Zheng Li’s research while affiliated with Academy of Chinese Culture and Health Sciences and other places

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Publications (5)


The flow chart of the experimental design for all groups
AP supplementation alleviates the hyperglycemia of HDF KKAy mice. Male C57BL/6 mice were treated with a regular diet (CT). KKAy mice were treated with a high-fat diet without (HFD) or with AP supplementation (AP). The experiment lasted for four weeks. A The effects of AP supplementation on FBG level. B The effects of AP supplementation on body weight level. C The effects of AP supplementation on the fasting serum insulin level. Mean ± SEM (n = 5). **p < 0.01 compared with CT group; #p < 0.05 and ##p < 0.01 compared with HFD group
16S full-length rRNA sequencing discovered that AP reversed gut dysbiosis in HFD KKAy mice (n = 5). A Shannon index analysis based on Bray–Curtis distance showed no significant differences were observed among CT, HFD, and AP groups at the OTU level. B Bray–Curtis PERMANOVA analysis showed a significant difference between the three groups (p = 0.001). C The number of OTUs found in the CT, HFD, and AP groups; the total number of OTUs. D The Venn diagram showed the extent of overlapped and specific OTUs among the three groups. E Bray–Curtis PCoA analysis displayed clear separation among the three groups at the OTU level. F Bray–Curtis PCoA analysis displayed clear separation among the three groups at the genus level. G The bar graph showed each group's top 10 relative abundance gut microbiota at the genus level. H The top 10 relative abundance gut microbiota at the phyla level in each group. Most of the dominant bacteria changed by HFD were reversed by AP treatment. I The ratio of Firmicutes/Bacteroidetes was higher in the HFD group than in the CT group and reversed by AP treatment. J Heatmap based on Bray–Curtis distance showed that the distance between AP and CT groups was relatively closer than the distance between HDF and CT groups. The color gradient on the adjacent bar chart, transitioning from blue to red, represents the magnitude of differences between the samples, with blue indicating minimal differences and red indicating maximal differences
Metagenomics sequencing discovered that AP reversed gut dysbiosis in HFD KKAy mice (n = 3). A Venn diagram showed the extent of overlapped and specific bacterial species among the three groups. B Bray–Curtis PCoA analysis displayed clear separation among the three groups at the species level. C Based on the criteria of p < 0.05, 416 species abundance significantly increased by HFD and reversed by AP. D Based on the criteria of p < 0.05, 30 species significantly decreased by HFD and reversed by AP. E Venn diagram showed the extent of overlapped and specific KO among the three groups. F Bray–Curtis PCoA analysis displayed clear separation among the three groups at the KO level. G The different KEGG pathways related to metabolism between HFD and AP groups
LC–MS/MS-based untargeted metabolic profiling in positive and negative modes discovered that AP changes gut metabolome in HFD KKAy mice (n = 5). A, B The PLS-DA analysis showed clear separation among three groups in the positive model (R2X = 0.555, R2Y = 0.99, Q2Y = 0.798) and in the negative model (R2X = 0.582, R2Y = 0.993, Q2Y = 0.781). C, D With the criteria of either VIP > 1 and p < 0.05, the Venn diagram showed the number of differential metabolites between groups. 42 metabolites were up-regulated by HFD and reversed by AP, 29 metabolites were down-regulated by HFD and reversed by AP. E The differential metabolites class categories between HFD and AP groups. F The top 20 of KEGG enrichment analysis based on the differential metabolites between HFD and AP groups

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Angelica polysaccharides relieve blood glucose levels in diabetic KKAy mice possibly by modulating gut microbiota: an integrated gut microbiota and metabolism analysis
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  • Full-text available

October 2023

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83 Reads

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4 Citations

BMC Microbiology

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Lixia Yang

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Background Angelica polysaccharides (AP) have numerous benefits in relieving type 2 diabetes (T2D). However, the underlying mechanisms have yet to be fully understood. Recent many reports have suggested that altering gut microbiota can have adverse effects on the host metabolism and contribute to the development of T2D. Here, we successfully established the T2D model using the male KKAy mice with high-fat and high-sugar feed. Meanwhile, the male C57BL/6 mice were fed with a normal feed. T2D KKAy mice were fed either with or without AP supplementation. In each group, we measured the mice's fasting blood glucose, weight, and fasting serum insulin levels. We collected the cecum content of mice, the gut microbiota was analyzed by targeted full-length 16S rRNA metagenomic sequencing and metabolites were analyzed by untargeted-metabolomics. Results We found AP effectively alleviated glycemic disorders of T2D KKAy mice, with the changes in gut microbiota composition and function. Many bacteria species and metabolites were markedly changed in T2D KKAy mice and reversed by AP. Additionally, 16 altered metabolic pathways affected by AP were figured out by combining metagenomic pathway enrichment analysis and metabolic pathway enrichment analysis. The key metabolites in 16 metabolic pathways were significantly associated with the gut microbial alteration. Together, our findings showed that AP supplementation could attenuate the diabetic phenotype. Significant gut microbiota and gut metabolite changes were observed in the T2D KKAy mice and AP intervention. Conclusions Administration of AP has been shown to improve the composition of intestinal microbiota in T2D KKAy mice, thus providing further evidence for the potential therapeutic application of AP in the treatment of T2D.

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Single‐cell RNA‐seq and bulk RNA‐seq explore the prognostic value of exhausted T cells in hepatocellular carcinoma

July 2023

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99 Reads

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1 Citation

Hepatocellular carcinoma (HCC) remains a worldwide health problem. Mounting evidence indicates that exhausted T cells play a critical role in the progress and treatment of HCC. Therefore, a detailed characterisation of exhausted T cells and their clinical significance warrants further investigation in HCC. Based on the GSE146115, we presented a comprehensive single‐cell Atlas in HCC. Pseudo‐time analysis revealed that tumour heterogeneity progressively increased, and the exhausted T cells gradually appeared during tumour progression. Functional enrichment analysis revealed that the evolutionary process of exhausted T cells mainly contained the pathway of cadherin binding, proteasome, cell cycle, and T cell receptor regulation of apoptosis. In the International Cancer Genome Consortium database, we divided patients into three clusters with the T cell evolution‐associated genes. We found that the exhausted T cells are significantly related to poor outcomes through immunity and survival analysis. In The Cancer Genome Atlas database, the authors enrolled weighted gene co‐expression network analysis, univariate Cox analysis, and Lasso Cox analysis, then screened the 19 core genes in T cells evolution and built a robust prognostic model. This study offers a fresh view on evaluating the patients' outcomes from an exhausted T cells perspective and might help clinicians develop therapeutic systems.


Schematic diagram of some essential physiological functions and metabolic processes of copper. Copper is primarily transported into cells by CTR1. Upon entering the cell, copper is transferred to CCS, COX17, and ATOX1. CCS delivers copper to SOD1, which is involved in defense against oxygen toxicity. COX17 transfers copper to CCO, which participates in maintaining mitochondrial respiration. ATOX1 can carries copper into the cell nucleus, leading to the expression of G1/S-specific cyclin D1 and inducing cell proliferation. ATOX1 also transports copper to ATP7A and ATP7B across the Golgi network and regulates copper subcellular distribution through the complex transport mechanisms of the Golgi network. Excess copper in the cell is bound by MT and GSH to prevent copper toxicity. In addition, ATP7A and ATP7B primarily function in the efflux of copper ions from cells.
Schematic diagram of molecular mechanisms linking copper with oncology. The small yellow dots represent copper, arrows indicate promotion or stimulation, and blunt end line signify inhibition or suppression.
Potential oncology treatment strategies of copper. (A) Based on the higher demand for copper in tumor cells, copper bioavailability can be reduced using Cu chelators to achieve the goal of cancer therapy. (B) Exploiting the higher copper burden in tumor cells, Cu ionophores can be utilized to increase intracellular copper concentration, inducing copper toxicity to achieve the goal of cancer treatment.
FDA approved and experimental drugs targeting copper metabolism in cancer treatment.
Copper in cancer: from limiting nutrient to therapeutic target

June 2023

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178 Reads

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44 Citations

As an essential nutrient, copper’s redox properties are both beneficial and toxic to cells. Therefore, leveraging the characteristics of copper-dependent diseases or using copper toxicity to treat copper-sensitive diseases may offer new strategies for specific disease treatments. In particular, copper concentration is typically higher in cancer cells, making copper a critical limiting nutrient for cancer cell growth and proliferation. Hence, intervening in copper metabolism specific to cancer cells may become a potential tumor treatment strategy, directly impacting tumor growth and metastasis. In this review, we discuss the metabolism of copper in the body and summarize research progress on the role of copper in promoting tumor cell growth or inducing programmed cell death in tumor cells. Additionally, we elucidate the role of copper-related drugs in cancer treatment, intending to provide new perspectives for cancer treatment.


Prognostic and Immunological Significance of the Molecular Subtypes and Risk Signatures Based on Cuproptosis in Hepatocellular Carcinoma

April 2023

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54 Reads

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9 Citations

Background: Hepatocellular carcinoma (HCC) remains a challenging medical problem. Cuproptosis is a novel form of cell death that plays a crucial role in tumorigenesis, angiogenesis, and metastasis. However, it remains unclear whether cuproptosis-related genes (CRGs) influence the outcomes and immune microenvironment of HCC patients. Method: From The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we obtained the mRNA expression file and related clinical information of HCC patients. We selected 19 CRGs as candidate genes for this study according to previous literature. We performed a differential expression analysis of the 19 CRGs between malignant and precancerous tissue. Based on the 19 CRGs, we enrolled cluster analysis to identify cuproptosis-related subtypes of HCC patients. A prognostic risk signature was created utilizing univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. We employed independent and stratification survival analyses to investigate the predictive value of this model. The functional enrichment features, mutation signatures, immune profile, and response to immunotherapy of HCC patients were also investigated according to the two molecular subtypes and the prognostic signature. Results: We found that 17 CRGs significantly differed in HCC versus normal samples. Cluster analysis showed two distinct molecular subtypes of cuproptosis. Cluster 1 is preferentially related to poor prognosis, high activity of immune response signaling, high mutant frequency of TP53, and distinct immune cell infiltration versus cluster 2. Through univariate and LASSO Cox regression analyses, we created a cuproptosis-related prognostic risk signature containing LIPT1, DLAT, MTF1, GLS, and CDKN2A. High-risk HCC patients were shown to have a worse prognosis. The risk signature was proved to be an independent predictor of prognosis in both the TCGA and ICGC datasets, according to multivariate analysis. The signature also performed well in different stratification of clinical features. The immune cells, which included regulatory T cells (Treg), B cells, macrophages, mast cells, NK cells, and aDCs, as well as immune functions containing cytolytic activity, MHC class I, and type II IFN response, were remarkably distinct between the high-risk and low-risk groups. The tumor immune dysfunction and exclusion (TIDE) score suggested that high-risk patients had a higher response rate to immune checkpoint inhibitors than low-risk patients. Conclusion: This research discovered the potential prognostic and immunological significance of cuproptosis in HCC, improved the understanding of cuproptosis, and may deliver new directions for developing more efficacious therapeutic techniques for HCC patients.


Mendelian Randomization Study Suggests Circulating Copper Level as a Risk Factor for Liver Cirrhosis

March 2023

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28 Reads

Cirrhosis is a serious liver disease with an unclear etiology and pathogenesis. Previous studies suggest a correlation between circulating copper and cirrhosis. However, whether circulating copper is a risk factor for cirrhosis is currently controversial because the liver is a major organ of copper metabolism and cirrhosis affects copper circulation. To address this, we used a mendelian randomization to explore the effect of circulating copper concentration on the risk of cirrhosis. We selected instrumental variables (IVs) of circulating copper from genome-wide association studies and analyzed two datasets from FinnGen, one for cirrhosis in general and the other for cirrhosis caused by non-alcoholic fatty liver disease (NAFLD). The inverse-variance weighted method was primarily used for mendelian randomization analysis. We created two SNP IVs that were associated with circulating copper, and their genetic associations with cirrhosis were extracted from the two datasets. The cirrhosis-related dataset included 811 cirrhosis patients and 273,592 controls, while the dataset for cirrhosis caused by NAFLD included 437 cirrhosis patients and 216,861 controls. Mendelian randomization analysis predicted a significant association between higher levels of circulating copper and increased risk of cirrhosis of liver (OR = 1.82, 95% CI: 1.30 to 2.54, P < 0.001). Additionally, higher levels of circulating copper were also associated with increased risk of cirrhosis of liver caused by NAFLD (OR = 1.68, 95% CI: 1.08 to 2.60, P = 0.021). The study suggests that higher levels of circulating copper may be a pathogenic risk factor for cirrhosis, providing important insights for the prevention and treatment of cirrhosis.

Citations (4)


... Chronic low-grade inflammation is a key factor in insulin resistance and ultimately contributes to the beta-cell dysfunction observed in T2D [15,16]. The limitations of current pharmacological therapies for T2D, including their financial burden and potential side effects, have invigorated interest in alternative treatment modalities; numerous natural products have demonstrated promise in modulating gut microbiota composition, thereby exerting favorable metabolic effects [17][18][19]. Particularly intriguing are phytochemicals such as polyphenols, alkaloids, and terpenes, which not only exert antioxidant and anti-inflammatory effects but also have been shown to selectively promote the growth of beneficial gut bacteria [20]. For instance, curcumin, a polyphenol derived from turmeric, has been shown to increase the abundance of butyrate-producing bacteria, thereby enhancing insulin sensitivity [21•]. ...

Reference:

Gut Microbiota Targeted Approach by Natural Products in Diabetes Management: An Overview
Angelica polysaccharides relieve blood glucose levels in diabetic KKAy mice possibly by modulating gut microbiota: an integrated gut microbiota and metabolism analysis

BMC Microbiology

... Another study by Li et al. developed a model based on NK cell marker genes, demonstrating its efficacy in predicting patient outcomes and therapeutic responses [29]. Tang et al. (2023) explored the prognostic value of exhausted T cells, constructing a robust model from bulk and scRNA-seq data to predict patient survival [30]. However, most of these studies focused on the relationship between tumor and the tumor microenvironment (TME), which might cause researchers to overlook the impact of the characteristics of tumor cells themselves on tumor development. ...

Single‐cell RNA‐seq and bulk RNA‐seq explore the prognostic value of exhausted T cells in hepatocellular carcinoma

... Higher blood lead concentrations have been reported in PC cases, suggesting that environmental lead exposure may in uence prostate pathology risk. The consistent association of urinary lead with PC, even after adjustment for confounders, highlights its potential as a robust biomarker for prostate cancer risk [47,48]. ...

Copper in cancer: from limiting nutrient to therapeutic target

... Even though notable advances in HCC treatment were made, the overall prognosis of treated HCC-individuals still remains unfavorable [2,3]. According to extensive investigations, it has been conducted in previous studies the development of a prognostic model for liver cancer by the comprehensive research institute of bioinformatics, including HCC [4,5]. Nevertheless, the prognosis assessment, personalized diagnosis, and treatment for patients who were diagnosed with HCC continue to pose a considerable obstacle, primarily due to the insufficient exploration and practical application of prognostic tumor markers and therapeutic targets in research and clinical settings. ...

Prognostic and Immunological Significance of the Molecular Subtypes and Risk Signatures Based on Cuproptosis in Hepatocellular Carcinoma