Antitumor Activity and Mechanistic Insights of a Mitochondria-Targeting Cu(I) Complex.

Using copper-ionophores to translocate extracellular copper into mitochondria is a clinically validated anticancer strategy that has been identified as a new type of regulated cell death termed "cuproptosis." This study reports a mitochondria-targeting Cu(I) complex, Cu(I)Br(PPh3)3 (CBP), consisting of a cuprous ion coordinated by three triphenylphosphine moieties and a Br atom. CBP exhibited antitumor and antimetastatic efficacy in vitro and in vivo by specifically targeting mitochondria instigating mitochondrial dysfunction. The cytotoxicity of CBP could only be reversed by a copper chelator rather than inhibitors of the known cell death, indicating copper-dependent cytotoxicity. Furthermore, CBP induced the oligomerization of lipoylated proteins and the loss of Fe-S cluster proteins, consistent with characteristic features of cuproptosis. Additionally, CBP induced remarkable intracellular generation of reactive oxygen species (ROS) through a Fenton-like reaction, indicating a complex antitumor mechanism. This is a proof-of-concept study exploiting the antitumor activity and mechanism of the Cu(I)-based mitochondria-targeting therapy.

Novel salty peptides derived from bovine bone: Identification, taste characteristic, and salt-enhancing mechanism.

Excessive sodium intake is a major contributor to the incidence of cardiovascular diseases. The objective of this study was to prepare, isolate, and characterize peptides from bovine bone protein and investigate the salty/salt-enhancing mechanism of peptides. 1032 peptides were identified in the enzymatic hydrolysates of bovine bone protein and were further screened by the composition of amino acid residues and molecular docking analysis. 5 peptides were finally selected for solid-phase synthesis, and KER showed a better salty taste by sensory verification. Moreover, the synergistic effect of KER in NaCl and MSG solution could enhance the salty intensity by 65.26 %. The binding of KER to the salty receptor (TMC4) was driven by hydrogen bonding and electrostatic interactions with a binding energy of -88.0734 kcal/mol. This work may provide a new approach to efficiently screen salty peptides from natural food materials, which were expected as a taste enhancer used in salt-reducing foods.

The Regulation of Ferroptosis by Noncoding RNAs.

As a novel form of regulated cell death, ferroptosis is characterized by intracellular iron and lipid peroxide accumulation, which is different from other regulated cell death forms morphologically, biochemically, and immunologically. Ferroptosis is regulated by iron metabolism, lipid metabolism, and antioxidant defense systems as well as various transcription factors and related signal pathways. Emerging evidence has highlighted that ferroptosis is associated with many physiological and pathological processes, including cancer, neurodegeneration diseases, cardiovascular diseases, and ischemia/reperfusion injury. Noncoding RNAs are a group of functional RNA molecules that are not translated into proteins, which can regulate gene expression in various manners. An increasing number of studies have shown that noncoding RNAs, especially miRNAs, lncRNAs, and circRNAs, can interfere with the progression of ferroptosis by modulating ferroptosis-related genes or proteins directly or indirectly. In this review, we summarize the basic mechanisms and regulations of ferroptosis and focus on the recent studies on the mechanism for different types of ncRNAs to regulate ferroptosis in different physiological and pathological conditions, which will deepen our understanding of ferroptosis regulation by noncoding RNAs and provide new insights into employing noncoding RNAs in ferroptosis-associated therapeutic strategies.

The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer.

The tumor suppressor TP53 is the most frequently mutated gene in human cancers. Mutant p53 (mutp53) proteins often accumulate to very high levels in human cancers to promote cancer progression through the gain-of-function (GOF) mechanism. Currently, the mechanism underlying mutp53 accumulation and GOF is incompletely understood. Here, we identified TRIM21 as a critical E3 ubiquitin ligase of mutp53 by screening for specific mutp53-interacting proteins. TRIM21 directly interacted with mutp53 but not WT p53, resulting in ubiquitination and degradation of mutp53 to suppress mutp53 GOF in tumorigenesis. TRIM21 deficiency in cancer cells promoted mutp53 accumulation and GOF in tumorigenesis. Compared with p53R172H knockin mice, which displayed mutp53 accumulation specifically in tumors but not normal tissues, TRIM21 deletion in p53R172H knockin mice resulted in mutp53 accumulation in normal tissues, an earlier tumor onset, and a shortened life span of mice. Furthermore, TRIM21 was frequently downregulated in some human cancers, including colorectal and breast cancers, and low TRIM21 expression was associated with poor prognosis in patients with cancers carrying mutp53. Our results revealed a critical mechanism underlying mutp53 accumulation in cancers and also uncovered an important tumor-suppressive function of TRIM21 and its mechanism in cancers carrying mutp53.

Metabolic enzyme LDHA activates Rac1 GTPase as a noncanonical mechanism to promote cancer.

The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been attributed to its glycolytic enzyme activity. Here we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote cancer independently of its glycolytic enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1-GTP, to inhibit Rac1-GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in cancer cells and mouse tissues. In clinical breast cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression.

Unsupported MoS2-Based Catalysts for Bio-Oil Hydrodeoxygenation: Recent Advances and Future Perspectives.

In recent years, unsupported MoS2-based catalysts have been reported as promising candidates in the hydrodeoxygenation (HDO) of bio-oil. However, preparing MoS2-based catalysts with both high activity and good stability for HDO reaction is still challenging and of great importance. Hence, this mini-review is focused on the recent development of unsupported MoS2-based HDO catalysts from the understanding of catalyst design. The three aspects including morphology and defect engineering, metal doping, and deactivation mechanism are highlighted in adjusting the HDO performance of MoS2-based catalysts. Finally, the key challenges and future perspectives about how to design efficient catalysts are also summarized in the conclusions.

Soy oil and SPI based-oleogels structuring with glycerol monolaurate by emulsion-templated approach: Preparation, characterization and potential application.

In this study, soybean oil-based oleogels were prepared using soy-protein isolate (SPI) and glycerol monolaurate (GML) in an emulsion-template approach. The rheological, texture, microstructure, and oil-retention properties of the obtained oleogels were analyzed. Results showed that the soy oil-based oleogel prepared with 6 wt% GML exhibited high oil loss, low-hardness, and needle-like morphology compared to the soy-oil/SPI-based oleogel. On the other hand, soy oil-based /SPI-based oleogels structured by 3 or 6 wt% GML presented moderate thermal-stability and lowest oil loss than those prepared without GML. Furthermore, SPI-based oleogel containing 6 wt% GML showed highest free fatty acids release (62.07%) with significantly improved elastic modulus and apparent viscosity. Additionally, the obtained oleogels displayed the occurrence of van der Waals interactions and intermolecular hydrogen bonds, presenting enhanced thermal stability. These results contribute to a better understanding of oleogelation-based emulsions for formulating trans-free and low-saturated foodstuffs with desired physical and functional properties.

Detection and Significance of Cell-Free DNA Mutation in Pleural Effusion in Patients with Advanced NSCLC.

Objective: To detect EGFR/KRAS genes in pleural effusion cell-free DNA in patients with advanced non-small-cell lung cancer (NSCLC) and to explore the clinical significance of EGFR/KRAS mutation status in pleural effusion. Methods: A retrospective collection was performed on the specimens of pleural effusion and matched tissues from 50 patients with advanced NSCLC admitted to the hospital between January 2019 and January 2021. DNA mutation status of EGFR/KRAS in different specimens was detected and compared by pyrosequencing. The clinicopathological data and follow-up data of survival were collected. The relationship between DNA mutation and clinicopathological characteristics and prognosis was analyzed. Results: In the 50 pleural effusion specimens, there were 22 cases (44.00%) with EGFR mutations (19/21 exon mutations), including 12 cases with EGFR19 deletion mutation and 10 cases with EGFR21 exon L858R mutation. There were 6 cases (12.00%) with KRAS mutations (single-base substitution mutations), including 4 cases with 12-codon mutation and 2 cases with 13-codon mutation. In the 50 tissue specimens, there were 24 cases (48.00%) with EGFR mutations and 4 cases (8.00%) with KRAS mutations. There was no significant difference between pleural effusion specimens and tissue specimens, with good consistency (kappa = 0.920-0.779, P > 0.05). EGFR mutation in pleural effusion was related to smoking history, types of pathological tissues, and lymph node metastasis (P < 0.05). The incidence of EGFR mutation was higher in nonsmokers, patients with lung adenocarcinoma, and patients with lymph node metastasis. The carcinoembryonic antigen (CEA) in patients with EGFR mutation was higher than that with wild-type EGFR, while the level of cytokeratin 19 fragment (Cy21-1) was lower than that with wild-type EGFR (P < 0.05). The 1-year overall survival rate in the EGFR mutation group was significantly higher than that in the EGFR wild group (68.18% vs. 42.86%) (HR = 0.419, 95% CI = 0.178-0.989, and P < 0.001). Conclusion: For the detection of EGFR gene mutation, the results of the pleural effusion specimens and the tumor pathological tissue specimens were well consistent and the detection of pleural effusion could be used as an alternative method when tissue specimens cannot be obtained. EGFR gene mutations are present in majority in patients with advanced NSCLC. The incidence of EGFR mutation is higher in nonsmokers, patients with lung adenocarcinoma, those with lymph node metastasis, those with high-expression CEA, and those with low-expression Cy21-1. The prognosis is better in patients with EGFR mutation.

Fabrication of aerogel-templated oleogels from alginate-gelatin conjugates for in vitro digestion.

In this work, the alginate-gelatin conjugates were developed by Maillard reaction. The aerogel templates were obtained by freeze-drying the conjugates, and they were transformed into oleogels by being immersed in camellia oil. Degree of graft and browning index revealed the occurrence of Maillard reaction. Compared with pure alginate/gelatin samples, the rheology and mechanical properties of mixing samples were improved, indicating the interaction of alginate and gelatin. Aerogel templates formed by Maillard reaction presented the micromorphology of lamellar aggregation, obvious changes of peak intensity in infrared spectrum and better thermal stability. The materials reached a considerable oil adsorption capacity of 23.31 g/g and oil holding capacity of 84.75%. Through Maillard reaction, oleogels showed good in vitro digestion properties. This work suggested that oleogels could be constructed from alginate-gelatin conjugates that formed the aerogel templates for oil adsorption, and Maillard reaction significantly affected the physical structures and oil capacities of alginate-gelatin compound systems.

Physiochemical characteristics and rheological investigations of camellia oil body emulsions stabilized by gum tragacanth as a coating layer.

In this work, gum tragacanth (GT) was coated on the camellia oil body (OB) emulsions using an electrostatic deposition technique, and effects were investigated over a wide range of pH values, ionic strengths, temperatures, and freeze-thaw cycles. Special attention has been paid to the rheological features as a function of hydrocolloid concentration, thixotropy (hysteresis loop and in-shear structure recovery), temperature, and frequency. The electrostatic GT-OB surface protein interactions, confirmed by ζ-potential and confocal laser scanning microscopy measurements, led to the reduction of flocculation effects and enhancement of steric stabilization due to the adsorption of polysaccharides to OB surfaces. The activation energy values (Ea) appeared in the range of 21.92 to 8.02 kJ/mol at pH 4 as GT concentration increased from 0 to 1 wt%. The OBs are soft droplets with the degree of structure recovery (DSR) ranged from 0.451 to 0.533; however, GT coating showed synergistic effect on the DSR.

Improved Oxidation Stability of Camellia Oil-in-Water Emulsions Stabilized by the Mixed Monolayer of Soy Protein Isolate/Bamboo Shoot Protein Complexes.

The complex of soy protein isolate (SPI)/bamboo shoot protein concentrate (BPC) was developed to stabilize camellia oil-in-water (O/W) emulsions. The surface hydrophobicity of the BPC/SPI complex driven by hydrogen bonds and electrostatic attractions was improved. With the increasing ratio of BPC in the complex, a tighter network layer structure of the complex was formed due to the rearrangement of proteins, and the emulsions showed a progressive enhancement in the gel-like structures. At the SPI/BPC ratio of 2:1, the emulsions had smaller droplet size and lower creaming index of 230 nm and 30%, and the emulsifying activity and stability indices of the emulsions were 803.72 min and 11.85 g/m2, respectively, indicating a better emulsifying activity and stability of emulsions. Meanwhile, the emulsions stabilized by the complex at the ratio of 2:1 showed better storage and antioxidant stability. These findings are expected to develop the application of bamboo shoots in emulsion-based food products such as mayonnaise, salad dressings, and sauces.

A Five-MicroRNA Signature Predicts the Prognosis in Nasopharyngeal Carcinoma.

BACKGROUND: There is no effective prognostic signature that could predict the prognosis of nasopharyngeal carcinoma (NPC). METHODS: We constructed a prognostic signature based on five microRNAs using random forest and Least Absolute Shrinkage And Selection Operator (LASSO) algorithm on the GSE32960 cohort (N = 213). We verified its prognostic value using three independent external validation cohorts (GSE36682, N = 62; GSE70970, N = 246; and TCGA-HNSC, N = 523). Through principal component analysis, receiver operating characteristic curve analysis, and C-index calculation, we confirmed the predictive accuracy of this prognostic signature. RESULTS: We calculated the risk score based on the LASSO algorithm and divided the patients into high- and low-risk groups according to the calculated optimal cutoff value. The patients in the high-risk group tended to have a worse prognosis outcome and chemotherapy response. The time-dependent receiver operating characteristic curve showed that the 1-year overall survival rate of the five-microRNA signature had an area under the curve of more than 0.83. A functional annotation analysis of the five-microRNA signature showed that the patients in the high-risk group were usually accompanied by activation of DNA repair and MYC-target pathways, while the patients in the low-risk group had higher immune-related pathway signals. CONCLUSIONS: We constructed a five-microRNA prognostic signature, which could accurately predict the prognosis of nasopharyngeal carcinoma, and constructed a nomogram that could conveniently predict the overall survival of patients.

Tumor suppressor p53 cross-talks with TRIM family proteins.

p53 is a key tumor suppressor. As a transcription factor, p53 accumulates in cells in response to various stress signals and selectively transcribes its target genes to regulate a wide variety of cellular stress responses to exert its function in tumor suppression. In addition to tumor suppression, p53 is also involved in many other physiological and pathological processes, e.g. anti-infection, immune response, development, reproduction, neurodegeneration and aging. To maintain its proper function, p53 is under tight and delicate regulation through different mechanisms, particularly the posttranslational modifications. The tripartite motif (TRIM) family proteins are a large group of proteins characterized by the RING, B-Box and coiled-coil (RBCC) domains at the N-terminus. TRIM proteins play important roles in regulation of many fundamental biological processes, including cell proliferation and death, DNA repair, transcription, and immune response. Alterations of TRIM proteins have been linked to many diseases including cancer, infectious diseases, developmental disorders, and neurodegeneration. Interestingly, recent studies have revealed that many TRIM proteins are involved in the regulation of p53, and at the same time, many TRIM proteins are also regulated by p53. Here, we review the cross-talk between p53 and TRIM proteins, and its impact upon cellular biological processes as well as cancer and other diseases.

The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer.

Hypoxia is a hallmark of solid tumors and plays a critical role in different steps of tumor progression, including proliferation, survival, angiogenesis, metastasis, metabolic reprogramming, and stemness of cancer cells. Activation of the hypoxia-inducible factor (HIF) signaling plays a critical role in regulating hypoxic responses in tumors. As a key tumor suppressor and transcription factor, p53 responds to a wide variety of stress signals, including hypoxia, and selectively transcribes its target genes to regulate various cellular responses to exert its function in tumor suppression. Studies have demonstrated a close but complex interplay between hypoxia and p53 signaling pathways. The p53 levels and activities can be regulated by the hypoxia and HIF signaling differently depending on the cell/tissue type and the severity and duration of hypoxia. On the other hand, p53 regulates the hypoxia and HIF signaling at multiple levels. Many tumor-associated mutant p53 proteins display gain-of-function (GOF) oncogenic activities to promote cancer progression. Emerging evidence has also shown that GOF mutant p53 can promote cancer progression through its interplay with the hypoxia and HIF signaling pathway. In this review, we summarize our current understanding of the interplay between the hypoxia and p53 signaling pathways, its impact upon cancer progression, and its potential application in cancer therapy.

Genetic and stochastic influences upon tumor formation and tumor types in Li-Fraumeni mouse models.

p53 is the most frequently mutated gene in human cancers. Li-Fraumeni syndrome patients inheriting heterozygous p53 mutations often have a much-increased risk to develop cancer(s) at early ages. Recent studies suggest that some individuals inherited p53 mutations do not have the early onset or high frequency of cancers. These observations suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype. To test this possibility, this study explored dominant genetic modifiers of Tp53 mutations in heterozygous mice with different genetic backgrounds. Both genetic and stochastic effects upon tumor formation were observed in these mice. The genetic background of mice carrying Tp53 mutations has a strong influence upon the tissue type of the tumor produced and the number of tumors formed in a single mouse. The onset age of a tumor is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. These observations help to explain the great diversity of cancers in different Li-Fraumeni patients over lifetimes.

The emerging role of leukemia inhibitory factor in cancer and therapy.

Leukemia inhibitory factor (LIF) is a multi-functional cytokine of the interleukin-6 (IL-6) superfamily. Initially identified as a factor that inhibits the proliferation of murine myeloid leukemia cells, LIF displays a wide variety of important functions in a cell-, tissue- and context-dependent manner in many physiological and pathological processes, including regulating cell proliferation, pluripotent stem cell self-renewal, tissue/organ development and regeneration, neurogenesis and neural regeneration, maternal reproduction, inflammation, infection, immune response, and metabolism. Emerging evidence has shown that LIF plays an important but complex role in human cancers; while LIF displays a tumor suppressive function in some types of cancers, including leukemia, LIF is overexpressed and exerts an oncogenic function in many more types of cancers. Further, targeting LIF has been actively investigated as a novel strategy for cancer therapy. This review summarizes the recent advances in the studies on LIF in human cancers and its potential application in cancer therapy. A better understanding of the role of LIF in different types of cancers and its underlying mechanisms will help to develop more effective strategies for cancer therapy.

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway.

Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely accepted that the role of p53 in regulation of cell cycle arrest, senescence and apoptosis contributes greatly to the function of p53 in tumor suppression, emerging evidence has implicated that p53 also exerts its tumor suppressive function through regulation of many other cellular processes, such as metabolism, anti-oxidant defense and ferroptosis. Ferroptosis is a unique iron-dependent form of programmed cell death driven by lipid peroxidation in cells. Ferroptosis has been reported to be involved in cancer, tissue ischemia/reperfusion injuries and neurodegenerative diseases. Recent studies have shown that ferroptosis can be regulated by p53 and its signaling pathway as well as tumor-associated mutant p53. Interestingly, the regulation of ferroptosis by p53 appears to be highly context-dependent. In this review, we summarize recent advances in the regulation of ferroptosis by p53 and its signaling pathway. Further elucidation of the role and molecular mechanism of p53 in ferroptosis regulation will yield new therapeutic strategies for cancer and other diseases, including neurodegenerative diseases and tissue ischemia/reperfusion injuries.

Identification of Apolipoprotein E as a Potential Diagnostic Biomarker of Nasopharyngeal Carcinoma.

PURPOSE: Apo-E, a secreted protein, is closely related to the migration and invasion of tumor cells. In this study, we aimed to analyze the expression of Apo-E in nasopharyngeal carcinoma (NPC) patients and cell lines, as well as its effects on NPC cell behavior. PATIENTS AND METHODS: Our study included 35 patients with NPC from Zhongnan Hospital. Expression levels of Apo-E in patients with NPC were examined by quantitative reverse transcription-polymerase chain reaction, Western blot, and immunohistochemical (IHC) staining. Receiver operating characteristic (ROC) curves were analyzed using the SPSS 22 software to estimate the sensitivity and specificity of the Apo-E protein in diagnosing NPC. Additionally, the level of Apo-E in NPC cell lines (NP69, 6-10B, and 5-8F) was investigated by Western blotting and IHC. RESULTS: Levels of Apo-E were higher in NPC patients than in controls. Moreover, ROC analysis revealed that increased Apo-E in the serum of NPC patients may act as a potential biomarker for NPC diagnosis (Area under the curve 0.917). Furthermore, similar results were also identified in NPC cancer cell lines. RNA interference technology was used to overexpress the endogenous Apo-E in the NPC cell line 6-10B. Wound healing and transwell assays indicated that the overexpression of Apo-E increased the number of cell colonies and migration ability, respectively. CONCLUSION: In this study, we found that Apo-E was elevated in NPC patients and may act as a potential biomarker for NPC diagnosis. In addition, Apo-E was upregulated in NPC cell lines and promoted cell growth, migration, and invasion.

Gain-of-function mutant p53 in cancer progression and therapy.

p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in >50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers.