Discovery medicine最新文献

Background: Zinc finger proteins (ZNFs) have been proved to play important roles in driving the progression of breast cancer (BC), one of the most common cancers among women. This study aimed to investigate the involvement of zinc-finger SWIM domain-containing protein 3 (ZSWIM3) in promoting BC cell progression by regulating lipid metabolism.

Methods: Differential expression of ZSWIM3 in BC was confirmed by comparing its expression in normal human mammary epithelial cells and BC cells. MCF7 cells, a BC cell line, were subjected to ZSWIM3 knockdown/overexpression experiments. The lipid contents in MCF7 cells were measured by assay kits and immunofluorescence test. The lipogenic enzymes in the cells were detected by enzyme-linked immunosorbent assay (ELISA). The cells were also subjected to further transfection experiments to manipulate the expression of sterol regulatory element-binding transcription factor 1 (SREBF1)/SREBF2 in ZSWIM3-regulated MCF7 cells to verify whether the ZSWIM3 targets SREBF1/SREBF2. Subsequently, the lipid contents in the transfected cells were determined, and the cell viability, proliferation and metastasis were measured.

Results: ZSWIM3 was overexpressed in BC cells. ZSWIM3 knockdown/overexpression led to a significant decrease/increase of the lipid contents including triglyceride, free fatty acid, cholesterol, phospholipid and neutral lipid, and lipogenic enzymes (p < 0.01). The ZSWIM3 knockdown decreased the expression of SREBF1 and SREBF2 (p < 0.01). Our findings showed that lipid content reduction induced by ZSWIM3 knockdown was reversed by SREBF1/SREBF2 overexpression. MCF7 cell viability, proliferation and metastasis, which were all suppressed by ZSWIM3 knockdown (p < 0.001), were reversible through SREBF1/SREBF2 overexpression (p < 0.001). On the other hand, the ZSWIM3 overexpression increased SREBF1 and SREBF2 expression (p < 0.001). Lipid content elevation, as well as increased MCF7 cell viability, proliferation and metastasis, which were induced by ZSWIM3 overexpression, could be counteracted by SREBF1/SREBF2 downregulation (p < 0.001).

Conclusion: ZSWIM3 promotes BC progression by enhancing lipid synthesis. This study reveals the malevolent effect of ZSWIM3 on BC, underpinned by the reprogramming of lipid metabolism, providing insights into potential therapeutic targets for BC treatments.

Background: Cytoskeleton-associated protein 2 like (CKAP2L) has been demonstrated to mediate the cell cycle in cancer cells. However, it is unknown whether CKAP2L impacts colorectal cancer (CRC). The purpose of this study was to investigate the role of CKAP2L in CRC.

Methods: CKAP2L and regulatory factor X 5 (RFX5) expression profiles in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) were analyzed in UALCAN. Human colorectal adenocarcinoma epithelial cells, DLD1, were transfected with small interfering RNA targeting RFX5 and CKAP2L-overexpressing vectors (OE-CKAP2L). The interaction between CKAP2L and RFX5 was identified by dual-luciferase assay and chromatin immunoprecipitation. Epithelial-mesenchymal transition (EMT)- and protein kinase B/mammalian target of the rapamycin (AKT/mTOR) pathway-associated proteins were evaluated by western blotting.

Results: RFX5 and CKAP2L expression was increased in CRC based on the UALCAN database. RFX5 downregulation inhibited proliferation, migration, invasion, and EMT while promoting G1/S phase arrest (p < 0.01). RFX5 knockdown downregulated CKAP2L expression and mediated the inactivation of the AKT/mTOR pathway (p < 0.001). RFX5 acted as an upstream transcription factor of CKAP2L. CKAP2L overexpression attenuated the restriction of RFX5 downregulation on CRC cell malignant phenotypes (p < 0.01).

Conclusion: CKAP2L transcriptionally activated by RFX5 accelerates CRC proliferation and metastasis by promoting the cell cycle and EMT. This study provides potential molecular targets for treating CRC.

Background: Long non-coding RNA (lncRNA) zinc finger protein 667-antisense RNA 1 (ZNF667-AS1) is closely related to the advancement of a variety of cancers, but its functional role in colorectal cancer remains unclear. This study was designed to explore the function and molecular mechanisms of lncRNA ZNF667-AS1 in colorectal cancer.

Methods: Reverse transcriptase real-time quantitative polymerase chain reaction (RT-qPCR) was used for the detection of ZNF667-AS1 and proline-rich nuclear receptor co-activator protein 2 (PNRC2) expression level. Cell counting kit-8 (CCK-8), 5-Ethynyl-2'- deoxyuridine (EdU), and colony formation assays were conducted to assess cell proliferation; flow cytometry and transwell invasion assay were performed separately to measure cell apoptosis and invasion. RNA immunoprecipitation (RIP) assay was utilized to analyze the relationship between ZNF667-AS1 and PNRC2. Western blot was to test the PNRC2 protein expression. The in vivo role of ZNF667-AS1 in the advancement of colorectal cancer was evaluated by tumor xenograft assay.

Results: LncRNA ZNF667-AS1 and PNRC2 were both decreased in colorectal cancer tissue samples and cells (p < 0.05). ZNF667-AS1 overexpression remarkably restrained proliferation and invasion in HCT-116 and LOVO cells, but enhanced cell apoptosis (p < 0.0001). Moreover, ZNF667-AS1 directly targeted PNRC2, and positively regulated its expression. The influence of ZNF667-AS1 overexpression on invasion, apoptosis, and proliferation was suppressed by PNRC2 knockdown in HCT-116 and LOVO cells. Additionally, ZNF667-AS1 overexpression markedly inhibited tumor growth via upregulation of PNRC2 in mice in vivo (p < 0.05).

Conclusion: LncRNA ZNF667-AS1 expressed low in colorectal cancer. LncRNA ZNF667-AS1 repressed proliferation and invasion, and enhanced apoptosis of colorectal cancer cells by targeting PNRC2.

Background: Glioblastoma multiforme (GBM) is one of the deadliest and most heterogeneous forms of brain cancer, characterized by its resistance to conventional therapies. Within GBM, a subpopulation of slow-cycling cells, often linked to quiescence and stemness, plays a crucial role in treatment resistance and tumor recurrence. This study aimed to identify novel biomarkers associated with these slow-cycling GBM cells.

Methods: We utilized The Cancer Genome Atlas (TCGA)-GBM dataset and presented the reproducible bioinformatics analysis for our results.

Results: Our analysis highlighted Membrane-Associated Protein 17 (MAP17) as strongly associated with the slow-cycling phenotype. We found that the protein cargo MAP17 expression is related to mesenchymal signatures and stem cell-related pathways. Also, MAP17 was linked to a distinct metabolic profile, characterized by significant enrichment in pathways related to folate, zinc, and fatty acids. Moreover, the immune cell distribution analysis revealed that MAP17 correlates with key molecular immune processes, including interferon-gamma (IFN-γ) signaling and antigen presentation, as well as immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) and macrophages. MAP17-high tumors also showed elevated expression of several immune checkpoint inhibitors, indicating an immunosuppressive microenvironment.

Conclusion: These findings provide insight into the role of MAP17 in quiescence, stemness, and immune evasion, positioning it as a promising therapeutic target.

Two billion people worldwide suffer from anemia, which can lead to the onset of cardiac disorders; nevertheless, the precise mechanisms remain unclear. There are at least three distinct mechanisms by which iron deficiency (ID) contributes to the development of cardiac disorders. First, ID increases concentrations of intact fibroblast growth factor-23 (iFGF-23), which promotes left ventricular hypertrophy. Additionally, individuals with ID typically have low circulating levels of vitamin D and an increased body burden of cadmium (Cd). Both factors-high Cd levels and a lack of vitamin D-elevate the risk of various cardiac disorders. Cd is transported in the body via transferrin and as non-transferrin-bound cadmium (NTBCd), with around 50% carried by transferrin. Transferrin-bound Cd is internalized into cells through the transferrin receptor 1 (TfR1), whereas NTBCd uptake occurs via receptors involved in iron transport, such as divalent metal transporter 1 (DMT1), ZIP8, and ZIP14. These receptors, expressed in tissues like the myocardium, contribute to Cd accumulation in the heart. In cases of coronary artery disease, regions of the heart affected by hypoxia, due to reduced blood flow, overexpress TfR1, DMT1, ZIP8, and ZIP14. This increases the uptake of Cd into cardiomyocytes. Cd, once inside the cells, damages mitochondria through oxidative stress, lipid peroxidation, and DNA alterations, leading to cell death. Once destroyed, cardiomyocytes release intracellular potassium which can potentially cause fatal arrhythmia. Cardiac iron bioaccumulation is primarily influenced by two factors: blood iron concentrations and the density of TfR1. Numerous studies have explored the potential benefits of iron supplementation, with varying results. We hypothesize that the extent of beneficial effects from iron supplementation may depend on the presence of specific comorbidities, such as chronic kidney disease or hyperaldosteronism. This hypothesis is based on the observation that certain hormones, including aldosterone and noradrenaline, downregulate the expression of TfR1. Therefore, we propose that co-treatment with iron and aldosterone antagonists could enhance cardiac iron uptake and improve the overall effectiveness of the therapy. Additionally, vitamin D supplementation prior to the onset of disease and chelation therapy after diagnosis could provide some benefits.

Ischemia-induced brain neurodegeneration is a leading cause of mortality and permanent disability worldwide, with no definitive cure. The development of neuroinflammation following ischemic events plays a dual role; it is essential for brain repair and homeostasis and can also exacerbate post-ischemic damage and worsen neurological outcomes. Neuroinflammation represents a complex process involving interactions between infiltrating immune cells from the bloodstream and resident immune cells within the affected brain regions. This inflammatory response begins immediately after ischemia and can persist for years. This review focuses on the intricate relationship between neuroinflammation, amyloid accumulation, tau protein pathology and glial cells in the post-ischemic brain. Notably, it examines whether amyloid and tau protein amplify neuroinflammation and whether neuroinflammatory responses influence the behavior and aggregation of these molecules. Understanding these interactions is critical, as they contribute to the progression of post-ischemic brain neurodegeneration. Additionally, this review highlights the role of neuroinflammation as a functionally complex immune response regulated by transcription factors and mediated by cytokines. It explores how the presence of amyloid and modified tau protein may shape the inflammatory landscape. This review aims to advance our understanding of post-ischemic neuroinflammation and its implications for long-term brain health and neurodegenerative diseases.

Background: Preventing the progression and recurrence of colorectal cancer (CRC) remains a clinical challenge due to its heterogeneity and drug resistance. This underscores the need to discover new targets and elucidate their cancer-promoting mechanisms. This study analyzed the cancer-promoting mechanisms of tryptophanyl-tRNA synthetase 1 (WARS1) in CRC.

Methods: Clinical data and RNA expression profiles of CRC patients in public databases were analyzed using bioinformatics to determine the expression of WARS1. A WARS1 knockdown assay was conducted with HCT116 and RKO cell lines to systematically assess the effects of WARS1 on CRC cell proliferation, migration, cell cycle, and apoptosis. These assessments employed reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, wound healing and transwell assays, flow cytometry, and xenograft tumor assays. Additionally, RNA sequencing and gene enrichment-based analysis were performed following WARS1 knockdown to detect gene expression changes and related pathways.

Results: WARS1 was overexpressed in CRC tissues (p < 0.05). Downregulation of WARS1 inhibited the growth and migration of RKO and HCT116 cell lines (p < 0.05). This inhibitory effect on tumor growth was also observed in xenografts in nude mice after WARS1 knockdown (p < 0.01). Flow cytometry revealed an increase in apoptosis and cell cycle arrest following WARS1 knockdown (p < 0.05). Transcriptome sequencing analysis showed that reduced expression of WARS1 activated the p53 signaling pathway and apoptosis while suppressing DNA replication and the cell cycle. The p53 transcriptional inhibitor pifithrin-α partially prevented the activation of caspase 3 and reduced the levels of c-poly-ADP-ribose polymerases 1 (PARP1) and cyclin-dependent kinase inhibitor 1A (CDKN1A).

Conclusion: WARS1 was highly expressed in CRC, and its low expression was identified as a risk factor for CRC progression and recurrence. The current findings provide a theoretical basis for the development of therapeutic agents targeting WARS1 and elucidate its mechanism in CRC progression.

Backgrounds: Ultraviolet (UV) radiation-induced photoaging is a multifaceted biological process. Fruit acids have shown promise in combating photoaging. This study aims to investigate the mechanisms underlying the protective effects of fruit acids on UV-induced skin photoaging.

Methods: Initially, we induced skin photoaging in rats through UV irradiation. Subsequently, the model group received glycolic acid treatment. The reparative effects of glycolic acid on skin tissue morphology and structure were assessed using Hematoxylin-eosin (HE) staining. The influence of glycolic acid on oxidative stress indicators (Superoxide Dismutase (SOD), Glutathione Peroxidase (GSH-Px), Malondialdehyde (MDA), Catalase (CAT)) and levels of cellular inflammatory factors (Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), IL-1β, Interferon-gamma (IFN-γ)) in photoaged skin was evaluated via Enzyme-Linked Immunosorbent Assay (ELISA). Additionally, alterations in collagen expression and levels of proteins associated with the Phosphoinositide 3-kinase/Protein Kinase B (PI3K/Akt) and Nuclear Factor kappa B (NF-κB) signaling pathways were determined through Western blot analysis.

Results: Compared to the model group, the fruit group exhibited a decrease in the thickness of the skin epidermal keratinization layer, an increase in dermal thickness, and more vigorous cortical secretion. Moreover, compared with the model group, the fruit group showed significant increases in SOD activity, CAT, GSH-Px, Collagen I, Collagen III, Collagen VII, and elastin. Conversely, levels of MDA, IL-6, IL-1β, IFN-γ, and TNF-α were lower in the fruit acid group than in the model group. Additionally, fruit acid treatment inhibited the phosphorylation levels of PI3K, Akt, and p65 induced by UV.

Conclusion: Fruit acid demonstrates the ability to diminish the oxidative stress and inflammatory responses in skin photoaging rat models, thereby facilitating collagen recovery and ameliorating symptoms of skin photoaging. Its potential mechanism may entail the inhibition of the activation of the PI3K/Akt and NF-κB signaling pathways.

Background: Autoimmune hepatitis (AIH) is an autoimmune disease accompanied by an autoimmune inflammatory response that often leads to severe liver damage. In addition, it may further lead to complications such as liver fibrosis, cirrhosis and liver failure. Dihydromyricetin (DHM) possesses various pharmacological properties, such as being anti-inflammatory, antioxidant, and antibacterial. In this experiment, we investigated the effect of DHM on autoimmune hepatitis mice based on the level of M1/M2 type macrophages.

Methods: An autoimmune hepatitis mouse model was established by the administration of DHM followed by tail vein injection of Concanavalin A (Con A). Liver tissues were examined for pathological and morphological changes. Interleukin-1β (IL-1β), interleukin-10 (IL-10), interleukin-6 (IL-6), and interleukin-4 (IL-4) levels in liver tissues were assessed. Serum hepatic function indexes were measured, including alanine aminotransferase (ALT), aspartate transaminase (AST), and lactatedehydrogenase (LDH). Oxidative stress indexes, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and Nitric oxide (NO), were quantified. Additionally, tumor necrosis factor-α (TNF-α) and nuclear factor kappa-B (NF-κB) p65 mRNA and protein expression polarization were determined. The presence of M1/M2-type macrophages was also investigated.

Results: Compared to the model group, mice in the DHM group exhibited a significant reduction in serum hepatic function indexes (p < 0.05). Liver tissues from the DHM group showed a noteworthy decrease in MDA and NO levels, along with a significant increase in SOD and GSH-Px levels (p < 0.05). Furthermore, in the liver tissues of mice from the DHM group, there was a notable reduction in the count of M1-type macrophages and a considerable elevation in the M2-type macrophages (p < 0.05). IL-1β and IL-6 expression levels exhibited a significant decrease, whereas IL-10 and IL-4 levels displayed a significant increase (p < 0.05). Additionally, both TNF-α and NF-κB p65 mRNA levels and protein expression experienced a noteworthy decrease (p < 0.05).

Conclusion: DHM mitigates the inflammatory response in AIH mice by reducing oxidative stress and modulating macrophage polarization and the TNF-α/NF-κB pathway.

Salivary gland dysfunctions are common conditions variously related to aging, inflammatory players, and any other factor able to alter their normal physiology. These conditions may significantly impact oral and systemic health, affecting the overall quality of life. Over time, numerous therapeutic strategies have been explored to regenerate, repair, or replace injured salivary glands, focusing on those molecular and cellular mechanisms able to be safely translated into a clinical landscape. In this context, stem cells, tissue engineering, and the novel organoids technology, have gained exciting results, even if such approaches may require some optimization for their long-term maintenance. Despite extensive research, a composite stem cell population capable of regenerating functional glandular tissue remains elusive; nonetheless, to overcome these current limitations, recently, the transplantation of allogeneic stem cells has emerged as a reliable solution. This overview comprehensively examines the salivary glands in the light of modern biotechnologies, with the aim of better understanding the current state of the art in salivary gland regeneration and repair by using tissue engineering, biomimetic strategies, target therapies, and three-dimensional (3D) organoids technology. This work investigates the main salivary gland dysfunctions and their impact on oral and systemic health. It then discusses the most promising advanced strategies for oral tissue bioengineering, focusing on the potential of stem cells and organoids.