Advances in the interaction of glycolytic reprogramming with lactylation.

Lactylation is a novel post-translational modification (PTM) involving proteins that is induced by lactate accumulation. Histone lysine lactylation alters chromatin spatial configuration, influencing gene transcription and regulating the expression of associated genes. This modification plays a crucial role as an epigenetic regulatory factor in the progression of various diseases. Glycolytic reprogramming is one of the most extensively studied forms of metabolic reprogramming, recognized as a key hallmark of cancer cells. It is characterized by an increase in glycolysis and the inhibition of the tricarboxylic acid (TCA) cycle, accompanied by significant lactate production and accumulation. The two processes are closely linked by lactate, which interacts in various physiological and pathological processes. On the one hand, lactylation levels generally correlate positively with the extent of glycolytic reprogramming, being directly influenced by the lactate concentration produced during glycolytic reprogramming. On the other hand, lactylation can also regulate glycolytic pathways by affecting the transcription and structural functions of essential glycolytic enzymes. This review comprehensively outlines the mechanisms of lactylation and glycolytic reprogramming and their interactions in tumor progression, immunity, and inflammation, with the aim of elucidating the relationship between glycolytic reprogramming and lactylation.

A Novel Gene Signature Based on CDC20 and FCN3 for Prediction of Prognosis and Immune Features in Patients with Hepatocellular Carcinoma.

Long-term survivals of patients with hepatocellular carcinoma (HCC) remain unfavorable, which is largely attributed to active carcinogenesis. Growing studies have suggested that the reliable gene signature could act as an independent prognosis factor for HCC patients. We tried to screen the survival-related genes and develop a prognostic prediction model for HCC patients based on the expression profiles of the critical survival-related genes. In this study, we analyzed TCGA datasets and identified 280 genes with differential expressions (125 increased genes and 155 reduced genes). We analyzed the prognosis value of the top 10 dysregulated genes in HCC patients and identified three critical genes, including FCN3, CDC20, and E2F1, which were confirmed to be associated with long-term survival in both TCGA and ICGC datasets. The results of the LASSO model screened CDC20 and FCN3 for the development of the prognostic model. The CDC20 expression was distinctly increased in HCC specimens, while the FCN3 expression was distinctly decreased in HCC. At a suitable cutoff, patients were divided into low-risk and high-risk groups. Survival assays revealed that patients in high-risk groups exhibited a shorter overall survival than those in low-risk groups. Finally, we examine the relationships between risk score and immune infiltration abundance in HCC and observed that risk score was positively correlated with infiltration degree of B cells, T cell CD4+ cells, neutrophil, macrophage, and myeloid dendritic cells. Overall, we identified three critical survival-related genes and used CDC20 and FCN3 to develop a novel model for predicting outcomes and immune landscapes for patients with HCC. The above three genes also have a high potential for targeted cancer therapy of patients with HCC.

The Systemic Immune-Inflammation Index May Be a Novel and Strong Marker for the Accurate Early Prediction of Acute Kidney Injury in Severe Acute Pancreatitis Patients.

OBJECTIVE: This research was performed to investigate the correlation between acute kidney injury (AKI) and systemic immune-inflammation index (SII) in severe acute pancreatitis (SAP) patients. METHODS: The study included 218 SAP patients from Chongqing Jiangjin Center Hospital during January 2016 to October 2020. The SII was defined as platelet × neutrophil/lymphocyte ratio. After univariate analysis, logistic regression analysis was used for analyzing independent risk factors of AKI in SAP patients. Receiver operating characteristic (ROC) curve was used for analyzing the prognostic value of the SII. RESULTS: AKI occurred in 74 cases and its incidence rate was 33.9%. The median SII value of AKI patients was higher than that of patients without AKI. After multivariate analysis, SII, age, triglyceride (TG), neutrophil ratio (NEU-R), C-reactive protein (CRP), aspartate aminotransferase (AST), and serum albumin (ALB) were independent predictors of AKI. Serum ALB was an independent protective factor. The optimum threshold truncation value of SII was 2880.1*10^9/L. Compared with other inflammatory factors, SII had a better prediction efficiency. CONCLUSION: The SII, TG, NEU-R, CRP, and ALB were significant independent predictors of AKI in SAP patients. Serum TG, NEU-R, CRP, and SII were risk factors. Serum ALB was a protective factor. The SII may be a novel, simple, and strong marker for the accurate early prediction of AKI in SAP patients.

The application of the fibroblast activation protein α-targeted immunotherapy strategy.

Cancer immunotherapy has primarily been focused on attacking tumor cells. However, given the close interaction between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), CAF-targeted strategies could also contribute to an integrated cancer immunotherapy. Fibroblast activation protein α (FAP α) is not detectible in normal tissues, but is overexpressed by CAFs and is the predominant component of the stroma in most types of cancer. FAP α has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. When all FAP α-expressing cells (stromal and cancerous) are destroyed, tumors rapidly die. Furthermore, a FAP α antibody, FAP α vaccine, and modified vaccine all inhibit tumor growth and prolong survival in mouse models, suggesting FAP α is an adaptive tumor-associated antigen. This review highlights the role of FAP α in tumor development, explores the relationship between FAP α and immune suppression in the TME, and discusses FAP α as a potential immunotherapeutic target.

Curcumin combined with FAPαc vaccine elicits effective antitumor response by targeting indolamine-2,3-dioxygenase and inhibiting EMT induced by TNF-α in melanoma.

Fibroblast activation protein α (FAPα) is a potential target for cancer therapy. However, elimination of FAPα+ fibroblasts activates secretion of IFN-γ and TNF-α. IFN-γ can in turn induce expression indolamine-2,3-dioxygenase (IDO), thereby contributing to immunosuppression, while TNF-α can induce EMT. These two reactive effects would limit the efficacy of a tumor vaccine. We found that curcumin can inhibit IDO expression and TNF-α-induced EMT. Moreover, FAPαc vaccine and CpG combined with curcumin lavage inhibited tumor growth and prolonged the survival of mice implanted with melanoma cells. The combination of FAPαc vaccine, CpG and curcumin stimulated FAPα antibody production and CD8+ T cell-mediated killing of FAPα-expressing stromal cells without adverse reactive effects. We suggest a combination of curcumin and FAPαc vaccine for melanoma therapy.

A spectroscopic study of uranyl-cytochrome b5/cytochrome c interactions.

Uranium is harmful to human health due to its radiation damage and the ability of uranyl ion (UO2(2+)) to interact with various proteins and disturb their biological functions. Cytochrome b5 (cyt b5) is a highly negatively charged heme protein and plays a key role in mediating cytochrome c (cyt c) signaling in apoptosis by forming a dynamic cyt b5-cyt c complex. In previous molecular modeling study in combination with UV-Vis studies, we found that UO2(2+) is capable of binding to cyt b5 at surface residues, Glu37 and Glu43. In this study, we further investigated the structural consequences of cyt b5 and cyt c, as well as cyt b5-cyt c complex, upon uranyl binding, by fluorescence spectroscopic and circular dichroism techniques. Moreover, we proposed a uranyl binding site for cyt c at surface residues, Glu66 and Glu69, by performing a molecular modeling study. It was shown that uranyl binds to cyt b5 (KD=10 µM), cyt c (KD=87 µM), and cyt b5-cyt c complex (KD=30 µM) with a different affinity, which slightly alters the protein conformation and disturbs the interaction of cyt b5-cyt c complex. Additionally, we investigated the functional consequences of uranyl binding to the protein surface, which decreases the inherent peroxidase activity of cyt c. The information of uranyl-cyt b5/cyt c interactions gained in this study likely provides a clue for the mechanism of uranyl toxicity.

[Cloning and expression of outer membrane protein gene Gpd from Treponema pallidum and preliminary studies on its immunogenicity in rabbits].

To construct the recombinant plasmid of Eukaryotic expression containing Gpd gene from Treponema Pallidum and study its immunogenicity in New Zealand White rabbits. Gpd gene was amplified from the genomic DNA of T. pallidum and cloned into appropriate site of pcDNA3. 1 ( + ) vector. After verified that the Gpd antigen gene could be expressed in HeLa cells by Western blot and immunocytochemistry, recombinant plasmids pcDNA3.1 ( + )-Gpd, control plasmid pcDNA3. 1 ( + ) or PBS buffer were administered in three groups of New Zeal and White rabbits. Booster immunizations were employed at 2-week interval for three times. ELISA was used for the quantitative detection of the specific antibody in the sera of rabbits. The proliferation response of spleen cells was detected by MTT assay. The results of the Western blot and immunocytochemistry showed that Gpd gene constructed in pcDNA3.1 ( + ) vector could express a fusion protein with a calculated molecular mass of 41kD in HeLa cells and react with positive blood serum from syphilis patients. The significant specific antibody IgG titers were observed and the highest titer was 1:1024 in rabbits after three times with pcDNA3.1 ( + )-Gpd. The proliferation response of spleen cells were significantly higher than that of rabbits injected with pcDNA3.1 ( + ) (p < 0.05). All above results establish a solid basis for future studying the biological activities of Gpd and benefit the development of the Syphilis DNA vaccine.