriptome level, genomic profiles and its relationship with clinical practice were obtained from TCGA and CGGA database. The "Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT)" algorithm was used to estimate the fraction of 22 immune cell types. We divided the TCGA and CGGA set into an experiment set (n = 174) and a validation set (n = 74) by random number table method. Univariate and multivariate analyses were performed to evaluate the 22 TIICs' value for MT in LGG. ROC curve was plotted to calculate area under curve (AUC) and cut-off value. RESULTS: Heterogeneity between TIICs exists in both intra- and inter-groups. Several TIICs are notably associated with tumor grade, molecular subtypes and survival. T follicular helper (TFH) cells, activated NK Cells and M0 macrophages were screened out to be independent predictors for MT in LGG and formed an immune risk score (IRS) (AUC = 0.732, p < 0.001, 95% CI 0.657-0.808 cut-off value = 0.191). In addition, the IRS model was validated by validation group, Immunohistochemistry (IHC) and functional enrichment analyses. CONCLUSIONS: The proposed IRS model provides promising novel signatures for predicting MT from LGG to HGG and may bring a better design of glioma immunotherapy studies in years to come.

Plant diversity increases N removal in constructed wetlands when multiple rather than single N processes are considered.

Biodiversity has a close relationship with ecosystem functioning. For most biodiversity-ecosystem-functioning studies, biodiversity has been linked to a single indicator variable of ecosystem functioning. However, there are generally multiple ecosystem processes contributing to ecosystem functioning and they differ in their dependence on biodiversity. Thus, the relationship between biodiversity and ecosystem functioning can be stronger when multiple rather than single ecosystem processes are considered. Using both mass-balance and stable-isotope approaches, we explored the effects of plant diversity on nitrogen (N) removal sustained by multiple N-cycling processes in experimental microcosms simulating constructed wetlands, an ecosystem treating wastewater with high N loading. Four species were used to assemble different plant communities, ranging in richness from one to four species. The removal of N, indicated by low levels of total inorganic N concentration (TIN) present in the effluent, was considered as an integrated measure of ecosystem functioning, combining three constituent N-cycling processes: plant uptake, denitrification, and substrate adsorption. Our results showed that (1) species richness had a positive effect on N removal, in particular, the four-species mixture reduced effluent TIN to a lower level than any monoculture; however, polycultures (two-, three-, and four-species mixtures) did not outperform the most efficient monoculture when each of the three constituent N-cycling processes was considered by itself; (2) species identity had significant impacts on single processes. Communities with the species Coix lacryma-jobi showed the greatest capacity for N uptake and communities with Phragmites australis had the highest denitrification rates; (3) isotope fractionation in the rhizosphere of Coix lacryma-jobi was primarily due to microbial denitrification while multistep isotope fractionation was detected for Phragmites australis and Acorus calamus (indicating recycling of N), suggesting that species differed in the way they transformed N; (4) the enhanced N removal at high diversity may be due to mutualistic interactions among species belonging to different functional types. Our findings demonstrated that although plant species richness had negligible effects on individual N-cycling processes, it enhanced the overall ecosystem functioning (N removal) when these processes were considered collectively. Our study thus contributes to improve the treatment efficiency of constructed wetlands through proper vegetation management.

Genetic association between IL-27 rs153109 polymorphism and cancer risk in Chinese population: a meta-analysis.

IL-27 plays an important role in anti-cancer activity. The -964A/G polymorphism in IL-27 gene has been implicated in susceptibility to cancer, but the results were conflicting. The aim of this study was to assess the association between this polymorphism and cancer risk. Pubmed and Wanfang database were searched for all publications concerning IL-27 -964A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association. Statistical analysis was performed using Stata 11.0 software. A total of eight case-control studies including 2044 cancer cases and 2197 controls were identified. Overall, significant association between IL-27 -964A/G polymorphism and cancer risk was observed (GG versus AA: OR = 1.26, 95% CI = 1.03-1.52; GG versus AG + AA: OR = 1.20, 95% CI = 1.00-1.44). In subgroup analysis based on cancer type, significant association was found in colorectal cancer (GG versus AA: OR = 1.55, 95% CI = 1.07-2.27; AG versus AA: OR = 1.31, 95% CI = 1.02-1.67). The current meta-analysis suggests that IL-27 -964A/G polymorphism might enhance cancer risk. However, large-scale and well-designed studies are still needed to confirm the result of our meta-analysis. The association of IL-27 polymorphism with colorectal cancer may provide insight for future therapies.

Tumor Suppressor Candidate 1 Suppresses Cell Growth and Predicts Better Survival in Glioblastoma.

Glioblastoma (GBM) is the most common malignant brain tumor with poor prognosis and limited treatment options. Tumor suppressor candidate 1 (TUSC1) was recently identified as a potential tumor suppressor in human cancers. However, the expression and potential function of TUSC1 in GBM remain unclear. Herein, we report that TUSC1 is significantly decreased in GBM tissues and cell lines. Patients with high levels of TUSC1 displayed a significant better survival compared with those with low levels of TUSC1. Functional experiments demonstrated that exogenous expression of TUSC1 inhibited GBM cell proliferation and induced G1 phase arrest by down-regulating CDK4. Moreover, overexpression of TUSC1 retarded tumor growth in vivo. Together, our findings revealed that TUSC1 might be a crucial tumor suppressor gene and a novel therapeutic target for GBM.

c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma.

Resistance to temozolomide poses a major clinical challenge in glioblastoma multiforme treatment, and the mechanisms underlying the development of temozolomide resistance remain poorly understood. Enhanced DNA repair and mutagenesis can allow tumour cells to survive, contributing to resistance and tumour recurrence. Here, using recurrent temozolomide-refractory glioblastoma specimens, temozolomide-resistant cells, and resistant-xenograft models, we report that loss of miR-29c via c-Myc drives the acquisition of temozolomide resistance through enhancement of REV3L-mediated DNA repair and mutagenesis in glioblastoma. Importantly, disruption of c-Myc/miR-29c/REV3L signalling may have dual anticancer effects, sensitizing the resistant tumours to therapy as well as preventing the emergence of acquired temozolomide resistance. Our findings suggest a rationale for targeting the c-Myc/miR-29c/REV3L signalling pathway as a promising therapeutic approach for glioblastoma, even in recurrent, treatment-refractory settings.

MiR-622 suppresses proliferation, invasion and migration by directly targeting activating transcription factor 2 in glioma cells.

Malignant gliomas are the most common and devastating primary brain tumors in adults. The rapid invasion of tumor cells into the adjacent normal brain tissues is a major cause of treatment failure, yet the mechanisms that regulate this process remain poorly understood. MicroRNAs have recently emerged as regulators of invasion and metastasis by acting on multiple signaling pathways. In this study, we found that miR-622 is significantly downregulated in glioma tissues and cell lines. Functional experiments showed that increased miR-622 expression reduced glioma cell invasion and migration, whereas decreased miR-622 expression enhanced cell invasion and migration. Moreover, activating transcription factor 2 (ATF2), an important transcription factor that regulate tumor invasion, was identified as a direct target of miR-622. Knockdown of ATF2 using small interefering RNA recapitulated the anti-invasive function of miR-622, whereas restoring the ATF2 expression attenuated the function of miR-622 in glioma cells. Furthermore, clinical data indicated that miR-622 and ATF2 were inversely expressed in glioma specimens. Our findings provide insight into the specific biological behavior of miR-622 in tumor invasion and migration. Targeting miR-622/ATF2 axis is a novel therapeutic approach for blocking glioma invasion.

Exploring global research trends in Chinese medicine for atherosclerosis: a bibliometric study 2012-2023.

Background: While Traditional Chinese Medicine (TCM) boasts an extensive historical lineage and abundant clinical expertise in addressing atherosclerosis, this field is yet to be penetrated adequately by bibliometric studies. This study is envisaged to evaluate the contemporary scenario of TCM in conjunction with atherosclerosis over the preceding decade while also identifying forthcoming research trends and emerging topics via the lens of bibliometric analysis. Methods: Literature pertaining to TCM and atherosclerosis, circulated between January 1, 2012 and November 14, 2023, was garnered for the purpose of this research. The examination embraced annual publications, primary countries/regions, engaged institutions and authors, scholarly journals, references, and keywords, utilizing analytical tools like Bibliometrix, CiteSpace, ScimagoGraphica, and VOSviewer present in the R package. Result: This field boasts a total of 1,623 scholarly articles, the majority of which have been contributed by China in this field, with significant contributions stemming from the China Academy of Traditional Chinese Medicine and the Beijing University of Traditional Chinese Medicine. Moreover, this field has received financial support from both the National Natural Science Foundation of China and the National Key Basic Research Development Program. Wang Yong tops the list in terms of publication count, while Xu Hao's articles take the lead for the total number of citations, positioning them at the core of the authors' collaborative network. The Journal of Ethnopharmacology leads with the most publications and boasts the greatest total number of citations. Principal research foci within the intersection of Chinese Medicine and Atherosclerosis encompass disease characteristics and pathogenic mechanisms, theoretical underpinnings and syndrome-specific treatments in Chinese medicine, potentialities of herbal interventions, and modulation exerted by Chinese medicines on gut microbiota. Conclusion: This analysis offers a sweeping survey of the contemporary condition, principal foci, and progressive trends in worldwide research related to Traditional Chinese Medicine (TCM) and atherosclerosis. It further delves into an in-depth dissection of prominent countries, research institutions, and scholars that have made noteworthy strides in this discipline. Additionally, the report analyzes the most cited articles, research developments, and hotspots in the field, providing a reference for future research directions for clinical researchers and practitioners.

Recent Progress in Human Milk Oligosaccharides and Its Antiviral Efficacy.

Gastrointestinal (GI)-associated viruses, including rotavirus (RV), norovirus (NV), and enterovirus, usually invade host cells, transmit, and mutate their genetic information, resulting in influenza-like symptoms, acute gastroenteritis, encephalitis, or even death. The unique structures of human milk oligosaccharides (HMOs) enable them to shape the gut microbial diversity and endogenous immune system of human infants. Growing evidence suggests that HMOs can enhance host resistance to GI-associated viruses but without a systematic summary to review the mechanism. The present review examines the lactose- and neutral-core HMOs and their antiviral effects in the host. The potential negative impacts of enterovirus 71 (EV-A71) and other GI viruses on children are extensive and include neurological sequelae, neurodevelopmental retardation, and cognitive decline. However, the differences in the binding affinity of HMOs for GI viruses are vast. Hence, elucidating the mechanisms and positive effects of HMOs against different viruses may facilitate the development of novel HMO derived oligosaccharides.

Dual-stage feedback network for lightweight color image compression artifact reduction.

Lossy image coding techniques usually result in various undesirable compression artifacts. Recently, deep convolutional neural networks have seen encouraging advances in compression artifact reduction. However, most of them focus on the restoration of the luma channel without considering the chroma components. Besides, most deep convolutional neural networks are hard to deploy in practical applications because of their high model complexity. In this article, we propose a dual-stage feedback network (DSFN) for lightweight color image compression artifact reduction. Specifically, we propose a novel curriculum learning strategy to drive a DSFN to reduce color image compression artifacts in a luma-to-RGB manner. In the first stage, the DSFN is dedicated to reconstructing the luma channel, whose high-level features containing rich structural information are then rerouted to the second stage by a feedback connection to guide the RGB image restoration. Furthermore, we present a novel enhanced feedback block for efficient high-level feature extraction, in which an adaptive iterative self-refinement module is carefully designed to refine the low-level features progressively, and an enhanced separable convolution is advanced to exploit multiscale image information fully. Extensive experiments show the notable advantage of our DSFN over several state-of-the-art methods in both quantitative indices and visual effects with lower model complexity.

Important nutrient sources and carbohydrate metabolism patterns in the growth and development of spargana.

BACKGROUND: Sparganosis is a worldwide food-borne parasitic disease caused by spargana infection, which infects the muscle of frogs and snakes as well as many tissues and organs in humans. There are currently no viable treatments for sparganosis. Understanding spargana's nutrition source and carbohydrate metabolism may be crucial for identifying its energy supply and establishing methods of treatment for sparganosis. METHODS: Using an amino acid analyzer and nutrient concentration detection kits, we assessed nutrient concentrations in the muscles of Fejervarya limnocharis and Pelophylax plancyi infected or not infected with spargana. Quantitative polymerase chain reaction (PCR) was used to quantify the major enzymes involved in five glucose metabolism pathways of spargana developing in vivo. We also used quantitative PCR to assess key enzymes and transcriptome sequencing to explore the regulation of carbohydrate metabolic pathways in vitro in response to different 24-h food treatments. RESULTS: Infected muscle tissues had considerably higher concentrations of glucogenic and/or ketogenic amino acids, glucose, and glycogen than non-infected muscle tissues. We discovered that the number of differentially expressed genes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was larger in low-glucose than in other dietary groups. We examined differences in the expression of genes producing amino acid transporters, glucose transporters, and cathepsins in spargana grown in various nutritional environments. In the normal saline group, only the major enzymes in the tricarboxylic acid cycle (TCA), glycogenesis, and glycogenolysis pathways were expressed. The L-glutamine group had the greatest transcriptional levels of critical rate-limiting enzymes of gluconeogenesis and glycogenesis. Furthermore, the low-glucose group had the highest transcriptional levels of critical rate-limiting enzymes involved in the TCA, glycolytic, and glycogenolysis pathways. Surprisingly, when compared to the in vitro culturing groups, spargana developing in vivo exhibited higher expression of these critical rate-limiting enzymes in these pathways, with the exception of the pentose phosphate pathway. CONCLUSIONS: Spargana have a variety of nutritional sources, and there is a close relationship between nutrients and the carbohydrate metabolism pathways. It takes a multi-site approach to block nutrient absorption and carbohydrate metabolism pathways to provide energy to kill them.

Deubiquitinase PSMD14 promotes tumorigenicity of glioblastoma by deubiquitinating and stabilizing ß-catenin.

The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a member of the JAB1/MPN/Mov34 metalloenzyme (JAMM) family, has been shown to function as an oncogene in various human cancers. However, the function of PSMD14 in glioma and the underlying mechanism remain unclear. In this study, our findings reveal a dramatic upregulation of PSMD14 in GBMs, which is associated with poor survival outcomes. Knocking down PSMD14 is associated with decreased proliferation and invasion of GBM cells in vitro and inhibited tumor growth in a xenograft mouse model. Mechanistically, PSMD14 directly interacts with ß-catenin, leading to a decrease in the K48-linked ubiquitination of ß-catenin and subsequent ß-catenin stabilization. Increased ß-catenin expression significantly reverses the inhibitory effects of PSMD14 knockdown on the migration, invasion, and tumor growth of GBM cells. Moreover, we observed a significant correlation between PSMD14 and ß-catenin expression in human GBM samples. In summary, our results reveal that PSMD14 is a crucial deubiquitinase that is responsible for stabilizing the ß-catenin protein, highlighting its potential for use as a therapeutic target for GBM.

E2F1-regulated USP5 contributes to the tumorigenic capacity of glioma stem cells through the maintenance of OCT4 stability.

Mesenchymal glioma stem cells (MES GSCs) are a subpopulation of cells in glioblastoma (GBM) that contribute to a worse prognosis owing to their highly aggressive nature and resistance to radiation therapy. Here, OCT4 is characterized as a critical factor in sustaining the stemness phenotype of MES GSC. We find that OCT4 is expressed intensively in MES GSC and is intimately associated with poor prognosis, moreover, OCT4 depletion leads to diminished invasive capacity and impairment of the stem phenotype in MES GSC. Subsequently, we demonstrated that USP5 is a deubiquitinating enzyme which directly interacts with OCT4 and preserves OCT4 stability through its deubiquitination. USP5 was additionally proven to be aberrantly over-expressed in MES GSCs, and its depletion resulted in a noticeable diminution of OCT4 and consequently a reduced self-renewal and tumorigenic capacity of MES GSCs, which can be substantially restored by ectopic expression of OCT4. In addition, we detected the dominant molecule that regulates USP5 transcription, E2F1, with dual luciferase reporter gene analysis. In combination, targeting the E2F1-USP5-OCT4 axis is a potentially emerging strategy for the therapy of GBM.

Modulation of gut microbiota and lipid metabolism in rats fed high-fat diets by Ganoderma lucidum triterpenoids.

Ganoderma lucidum triterpenoids (GP) have been reported to help prevent and improve hyperlipidemia. Modulation of the gut microbiota was proposed as underlying factor as well as a novel measure to prevent and treat hyperlipidemia. The effects of GP on high-fat diet (HFD)-induced hyperlipidemia and gut microbiota modulation were determined in rats. Ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-QTOF MS-MS) indicated that GP were enriched with ganoderic acids G, B, H, A, and F. After feeding with GP supplementation, serum lipid levels including total triglyceride, total cholesterol, and low-density-lipoprotein cholesterol were significantly decreased in hyperlipidemic rats. Furthermore, administration of GP also has reversed the HFD-induced gut microbiota dysbiosis, including a significant increase in Alloprevotella and reduced proportion of Blautia. The result above suggests that GP would be developed as a functional food to ameliorate lipid metabolic disorders and hyperlipidemia.