Discovery medicine最新文献

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.

Background: High-mobility group box 1 (HMGB1) participates in the progression of osteosarcoma (OS) through the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Corylin, one of the active components of Psoralea corylifolia L., has anti-oxidant, anti-inflammatory, and anti-tumor effects. This study investigates the association between corylin and HMGB1, and their impact and mechanism of action on OS.

Methods: OS cells and osteoblasts were transfected with/without HMGB1 overexpression plasmid and siHMGB1. Cell viability was examined using the Cell Counting Kit-8 (CCK-8) assay after treatment with corylin (0, 2.5, 5, 10, 30 μM). The effects of corylin on cell malignant behaviors were examined by cell function assays. The mRNA expression level of high-mobility group box 1 (HMGB1) was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The protein levels of HMGB1, matrix metalloproteinase-2 (MMP-2), MMP-9, and alpha-smooth muscle actin (α-SMA) were measured by western blotting. The effects of corylin and HMGB1 on the expression of p38 MAPK signaling pathway-related proteins were also assessed.

Results: Corylin decreased OS cell viability, proliferation, migration, and invasion but increased apoptosis in a concentration-dependent manner. Corylin concentration-dependently suppressed the levels of HMGB1, MMP-2, MMP-9, and α-SMA. Overexpression of HMGB1 was partially reversed, while knockdown of HMGB1 enhanced the above effects of corylin.

Conclusion: Corylin inhibits OS cell migration and invasion through regulation of the HMGB1-mediated p38 MAPK signaling pathway.

Correction of Discovery Medicine 2023, 35 (179) https://www.discovmed.com/EN/10.24976/Discov.Med.202335179.90 The authors wish to make the following correction to this paper [1]: The authors would like to correct the name of their affiliated institution, the corrected author's affiliation is provided below: 1Department of Emergency Medicine, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, 210002 Nanjing, Jiangsu, China.

Background: Lung cancer is one of the leading causes of cancer-related deaths worldwide, with treatment failure resulting from metastasis. C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in tumor cell migration and metastasis. Recent studies have suggested that the commonly used antiepileptic drug, carbamazepine (CBZ), may impede tumor metastasis; however, its specific mechanism remains unclear.

Methods: In this study, we evaluated the effects of CBZ on the migration and invasion of lung cancer cells through in vitro cell cultures and in vivo animal models. The regulatory effect of CBZ on CXCR4 expression was analyzed using western blot and reverse transcription-quantitative polymerase chain reaction techniques. To further validate whether CBZ's anti-metastatic effect is mediated through CXCR4, we used the CXCR4 agonist NUCC-390 and overexpression of the CXCR4 gene in lung cancer cell lines.

Results: The results demonstrated that CBZ significantly inhibited the migration and invasion of lung cancer cells (*p < 0.001). In animal experiments, CBZ treatment significantly reduced the extent of metastasis in the lungs (*p < 0.01). Moreover, CBZ downregulated the expression of CXCR4 (*p < 0.001). When NUCC-390 was used or CXCR4 was overexpressed, the anticancer effect of CBZ was reversed, indicating the anti-metastatic effect of CBZ is closely associated with its inhibition of CXCR4 expression.

Conclusion: This study reveals, for the first time, a novel mechanism by which CBZ inhibits lung cancer metastasis through the suppression of CXCR4 expression. These findings offer a new avenue for the treatment of lung cancer using CBZ as a potential agent against lung cancer metastasis. Further research is warranted to explore the clinical potential of CBZ and to offer more treatment options for lung cancer patients.

Background: Acute pancreatitis (AP) is a prevalent pathological condition of abdomen characterized by sudden onset, high incidence and complex progression. Timely assessment of AP severity is crucial for informing intervention decisions so as to delay deterioration and reduce mortality rates. Existing AP-related scoring systems can only assess current condition of patients and utilize only a single type of clinical data, which is of great limitation. Therefore, it is imperative to establish more accurate and data-compatible methods for predicting the severity of AP. The artificial intelligence (AI) algorithm based on artificial neural network (ANN) allow for the adaptive feature extraction for objective task through its internal complex network, instead of the hand-crafted methods commonly used in traditional machine learning (ML) algorithms. In this study, we delve into the final severity classification prediction of newly admitted AP patients, using deep learning (DL) algorithm to develop multi-view models, incorporated with patients' demographic information, vital signs, AP-related laboratory indexes and admission computed tomography (CT) images.

Methods: The pancreatitis database in the platform of Clinical Data Research Center of Acute Abdominal Surgery at the First Affiliated Hospital of Dalian Medical University was used to gather AP cases. Deep neural network (DNN) and convolutional neural network (CNN) were utilized to construct models. The DNN prediction models with clinical data as input, the CNN prediction models with admission CT as input, and the multi-view models combining the two inputs were respectively established to predict the severity of AP.

Results: DL models for AP severity classification based on clinical indexes, imaging data and merged data were constructed. The multi-view model based on merged data offered more accurate prediction of the final severity classification of AP, with an overall accuracy rate of 80.26% (95% confidence interval (CI): 79.58%-80.94%). The constituent accuracy rates for mild acute pancreatitis, moderately severe acute pancreatitis, and severe acute pancreatitis were 91.69% (95% CI: 87.80%-95.57%), 64.90% (95% CI: 58.85%-70.95%), and 75.56% (95% CI: 68.58%-82.53%), respectively.

Conclusion: The multi-view models using clinical indexes and imaging data as input outperform single-view models in AP severity prediction.