Tissue Cells Research Articles

The Dual Role of Cellular Senescence in Macrophages: Unveiling the Hidden Driver of Age-Related Inflammation in Kidney Disease.

Aging is a complex biological process that involves the gradual decline of cellular, tissue, and organ functions. In kidney, aging manifests as tubular atrophy, glomerulosclerosis, and progressive renal function decline. The critical role of senescence-associated macrophage in diseases, particularly kidney diseases, is increasingly recognized. During this process, macrophages exhibit a range of pro-damage response to senescent tissues and cells, while the aging of macrophages themselves also significantly influences disease progression, creating a bidirectional regulatory role between aging and macrophages. To explore this bidirectional mechanism, this review will elucidate the origin, characteristic, phenotype, and function of macrophages in response to the senescence-associated secretory phenotype (SASP), extracellular vesicles from senescent cells, and the senescence cell-engulfment suppression (SCES), particularly in the context of kidney disease. Additionally, it will discuss the characteristics of senescent macrophage, such as common markers, and changes in autophagy, metabolism, gene regulation, phagocytosis, antigen presentation, and exosome secretion, along with their physiological and pathological impacts on renal tissue cells. Furthermore, exploring therapies and drugs that modulate the function of senescent macrophages or eliminate senescent cells may help slow the progression of kidney aging and damage.

Interaction Between Sclerostin and Mast Cells in Fibro-Osseous Lesions of the Jaws.

To assess the sclerostin, β-catenin, and tryptase expression in fibro-osseous lesions (FOL) of the jaws. Immunohistochemistry analysis was performed for these proteins on FOL and non-lesional bone. The sclerostin-positive cells were scored from 0 (no expression) to 3 (high expression). We analyzed 46 FOL biopsies and selected 38 patients. Categorization showed 15 fibrous dysplasia (FD), eight juvenile trabecular ossifying fibroma (JTOF), two psammomatoid ossifying fibroma (PsOF), and 13 FOL. We found more sclerostin-positive cells in fibrous tissue than in bone, showing a phenotype like mast cells with strong dot-cytoplasmic positivity. The analysis of sclerostin-positive cell lesions (scored as 2 and 3) showed also tryptase positivity in 80.9% of 21 biopsies. β-catenin was diffusely expressed on the fibrous component, mostly with cytosol staining. Non-lesional bone showed sclerostin expression in medullary spaces and a few osteocytes. Sclerostin-positive cells are mostly found in the fibrous tissue of FOL, and the tryptase mast cell marker was present in most of the lesions that were positive for sclerostin.

Evaluation of Pentraxin-3 and Interleukin-6 Levels in Serum and Gingival Crevicular Fluid in Patients with Generalized Periodontitis and Periodontal Health Controls Before and After Scaling and Root Planing

Objectives: Pentraxin-3 (PTX3) and interleukin-6 (IL-6) are two of the most important inflammatory cytokines produced by cells in periodontal tissues. The present study aims to evaluate the levels of PTX3 and IL-6 in serum and gingival crevicular fluid (GCF) in patients with generalized periodontitis stages II and III, grades A and B, and periodontal health individuals before and after scaling and root planing (SRP). Materials and Methods: In this study, 22 patients with periodontitis (12 males and 10 females) and 22 periodontal health controls (11 males and 11 females) were selected. All patients underwent full-mouth SRP. Serum and GCF samples were collected before and one month after SRP. PTX3 and IL-6 levels in serum and GCF samples were evaluated by enzyme-linked immunosorbent assay. Data analysis was performed using Mann-Whitney U and Wilcoxon tests (P<0.05). Results: Serum levels of PTX3 were significantly higher in the periodontitis group than the controls (P<0.05). GCF PTX3 levels and serum and GCF IL-6 levels were not significantly different between the groups. Furthermore, this study did not show any significant changes in the levels of these cytokines before and after SRP. Conclusion: Among the studied cytokines and media, only serum PTX3 levels showed a significant difference between periodontitis patients and healthy controls and could serve as a diagnostic marker of periodontal inflammation. SRP did not affect the levels of these cytokines, suggesting that other inflammatory factors may be involved in disease process. However, additional longitudinal prospective studies are needed to confirm these results.

Effects of moderate intensity exercise on liver metabolism in mice based on multi-omics analysis

Physical exercise is beneficial to keep physical and mental health. The molecular mechanisms underlying exercise are still worth exploring. The healthy adult mice after six weeks of moderate-intensity exercise (experimental group) and sedentary mice (control group) were used to perform transcriptomic, proteomic, lactylation modification, and metabolomics analysis. In addition, gene sets related to hypoxia, glycolysis, and fatty acid metabolism were used to aid in the screening of hub genes. The mMCP-counter was employed to evaluate infiltration of immune cells in murine liver tissues. Transcriptomics analysis revealed 82 intersection genes related to hypoxia, glycolysis, and fatty acid metabolism. Proteomics and lactylation modification analysis identified 577 proteins and 141 differentially lactylation modification proteins. By overlapping 82 intersection genes with 577 differentially expressed proteins and 141 differentially lactylation modification proteins, three hub genes (Aldoa, Acsl1, and Hadhb) were obtained. The immune infiltration analysis revealed a decreased score for monocytes/macrophages and an increased score for endothelial cells in the experimental group. Then, 459 metabolites in positive mode and 181 metabolites in negative mode were identified. The “Metabolic pathways” (mmu01100) was a common pathway between intersection genes-enriched pathways and metabolites-enriched pathways. These findings highlight the pivotal roles of hub genes in the glycolysis and fatty acid metabolism under the context of chronic exercise.

Unveiling chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing

Chemotherapy is widely used to treat lung adenocarcinoma (LUAD) patients comprehensively. Considering the limitations of chemotherapy due to drug resistance and other issues, it is crucial to explore the impact of chemotherapy and immunotherapy on these aspects. In this study, tumor samples from nine LUAD patients, of which four only received surgery and five received neoadjuvant chemotherapy, were subjected to scRNA-seq analysis. In vitro and in vivo assays, including flow cytometry, immunofluorescence, Seahorse assay, and tumor xenograft models, were carried out to validate our findings. A total of 83,622 cells were enrolled for subsequent analyses. The composition of cell types exhibited high heterogeneity across different groups. Functional enrichment analysis revealed that chemotherapy drove significant metabolic reprogramming in tumor cells and macrophages. We identified two subtypes of macrophages: Anti-mac cells (CD45+CD11b+CD86+) and Pro-mac cells (CD45+CD11b+ARG +) and sorted them by flow cytometry. The proportion of Pro-mac cells in LUAD tissues increased significantly after neoadjuvant chemotherapy. Pro-mac cells promote tumor growth and angiogenesis and also suppress tumor immunity. Moreover, by analyzing the remodeling of T and B cells induced by neoadjuvant therapy, we noted that chemotherapy ignited a relatively more robust immune cytotoxic response toward tumor cells. Our study demonstrates that chemotherapy induces metabolic reprogramming within the tumor microenvironment of LUAD, particularly affecting the function and composition of immune cells such as macrophages and T cells. We believe our findings will offer insight into the mechanisms of drug resistance and provide novel therapeutic targets for LUAD in the future.

Unveiling chemotherapy-induced immune landscape remodeling and metabolic reprogramming in lung adenocarcinoma by scRNA-sequencing.

Chemotherapy is widely used to treat lung adenocarcinoma (LUAD) patients comprehensively. Considering the limitations of chemotherapy due to drug resistance and other issues, it is crucial to explore the impact of chemotherapy and immunotherapy on these aspects. In this study, tumor samples from nine LUAD patients, of which four only received surgery and five received neoadjuvant chemotherapy, were subjected to scRNA-seq analysis. In vitro and in vivo assays, including flow cytometry, immunofluorescence, Seahorse assay, and tumor xenograft models, were carried out to validate our findings. A total of 83,622 cells were enrolled for subsequent analyses. The composition of cell types exhibited high heterogeneity across different groups. Functional enrichment analysis revealed that chemotherapy drove significant metabolic reprogramming in tumor cells and macrophages. We identified two subtypes of macrophages: Anti-mac cells (CD45+CD11b+CD86+) and Pro-mac cells (CD45+CD11b+ARG +) and sorted them by flow cytometry. The proportion of Pro-mac cells in LUAD tissues increased significantly after neoadjuvant chemotherapy. Pro-mac cells promote tumor growth and angiogenesis and also suppress tumor immunity. Moreover, by analyzing the remodeling of T and B cells induced by neoadjuvant therapy, we noted that chemotherapy ignited a relatively more robust immune cytotoxic response toward tumor cells. Our study demonstrates that chemotherapy induces metabolic reprogramming within the tumor microenvironment of LUAD, particularly affecting the function and composition of immune cells such as macrophages and T cells. We believe our findings will offer insight into the mechanisms of drug resistance and provide novel therapeutic targets for LUAD in the future.

CHARACTERISTICS OF MITOCHONDRIAL CYTOCHROME C DISTRIBUTION IN PATIENTS WITH COLORECTAL CANCER

Understanding the mechanisms of colorectal cancer development and progression is important for disease management. Mitochondria being the energy source of eukaryotic cells play a significant role in intestinal homeostasis. Objective: The aim of the study is to examine cytochrome C level in mitochondria isolated from cells of different parts of the colon in men and women. Materials and Methods. The authors analyzed the materials obtained from 132 patients with colon cancer T2-3N0M0 (52 women and 80 men). Mitochondria from human intestinal and tumor tissue cells were isolated by differential centrifugation. Then, cytochrome C concentration (ng/mg protein) was determined by ELISA. Results. When studying the cytochrome C level in tumor tissue from various parts of the colon in men, we found that cytochrome C level in tumor mitochondria of the rectum, sigmoid colon and ascending colon was higher than that in the mitochondrial cells of the corresponding tissues by 1.8, 1.5 and 2.0 times, respectively. In women, cytochrome C level in the mitochondrial tumors of the same parts of the colon was higher than that in the mitochondria of the corresponding tissues by 2.9, 1.4 and 2.0 times, respectively. Conclusion. A common pathological characteristics of tumor mitochondria in all parts of the colon was a high cytochrome C level. It may be associated with the intensification of cellular respiration processes in the tumor contributing to its growth.

Three-dimensional single-cell transcriptome imaging of thick tissues.

Multiplexed error-robust fluorescence in situ hybridization (MERFISH) allows genome-scale imaging of RNAs in individual cells in intact tissues. To date, MERFISH has been applied to image thin-tissue samples of ~10 µm thickness. Here, we present a thick-tissue three-dimensional (3D) MERFISH imaging method, which uses confocal microscopy for optical sectioning, deep learning for increasing imaging speed and quality, as well as sample preparation and imaging protocol optimized for thick samples. We demonstrated 3D MERFISH on mouse brain tissue sections of up to 200 µm thickness with high detection efficiency and accuracy. We anticipate that 3D thick-tissue MERFISH imaging will broaden the scope of questions that can be addressed by spatial genomics.

Quantitative Live Imaging Reveals Phase Dependency of PDAC Patient-Derived Organoids on ERK and AMPK Activity.

Patient-derived organoids represent a novel platform to recapitulate the cancer cells in the patient tissue. While cancer heterogeneity has been extensively studied by a number of omics approaches, little is known about the spatiotemporal kinase activity dynamics. Here we applied a live imaging approach to organoids derived from 10 pancreatic ductal adenocarcinoma (PDAC) patients to comprehensively understand their heterogeneous growth potential and drug responses. By automated wide-area image acquisitions and analyses, the PDAC cells were non-selectively observed to evaluate their heterogeneous growth patterns. We monitored single-cell ERK and AMPK activities to relate cellular dynamics to molecular dynamics. Furthermore, we evaluated two anti-cancer drugs, a MEK inhibitor, PD0325901, and an autophagy inhibitor, hydroxychloroquine (HCQ), by our analysis platform. Our analyses revealed a phase-dependent regulation of PDAC organoid growth, where ERK activity is necessary for the early phase and AMPK activity is necessary for the late stage of organoid growth. Consistently, we found PD0325901 and HCQ target distinct organoid populations, revealing their combination is widely effective to the heterogeneous cancer cell population in a range of PDAC patient-derived organoid lines. Together, our live imaging quantitatively characterized the growth and drug sensitivity of human PDAC organoids at multiple levels: in single cells, single organoids, and individual patients. This study will pave the way for understanding the cancer heterogeneity and promote the development of new drugs that eradicate intractable cancer.

Artificial intelligence-based tissue segmentation and cell identification in multiplex-stained histological endometriosis sections.

How can we best achieve tissue segmentation and cell counting of multichannel-stained endometriosis sections to understand tissue composition? A combination of a machine learning-based tissue analysis software for tissue segmentation and a deep learning-based algorithm for segmentation-independent cell identification shows strong performance on the automated histological analysis of endometriosis sections. Endometriosis is characterized by the complex interplay of various cell types and exhibits great variation between patients and endometriosis subtypes. Endometriosis tissue samples of eight patients of different subtypes were obtained during surgery. Endometriosis tissue was formalin-fixed and paraffin-embedded before sectioning and staining by (multiplex) immunohistochemistry. A 6-plex immunofluorescence panel in combination with a nuclear stain was established following a standardized protocol. This panel enabled the distinction of different tissue structures and dividing cells. Artificial intelligence-based tissue and cell phenotyping were employed to automatically segment the various tissue structures and extract quantitative features. An endometriosis-specific multiplex panel comprised of PanCK, CD10, α-SMA, calretinin, CD45, Ki67, and DAPI enabled the distinction of tissue structures in endometriosis. Whereas a machine learning approach enabled a reliable segmentation of tissue substructure, for cell identification, the segmentation-free deep learning-based algorithm was superior. The present analysis was conducted on a limited number of samples for method establishment. For further refinement, quantification of collagen-rich cell-free areas should be included which could further enhance the assessment of the extent of fibrotic changes. Moreover, the method should be applied to a larger number of samples to delineate subtype-specific differences. We demonstrate the great potential of combining multiplex staining and cell phenotyping for endometriosis research. The optimization procedure of the multiplex panel was transferred from a cancer-related project, demonstrating the robustness of the procedure beyond the cancer context. This panel can be employed for larger batch analyses. Furthermore, we demonstrate that the deep learning-based approach is capable of performing cell phenotyping on tissue types that were not part of the training set underlining the potential of the method for heterogenous endometriosis samples. All funding was provided through departmental funds. The authors declare no competing interests. N/A.

A Single Centre Study of the Prevalence of Haematological Malignancies in the South-South Region of Nigeria

Background: Haematological malignancies are clonal haemopoietic disorders characterised by the accumulation of malignant haemopoietic cells in various body tissues. They arise due to varied genetic damages to several key biochemical pathways in cellular differentiation, proliferation and maturation. Objective: To determine the prevalence of haematological malignancies in Delta State, Nigeria. Methods: The study was a longitudinal study carried out at Delta State University Teaching Hospital, Oghara. Patients were recruited consecutively as diagnoses were made. Results: Seventy-three patients diagnosed with haematological malignancies were involved in this study. Females were slightly more affected than males (50.7% vs 49.3%), and patients of 40 - 65 years were most affected (28.8%). Non-Hodgkin Lymphoma (16.4%) and Chronic Lymphocytic Leukaemia (16.4%) were the most common haematological malignancies. More female had CLL (91.7%), Myelodysplastic syndrome (MDS) (57.1%), Acute Myeloid Leukaemia (AML) (100%) and Polycythaemia vera (PV) (100%). Conclusion: Haematological malignancies are common and on the rise in the centre of study and generally in Nigeria, with a notable change in the spectrum of the diseases.

The Anticancer Potential of Gold Nanoparticles from Flavonoid Fractions of Soursop Leaves (Annona muricata) Polymerized with PLGA on HER-2 Receptor Expression in Breast Cancer: A Literature Review

Breast cancer is a malignant disease affecting cells in the breast tissue, causing the highest mortality rate among women worldwide. As of now, the exact cause of breast cancer remains unknown, but several factors increase the risk for women, including genetics, lifestyle, direct radiation exposure, and others. In the development of breast cancer, numerous substances can influence the differentiation, adhesion, and motility of cancer cells, including the oncogene human epidermal growth factor receptor-2 (HER-2). Various treatment methods for cancer have been developed, including chemotherapy, radiotherapy, and surgery. However, due to the significant side effects and limitations of existing treatments, innovation is needed to support the success of breast cancer treatment. Recent research has explored green synthesis-based gold nanoparticles (AuNPs) as a promising alternative anticancer therapy with several advantages. The rapid growth of natural herbal plants containing anticancer compounds like flavonoids can enhance the effectiveness of modified therapies in this modern era. The polymerization of gold nanoparticles with flavonoid fractions using Poly-Lactic-co-Glycolic Acid (PLGA) can facilitate the delivery of anticancer drugs to the target site. The research method employed is a literature review using e-resources from PubMed NCBI, ScienceDirect, and Google Scholar. Keywords include Gold Nanoparticle, Breast Cancer, flavonoid, PLGA. Article criteria include full text, abstract, and publication within the last ten years (2013-2024). A total of 157 articles were obtained, and 7 articles were found to be relevant to the topic. Literature review results indicate the high anti-oncogenic effectiveness of gold nanoparticles with flavonoid-polymerized PLGA for breast cancer treatment. This finding can serve as a reference for the application of molecular therapeutic development that has proven to influence the suppression of HER-2 receptor growth expression. Keywords: Gold Nanoparticle, Breast Cancer, Flavonoid, PLGA, HER-2

Activated DRP1 promotes mitochondrial fission and induces glycolysis in ATII cells under hyperoxia

BackgroudRecent studies have reported mitochondrial damage and metabolic dysregulation in BPD, but the changes in mitochondrial dynamics and glucose metabolic reprogramming in ATII cells and their regulatory relationship have not been reported.MethodsNeonatal rats in this study were divided into model (FIO2:85%) and control (FIO2: 21%) groups. Lung tissues were extracted at 3, 7, 10 and 14 postnatal days and then conducted HE staining for histopathological observation. We assessed the expression of mitochondria dynamic associated proteins and glycolysis associated enzymes in lung tissues, primary ATII cells and RLE-6TN cells. Double immunofluorescence staining was used to confirm the co-localization of DRP1 and ATII cells. Real-time analyses of ECAR and OCR were performed with primary ATII cells using Seahorse XF96. ATP concentration was measured using an ATP kit. We treated RLE-6TN cells at 85% hyperoxia for 48 h with mitochondrial fission inhibitor Mdivi-1 to verify the role of DRP1 in regulating glucose metabolic reprogramming.FindingsWe found that hyperoxia causes ATII cells’ mitochondrial morphological change. The expression of DRP1 and p-DRP1 increased in lung tissue and primary ATII cells of neonatal rats exposed to hyperoxia. Glycolysis related enzymes including PFKM, HK2, and LDHA were also increased. Hyperoxia inhibited ATP production in ATII cells. In RLE-6TN cells, we verified that the administration of Mdivi-1 could alleviate the enhancement of aerobic glycolysis and fragmentation of mitochondria caused by hyperoxia.InterpretationsHyperoxia exposure leads to increased mitochondrial fission in ATII cells and mediates the reprogramming of glucose metabolism via the DRP1 signaling pathway. Inhibiting the activation of DRP1 signaling pathway may be a promising therapeutic target for BPD.

A Recombinant Human Collagen and RADA-16 Fusion Protein Promotes Hemostasis and Rapid Wound Healing.

In this study, we designed a fusion protein, rhCR, by combining human collagen with the self-assembling peptide RADA-16 using genetic engineering technology. The rhCR protein was successfully expressed in Pichia pastoris. The rhCR can self-assemble into a three-dimensional nanofiber network under physiological conditions. The lyophilized rhCR sponge exhibited high elasticity modulus and stable swelling properties. In vitro experiments confirmed that the rhCR had good biocompatibility and could significantly promote the adhesion, proliferation, and migration of fibroblasts (L929), upregulating the expression of genes such as Vim, Fgf, Vegf, and Tgf-β3 in L929 cells. When applied to a mouse liver hemorrhage model, rhCR hemostatic sponges rapidly formed nanofibers on the ruptured liver surface, activated platelet CD62P, and significantly reduced blood loss and bleeding duration compared to the recombinant human collagen (rhCol) alone. Furthermore, the rhCR application markedly accelerated wound healing in a mouse full-thickness skin defect model, with the wound healing rate in the rhCR group being 2.6 times that of the untreated group and 1.7 times that of the rhCol group on day 6 postinjury. Histological and immunofluorescence analyses revealed that the rhCR promoted collagen deposition and epidermal regeneration and improved the quality of skin tissue repair by stimulating tissue cells to produce cytokines, growth factors, and immune factors through immunological regulation. The rhCR fusion protein combines the advantages of collagen and RADA-16, overcoming the limitations of their separate use in hemostatic and tissue engineering applications. This biomaterial and its design idea hold promise for a variety of regenerative applications.

The Specific Mechanism of Th1Th2 Balance in Tumor Immunity

With the development of modern science, tumor immune microenvironment (TME) has become the mainstream of research. There are many related studies on Th1/Th2, so it is important to bring together such studies. At present, the research on Th1/Th2 mainly focuses on the following aspects: the mechanism of Th1/Th2 cells in TME, the inhibitory effect of Th1 cells in tumor tissues, and the related therapies for Th1/Th2 cell balance. However, there are few studies that summarize the above research directions. In this paper, the interaction between Th1 and Th2 was elaborated and found that Th2 interfered with the normal anti-tumor function of Th1 inhibition in TME, and MDSC was produced and accumulated in tumor tissues, resulting in the increase of MDSC. MDSCs can show effective immunosuppressive and tumor-promoting functions in TME through a variety of mechanisms, and together with M2 macrophages, they can assist Th2 to exert inhibitory effects on Th1 and CD8+ T cells. Saikosaponin A and xanthohumol can effectively balance Th1/Th2 to achieve the effect of treating tumors. This study reveals the specific interaction mechanism of Th2 and Th1 in TME, elucidates the inhibitory role of Th1 cells in tumor tissues, and summarizes the research results in related fields in recent years, as well as the current research progress in related fields.

Curzerenone inactivates the nuclear factor-kappa B signaling to suppress malignancy and immune evasion in cervical cancer by targeting CSNK2B.

Curzerenone is a major component of the traditional herbal medicine Curcumae Rhizoma with potential cancer-suppressing effects. This study aims to investigate the treatment effect of Curzerenone on cervical cancer cells and the underpinning mechanism. HeLa and SiHa cells were treated with Curzerenone. The 100μM Curzerenone treatment repressed proliferation, migration, and invasion of the cells. The Curzerenone treatment also reduced cellular expression of programmed death ligand 1, which increased the proliferation and activity of CD8+ T cells in a co-culture system with cancer cells. Casein kinase 2 beta (CSNK2B), a predicted physiological target of Curzerenone, was found to be suppressed by Curzerenone. Further overexpression of CSNK2B blocked the treatment effects of Curzerenone. Curzerenone inhibited while CSNK2B triggered activation of the nuclear factor-kappa B (NF-κB) pathway. The oncogenic and immunosuppressive effects of CSNK2B were blocked by an NF-κB-specific inhibitor. In vivo, Curzerenone treatment inhibited the tumorigenic activity of cancer cells, and it increased the proportion of CD8+ T cells in the xenograft tumor tissues. However, these anti-tumor effects were diminished by the CSNK2B overexpression as well. In conclusion, this research suggests that Curzerenone targets CSNK2B and inactivates the NF-κB signaling to suppress malignancy and immune evasion in cervical cancer.

CST1 promoted gastric cancer development by activating the AKT pathway.

Gastric Cancer (GC) was the third highest mortality rate among malignant tumors. Currently, no specific treatment is utilized to prevent the progression of GC. The detailed mechanism of GC was still elusive and this study aimed to clarify the mechanism of GC occurrence and development. This study was performed to clarify the molecular mechanisms of CST1 promoting GC development through activating AKT. The normal gastric tissue cells and GC cell was obtained, followed by transfection with oe-CST1 or sh-CST1, and their apoptosis and viability were evaluated. Finally, Western blot, Flow cytometry assay, Transwell assay, and Scratch assay were used to elucidate the molecular mechanisms of CST1 promoting GC development through activating the AKT pathway. Research outcomes show a significant elevation in CST1 and AKT protein as well as mRNA quantities in both the model and CST1-activator cohorts in relation to the control. Conversely, these proteins and mRNA concentrations were notably decreased in the presence of the CST1 inhibitor when compared to the model group, a difference that was statistically significant as evidenced by the p-value. CST1 can promote the gastric cancer process by targeting the AKT pathway.

Stemness regulation in prostate cancer: prostate cancer stem cells and targeted therapy.

Increasing evidence indicates that cancer stem cells (CSCs) and cancer stem-like cells form a special subpopulation of cells that are ubiquitous in tumors. These cells exhibit similar characteristics to those of normal stem cells in tissues; moreover, they are capable of self-renewal and differentiation, as well as high tumorigenicity and drug resistance. In prostate cancer (PCa), it is difficult to kill these cells using androgen signaling inhibitors and chemotherapy drugs. Consequently, the residual prostate cancer stem cells (PCSCs) mediate tumor recurrence and progression. This review aims to provide a comprehensive and up-to-date overview of PCSCs, with a particular emphasis on potential therapeutic strategies targeting these cells. After searching in PubMed and Embase databases using 'prostate cancer' and 'cancer stem cells' as keywords, studies related were compiled and examined. In this review, we detail the origin and characteristics of PCSCs, introduce the regulatory pathways closely related to CSC survival and stemness maintenance, and discuss the link between epithelial-mesenchymal transition, tumor microenvironment and tumor stemness. Furthermore, we introduce the currently available therapeutic strategies targeting CSCs, including signaling pathway inhibitors, anti-apoptotic protein inhibitors, microRNAs, nanomedicine, and immunotherapy. Lastly, we summarize the limitations of current CSC research and mention future research directions. A deeper understanding of the regulatory network and molecular markers of PCSCs could facilitate the development of novel therapeutic strategies targeting these cells. Previous preclinical studies have demonstrated the potential of this treatment approach. In the future, this may offer alternative treatment options for PCa patients.

SQLE-mediated squalene metabolism promotes tumor immune evasion in pancreatic cancer

BackgroundSqualene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and has been shown to negatively affect tumor immunity and is associated with poor outcomes of immunotherapy in various cancers. While most research in this area has focused on the impact of cholesterol on immune functions, the influence of SQLE-mediated squalene metabolism within the tumor immune microenvironment (TIME) remains unexplored.MethodsWe established an immune-competent mouse model (C57BL/6) bearing mouse pancreatic cancer xenografts (KPC cells) with or without stable SQLE-knockdown (SQLE-KD) to evaluate the impact of SQLE-mediated metabolism on pancreatic cancer growth and immune functions. The effect of squalene on tumor growth and immune cells was tested by direct administration of squalene to C57BL/6 mice bearing KPC tumors. Flow cytometry analysis and immunohistochemical (IHC) staining of immune cells from the tumor tissues were performed to evaluate changes in immune function. We also employed RNA-sequencing to analyze the gene expression profiles in pancreatic cancer cells (PANC-1) treated with or without squalene. RT-PCR and Western blot analyses were used to investigate the relevant molecular mechanisms.ResultsWe show that SQLE is significantly overexpressed in pancreatic cancer, and abrogation of SQLE results in a significant increase in squalene accumulation within tumor cells. The elevated squalene inhibits CXCL1 transcription through its impact on the NF-κB pathway via p65, and thus reduces the recruitment of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) into the tumor microenvironment. Silencing of SQLE also leads to an increased proportion of CD8+ T cells in the tumor tissues and suppresses tumor growth in vivo. Importantly, direct administration of squalene, the metabolic substrate of SQLE, to immune-competent mice bearing KPC pancreatic cancer tumors causes a substantial decrease in CD206+ TAMs and MDSCs, thus releasing immune suppression and inhibiting tumor growth.ConclusionOur study shows that squalene is an important immune-modulating metabolite that inhibits the infiltration of immune-suppressive cells in TIME, and that SQLE exerts its tumor immune evasion effect by metabolic removal of squalene. Thus, SQLE-mediated squalene metabolic pathway could be a potential target to enhance antitumor immunity in pancreatic cancer.

Features of the condition of the perilimbal tissues of the eye during the surgical treatment of patients with open-angle glaucoma

primary open-angle glaucoma is a multifactorial chronic neurodegenerative disease characterized by acquired loss of retinal ganglion cells and subsequent optic nerve atrophy, and is often associated with increased intraocular pressure (IOP). As the leading cause of blindness and vision loss, glaucoma affects more than 70 million people worldwide (Tang et al., 2021), and unfortunately, there is no downward trend. Most currently available glaucoma treatments tend to target the formation of the aqueous humor or the uveal-scleral outflow pathway. They do not affect the primary outflow pathway, which is usually responsible for 70–90% of aqueous humor drainage into the circulatory system. However, dysfunction and blockage of this major pathway can lead to increased outflow resistance, increased IOP, and ultimately the development of glaucoma. Purpose: to investigate the condition of the perilimbal tissues of the eye during the surgical treatment of patients with open-angle glaucoma. Materials and methods: 22 patients with primary open-angle glaucoma who underwent combined treatment for glaucoma and age-related cataract were included in the examination and made up the main group of the examination. The comparison group, which consisted of 7 patients, included patients who had age-related cataracts and did not have glaucoma. The main group of patients was divided into two subgroups. In the first subgroup of the main group, the Tenon's sheath of the area where anti-glaucomatous intervention was performed was studied. Trabecula examination was performed in patients of the second subgroup of the main group. Results: on the histological preparations of the patients of the main group, unlike the comparison group, signs of a chronic inflammatory process were revealed: neovascularization with proliferation of endotheliocytes. It was established that the nuclei of cells of fibrous tissue are changed, namely, they are increased in size and more intensely colored. Significant swelling of the surrounding tissue was observed, which pathologically changed the very structure of the tissue. Pathological deposition of diffusely located pigment was noted extracellularly in tissue structures. Conclusions: The results obtained during the study of changes in the perilimbal tissues of the eye in patients with primary open-angle glaucoma will open new ways of personalized management of this category of patients, which will make it possible to formulate additional criteria for the diagnosis and treatment of glaucoma, aimed at overcoming the inflammatory process and prolonging the postoperative result.