Targeting tumor­associated macrophages: Critical players in tumor progression and therapeutic strategies (Review).

Tumor­associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor­promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage­based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM­targeting therapeutic strategies and discussed the obstacles and perspectives of TAM­targeting therapies for cancers.

Protocadherin-1 serves as a prognostic biomarker and promotes pancreatic cancer progression by suppressing CD8+ T cell infiltration through CCL5-CCR5 axis.

Previous studies have shown that Protocadherins (PCDHs) enhance tumor proliferation, invasion, and metastasis; yet their role in pancreatic cancer (PC) progression and the tumor immune microenvironment remains unclear. This study aims to elucidate the role of PCDH1 in different cancer types, with a particular focus on its impact on immune suppression in PC. Utilizing data from TCGA, GTEx, and Gent2 databases, we assessed the expression of PCDH1 across various cancer types. The prognostic value of PCDH1 was demonstrated through Cox regression, Kaplan-Meier analysis, and ROC curve, while its relationship with gene mutations, tumor mutational burden (TMB), immune cell infiltration, and other clinical factors was investigated using Spearman correlation. Furthermore, the effect of PCDH1 on PC malignancy was experimentally validated by a series of in vitro and in vivo assays. Our results show a significant upregulation of PCDH1 in various tumor types, which is associated with poor prognosis, suggesting its potential application as an independent prognostic biomarker. Notably, in PC, PCDH1 exhibited significant associations with gene mutations, TMB, and immune cell infiltration. Clinical validations revealed a correlation between high PCDH1 expression and poor prognosis, coupled with a low level of CD8+ T cell infiltration. Furthermore, both in vitro and in vivo experiments confirmed the role of PCDH1 in promoting PC cell proliferation and migration while inhibiting CD8+ T cell recruitment through its modulation of CCL5-CCR5 axis. In conclusion, PCDH1 regulates the proliferation and migration of PC cells as well as CD8+ T cell infiltration in PC. PCDH1 may serve as a prognostic biomarker in multiple tumor types.

Improving the prognosis of pancreatic cancer: insights from epidemiology, genomic alterations, and therapeutic challenges.

Pancreatic cancer, notorious for its late diagnosis and aggressive progression, poses a substantial challenge owing to scarce treatment alternatives. This review endeavors to furnish a holistic insight into pancreatic cancer, encompassing its epidemiology, genomic characterization, risk factors, diagnosis, therapeutic strategies, and treatment resistance mechanisms. We delve into identifying risk factors, including genetic predisposition and environmental exposures, and explore recent research advancements in precursor lesions and molecular subtypes of pancreatic cancer. Additionally, we highlight the development and application of multi-omics approaches in pancreatic cancer research and discuss the latest combinations of pancreatic cancer biomarkers and their efficacy. We also dissect the primary mechanisms underlying treatment resistance in this malignancy, illustrating the latest therapeutic options and advancements in the field. Conclusively, we accentuate the urgent demand for more extensive research to enhance the prognosis for pancreatic cancer patients.

Causal effect between gut microbiota and pancreatic cancer: a two-sample Mendelian randomization study.

BACKGROUND: Gut microbiota (GM) comprises a vast and diverse community of microorganisms, and recent studies have highlighted the crucial regulatory roles of various GM and their secreted metabolites in pancreatic cancer (PC). However, the causal relationship between GM and PC has yet to be confirmed. METHODS: In the present study, we used two-sample Mendelian randomization (MR) analysis to investigate the causal effect between GM and PC, with genome-wide association study (GWAS) from MiBioGen consortium as an exposure factor and PC GWAS data from FinnGen as an outcome factor. Inverse variance weighted (IVW) was used as the primary method for this study. RESULTS: At the genus level, we observed that Senegalimassilia (OR: 0.635, 95% CI: 0.403-0.998, P = 0.049) exhibited a protective effect against PC, while Odoribacter (OR:1.899, 95%CI:1.157-3.116, P = 0.011), Ruminiclostridium 9(OR:1.976,95%CI:1.128-3.461, P = 0.017), Ruminococcaceae (UCG011)(OR:1.433, 95%CI:1.072-1.916, P = 0.015), and Streptococcus(OR:1.712, 95%CI:1.071-1.736, P = 0.025) were identified as causative factors for PC. Additionally, sensitivity analysis, Cochran's Q test, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger regression indicated no heterogeneity, horizontal pleiotropy, or reverse causality between GM and PC. CONCLUSIONS: Our analysis establishes a causal effect between specific GM and PC, which may provide new insights into the potential pathogenic mechanisms of GM in PC and the assignment of effective therapeutic strategies.

The Diversity and Metabolism of Culturable Nitrate-Reducing Bacteria from the Photic Zone of the Western North Pacific Ocean.

To better understand bacterial communities and metabolism under nitrogen deficiency, 154 seawater samples were obtained from 5 to 200 m at 22 stations in the photic zone of the Western North Pacific Ocean. Total 634 nitrate-utilizing bacteria were isolated using selective media and culture-dependent methods, and 295 of them were positive for nitrate reduction. These nitrate-reducing bacteria belonged to 19 genera and 29 species and among them, Qipengyuania flava, Roseibium aggregatum, Erythrobacter aureus, Vibrio campbellii, and Stappia indica were identified from all tested seawater layers of the photic zone and at almost all stations. Twenty-nine nitrate-reducing strains representing different species were selected for further the study of nitrogen, sulfur, and carbon metabolism. All 29 nitrate-reducing isolates contained genes encoding dissimilatory nitrate reduction or assimilatory nitrate reduction. Six nitrate-reducing isolates can oxidize thiosulfate based on genomic analysis and activity testing, indicating that nitrate-reducing thiosulfate-oxidizing bacteria exist in the photic zone. Five nitrate-reducing isolates obtained near the chlorophyll a-maximum layer contained a dimethylsulfoniopropionate synthesis gene and three of them contained both dimethylsulfoniopropionate synthesis and cleavage genes. This suggests that nitrate-reducing isolates may participate in dimethylsulfoniopropionate synthesis and catabolism in photic seawater. The presence of multiple genes for chitin degradation and extracellular peptidases may indicate that almost all nitrate-reducing isolates (28/29) can use chitin and proteinaceous compounds as important sources of carbon and nitrogen. Collectively, these results reveal culturable nitrate-reducing bacterial diversity and have implications for understanding the role of such strains in the ecology and biogeochemical cycles of nitrogen, sulfur, and carbon in the oligotrophic marine photic zone.

The Functional Role of LncRNA UCA1 in Pancreatic Cancer: a mini-review.

Pancreatic cancer (PaC) is a common malignant tumor of the digestive tract, with a 5-year survival rate of less than 5% and high mortality rate in the world. LncRNAs have been showed to possess multiple biological functions in growth, differentiation, and proliferation, which play an important role in different biological processes and diseases, especially in the development of tumors. LncRNA UCA1, which is firstly identified in human bladder cancer, has been showed to be a tumor promoter in pancreatic cancer. Recent researches have showed that UCA1 might promote pancreatic carcinogenesis and progression, and correlate with drug resistance. In this review, we address the biological function and regulatory mechanism of UCA1 in pancreatic cancer, which might give a new approach for clinical diagnosis and treatment.

Marinigracilibium pacificum gen. nov., sp. nov., a starch-degrading bacterium isolated from tropical western Pacific.

The Gram-stain-negative, golden-yellow-colored, non-spore-forming, strictly aerobic, slender rod-shaped bacterial strain, designated KN852T, was isolated from a seamount in the tropical western Pacific. The predominant respiratory quinone was MK-7 and the polar lipid profiles contained phosphatidylethanolamine, one unidentified phospholipid and six unidentified polar lipids. The predominant cellular fatty acids were iso-C15:0, summed feature 3(C16:1ω7c and/or iso-C15:0 2OH), iso-C17:0 3OH and iso-C15:1 G. Phylogenetic analyses of 16S rRNA gene sequence revealed that strain KN852T was affiliated with the family Flammeovirgaceae of the phylum Bacteroidota and formed a distinct lineage. The genomic DNA G + C content of strain KN852T was 34.8%. Collectively, based on phenotypic, chemotaxonomic, phylogenetic and genomic evidence presented, strain KN852T represents a novel species of a novel genus of the family Flammeovirgaceae, for which the name Marinigracilibium pacificum gen. nov., sp. nov. is proposed. The type strain is KN852T (= CGMCC 1.17119T = KCTC 72433T).

Functions and clinical applications of exosomes in pancreatic cancer.

Pancreatic cancer (PC) is one of the most malignant tumors and has an abysmal prognosis, with a 5-year survival rate of only 11%. At present, the main clinical dilemmas in PC are the lack of biomarkers and the unsatisfactory therapeutic effects. The treatments for and outcomes of PC have improved, but remain unsatisfactory. Exosomes are nanosized extracellular vesicles, and an increasing number of studies have found that exosomes play an essential role in tumor pathology. In this review, we describe the process of exosome biogenesis, as well as exosome extraction methods and identification strategies, and we then explain in detail the roles and mechanisms of exosomes in invasion, metastasis, chemoresistance and immunosuppression in PC. Finally, we summarize the clinical applications of exosomes. Our observations indicate that exosomes represent a novel direction in the clinical treatment of PC.

Itaconate attenuates osteoarthritis by inhibiting STING/NF-κB axis in chondrocytes and promoting M2 polarization in macrophages.

Osteoarthritis (OA) is a progressive joint disease characterized by the degradation and destruction of articular cartilage, which is involved with pathological microenvironmental alterations induced by damaged chondrocytes and inflammatory macrophages. However, the current therapies cannot effectively alleviate the progression of OA. Our previous studies have shown that the pathological process of OA progression is accompanied by DNA damage, and inhibition of STING, a key molecule in DNA damage, may become a potential method for the treatment of OA. Itaconate, a metabolite highly expressed in macrophages under inflammatory conditions, has shown a wide range of anti-inflammatory effects, but its effect on OA and its underlying mechanism has not yet been studied. In this study, we found that exogenous supplementation of itaconate can activate Nrf2, and accordingly inhibit the STING-dependent NF-κB pathway, thereby alleviating the inflammation, ECM degeneration and senescence of chondrocytes stimulated by IL-1ß. In addition, itaconate can regulate the polarization of RAW264.7 macrophages, further reducing the apoptosis of chondrocytes. In vivo, intra-articular injection of itaconate reduces the degradation of cartilage and inflammation of synovial membrane in the mouse OA model. In conclusion, the present work suggests that exogenous supplementation of itaconate inhibits the inflammation, senescence and ECM degeneration of chondrocytes through the Nrf2/STING/NF-κB axis and regulates the polarization of synovial macrophages, thereby ameliorating the progression of OA, which supports that itaconate as a potential drug for the treatment of OA.

The role of NLRP3 inflammasome in digestive system malignancy.

Digestive system malignancies, the most common types of cancer and a major cause of death in the worldwide, are generally characterized by high morbidity, insidious symptoms and poor prognosis. NLRP3 inflammasome, the most studied inflammasome member, is considered to be crucial in tumorigenesis. In this paper, we reviewed its pro-tumorigenic and anti-tumorigenic properties in different types of digestive system malignancy depending on the types of cells, tissues and organs involved, which would provide promising avenue for exploring new anti-cancer therapies.

Cycloastragenol and Astragaloside IV activate telomerase and protect nucleus pulposus cells against high glucose-induced senescence and apoptosis.

In diabetes-induced intervertebral disc degeneration (Db-IVDD), senescence and apoptosis of nucleus pulposus cells (NPCs) are major contributing factors. Telomere attrition and telomerase downregulation are some of the main reasons for senescence and eventual apoptosis. The derivatives of the Chinese herb Astragalus membranaceus, Cycloastragenol (CAG) and Astragaloside IV (AG-IV), are reportedly effective telomerase activators against telomere shortening; however, their effect in Db-IVDD have not been explored. The present study simultaneously investigated the regulation of these derivatives on senescence, apoptosis, telomeres and telomerase a model of high-glucose (HG)-induced stress using rat primary NPCs. The NPCs were stimulated with HG (50 mM) to evoke HG-induced stress, and the effects of CAG and AG-IV were observed on: i) The expression level of senescence marker p16; ii) ß-Gal staining; iii) the expression levels of apoptosis markers cleaved-caspase 3 (c-C3), BAX and Bcl-2; iv) telomerase activation with telomerase reverse transcriptase (TERT) mRNA and protein expression, while telomere length was measured with reverse transcription-quantitative PCR. Cell proliferation was determined using the Cell Counting Kit-8 assay. Results demonstrated an upregulation in the expression levels of p16, c-C3 and BAX, and increased ß-Gal staining; while the expression level of Bcl-2 was downregulated in a concentration-dependent manner. Pre-treatment of the NPCs with CAG and AG-IV downregulated the protein expression levels of p16, c-C3 and BAX, and decreased the percentage of ß-Gal and FITC staining; while upregulating the Bcl-2 expression. These effects protected the cells from HG stress-induced senescence and apoptosis. HG also downregulated the expression profile of TERT and shortened the telomere length in a glucose concentration-dependent manner. While pretreatment with CAG and AG-IV upregulated TERT expression and ameliorated the telomere attrition. CAG and AG-IV also increased cell proliferation and improved cell morphology in HG conditions. Overall, these findings indicated that CAG and AG-IV suppressed HG stress-induced senescence and apoptosis, in addition to enhancing telomerase activation and lengthening of the Telomere. Therefore, CAG and AG-IV prolonged the replicative capability and longevity of the NPCs and they have the potential to be therapeutic agents in Db-IVDD.