Search Results (545)

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by complex pathogenesis involving dysregulated immunity and gut microbiota imbalance, demanding innovative therapeutic strategies. This study investigates the synergistic therapeutic potential of pomegranate peel–hawthorn combinations and their active constituents (ellagic acid and maslinic acid) through an integrative approach combining network pharmacology, in vitro/in vivo experiments, and gut microbiota analysis. Network pharmacology identified 61 shared therapeutic targets (p < 0.05 for pathway enrichment) and revealed complementary mechanisms: pomegranate peel primarily modulated AGE-RAGE/PI3K-Akt pathways, while hawthorn targeted IL-17/NF-κB signaling. Experimental validation demonstrated potent synergistic anti-inflammatory effects (combination index < 1), with optimal combinations reducing nitric oxide production by 52.35% (herbal extracts, p < 0.05) and 74.4% (active monomers, p < 0.05). In DSS-induced UC mice, combinatorial therapies significantly suppressed pro-inflammatory cytokines (TNF-α: 204.78 vs. 446.52 pg/mL in UC group, p < 0.05; IL-6: 33.19 vs. 64.86 pg/mL, p < 0.05), restored colonic SOD activity (72.31 vs. 50.10 U/mg·prot in UC group, p < 0.01), and alleviated histopathological damage, outperforming monotherapeutics. Gut microbiota analysis revealed the recovery of α-diversity indices and normalized Bacteroidota/Bacillota ratios. Mechanistically, the combinations suppressed MAPK/NF-κB signaling cascades, reducing p-p38/p38 (p < 0.01 vs. UC group) and p-ERK1/2/ERK1/2 (p < 0.01 vs. UC group) phosphorylation. These findings establish that pomegranate peel–hawthorn formulations exert multi-modal therapeutic effects through the synergistic inhibition of pathways, mitigation of oxidative stress, and restoration of the microbiota, offering a scientifically validated approach for UC management rooted in traditional medicine principles. Full article

Fuchs Endothelial Corneal Dystrophy (FECD) is a corneal endothelial disease that causes microenvironment alterations and endothelial cell loss, which leads to vision impairment. It has a high global prevalence, especially in elderly populations. FECD is also one of the leading indications of corneal transplantation globally. Currently, there is no clearly defined canonical pathway for this disease, and it has been proposed that the combinatorial effects of genetic mutations and exogenous factors cause FECD. Clinical studies and observations have provided valuable knowledge and understanding of FECD, while preclinical studies are essential for gaining insights into disease progression and mechanisms for the development and testing of regenerative medicine therapies. In this review, we first introduce the proposed genetic and molecular pathologies of FECD. Notably, we discuss the impact of abnormal extracellular matrix deposition (guttata), endothelial-to-mesenchymal transition, cell senescence, and oxidative stress on the pathology and etiology of FECD. We review and summarize the in vitro cell models, ex vivo tissues, and in vivo animal models used to study FECD. The benefits and challenges of each model are also discussed. Full article

Objective: Because of the evolving nature of tissue engineering scaffolds in the treatment of spinal cord injury (SCI), the current study was carried out to evaluate the research productivity of tissue engineering scaffolds in the treatment of SCI. Methods: Studies published from 2000 to 2025 were retrieved from the Web of Science core collection with topics of spinal cord injury and tissue engineering scaffolds. The data were analyzed and visualized using the VOSviewer network analysis software. Results: Among 1542 articles analyzed, annual publications surged from 2000 to 2019, stabilizing thereafter. The U.S., China, and Canada led in productivity, with Northwestern University and the Biomaterials journal being top contributors. Keyword analysis revealed research hotspots such as functional recovery, axonal regeneration, stem cells, and hydrogels. Notably, hydrogels embedded with genetically engineered cells emerged as a pivotal trend, reflecting a shift toward biomimetic and combinatorial therapies. Collaboration networks highlighted intensified partnerships between Chinese and North American institutions, signaling global interdisciplinary efforts. Conclusions: This study provides the first bibliometric roadmap for tissue engineering scaffolds in SCI, identifying key trends, influential entities, and underexplored areas. The rise in hydrogels and international collaborations underscores opportunities for targeted research. These findings guide researchers in prioritizing high-impact journals, fostering partnerships, and advancing novel scaffold designs to bridge translational gaps in SCI treatment. Full article

The Enhanced Permeability and Retention (EPR) effect is a key mechanism for passive tumor targeting, which involves the selective accumulation of therapeutic nanoparticles in tumors due to their unique vascular characteristics. While previous reviews have explored this phenomenon, the present review offers a comprehensive, multidisciplinary approach, highlighting recent advancements in strategies to enhance the EPR effect, as well as novel insights into the role of tumor microenvironment heterogeneity and the multifaceted approaches to overcome EPR-related challenges. This review provides a detailed analysis of the latest developments in nanocarriers’ design, including size, shape, and surface modifications, as well as cutting-edge multi-stage drug delivery systems. Furthermore, the integration of physical, pharmacological, and combinatory therapies to optimize the EPR effect is also discussed, aiming to improve the clinical translation of nanomedicines. Unlike other reviews, this work emphasizes the dynamic interaction between the tumor microenvironment and the vascular network, which remains underexplored in the current literature. In addition, specific clinical trials’ outcomes are highlighted and future directions to address existing limitations are proposed, offering a clearer roadmap regarding clinical applications in cancer therapy. Full article

Glioblastoma (GMB) is a remarkably aggressive brain malignancy characterized by high mortality rates, despite continuous advances in therapeutic approaches. Compounds derived from plants are being studied for their potent medicinal properties in the quest for more efficient therapies. This study investigated the anti-glioma properties of Methyl rosmarinate, a hydroxycinnamic acid isolated from Thymus thracicus Velen, which has previously demonstrated anti-cancer activity in various cell lines. Human glioblastoma cell lines U87 and T98 were treated with Methyl rosmarinate to assess its effect on cell viability, cell cycle distribution and migratory capacity using Trypan blue assay, flow cytometry and scratch wound healing assay, respectively. The combinatorial effects of Methyl rosmarinate and temozolomide were also analyzed with CompoSyn software. According to the outcomes, Methyl rosmarinate significantly reduced cell viability, induced cell death by interfering in cell cycle checkpoints, and inhibited migration in both GMB cell lines. Notably, in U87 cells, the compound showed a synergistic impact with temozolomide, whereas in T98 cells, there was an antagonistic relationship. These results suggest that Methyl rosmarinate has potential anti-glioma properties; however, more in vivo research is needed. Full article

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy targeting the PD-1/PD-L1 axis has revolutionized treatment, providing durable responses in a subset of patients. However, with fewer than 50% of patients achieving significant benefits, there is a critical need to expand therapeutic strategies. This review explores emerging targets in immune checkpoint inhibition beyond PD-1/PD-L1, including CTLA-4, TIGIT, LAG-3, TIM-3, NKG2A, and CD39/CD73. We highlight the biological basis of CD8 T cell exhaustion in shaping the antitumor immune response. Novel therapeutic approaches targeting additional inhibitory receptors (IR) are discussed, with a focus on their distinct mechanisms of action and combinatory potential with existing therapies. Despite significant advancements, challenges remain in overcoming resistance mechanisms and optimizing patient selection. This review underscores the importance of dual checkpoint blockade and innovative bispecific antibody engineering to maximize therapeutic outcomes for NSCLC patients. Full article

Neurodegenerative diseases encompass a number of very heterogeneous disorders, primarily characterized by neuronal loss and a concomitant decline in neurological function. Examples of this type of clinical condition are Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and Amyotrophic Lateral Sclerosis. Age has been identified as a major risk in the etiology of these disorders, which explains their increased incidence in developed countries. Unfortunately, despite continued and intensive efforts, no cure has yet been found for any of these diseases; reliable markers that allow for an early diagnosis of the disease and the identification of key molecular events leading to disease onset and progression are lacking. Altered adult neurogenesis appears to precede the appearance of severe symptoms. Given the scarcity of human samples and the considerable differences with model species, increasingly complex human stem-cell-based models are being developed. These are shedding light on the molecular alterations that contribute to disease development, facilitating the identification of new clinical targets and providing a screening platform for the testing of candidate drugs. Moreover, the secretome and other promising features of these cell types are being explored, to use them as replacement cells of high plasticity or as co-adjuvant therapy in combinatorial treatments. Full article

Background: The development of nanostructured materials for cancer therapy has garnered significant interest due to their unique physicochemical properties, including enhanced surface area and tunable electronic structures, which can facilitate targeted drug delivery and oxidative stress modulation. This study investigates the anticancer potential of monoclinic silver dimolybdate nanorods (m-Ag₂Mo₂O₇) against aggressive breast (MDA-MB-231) and prostate (PC-3) cancer cells and explores their in vivo pharmacokinetic behavior. Methods: m-Ag₂Mo₂O₇ nanorods were synthesized via a hydrothermal method and characterized using XRD, SEM, Raman, and FTIR spectroscopy. In vitro cytotoxicity was evaluated using MTT assays on MDA-MB-231 and PC-3 cell lines across concentrations ranging from 1.56 to 100 µg/mL. In vivo biodistribution and radiopharmacokinetics were assessed using technetium-99m-labeled nanorods in male Swiss rats, with gamma counting employed for tissue uptake analysis and pharmacokinetic parameter determination. Results: m-Ag₂Mo₂O₇ nanorods exhibited a modest cytotoxic effect on MDA-MB-231 cells, with 50 µg/mL reducing cell viability by 23.5% (p < 0.05), while no significant cytotoxicity was observed in PC-3 cells. In vivo studies revealed predominant accumulation in the stomach, liver, spleen, and bladder, indicating reticuloendothelial system uptake and renal clearance. Pharmacokinetic analysis showed a rapid systemic clearance (half-life ~6.76 h) and a low volume of distribution (0.0786 L), suggesting primary retention in circulation with minimal off-target diffusion. Conclusions: While m-Ag₂Mo₂O₇ nanorods display limited standalone cytotoxicity, their ability to induce oxidative stress and favorable pharmacokinetic profile support their potential as adjuvant agents in cancer therapy, particularly for chemoresistant breast cancers. Further studies are warranted to elucidate their molecular mechanisms, optimize combinatorial treatment strategies, and assess long-term safety in preclinical models. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a poor prognosis. Currently, chemotherapy is the only option for most patients with advanced-stage PDAC. Further, conventional immunotherapies and targeted therapies improve survival outcomes only in rare PDAC patient subgroups. To date, combinatory immunotherapeutic strategies to overcome the immune-hostile PDAC tumor microenvironment (TME) have resulted in limited efficacy in clinical studies. However, efforts are ongoing to develop new treatment strategies for patients with PDAC with the evolving knowledge of the TME, molecular characterization, and immune resistance mechanisms. Further, the growing arsenal of various immunotherapeutic agents, including novel classes of immune checkpoint inhibitors and oncolytic, chimeric antigen receptor T cell, and vaccine therapies, reinforces these efforts. This review will focus on the place of immunotherapy and future possible strategies in PDAC. Full article

Severe asthma (SA) is a chronic inflammatory condition affecting approximately 10% of asthmatic patients, and eosinophils are considered key pathogenetic actors in a significant number of patients. Biological therapies have been demonstrated to improve asthma control by decreasing exacerbation rates and reducing the use of oral corticosteroids. In this context, phenotyping and endotyping patients with SA is essential for selecting the most effective therapeutic approach. For this purpose, biomarkers such as IgE, absolute blood eosinophil count, and fractional exhaled nitric oxide (FeNO) are crucial in defining a patient’s inflammatory profile. Their integration provides a framework for classifying asthma into T2-high, T2-mild, or T2-low categories, guiding personalized treatment strategies. By incorporating multiple biomarkers into a unified model, it is possible to better stratify patients and optimize biologic therapy selection, paving the way for improved outcomes in SA management. This review aims to evaluate the role of phenotyping and endotyping SA patients, with particular attention to the impact of eosinophilic inflammation and combinatory biomarkers on decision-making processes for the selection of biological therapies. Full article

Epigenetics encompasses heritable and stable changes in gene expression caused by external chromosomal modifications, without altering the underlying DNA sequence. Epigenetic modifications, established during early development and maintained through successive cell divisions, play a critical role in regulating gene expression. Post-translational modifications (PTMs) are a key aspect of epigenetics and are essential for modulating protein functionality, as well as regulatory cellular processes, including proliferation, differentiation, metabolic pathways, and tumorigenic events. Among these, the small ubiquitin-related modifier (SUMOylation) system is a reversible PTM mechanism that alters target protein interaction surfaces through covalent binding to lysine residues, thereby influencing protein structure and function. Acute myeloid leukemia (AML) is a highly aggressive malignancy characterized by the clonal expansion of primitive hematopoietic stem cells of the myeloid lineage in the bone marrow. Despite recent advancements in therapeutic strategies and an improved understanding of leukemogenic pathways, patient outcomes remain poor, particularly in elderly populations. Consequently, efforts have focused on developing novel agents, including co-targeting specific mutations or integrating targeted therapies into combinatorial chemotherapeutic regimens. Emerging evidence suggests that SUMOylation plays a significant role in AML pathogenesis and treatment response, representing a promising therapeutic target for advanced disease cases. This review provides a brief analysis of the functional role of the SUMOylation system in AML and highlights its potential as a therapeutic target. We also discuss current knowledge gaps and propose directions for future research to advance precision medicine approaches for AML treatment. Full article

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel localized on the plasma membrane of epithelial cells. Over the last three decades, high-throughput screening assays have been extensively employed in identifying drugs that target specific defects arising from CFTR mutations. The two main categories of such compounds are potentiators, which enhance CFTR gating by increasing the channel’s open probability, and correctors, which improve CFTR protein folding and trafficking to the plasma membrane. In addition to these, other investigational molecules include amplifiers and stabilizers, which enhance the levels and the stability of CFTR on the cell surface, and read-through agents that promote the insertion of correct amino acids at premature termination codons. Currently, four CFTR modulators are clinically approved: the potentiator ivacaftor (VX-770), either as monotherapy or in combination with the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Among these, the triple combination VX-445/VX-661/VX-770 (marketed as Trikafta^® in the US and Kaftrio^® in Europe) has emerged as the most effective CFTR modulator therapy to date, demonstrating significant clinical benefits in phase III trials for patients with at least one F508del CFTR allele. Despite these advancements, the mechanisms of action and binding sites of these modulators on CFTR have only recently begun to be elucidated. A deeper understanding of these mechanisms could provide essential insights for developing more potent and effective modulators, particularly in combination therapies. This narrative review delves into the mechanism of action, binding sites, and combinatorial effects of approved and investigational CFTR modulators, highlighting ongoing efforts to broaden therapeutic options for individuals with CF. Full article

Objective: Obesity is a major risk factor for endometrial cancer. In addition to hormone therapy with progestins, glucagon like peptide-1 receptor (GLP-1R) agonists such as semaglutide may be helpful to achieve weight loss during conservative treatment of endometrial hyperplasia or cancer. Methods: We theorized that the combination of semaglutide and the progestin levonorgestrel would be useful as a novel treatment or prevention regimen and tested this hypothesis using endometrial cancer cell lines and patient-derived organoids (PDOs). Results: Hec50, KLE, and Ishikawa endometrial cancer cells express GLP-1R, as determined by both qPCR and Western blotting, and GLP-1R agonist treatment induces GLP-1R mRNA transcription through positive feedback mechanisms in cell models. PDOs from six individuals with grade 1 endometrial carcinomas were treated with progesterone, levonorgestrel, semaglutide, or levonorgestrel + semaglutide. Multiple models demonstrated a significant reduction in viability in response to combinatorial treatment, and the effect was noted in models from both PR high- and PR low-expressing tumors. Most interesting was the induction not only of the membrane GLP-1R with treatment, but also the significant upregulation of nuclear and membrane progesterone receptors—PR and PGRMC1/2, respectively—indicating a potential positive feedback loop between semaglutide and progestins such as levonorgestrel. Conclusion: In summary, we identify synergistic molecular cross-talk between the GLP-1R and steroid hormone receptor pathways, with the potential to enhance the anticancer activity of levonorgestrel when combined with semaglutide. Full article

Ras proteins are pivotal in the regulation of cell proliferation signals, and their dysregulation is intricately linked to the pathogenesis of various malignancies. Peptide inhibitors hold distinct advantages in targeting Ras proteins, attributable to their extensive binding domains, which result from the smooth surfaces of the proteins. The array of specific strategies includes the employment of full hydrocarbon chains, cyclic peptides, linear peptides, and N-terminal nucleation polypeptides. These methods effectively suppress the Ras signaling pathway through distinct mechanisms, highlighting their potential as anti-neoplastic agents. Moreover, cutting-edge methodologies, including the N-terminal aspartate nucleation strategy and the utilization of hydrocarbon-stapled peptides, are transforming the landscape of therapeutics aimed at Ras proteins. These innovations highlight the promise of peptide libraries and combinatorial chemistry in augmenting binding affinity, specificity, and cellular permeability, which are pivotal for the development of potent anti-cancer agents. The incorporation of dual therapeutic strategies, such as the synergy between peptide inhibitors and conventional chemotherapy or the use of radiotherapy enhancers, emerges as a compelling strategy to bolster the efficacy of cancer treatments targeting the Ras-MAPK pathway. Furthermore, recent studies have demonstrated that Ras-targeting stabilized peptides can amplify the radio-sensitivity of cancer cells, offering an innovative approach to enhance the efficacy of radiation therapy within cancer management. Full article

Chimeric antigen receptor-T (CAR-T) cell therapy has demonstrated impressive efficacy in the treatment of blood cancers; however, its effectiveness against solid tumors has been significantly limited. The differences arise from a range of difficulties linked to solid tumors, including an unfriendly tumor microenvironment, variability within the tumors, and barriers to CAR-T cell infiltration and longevity at the tumor location. Research shows that the reasons for the decreased effectiveness of CAR-T cells in treating solid tumors are not well understood, highlighting the ongoing need for strategies to address these challenges. Current strategies frequently incorporate combinatorial therapies designed to boost CAR-T cell functionality and enhance their capacity to effectively target solid tumors. However, these strategies remain in the testing phase and necessitate additional validation to assess their potential benefits. CAR-NK (natural killer), CAR-iNKT (invariant natural killer T), and CAR-M (macrophage) cell therapies are emerging as promising strategies for the treatment of solid tumors. Recent studies highlight the construction and optimization of CAR-NK cells, emphasizing their potential to overcome the unique challenges posed by the solid tumor microenvironment, such as hypoxia and metabolic barriers. This review focuses on CAR cell therapy in the treatment of solid tumors. Full article