Search Results (1,799)

Background: Fracture healing requires a coordinated inflammatory response, and its dysregulation, as seen in polytrauma, can impair bone regeneration. Human mesenchymal stem cells (hMSCs) play a central role in fracture repair through osteogenic differentiation and also via their secretome, which regulates local inflammation, angiogenesis, and tissue regeneration. Interleukin-6 (IL-6), an early pro-inflammatory cytokine, contributes to fracture healing by promoting MSC recruitment and osteogenic differentiation, whereas bone morphogenetic protein-2 (BMP-2) is a key osteoinductive factor that drives bone formation. However, the combined effects of IL-6 and BMP-2 on the hMSC secretome remain poorly understood. Methods: We cultured hMSCs in osteogenic media supplemented with recombinant IL-6 (1–20 ng/mL) alone or combined with recombinant BMP-2 (1 ng/mL) on tissue culture plastic (TCP) and within gelatin methacryloyl (GelMA) hydrogels of low (~3 kPa), medium (~15 kPa), and high (~30 kPa) stiffness. Osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity and calcium deposition; cytokine profiling was performed using a multiplex antibody array. Results: When cultured on TCP, IL-6 suppressed ALP activity by day 21. Co-treatment with IL-6 and BMP-2 induced a dysregulated secretome with concurrent upregulation of pro-inflammatory markers (MIP-1α, TNF-α, and GM-CSF) and anti-inflammatory mediators (IL-10, TGF-β1, and VEGF). This hyperinflammatory response was attenuated when hMSCs were encapsulated in GelMA, with high-stiffness gels most effectively suppressing pro-inflammatory chemokines and medium-stiffness gels yielding the highest ALP activity. Conclusions: These findings suggest that mechanically tuned GelMA hydrogels modulate immune and osteogenic responses of hMSCs in vitro, warranting further investigation in the context of scaffold design for fracture care. Full article

Solid tumors typically expand in a “cold” immunosuppressive tumor microenvironment (TME) and resist killing by CAR T cells or conventional therapy. Herein, we show that intratumoral injection of C3a and C5a receptor 1 (C3ar/C5ar1) pharmaceutical antagonists in an in situ forming implant (ISFI) can robustly suppress such tumors. Antagonizing autocrine C3ar/C5ar1 signaling in eight human and murine cancers of diverse lineages was universally anti-mitotic and pro-apoptotic in vitro, and growth-repressive in vivo. In contrast to i.p. administration of C3ar/C5ar1 antagonists to tumor-bearing mice, injecting the antagonists intratumorally in slow release poly (lactic-co-glycolic acid) (PLGA) polymer caused near-complete tumor elimination. The focused blockade of C3ar/C5ar1 GPCR signaling in an intratumoral ISFI opposed solid cancers by jointly repressing cancer cell viability/growth, tumor-associated angiogenesis, and myeloid-derived suppressor cell (MDSC) recruitment. Thus, the sustained blockade of C3ar/C5ar1 signaling in an intratumoral ISFI uninterruptedly disrupts three processes essential for solid cancer growth while avoiding adverse effects on other cell types. Our findings may apply to multiple cancer types in which discrete tumor masses can be targeted. Full article

Caffeic acid (CA) is a phenolic compound commonly found in fruits, vegetables, and coffee, with preclinical evidence demonstrating its important role in disease management through different mechanisms of action. This review aimed to explore CA’s pharmacological effects in different pathological conditions, and sources were retrieved by using databases like PubMed, Scopus, Google Scholar, and Web of Science and based on preclinical studies. CA notably protects cells and tissues from oxidative stress and inflammation, highlighting its therapeutic role in the management of pathogenesis. The neuroprotective, cardioprotective, hepatoprotective, anti-microbial, and anti-obesity effects are reported through in vitro and in vivo studies. Moreover, its anticancer effects are linked to modulation of cell signaling pathways, together with angiogenesis, cell cycle, apoptosis, and the PI3K/Akt pathway. This article explores how caffeic acid influences health conditions, providing a comprehensive overview of its effects on disease processes. Reviewing the literature aims to enhance the understanding of caffeic acid’s role in disease management and as a natural therapeutic agent. Although several studies demonstrate the anticancer effects and its role in the management of various pathological conditions, most of the existing evidence is based on in vitro, in vivo, and xenograft models. Moreover, many natural compounds, including CA, that exhibit activity in preclinical settings fail to translate into clinical applications, due to restrictions of poor bioavailability, toxicity, rapid metabolism, and differences in the tumor microenvironment. Thus, future studies should emphasize well-designed in vivo studies as well as controlled clinical trials to better describe CA’s safety, efficacy, mechanism of action, and therapeutic application in humans. Further investigation of its interactions with other therapeutic agents may offer insights into synergistic effects that enhance treatment efficacy. Overall, a more comprehensive understanding of this compound will be indispensable for its development as a therapeutic agent in the treatment of chronic disease. Full article

Background/Objectives: Chronic inflammation is a key factor in the development and progression of colorectal cancer (CRC). When COX-2 levels and PGE₂ production increase, nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin (ASA) and selective COX-2 inhibitors, such as celecoxib and rofecoxib, are commonly employed. This paper presents the effect of anti-inflammatory drugs, primarilyNSAIDs, on the incidence of CRC. Methods: A comprehensive literature search (119 articles) was conducted with databases such as PubMed. During our research, we used keywords such as colorectal cancer (CRC), nonsteroidal anti-inflammatory drugs (NSAIDs), ASA, COX, precision oncology, and personalized medicine. Results: The development of CRC is primarily associated with chronic inflammation and the actions of COX-2 and prostaglandin E2 (PGE₂), which promote cancer cell proliferation and angiogenesis. Anti-inflammatory drugs act by inhibiting the secretion of COX-1 and COX-2 enzymes, which leads to reduced PGE₂ production and may limit tumor growth. Aspirin has the best-documented and studied anti-cancer effect; long-term use is associated with a reduced risk of CRC development and mortality through its anti-inflammatory and antiplatelet effects, thereby limiting metastasis. Particularly beneficial effects are observed in patients with mutations in the PIK3CA gene. Factors influencing the effectiveness of CRC treatment include molecular differences and tumor location. Conclusions: The future of CRC treatment and prevention lies in personalized medicine, which accounts for each patient’s genetic profile. Decisions regarding NSAIDs use and CRC prevention should consider the potential benefits and risks of side effects. Full article

Icariin (ICA), a prenylated flavonoid glycoside from Epimedium (Yin Yang Huo), exhibits multi-organ pharmacological effects and has emerged as a promising candidate for osteoporosis therapy and bone tissue regeneration because of its capacity to modulate diverse osteogenic, anti-inflammatory, and angiogenic signaling pathways. Preclinical studies in osteoporotic models suggest that ICA improves trabecular microarchitecture and increases bone mineral density. Mechanistically, ICA modulates bone remodeling bidirectionally: it promotes osteoblast differentiation and extracellular matrix mineralization via activation of pro-osteogenic pathways, including Wnt/β-catenin and PI3K/Akt signaling, while simultaneously inhibiting osteoclastogenesis and bone resorption by suppressing RANKL-mediated NF-κB activation, thus reestablishing remodeling equilibrium. Despite these benefits, clinical advancement is hindered by the suboptimal oral bioavailability of ICA, stemming from poor intestinal absorption and extensive first-pass metabolism. To address this, innovative delivery systems have been engineered to enhance localized bioavailability and sustain therapeutic efficacy, such as hydrogel depots, nanoparticle formulations, and 3D-printed scaffolds enabling precise, controlled release. In bone tissue engineering applications, ICA-incorporated biomaterials—either standalone or in combination with osteogenic factors or exosomes—foster a regenerative niche by mitigating inflammation and oxidative stress, while synergistically promoting osteogenesis and angiogenesis, thereby expediting bone defect healing and osseointegration. Overall, these mechanistic elucidations and delivery advancements underscore ICA’s potential as a translational candidate for osteoporosis treatment and bone regenerative therapies. This review aims to critically and systematically synthesize current evidence on ICA-mediated bone repair and regeneration, with a particular emphasis on the molecular regulation of osteogenic signaling, the restoration of bone-remodeling homeostasis, and delivery-system-enabled strategies that may facilitate translational application. Full article

Atherosclerosis (AS) is a chronic inflammatory disease of large arteries. It underlies many cardiovascular disorders, including coronary artery disease, myocardial infarction, stroke, and peripheral arterial disease. Current therapies have improved outcomes, especially lipid-lowering, antithrombotic, and anti-inflammatory treatments. Yet residual cardiovascular risk remains, and new molecular targets are still needed. Leucine-rich α-2-glycoprotein 1 (LRG1) is an inflammation-inducible secreted glycoprotein. It has drawn attention because it is linked to pathological angiogenesis, vascular dysfunction, tissue remodeling, and fibrosis. Recent studies indicate that LRG1 is related to AS at several levels. These include circulating clinical associations, plaque localization, and experimental models. In AS, LRG1 may not simply act as a biomarker. It may promote macrophage pro-inflammatory polarization, disturb endothelial homeostasis, support abnormal angiogenesis, and influence extracellular matrix remodeling and plaque structural change. This review examines the biological features of LRG1 and the current evidence connecting it with AS. It also discusses possible mechanisms, therapeutic feasibility, and current limitations. Overall, LRG1 appears to be a promising but still incompletely validated candidate target in AS. Full article

Background: Aspirin, initially recognized for its anti-inflammatory, antipyretic and analgesic properties, holds a prominent role in the treatment of cardiovascular disease. The utility of aspirin in cancer therapeutics has been explored and stratified into COX-dependent and -independent mechanisms. COX2 gene expression has been demonstrated to be significantly upregulated in colorectal cancer and various other gastrointestinal malignancies including pancreatic, esophageal, and gastric cancer. This study investigates the relationship of aspirin use and outcomes in patients with colorectal cancer. Methods: The Nationwide Inpatient Sample (NIS) database from 2017 to 2022 was analyzed for patients age > 18 who were hospitalized for colorectal cancer and its decompensations using ICD-10 diagnostic codes. These patients were further stratified based on the long-term use of aspirin. The principal outcome of this investigation are the odds of in-hospital mortality, with secondary outcomes including odds of pulmonary embolism, portal vein thrombosis, acute kidney injury, septic shock, requiring an ICU level of care and odds of hepatic, pulmonary, gastrointestinal and peritoneal or retroperitoneal metastatic disease. Multivariate logistic regression accounting for hospital and patient characteristics was implemented for analysis, with the Charlson Comorbidity Index used to adjust for coexisting comorbidity burden; a p-value (p) of <0.05 was considered statistically significant. Results: In our analysis of the NIS, 596,160 patients were identified with colorectal cancer and 11.7% (69,750) of this population were identified with long-term use of aspirin. Aspirin use was identified to have a significantly reduced odds of in-patient mortality (adjusted odds ratio) [aOR] 0.530, p value < 0.001 95% CI (confidence interval): 0.460–0.617. Patients with aspirin use also demonstrated significantly reduced odds of adverse outcomes and gastrointestinal, hepatic, pulmonary and retroperitoneal/peritoneal metastasis; (aOR 0.606, 95% CI: 0.564–0.653, p < 0.001), (aOR 0.628, 95% CI: 0.582–0.678, p < 0.001), (aOR 0.676, 95% CI: 0.605–0.755, p < 0.001) and (aOR 0.751, 95% CI: 0.685–0.825, p < 0.001) respectively. Conclusions: In recent years, there has been an alarming increase in incidence of colorectal cancer, particularly amongst younger individuals with increased associated mortality. This mortality increase, albeit alarming, is a driving force for treatment innovation with continual examination of our repertoire of medications for possible repurposed applications. COX2-mediated signaling serves as a key promotor of tumorigenic molecular signaling that directly contributes to tumor cell proliferation, angiogenesis and metastasis in colorectal cancer. Aspirin use and its inhibitory action on COX2 demonstrated a significantly reduced odds of in-hospital mortality. Aspirin use is also associated with significantly reduced odds of developing metastatic disease to the liver, gastrointestinal system, lungs and peritoneum in patients with colorectal cancer. These findings convey that aspirin use reduces the likelihood of in-hospital mortality, major comorbid conditions and of developing metastatic disease as compared to those who do not use aspirin. Full article

Natural bioactive compounds present promising avenues for the prevention and therapeutic intervention of cancer. Octacosanol has garnered significant attention for its distinctive biological properties, yet its specific antitumor effects and underlying mechanisms remain unclear. This study systematically evaluated its antitumor effects and elucidated the associated molecular mechanisms. We confirmed that it dose-dependently inhibited A549 cell proliferation in vitro. It also remarkably suppressed cell invasion and migration by downregulating MMP2 and MMP9 expression, an effect that was associated with reduced phosphorylation of JAK3/STAT3 and PI3K/AKT, suggesting a potential regulatory role of these signalling cascades. Meanwhile, it significantly inhibited tumor cell VEGF secretion and VEGF-mediated neoangiogenesis by modulating the PI3K/AKT signaling axis. Mouse experiments demonstrated that octacosanol significantly reduced tumor p-AKT, MMP2, and MMP9 levels, indicating its in vivo anti-metastatic effect. It also remarkably decreased tumor microvessel density, alongside reduced VEGF and vascular endothelial marker CD31 expression, further verifying its potent anti-angiogenic activity. This work provides evidence of octacosanol’s dual anti-metastatic and anti-angiogenic effects in lung cancer and offers novel mechanistic insights into its activity against this highly prevalent malignancy. These findings establish a solid foundation for further exploration and development of octacosanol as a promising adjuvant for clinical antitumor therapy. Full article

Antibody–drug conjugates (ADCs) are a promising therapeutic modality for treating cancer. TM4SF1 is an integral membrane protein that internalizes from the cell surface along microtubules to the nucleus and is highly expressed on the surface of both tumor endothelium and tumor cells. We previously reported that in human tumor xenografts in mice, an ADC directed to mouse TM4SF1 (2A7A-LP2) effectively regressed tumors through an anti-vascular mechanism, and an ADC directed to human TM4SF1 (v1.10-LP2) effectively regressed tumors through an anti-tumor cell mechanism. In this study, we investigated the actions of the mouse TM4SF1-directed ADC on VEGF-A-provoked angiogenic vessels. We employed an adenovirus expressing mouse VEGF-A¹⁶⁴ (Ad-VEGF-A) to induce surrogate tumor blood vessels in the ears of nude mice. We showed that an immune effector function-ablated ADC, 3m2A7A-LP2, was better tolerated than its parent 2A7A-LP2. Homing of 3m2A7A to Ad-VEGF-A-induced new blood vessels became evident within six hours after intraperitoneal injection. A single dose of 3m2A7A-LP2 at 3 mg/kg disrupted evolving Ad-VEGF-A-provoked blood vessels within forty-eight hours, and three doses of 3m2A7A-LP2 at 48 h intervals caused striking local ear necrosis; in each case, there was no apparent harm to vessels in the corresponding control virus-injected ears and the surrounding tissues of the same mice. Our studies demonstrate that an ADC-directed against mouse TM4SF1 specifically targeted the newly formed blood vessels induced by Ad-VEGF-A at multiple stages of their development. Thus, TM4SF1-directed ADCs, through their ability to target angiogenic vessels, represent an alternative anti-angiogenic approach for treating solid tumors. Full article

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8⁺ TILs exhibiting a progenitor stem-cell-like profile (CD39⁻ CD69⁻). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the “double-edged sword” nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome. Full article

Background: Impaired angiogenesis and persistent inflammation are hallmarks of chronic diabetic wounds. Extracellular vesicles derived from dental pulp stem cells (DPSC-EVs) represent a promising cell-free therapy for tissue repair; however, their clinical translation is hindered by suboptimal yields and attenuated bioactivity associated with conventional two-dimensional (2D) culture. This study investigated whether a biomimetic three-dimensional (3D) fibrin/gelatin hydrogel system could optimize the therapeutic potency of DPSC-EVs for diabetic wound healing. Methods: DPSCs were encapsulated within 3D fibrin/gelatin scaffolds, followed by comprehensive characterization of cell viability and morphology. 3D-EVs and 2D-EVs were isolated via ultracentrifugation and validated by transmission electron microscopy and nanoparticle tracking analysis. The pro-angiogenic capacity of 3D-EVs was evaluated using human umbilical vein endothelial cells (HUVECs) under high-glucose (HG) stress. Additionally, the immunomodulatory effects were assessed by monitoring macrophage polarization in lipopolysaccharide-stimulated RAW 264.7 cells. The therapeutic efficacy was further validated in vivo using a streptozotocin (STZ)-induced diabetic mouse model with full-thickness cutaneous wounds. Results: The 3D fibrin/gelatin hydrogel provided a supportive microenvironment that significantly augmented the secretory productivity of DPSCs. Compared to 2D-EVs, 3D-EVs exhibited superior functional resilience in restoring HUVEC migration and tube formation under HG-induced oxidative stress. Furthermore, 3D-EVs effectively orchestrated the macrophage transition from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype, thereby modulating the immune microenvironment. In vivo, topical administration of 3D-EVs markedly accelerated wound closure, promoted re-epithelialization, and enhanced microvascular density and collagen maturation in diabetic mice. Conclusions: Our findings demonstrate that the 3D fibrin/gelatin culture system effectively primes the therapeutic profile of DPSC-EVs. These engineered vesicles accelerate diabetic wound healing by synergistically promoting angiogenesis and resolving chronic inflammation, offering a robust and potent cell-free strategy for the management of chronic diabetic ulcers. Full article

Preeclampsia is a pregnancy-specific multisystem disorder and a major cause of maternal and perinatal morbidity and mortality worldwide. This narrative review summarizes current evidence on the principal risk factors and pathophysiological mechanisms involved in its development. The disease is best explained by the two-stage model: in stage 1, inadequate trophoblast invasion and incomplete spiral artery remodeling lead to placental hypoperfusion, hypoxia, and oxidative stress; in stage 2, the hypoxic placenta releases anti-angiogenic and pro-inflammatory factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which trigger systemic endothelial dysfunction and the maternal clinical syndrome. The review highlights the central role of angiogenic imbalance, immune dysregulation, and chronic inflammation in disease progression. Particular emphasis is placed on maternal risk factors such as primiparity, advanced maternal age, obesity, diabetes mellitus, chronic hypertension, multiple pregnancy, prior preeclampsia, genetic susceptibility, and epigenetic regulation. We also emphasize the contribution of microRNAs in relation to placental hypoxia, trophoblast invasion, angiogenesis, endothelial injury and microchimerism to the development of preeclampsia. The review also examines the role of T helper 1 (Th1)/Th2/Th17/regulatory T cells (Treg) imbalance and uterine natural killer cell dysfunction at the maternal–fetal interface. Improved understanding of these interconnected mechanisms may support earlier diagnosis, better risk stratification, and the development of targeted preventive and therapeutic strategies. Full article

Prostate cancer (PCa) management has evolved with biomarker-driven strategies, yet biological heterogeneity, adaptive resistance, and an immunosuppressive microenvironment limit their efficacy. Galectin-3 (Gal-3) has emerged as a central node in PCa pathobiology, influencing tumor survival, metastasis, and immune escape. This review comprehensively reviews Gal-3’s dual role as a biomarker and a therapeutic target. We first delineate the limitations of the current diagnostic, prognostic, and predictive biomarkers in PCa, establishing the unmet need. We then elucidate the multifunctional biology of Gal-3, detailing its compartment-specific roles in anti-apoptosis, angiogenesis, epithelial-to-mesenchymal transition, and, notably, its function as a master regulator of immunosuppression. The interaction between Gal-3 and prostate-specific antigen (PSA) is explored as a key regulatory interface. Furthermore, we catalog and analyze emerging Gal-3-targeted therapies, emphasizing their rationale for combination with immune checkpoint blockade to reverse therapeutic resistance. Finally, we outline a translational roadmap, advocating for standardized Gal-3 biomarker assays and biomarker-enriched clinical trials. Integrating Gal-3 into the PCa precision medicine toolkit offers a novel strategy to address heterogeneity and improve therapeutic durability. Full article

Colorectal cancer (CRC) is one of the most prevalent gastrointestinal malignancies worldwide and remains a major cause of cancer-related mortality. Although current treatment strategies, including surgery, chemotherapy, radiotherapy, and targeted therapies, have improved patient outcomes, their effectiveness is frequently limited by multidrug resistance, severe adverse effects, tumour recurrence, and restricted patient applicability. Consequently, there is an urgent need to develop novel therapeutic agents with improved efficacy and reduced toxicity. Marine bioactive peptides have emerged as promising candidates for CRC therapy because of their remarkable structural diversity, unique evolutionary adaptations, and broad spectrum of biological activities. Numerous marine-derived peptides exhibit potent anti-CRC effects by inducing apoptosis, regulating cell-cycle progression, suppressing invasion and metastasis, inhibiting angiogenesis, and modulating the tumour microenvironment while generally demonstrating low toxicity toward normal cells. Despite these advantages, the clinical translation of marine peptides remains constrained by several challenges, including poor stability, rapid enzymatic degradation, limited bioavailability, difficulties in large-scale production, insufficient target characterization, and a lack of long-term safety evaluation. Recent advances in peptide engineering and pharmaceutical technology have significantly accelerated progress in this field. Strategies such as structural modification, cyclization, nanoformulation, intelligent delivery systems, and artificial intelligence-assisted peptide design have improved peptide stability, targeting efficiency, pharmacokinetic properties, and production feasibility. These technological innovations provide new opportunities to overcome the major limitations associated with marine peptide therapeutics. This review systematically summarizes the sources, structural characteristics, extraction and purification methods, molecular mechanisms, and in vitro and in vivo anti-CRC activities of marine-derived peptides. In addition, the major translational challenges and current technological solutions are critically discussed, with particular emphasis on the integration of multidisciplinary approaches for the development of next-generation marine peptide-based therapeutics for colorectal cancer. Full article

CXCL14 is a highly conserved chemokine with potential roles in tumor progression and immune modulation. This study investigates the functional impact of CXCL14 on colon cancer by exploring its effects on tumor cell behavior and the immune microenvironment. We generated stable cell lines overexpressing CXCL14 in mouse MC38 and CT26 cells and human HCT15 colon cancer cells, and used these models to assess tumor growth, invasion, and immune cell infiltration. Our results demonstrate that CXCL14 suppresses colon cancer cell proliferation, migration, and metastasis. In vitro, CXCL14 inhibited the expression of matrix metalloproteinases (MMPs), key regulators of epithelial–mesenchymal transition (EMT), suggesting a role in promoting mesenchymal–epithelial transition (MET). Additionally, in vivo studies using a subcutaneous tumor model showed that CXCL14 not only suppressed tumor growth but also enhanced the infiltration of immune cells, including NK cells, dendritic cells (DCs), and T cells, converting the tumor microenvironment from a “cold” to a “hot” phenotype. RNA sequencing and pathway analyses revealed that CXCL14 regulates the expression of genes associated with angiogenesis, immune response, and cell signaling, particularly through the MAPK pathway. Furthermore, CXCL14’s influence on tumor progression was confirmed in a spleen-to-liver metastasis model, where its overexpression reduced metastatic spread. In conclusion, CXCL14 inhibits colon cancer progression by modulating both tumor cell behavior and the immune landscape, making it a promising candidate for targeted immunotherapy. Our findings highlight CXCL14’s potential to enhance anti-tumor immunity and provide new insights into its therapeutic applications in colon cancer. Full article