Discovery medicine最新文献

Background: Anti-cancer peptides are a powerful drug concept that induces cancer cell death through growth inhibition and membrane disruption, providing broad efficacy. The autocrine motility factor (AMF) interacts with the AMF receptor, regulating cancer cell motility, proliferation, metastasis, and angiogenesis through autocrine and paracrine pathways. However, studies verifying the synergistic effect of the combined use of anti-cancer drugs extracted from plants and AMF treatment are insufficient.

Methods: The effects of AMF-derived peptide sequences were evaluated in HT29 and SW620 colorectal cancer (CRC) cell lines. The study assessed the impact of AMF peptides on cell proliferation, colony formation, the Nicotinamide Adenine Dinucleotide Phosphate/Reduced Nicotinamide Adenine Dinucleotide Phosphate (NADP⁺/NADPH) ratio, and reactive oxygen species (ROS) generation in these CRC cells. Additionally, the combined effect of AMF peptides and glycyrrhetinic acid (GA), a compound derived from licorice plants, was investigated by analyzing cell proliferation, colony formation, ROS production, and cell cycle progression in CRC cells.

Results: AMF peptides significantly inhibited CRC cell growth (p < 0.05), decreased colony formation (p < 0.05), and increased the NADP⁺/NADPH ratio (p < 0.05) and ROS production (p < 0.001). When combined with GA, AMF peptides enhanced GA's effects on CRC cells, further suppressing cell growth (p < 0.05) and colony formation (p < 0.05) while increasing ROS generation (p < 0.05).

Conclusion: The synergy between AMF peptides and GA, derived from licorice plants, suggests the potential for combined peptide-phytochemical therapy for treating CRC.

This review predominantly acquaints the role of focal adhesion kinase (FAK) and cellular-Src (c-Src) in cell adhesion. Cell adhesion is a crucial phenomenon that causes the cells to interact with the extracellular matrix (ECM) or with each other. There are different proteins involved in cell adhesion including cell adhesion molecules (CAMs)/receptors that are present on the cell surface and various cytoplasmic proteins. FAK and c-Src are two proteins in the cytoplasm, which serve as regulators of different proteins involved in cell adhesion. They activate talin, vinculin and paxillin in turn connect the integrins with the cytoskeleton and in this way strengthen the integrin interaction with ECM. FAK-Src signalling also modulates cell-cell adhesion by regulating actin interactions. Being a key modulator of cell adhesion, FAK and c-Src signalling are linked with different pathological conditions like cancer, cardiovascular diseases, and embryonic developmental disorders. Thus, comprehensive research into FAK-Src signalling is of great importance in the exploration of different signalling targets for therapeutic interpretations. Different inhibitors and antibodies against various cell adhesion proteins, such as FAK, c-Src, and integrins, have already been used in preclinical and clinical trials to treat a variety of diseases, including cancer and chronic inflammatory conditions. Furthermore, this review presents different challenges to FAK-Src and cell adhesion signalling targeted drug development, which include, cytotoxicity and cell resistance to the drug. Finally, this review remarks that FAK and c-Src are important regulators of cell adhesion and are linked to various pathologies, nevertheless, more comprehensive research on these proteins would be a significant step forward in the development of effective therapies for the diseases associated with them.

Background: Primary open-angle glaucoma (POAG) is one of the most common insidious blinding eye diseases. Understanding the pathogenic mechanisms of it is extremely important. It is accepted that POAG attacks specific ocular tissue, such as trabecular meshwork and optic nerve damage, which causes elevated intraocular pressure and optic nerve damage. This study aimed to develop a preliminary prediction model for this disease by establishing the patient-specific induced pluripotent stem cells (iPSCs)-derived trabecular meshwork cells (TMCs) (p-iPSCs-TMCs) in the largest POAG family named "GZ.1" in China and preliminarily analyze the pathogenic mechanisms.

Methods: Peripheral blood of patients in GZ.1 and healthy individuals not belonging to the family were collected and reprogrammed into iPSCs. Then, the iPSCs were differentiated into iPSCs-TMCs. Next, their morphology and function were compared. Finally, their pathogenic mechanisms were analyzed.

Results: The patient-specific iPSCs (p-iPSCs) and healthy individual-specific iPSCs (n-iPSCs) were all successfully generated. Their morphology was quite similar to each other. However, p-iPSCs-TMCs exhibited compromised morphology and function. p-iPSCs-TMCs displayed the morphology of heterogeneous distribution and accumulation in clusters, while n-iPSCs-derived TMCs (n-iPSCs-TMCs) showed a uniformly distributed and homogenous appearance. Moreover, p-iPSCs-TMCs showed greater cell apoptosis (p < 0.01), impaired proliferating ability (24-h and 48-h time points: p < 0.05, 72-h and 96-h time points: p < 0.001), production of reactive oxygen species (p < 0.05), and impaired phagocytosis ability than n-iPSCs-TMCs (24-h, 48-h, and 72-h time points: p < 0.0001, 96-h time point: p < 0.001).

Conclusion: The p-iPSCs-TMCs can be successfully differentiated from peripheral blood, while the cells show impaired morphology and function compared with n-iPSCs-TMCs. Given this, p-iPSCs-TMCs can serve as an ideal disease model for POAG in GZ.1. Our study on the morphology and function of iPSCs-TMCs in GZ.1 may provide a valuable tool for elucidating the pathogenesis of POAG.

Atopic dermatitis, psoriasis, rosacea, seborrheic dermatitis, allergic contact dermatitis, and irritant contact dermatitis comprise a large proportion of chronic inflammatory dermatoses. This paper reviews the clinical presentations, pathophysiology, and therapeutics of inflammatory dermatoses, highlighting recent drug developments such as lebrikizumab for atopic dermatitis as well as deucravacitinib and spesolimab for psoriasis. Chronic inflammatory dermatoses significantly impact patient quality of life and contribute to substantial healthcare costs. Effective management of severe cases often requires systemic therapies and biological therapies. A thorough clinical evaluation with a tailored therapeutic approach is essential for delivering optimal care to individuals with chronic inflammatory skin diseases.

Hepatic ischemia-reperfusion injury (HIRI) is a major complication reported in various clinical scenarios such as liver transplantation (LTx), hepatectomy, and acute hepatic insult. This condition affects the restoration of hepatic functionalities post-LTx. Contemporary scientific inquiries have highlighted the involvement of intestinal microbiota and their metabolic by-products in the initiation and progression of HIRI. Perturbations in the gut microbiome, instigated by external stressors such as inflammatory processes, ischemic conditions, and reperfusion events, affect the biosynthesis of metabolites such as short-chain fatty acids (SCFAs), bile acids (BAs), and lipopolysaccharides (LPS). SCFAs can exert anti-inflammatory effects, modulate cellular apoptosis, and attenuate oxidative stress, thereby ameliorating hepatic injury. Other studies have shown that the intestinal microbiota confers hepatoprotective effects by modulating the host's immune response and synthesis of cytokines, controlling inflammation, and enhancing liver protection. This review comprehensively describes the mechanisms underlying the association of gut microbiota and its metabolites with hepatic disease and ischemia-reperfusion injury. The findings from recent studies investigating the gut-liver axis are reviewed to identify therapeutic avenues for the prevention and treatment of liver dysfunction and ischemia-reperfusion injury. In-so-doing, novel pathways and perspectives can be exploited to develop therapies for the control of inflammatory hepatic ischemia-reperfusion injury, particularly following liver transplantation or surgical intervention.

Background: To date, no studies have investigated the potential reactivation of human endogenous retroviruses (HERVs) in the pathogenesis of antiphospholipid syndrome (APS). HERV-derived syncytin-1 and syncytin-2 are localized in the plasma membrane of cells and physiologically expressed during pregnancy. The current study aimed to determine whether the epitopes of syncytins can trigger an immune response leading to APS in genetically predisposed individuals.

Methods: The TepiTool, ABCpred, and DiscoTope servers were utilized to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of syncytin-1, syncytin-2, and β2-glycoprotein I (β2GPI), which served as a reference antigen for APS. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) class II alleles associated with APS according to the literature. Epitope predictions for the different proteins were statistically compared using GraphPad Prism.

Results: For syncytin-1, we identified a total of 721 T-cell epitopes, 51 linear B-cell epitopes, and up to 40 conformational epitopes. For syncytin-2, we predicted 705 T-cell epitopes and 28 linear B-cell epitopes, but a lower number of conformational epitopes, which also exhibited lower B-cell receptor (BCR)-binding scores. The predicted T-cell and B-cell conformational epitopes of both syncytin-1 and syncytin-2 demonstrated significantly higher binding affinity to selected HLA alleles and BCR compared with β2GPI. Furthermore, syncytin-1 exhibited significantly higher immunogenicity than syncytin-2.

Conclusions: Both syncytin-1 and syncytin-2 are computationally endowed with potential epitopes that may activate either T cells or B cells in individuals genetically predisposed to APS. While these findings may illuminate the possible role of HERVs in the development of APS, they warrant validation in further laboratory studies.

Background: It has been reported that Sirtuin 2 (SIRT2) prevents phosphoenolpyruvate carboxykinase 1 (PCK1) degradation, which can be involved in aging-induced osteoarthritis (OA), but the molecular mechanism of SIRT2/PCK1 in chondrocytes has not been clarified. Therefore, this study aims to explore the mechanism of SIRT2/PCK1 in chondrocyte inflammation.

Method: To establish the OA model in vitro, chondrocytes cultured with interleukin-1β (IL-1β, 10 ng/mL) and manipulation of SIRT2 and PCK1 expression in the constructed cells to elucidate the interaction between the two genes. 1,9-Dimethyl-Methylene Blue (DMMB) was used to detect cellular glycosaminoglycan (GAG) content. Inflammatory factor levels were assessed using Enzyme-linked Immunosorbent Assay (ELISA). Apoptosis was detected by osmotic dye. The expression of B-cell lymphoma-2 (Bcl-2), Bcl-2 Associated X (Bax), Wnt Family Member 1 (Wnt1), catenin Beta 1 (β-catenin), Aggrecan, Collagen II, matrix metallopeptidase 13 (MMP-13) proteins in cells were analyzed using Western blot.

Results: PCK1 gained lower expressions in OA cell models. Overexpression of PCK1 or SIRT2 in the IL-1β chondrocyte model of inflammation promoted GAG content, inhibited apoptosis and Wnt/β-catenin protein expression, and lowered the levels of inflammatory factors. PCK1 silencing was proved to have the opposite effect. SIRT2 overexpression rescued the increased inflammation, MMP-13 expression, and apoptosis and the decreased Aggrecan and Collagen II expression caused by PCK1 silencing. PCK1 silencing also reversed the positive effects of SIRT2 overexpression on chondrocytes.

Conclusion: SIRT2 inhibits articular chondrocyte extracellular matrix (ECM) degradation, inflammatory factor expression, and apoptosis via PCK1.

Background: With the increase of environmental pollution and atypical pathogen infections, the incidence of cough variant asthma (CVA) has been increasing annually, making it a pressing issue of the medical community. This study aims to observe the ameliorative effect of curcumin on a rat model of cough variant asthma.

Methods: A rat model of cough variant asthma was induced by sensitization with ovalbumin combined with aluminum hydroxide (Al(OH)₃), followed by repeated excitations. The drug was administered on the day of the initial nebulized attack, and gavage was administered for 14 d. Pathological changes in the lung tissues were observed, along with the assessment of cough susceptibility and airway resistance. The number of inflammatory cell eosinophils and leukocytes were determined in alveolar lavage fluid. Additionally, serum inflammatory factors and lung tissues Matrix Metalloproteinase-9 (MMP-9) protein were assessed. The level of M1/M2 macrophages was also detected.

Results: Following the administration of curcumin, there was reduced inflammatory infiltration, less disordered arrangement of the lung tissue, and decreased abnormal proliferation of lung tissues in cough variant asthma rats compared to the model group. Curcumin treatment led toa notable reduction in cough frequency, a significant decrease in pro-inflammatory factor concentration levels in serum and inflammatory cell counts in the alveolar lavage fluid, and a marked increase in anti-inflammatory factor levels (p < 0.05). Additionally, curcumin administration led to a significant increase in M2-type macrophage levels, while simultaneously decreasing the levels of M1-type macrophages (p < 0.05).

Conclusions: The administration of curcumin effectively ameliorates ovalbumin-induced airway inflammation in cough-variant asthma rats. This effect is attributed to modulating macrophage polarization towards the anti-inflammatory M2 phenotype, thereby reducing airway inflammation, airway hyperresponsiveness, and lung tissue injury.

Background: Psoriasis is a prevalent cutaneous inflammatory disorder characterized by elevated keratinocyte inflammation. 5(S)-6(R)-7-trihydroxyheptanoic-acid-methyl-ester (BML-111), an established analogue of lipoxin A4, is known for its potent anti-inflammatory properties. However, the precise role of BML-111 within a murine psoriasis-like dermatitis model requires further clarification. This research aims to investigate the modulatory effects of BML-111 on inflammatory responses, the p38/mitogen-activated protein kinase (MAPK) signaling cascade, and T helper type 1 (Th1), Th2, and Th17 cell responses within the context of a murine psoriasis-like dermatitis model.

Methods: A psoriasis-like dermatitis model was established by applying 5% imiquimod (IMQ) cream to the backs of C57BL/6 mice, which were pretreated intraperitoneally with or without BML-111 prior to IMQ application. Hematoxylin-eosin staining was utilized to detect the pathological alterations of the murine dorsal skin tissue. Furthermore, the psoriasis area and severity index (PASI) scoring system was used to assess the dynamic cutaneous alterations in the mice. The levels of tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin (IL)-1β, IL-6, IL-4, and IL-17A in the murine serum samples were quantified by means of enzyme-linked immunosorbent assays (ELISA). Western blotting was conducted to detect the proteins of TNF-α, IL-1β, IL-6, phospho-p38 (p-p38), and p38 in murine skin tissues. Lastly, a flow cytometry analysis was executed to evaluate the expression of peripheral blood Th1/Th2/Th17 cell subsets.

Results: BML-111 attenuated IMQ-induced pathological changes in skin tissue of psoriasis-like dermatitis mice. BML-111 treatment substantially reduced TNF-α, IL-1β, IL-6, IFN-γ and IL-17A levels and elevated IL-4 levels in serum and skin lesion tissues of IMQ-induced mice (p < 0.01, p < 0.01, p < 0.01, p < 0.05, p < 0.05, p < 0.05, respectively). The ratio of Th1/Th17 cells in the peripheral blood of BML-111-treated mice was substantially diminished and the ratio of Th2 cells was substantially augmented (p < 0.05, p < 0.01, p < 0.001, respectively). Mechanistically, p-p38 protein level was substantially reduced in the skin tissues of BML-111-treated mice (p < 0.05). While, dehydrocorydaline (DHC, a p38/MAPK pathway agonists) reversed the reduction of p-p38 protein level induced by BML-111 treatment in psoriasis-like mice (p < 0.05).

Conclusion: BML-111 modulates the p38/MAPK signaling pathway and Th1/Th2/Th17 cytokine response, and alleviates psoriasis-like dermatitis in mice.

Background: The impact of remifentanil on hypogastric flap function following ischemia-reperfusion (I/R) injury remains largely unknown, limiting its potential clinical application in flap surgery. This study investigated the therapeutic effects of remifentanil on hypogastric flap I/R injury.

Methods: Aortic endothelial cells were extracted from the hypogastric flap I/R injury models established in-house using Sprague-Dawley rats, and were treated under hypoxic conditions. The cells were treated with 0.1, 1, 10 and 100 ng/mL remifentanil and 10 ng/mL anisomycin (the activator of c-Jun N-terminal kinase [JNK]). Histopathological changes and tumor necrosis factor alpha (TNF-α) content of the flaps were observed after hematoxylin-eosin staining and immunohistochemistry. Immunofluorescence, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and flow cytometry were employed for apoptosis evaluation. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were utilized to assess the protein and gene expression levels of TNF receptor 1 (TNFR1), JNK1, phosphorylated (p)-JNK1, malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO) and TNF-α in the flaps and cells.

Results: The endothelial necrosis and cell apoptosis of rat flaps induced by I/R injury were ameliorated by remifentanil, and declining aortic endothelial cell viability and augmented apoptosis induced by hypoxia were reversed by remifentanil (10, 100 ng/mL) (p < 0.05). Remifentanil reversed the increased expressions of TNFR1, JNK1, p-JNK1, MDA and TNF-α induced by I/R injury or hypoxia in the flaps and cells (p < 0.05), and counteracted the decreased levels of NO and SOD induced by I/R injury in the flaps (p < 0.05). Anisomycin reversed the effects of remifentanil on suppressing TNFR1, JNK1 and p-JNK1 levels and apoptosis in the cells (p < 0.05).

Conclusion: Remifentanil ameliorates cell apoptosis and vascular endothelial necrosis induced by I/R injury in the hypogastric flap, likely by downregulating the TNF-α/TNFR1 pathway and JNK1 signaling. These findings suggest that remifentanil may be a promising therapeutic agent for improving hypogastric flap survival in clinical settings.