Potential and application of abortive transcripts as a novel molecular marker of cancers.

Abortive transcript (AT) is a 2-19 nt long non-coding RNA that is produced in the abortive initiation stage. Abortive initiation was found to be closely related to RNA polymerase through in vitro experiments. Therefore, the distribution of AT length and the scale of abortive initiation are correlated to the promoter, discriminator, and transcription initiation sequence, and can be affected by transcription elongation factors. AT plays an important role in the occurrence and development of various diseases. Here we summarize the discovery of AT, the factors responsible for AT formation, the detection methods and biological functions of AT, to provide new clues for finding potential targets in the early diagnosis and treatment of cancers.

Squamous cell carcinoma of ear and temporal bone: A retrospective study on clinicopathological predictors.

BACKGROUND: Ear and temporal bone squamous cell carcinoma (ETBSCC) is a rare and aggressive malignant tumor with minimal clinicopathological studies. The object of this study was to retrospectively evaluate the predictive effect of clinicopathological variables on the 5-year overall survival (OS) rate of ETBSCC patients in a single tertiary medical center in Tianjin, China. METHODS: A cohort of 44 patients with diagnosed ETBSCC from December 2012 to August 2022 were retrospectively studied. Univariate and multivariate analysis were, respectively, performed for the assessment of clinicopathological predictors, including sex, age, history of chronic suppurative otitis media (CSOM), lesion side, diameter, the choice of surgical approach, parotidectomy, neck dissection, adjuvant therapies, T stage, lymph node metastasis, tumor grade, margin, perineural invasion (PNI), and Ki-67 index. RESULTS: Seventeen females and 27 males were included, with the mean age of 65 years old, ranging from 36 to 89 years. The 5-year OS rate was 43% (mean 51 months, 95% confidence interval [CI] = 39-64). Significant prediction of a worse prognosis for 5-year OS rate was observed under univariate analysis for advanced T stage, positive margin, identified PNI, and higher Ki-67 index, respectively. Advanced T stage was confirmed to be an independent prognostic factor strongly affecting 5-year OS rate among this cohort of patients using a multivariate cox proportional hazard model. CONCLUSION: We found that clinicopathological parameters, especially postoperative pathological parameters, play a critical role in predicting the prognosis of ETBSCC patients.

Structure optimization of Cmpd-15 as negative allosteric modulators for the ß2-adrenergic receptor.

19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H1-H19) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (J1-J5) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the ß2-adrenergic receptor (ß2AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at ß2AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against ß2AR than Cmpd-15, the first reported ß2AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for ß2AR. Furthermore, the active pyrazole derivatives have relative better drug-like profiles than Cmpd-15. Taken together, we discovered a series of derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides as a novel scaffold of ß2AR NAM.

Dissecting the abilities of murine Siglecs to interact with gangliosides.

Siglecs are cell surface receptors whose functions are tied to the binding of their sialoglycan ligands. Recently, we developed an optimized liposome formulation and used it to investigate the binding of human Siglecs (hSiglec) against a panel of gangliosides. Animal models, more specifically murine models, are used to understand human biology, however, species-specific differences can complicate the interpretation of the results. Herein, we used our optimized liposome formulation to dissect the interactions between murine Siglecs (mSiglecs) and gangliosides to assess the appropriateness of mSiglecs as a proxy to better understand the biological roles of hSiglec-ganglioside interactions. Using our optimized liposome formulation, we found that ganglioside binding is generally conserved between mice and humans with mSiglec-1, -E, -F, and -15 binding multiple gangliosides like their human counterparts. However, in contrast to the hSiglecs, we observed little to no binding between the mSiglecs and ganglioside GM1a. Detailed analysis of mSiglec-1 interacting with GM1a and its structural isomer, GM1b, suggests that mSiglec-1 preferentially binds α2-3-linked sialic acids presented from the terminal galactose residue. The ability of mSiglecs to interact or not interact with gangliosides, particularly GM1a, has implications for using mice to study neurodegenerative diseases, infections, and cancer, where interactions between Siglecs and glycolipids have been proposed to modulate these human diseases.

Microbial diversity and metabolic pathways linked to benzene degradation in petrochemical-polluted groundwater.

The rapid advance in shotgun metagenome sequencing has enabled us to identify uncultivated functional microorganisms in polluted environments. While aerobic petrochemical-degrading pathways have been extensively studied, the anaerobic mechanisms remain less explored. Here, we conducted a study at a petrochemical-polluted groundwater site in Henan Province, Central China. A total of twelve groundwater monitoring wells were installed to collect groundwater samples. Benzene appeared to be the predominant pollutant, detected in 10 out of 12 samples, with concentrations ranging from 1.4 µg/L to 5,280 µg/L. Due to the low aquifer permeability, pollutant migration occurred slowly, resulting in relatively low benzene concentrations downstream within the heavily polluted area. Deep metagenome sequencing revealed Proteobacteria as the dominant phylum, accounting for over 63 % of total abundances. Microbial α-diversity was low in heavily polluted samples, with community compositions substantially differing from those in lightly polluted samples. dmpK encoding the phenol/toluene 2-monooxygenase was detected across all samples, while the dioxygenase bedC1 was not detected, suggesting that aerobic benzene degradation might occur through monooxygenation. Sequence assembly and binning yielded 350 high-quality metagenome-assembled genomes (MAGs), with 30 MAGs harboring functional genes associated with aerobic or anaerobic benzene degradation. About 80 % of MAGs harboring functional genes associated with anaerobic benzene degradation remained taxonomically unclassified at the genus level, suggesting that our current database coverage of anaerobic benzene-degrading microorganisms is very limited. Furthermore, two genes integral to anaerobic benzene metabolism, i.e, benzoyl-CoA reductase (bamB) and glutaryl-CoA dehydrogenase (acd), were not annotated by metagenome functional analyses but were identified within the MAGs, signifying the importance of integrating both contig-based and MAG-based approaches. Together, our efforts of functional annotation and metagenome binning generate a robust blueprint of microbial functional potentials in petrochemical-polluted groundwater, which is crucial for designing proficient bioremediation strategies.

Synthesis of sinomenine derivatives with potential anti-leukemia activity.

In recent years, with sinomenine hydrochloride as the main ingredient, Qingfengteng had been formulated as various dosage forms for clinical treatment. Subsequent findings confirmed a variety of biological roles for sinomenine. Here, 15 H2S-donating sinomenine derivatives were synthesized. Target hybrids a11 displayed substantial cytotoxic effects on cancer cell lines, particularly against K562 cells, with an IC50 value of 1.36 µM. In-depth studies demonstrated that a11 arrested cell cycle at G1 phase, induced apoptosis via both morphological changes in nucleus and membrane potential collapse in mitochondria. These results indicated a11 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

Intraepithelial mast cells drive gasdermin C-mediated type 2 immunity.

A specialized population of mast cells residing within epithelial layers, currently known as intraepithelial mast cells (IEMCs), was originally observed over a century ago, yet their physiological functions have remained enigmatic. In this study, we unveil an unexpected and crucial role of IEMCs in driving gasdermin C-mediated type 2 immunity. During helminth infection, αEß7 integrin-positive IEMCs engaged in extensive intercellular crosstalk with neighboring intestinal epithelial cells (IECs). Through the action of IEMC-derived proteases, gasdermin C proteins intrinsic to the epithelial cells underwent cleavage, leading to the release of a critical type 2 cytokine, interleukin-33 (IL-33). Notably, mast cell deficiency abolished the gasdermin C-mediated immune cascade initiated by epithelium. These findings shed light on the functions of IEMCs, uncover a previously unrecognized phase of type 2 immunity involving mast cell-epithelial cell crosstalk, and advance our understanding of the cellular mechanisms underlying gasdermin C activation.

Spatial omics techniques and data analysis for cancer immunotherapy applications.

In-depth profiling of cancer cells/tissues is expanding our understanding of the genomic, epigenomic, transcriptomic, and proteomic landscape of cancer. However, the complexity of the cancer microenvironment, particularly its immune regulation, has made it difficult to exploit the potential of cancer immunotherapy. High-throughput spatial omics technologies and analysis pipelines have emerged as powerful tools for tackling this challenge. As a result, a potential revolution in cancer diagnosis, prognosis, and treatment is on the horizon. In this review, we discuss the technological advances in spatial profiling of cancer around and beyond the central dogma to harness the full benefits of immunotherapy. We also discuss the promise and challenges of spatial data analysis and interpretation and provide an outlook for the future.

Comprehensive analysis of the protein phosphatase 2A regulatory subunit B56ε in pan-cancer and its role and mechanism in hepatocellular carcinoma.

BACKGROUND: B56ε is a regulatory subunit of the serine/threonine protein phosphatase 2A, which is abnormally expressed in tumors and regulates various tumor cell functions. At present, the application of B56ε in pan-cancer lacks a comprehensive analysis, and its role and mechanism in hepatocellular carcinoma (HCC) are still unclear. AIM: To analyze B56ε in pan-cancer, and explore its role and mechanism in HCC. METHODS: The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Profiling Interactive Analysis, and Tumor Immune Estimation Resource databases were used to analyze B56ε expression, prognostic mutations, somatic copy number alterations, and tumor immune characteristics in 33 tumors. The relationships between B56ε expression levels and drug sensitivity, immunotherapy, immune checkpoints, and human leukocyte antigen (HLA)-related genes were further analyzed. Gene Set Enrichment Analysis (GSEA) was performed to reveal the role of B56ε in HCC. The Cell Counting Kit-8, plate cloning, wound healing, and transwell assays were conducted to assess the effects of B56ε interference on the malignant behavior of HCC cells. RESULTS: In most tumors, B56ε expression was upregulated, and high B56ε expression was a risk factor for adrenocortical cancer, HCC, pancreatic adenocarcinoma, and pheochromocytoma and paraganglioma (all P < 0.05). B56ε expression levels were correlated with a variety of immune cells, such as T helper 17 cells, B cells, and macrophages. There was a positive correlation between B56ε expression levels with immune checkpoint genes and HLA-related genes (all P < 0.05). The expression of B56ε was negatively correlated with the sensitivity of most chemotherapy drugs, but a small number showed a positive correlation (all P < 0.05). GSEA analysis showed that B56ε expression was related to the cancer pathway, p53 downstream pathway, and interleukin-mediated signaling in HCC. Knockdown of B56ε expression in HCC cells inhibited the proliferation, migration, and invasion capacity of tumor cells. CONCLUSION: B56ε is associated with the microenvironment, immune evasion, and immune cell infiltration of multiple tumors. B56ε plays an important role in HCC progression, supporting it as a prognostic marker and potential therapeutic target for HCC.

Dietary polyphenols regulate appetite mechanism via gut-brain axis and gut homeostasis.

Nowadays, due to the rise of fast-food consumption, the metabolic diseases are increasing as a result of high-sugar and high-fat diets. Therefore, there is an urgent need for natural, healthy and side-effect-free diets in daily life. Whole grain supplementation can enhance satiety and regulate energy metabolism, effects that have been attributed to polyphenol content. Dietary polyphenols interact with gut microbiota to produce intermediate metabolites that can regulate appetite while also enhancing prebiotic effects. This review considers how interactions between gut metabolites and dietary polyphenols might regulate appetite by acting on the gut-brain axis. In addition, further advances in the study of dietary polyphenols and gut microbial metabolites on energy metabolism and gut homeostasis are summarized. This review contributes to a better understanding of how dietary polyphenols regulate appetite via the gut-brain axis, thereby providing nutritional references for citizens' dietary preferences.

Autoimmune diseases exhibit shared alterations in the gut microbiota.

OBJECTIVE: Accumulating evidence from microbial studies have highlighted the modulatory roles of intestinal microbes in numerous human diseases, however, the shared microbial signatures across different diseases remain relatively unclear. METHODS: To consolidate existing knowledge across multiple studies, we performed meta-analyses of 17 disease types, covering 34 case-control datasets of 16S rRNA sequencing data, to identify shared alterations among different diseases. Furthermore, the impact of a microbial species, Lactobacillus salivarius, was established in a dextran sodium sulphate-induced colitis model and a collagen type II-induced arthritis mouse model. RESULTS: Microbial alterations among autoimmune diseases were substantially more consistent compared with that of other diseases (cancer, metabolic disease and nervous system disease), with microbial signatures exhibiting notable discriminative power for disease prediction. Autoimmune diseases were characterized by the enrichment of Enterococcus, Veillonella, Streptococcus and Lactobacillus and the depletion of Ruminococcus, Gemmiger, Oscillibacter, Faecalibacterium, Lachnospiracea incertae sedis, Anaerostipes, Coprococcus, Alistipes, Roseburia, Bilophila, Barnesiella, Dorea, Ruminococcus2, Butyricicoccus, Phascolarctobacterium, Parabacteroides and Odoribacter, among others. Functional investigation of L. salivarius, whose genus was commonly enriched in numerous autoimmune diseases, demonstrated protective roles in two separate inflammatory mouse models. CONCLUSION: Our study highlights a strong link between autoimmune diseases and the gut microbiota, with notably consistent microbial alterations compared with that of other diseases, indicating that therapeutic strategies that target the gut microbiome may be transferable across different autoimmune diseases. Functional validation of L. salivarius highlighted that bacterial genera associated with disease may not always be antagonistic, but may represent protective or adaptive responses to disease.

Dissecting Maillard reaction production in fried foods: Formation mechanisms, sensory characteristic attribution, control strategy, and gut homeostasis regulation.

Foods rich in carbohydrates or fats undergo the Maillard reaction during frying, which promotes the color, flavor and sensory characteristics formation. In the meanwhile, Maillard reaction intermediates and advanced glycation end products (AGEs) have a negative impact on food sensory quality and gut homeostasis. This negative effect can be influenced by food composition and other processing factors. Whole grain products are rich in polyphenols, which can capture carbonyl compounds in Maillard reaction, and reduce the production of AGEs during frying. This review summarizes the Maillard reaction production intermediates and AGEs formation mechanism in fried food and analyzes the factors affecting the sensory formation of food. In the meanwhile, the effects of Maillard reaction intermediates and AGEs on gut homeostasis were summarized. Overall, the innovative processing methods about the Maillard reaction are summarized to optimize the sensory properties of fried foods while minimizing the formation of AGEs.

Trioxidized cysteine in the aging proteome mimics the structural dynamics and interactome of phosphorylated serine.

Aging is the primary risk factor for the development of numerous human chronic diseases. On a molecular level, it significantly impacts the regulation of protein modifications, leading to the accumulation of degenerative protein modifications (DPMs) such as aberrant serine phosphorylation (p-Ser) and trioxidized cysteine (t-Cys) within the proteome. The altered p-Ser is linked to abnormal cell signaling, while the accumulation of t-Cys is associated with chronic diseases induced by oxidative stress. Despite this, the potential cross-effects and functional interplay between these two critical molecular factors of aging remain undisclosed. This study analyzes the aging proteome of wild-type C57BL/6NTac mice over 2 years using advanced proteomics and bioinformatics. Our objective is to provide a comprehensive analysis of how t-Cys affects cell signaling and protein structure in the aging process. The results obtained indicate that t-Cys residues accumulate in the aging proteome, interact with p-Ser interacting enzymes, as validated in vitro, and alter their structures similarly to p-Ser. These findings have significant implications for understanding the interplay of oxidative stress and phosphorylation in the aging process. Additionally, they open new venues for further research on the role(s) of these protein modifications in various human chronic diseases and aging, wherein exacerbated oxidation and aberrant phosphorylation are implicated.

Upregulation of FAM83F by c-Myc promotes cervical cancer growth and aerobic glycolysis via Wnt/ß-catenin signaling activation.

Cervical cancer (CC) seriously affects women's health. Therefore, elucidation of the exact mechanisms and identification of novel therapeutic targets are urgently needed. In this study, we identified FAM83F, which was highly expressed in CC cells and tissues, as a potential target. Our clinical data revealed that FAM83F protein expression was markedly elevated in CC tissues and was positively correlated with poor prognosis. Moreover, we observed that FAM83F knockdown significantly inhibited cell proliferation, induced apoptosis, and suppressed glycolysis in CC cells, while its overexpression displayed opposite effects. Mechanistically, FAM83F regulated CC cell growth and glycolysis by the modulation of Wnt/ß-catenin pathway. The enhancing effects of FAM83F overexpression on CC cell proliferation and glycolysis could be impaired by the Wnt/ß-catenin inhibitor XAV939. Moreover, we found that c-Myc bound to the FAM83F promoter and activated the transcription of FAM83F. Notably, knockdown of FAM83F impaired the enhancement of cell proliferation and glycolysis induced by ectopic c-Myc. Consistent with in vitro findings, results from a xenograft mouse model confirmed the promoting role of FAM83F. In summary, our study demonstrated that FAM83F promoted CC growth and glycolysis through regulating the Wnt/ß-catenin pathway, suggesting that FAM83F may be a potential molecular target for CC treatment. Schematic summary of c-Myc-activated FAM83F transcription to promote cervical cancer growth and glycolysis by targeting the Wnt/ß-catenin signal pathway.

Prediction model of no-response before the first transarterial chemoembolization for hepatocellular carcinoma: TACF score.

Previous clinic models for patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE) mainly focused on the overall survival, whereas a simple-to-use tool for predicting the response to the first TACE and the management of risk classification before TACE are lacking. Our aim was to develop a scoring system calculated manually for these patients. A total of 437 patients with hepatocellular carcinoma (HCC) who underwent TACE treatment were carefully selected for analysis. They were then randomly divided into two groups: a training group comprising 350 patients and a validation group comprising 77 patients. Furthermore, 45 HCC patients who had recently undergone TACE treatment been included in the study to validate the model's efficacy and applicability. The factors selected for the predictive model were comprehensively based on the results of the LASSO, univariate and multivariate logistic regression analyses. The discrimination, calibration ability and clinic utility of models were evaluated in both the training and validation groups. A prediction model incorporated 3 objective imaging characteristics and 2 indicators of liver function. The model showed good discrimination, with AUROCs of 0.735, 0.706 and 0.884 and in the training group and validation groups, and good calibration. The model classified the patients into three groups based on the calculated score, including low risk, median risk and high-risk groups, with rates of no response to TACE of 26.3%, 40.2% and 76.8%, respectively. We derived and validated a model for predicting the response of patients with HCC before receiving the first TACE that had adequate performance and utility. This model may be a useful and layered management tool for patients with HCC undergoing TACE.

Natural products modulate NLRP3 in ulcerative colitis.

Ulcerative colitis (UC) is a clinically common, progressive, devastating, chronic inflammatory disease of the intestine that is recurrent and difficult to treat. Nod-like receptor protein 3 (NLRP3) is a protein complex composed of multiple proteins whose formation activates cysteine aspartate protease-1 (caspase-1) to induce the maturation and secretion of inflammatory mediators such as interleukin (IL)-1ß and IL-18, promoting the development of inflammatory responses. Recent studies have shown that NLRP3 is associated with UC susceptibility, and that it maintains a stable intestinal environment by responding to a wide range of pathogenic microorganisms. The mainstay of treatment for UC is to control inflammation and relieve symptoms. Despite a certain curative effect, there are problems such as easy recurrence after drug withdrawal and many side effects associated with long-term medication. NLRP3 serves as a core link in the inflammatory response. If the relationship between NLRP3 and gut microbes and inflammation-associated factors can be analyzed concerning its related inflammatory signaling pathways, its expression status as well as specific mechanism in the course of IBD can be elucidated and further considered for clinical diagnosis and treatment of IBD, it is expected that the development of lead compounds targeting the NLRP3 inflammasome can be developed for the treatment of IBD. Research into the prevention and treatment of UC, which has become a hotbed of research in recent years, has shown that natural products are rich in therapeutic means, and multi-targets, with fewer adverse effects. Natural products have shown promise in treating UC in numerous basic and clinical trials over the past few years. This paper describes the regulatory role of the NLRP3 inflammasome in UC and the mechanism of recent natural products targeting NLRP3 against UC, which provides a reference for the clinical treatment of this disease.

Petroleum pollution changes microbial diversity and network complexity of soil profile in an oil refinery.

Introduction: Petroleum pollution resulting from spills and leakages in oil refinery areas has been a significant environmental concern for decades. Despite this, the effects of petroleum pollutants on soil microbial communities and their potential for pollutant biodegradation still required further investigation. Methods: In this study, we collected 75 soil samples from 0 to 5 m depths of 15 soil profiles in an abandoned refinery to analyze the effect of petroleum pollution on soil microbial diversity, community structure, and network co-occurrence patterns. Results: Our results suggested soil microbial a-diversity decreased under high C10-C40 levels, coupled with significant changes in the community structure of soil profiles. However, soil microbial network complexity increased with petroleum pollution levels, suggesting more complex microbial potential interactions. A module specific for methane and methyl oxidation was also found under high C10-C40 levels of the soil profile, indicating stronger methanotrophic and methylotrophic metabolic activities at the heavily polluted soil profile. Discussion: The increased network complexity observed may be due to more metabolic pathways and processes, as well as increased microbial interactions during these processes. These findings highlight the importance of considering both microbial diversity and network complexity in assessing the effects of petroleum pollution on soil ecosystems.