Search Results (42,184)

Bone integrity is maintained through continuous remodeling, orchestrated by the coordinated actions of osteocytes, osteoblasts, and osteoclasts. Once considered passive bystanders, osteocytes are now recognized as central regulators of this process, mediating biochemical signaling and mechanotransduction. Malfunctioning osteocytes contribute to serious skeletal disorders such as osteoporosis. Mesenchymal stromal cells (MSCs), multipotent stem cells capable of differentiating into osteoblasts, have emerged as promising agents for bone regeneration, primarily through the paracrine effects of their secreted exosomes. MSC-derived exosomes are nanoscale vesicles enriched with proteins, lipids, and nucleic acids that promote intercellular communication, osteoblast proliferation and differentiation, and angiogenesis. Notably, they deliver osteoinductive microRNAs (miRNAs) that influence osteogenic markers and support bone tissue repair. In vivo investigations validate their capacity to enhance bone regeneration, increase bone volume, and improve biomechanical strength. Additionally, MSC-derived exosomes regulate the immune response, creating pro-osteogenic and pro-angiogenic factors, boosting their therapeutic efficacy. Due to their cell-free characteristics, MSC-derived exosomes offer benefits such as diminished immunogenicity and minimal risk of off-target effects. These properties position them as promising and innovative approaches for bone regeneration, integrating immunomodulatory effects with tissue-specific regenerative capabilities. Full article

Saffron (Crocus sativus L.) contains bioactive compounds with potential health benefits, including modulation of protein function and gene expression. However, their ability to tune the epigenetic machine remains poorly understood. This study employs molecular docking (AutoDock Vina 1.4), dynamics simulations, and MM/PBSA calculations to investigate the interactions between four saffron-derived molecules—crocetin, beta-D-glucosyl trans-crocetin, picrocrocin and safranal—and four epigenetic enzymes—DNMT1, DNMT3a, HDAC2, and SIRT1. Our in silico screening identifies beta-D-glucosyl trans-crocetin, one of the saffron’s crocins, as a potential DNMT1 inhibitor. Along with crocetin, it also shows the ability to inhibit HDAC2 and activate SIRT1. Picrocrocin displays a resveratrol-like ability to activate SIRT1. None of the saffron-derived compounds effectively bind or inhibit DNMT3a. Among the tested molecules, safranal shows no interaction with the selected epigenetic targets. These findings highlight saffron’s nutriepigenomic potential and emphasize the need for functional validation within relevant in vitro and in vivo experimental methodologies. Full article

Glioma is a type of neoplasia that spontaneously arises from the glial cells of the brain in humans and dogs, and its prognosis is grave. Current treatment options for glioma include surgery, radiation therapy, chemotherapy, or symptomatic treatment. Evidence has shown that cannabidiol (CBD) may have anticancer, anti-angiogenic, and anti-inflammatory properties in both in vitro and in vivo studies. In this in vivo murine experiment, the canine glioma cell line J3TBG was injected into the frontoparietal cortex of immunodeficient mice using xenogeneic tissue transplantation. A total of 20 mice were randomly assigned to one of four treatment groups—Control group (C), CBD group (CBD), Radiation Therapy group (RT), and CBD plus Radiation Therapy group (CBD + RT). After transplantation of J3TBG, a single fraction of 5.5 Gy RT was administered to the RT and CBD + RT groups, and CBD was administered daily to the CBD and CBD + RT groups. Necropsies were performed to collect blood and brain tissue. Although there was not a statistically significant difference, the survival time among mice were longer in the CBD + RT group than the RT group. These results indicate that CBD may be used as an adjunctive therapy to enhance RT treatment. Larger cohort studies are required to substantiate the hypothesis. Full article

Chimeric antigen receptor (CAR)-T immunotherapy has revolutionized the management of patients with relapsed/refractory B-cell hematological malignancies. There is emerging evidence that CAR-engineered cells—not only T cells, but also natural killers and macrophages—might have a crucial role in the treatment of autoimmune disorders and solid tumors. Moreover, given the burden of chronic infectious diseases, the mortality and morbidity of infections in immunocompromised individuals, and the development of multidrug-resistant pathogens, including bacteria, fungi, and mycobacteria, a need for novel and personalized therapeutics in this field is emerging. To this end, the development of CAR cells for the management of chronic infections has been reported. In this literature review, we summarize the ongoing clinical and pre-clinical data about CAR cell products in the field of infectious diseases. Currently, clinical studies on CAR immunotherapy for infections mainly concern human immunodeficiency virus infection treatment, and data regarding other infections largely originate from preclinical in vitro and in vivo models. In the era of personalized medicine, effective and safe therapies for the management of chronic infections and infectious complications in immunocompromised patients are crucial. Full article

Background/Objectives: Metabolic syndrome (MetS) is a multifactorial condition characterized by abdominal obesity, dyslipidemia, insulin resistance, hypertension, and chronic inflammation. As its global prevalence rises, there is increasing interest in natural, multi-targeted approaches to manage MetS. Curcuma longa Linn. (turmeric), especially its active compound curcumin, has shown therapeutic promise in preclinical studies. This systematic review and meta-analysis evaluated the effects of Curcuma longa and its derivatives on MetS-related outcomes in rodent models. Methods: A comprehensive search was conducted across six databases (PubMed, Scopus, AMED, LILACS, MDPI, and Google Scholar), yielding 47 eligible in vivo studies. Data were extracted on key metabolic, inflammatory, and oxidative stress markers and analyzed using random-effects models. Results were presented as mean differences (MD) with 95% confidence intervals (CI). Results: Meta-analysis showed that curcumin significantly reduced body weight (rats: MD = −42.10; mice: MD = −2.91), blood glucose (rats: MD = −55.59; mice: MD = −28.69), triglycerides (rats: MD = −70.17; mice: MD = −24.57), total cholesterol (rats: MD = −35.77; mice: MD = −52.61), and LDL cholesterol (rats: MD = −69.34; mice: MD = −42.93). HDL cholesterol increased significantly in rats but not in mice. Inflammatory cytokines were markedly reduced, while oxidative stress improved via decreased malondialdehyde (MDA) and elevated superoxide dismutase (SOD) and catalase (CAT) levels. Heterogeneity was moderate to high, primarily due to variations in curcumin dosage (ranging from 10 to 500 mg/kg) and treatment duration (2 to 16 weeks) across studies. Conclusions: This preclinical evidence supports Curcuma longa as a promising functional food component for preventing and managing MetS. Its multi-faceted effects warrant further clinical studies to validate its translational potential. Full article

Although PD-1/PD-L1 inhibitors have transformed cancer immunotherapy, a substantial proportion of patients derive no clinical benefit due to resistance driven by the tumour microenvironment (TME). Transforming growth factor-β (TGF-β) is a key immunosuppressive cytokine implicated in this resistance. Several bifunctional antibodies that co-target PD-1 and TGF-β signalling have entered clinical trials and shown encouraging efficacy, but the mechanistic basis of their synergy is not fully understood. Here, we engineered 015s, a bifunctional fusion antibody that simultaneously targets murine PD-1 and TGF-β and evaluated its antitumour efficacy and mechanistic impact in pre-clinical models. Antibody 015s exhibited high affinity, dual target binding, and the effective inhibition of PD-1 and TGF-β signalling. In vivo, 015s significantly suppressed tumour growth compared with anti-mPD-1 or TGF-β receptor II (TGF-βRII) monotherapy. When combined with the CD24-targeted ADC, 015s produced even greater antitumour activity and achieved complete tumour regression. Mechanistic studies demonstrated that 015s significantly reduced tumour cell migration and invasion, reversed epithelial–mesenchymal transition (EMT), decreased microvascular density, and attenuated collagen deposition within the TME. Antibody 015s also decreased bioactive TGF-β1 and increased intratumoural IFN-γ, creating a more immunostimulatory milieu. These findings support further development of PD-1/TGF-β bifunctional antibodies for cancers with high TGF-β activity or limited response to immune checkpoint blockade. Full article

Background/Objectives: The functionalization of various forms of graphene, such as graphene nanoplatelets, graphene oxide, and reduced graphene oxide, in biomaterials is a promising strategy in dentistry, particularly regarding their antimicrobial potential. However, conclusive studies on the toxicity and biocompatibility of graphene-based materials remain limited, and standardized guidelines for their production, handling, and dental applications are still lacking. This scoping review aims to map the available studies on various types of graphene, synthesize evidence on their antimicrobial effectiveness, and describe the main biological responses when functionalized in dental biomaterials. Methods: An electronic search was conducted in the Clarivate, PubMed, and Scopus databases using the descriptors as follows: ‘graphene’ AND ‘antimicrobial effect’ AND ‘bactericidal effect’ AND (‘graphene oxide’ OR ‘dental biofilm’ OR ‘antibacterial properties’ OR ‘dental materials’). Article screening and eligibility assessment were performed based on predefined inclusion and exclusion criteria, following the PRISMA-ScR guidelines. Results: The search identified 793 articles. After removing duplicates, applying the eligibility criteria, and performing a full-text analysis of 64 articles, 21 studies were included in the review. Graphene oxide, particularly at low concentrations, was the most commonly studied graphene variant, demonstrating significant antimicrobial efficacy against S. mutans, S. faecalis, E. coli, P. aeruginosa, and C. albicans. Both mechanical and chemical mechanisms have been linked to the biological responses of graphene-doped biomaterials. The biocompatibility and cytotoxicity of these compounds remain controversial, with some studies reporting favorable outcomes, while others raise significant concerns. Conclusions: Graphene shows great promise as an antimicrobial agent in dental biomaterials. Despite encouraging results, more in vitro and in vivo studies are needed to better understand its biocompatibility and cytotoxicity in dental applications. Additionally, standardized production protocols, clearly defined clinical applications in dentistry, and regulatory guidelines from the World Health Organization concerning handling procedures and occupational risks remain necessary. Full article

Background/Objectives: Extracellular vesicles (EVs) are involved in cell-to-cell communication and delivery of signaling molecules and represent an interesting approach in targeted therapy. This project focused on EV-mediated facilitation and cell-specific delivery of effector antimiR molecules carried by biologically produced gold nanoparticles (AuNPs). Methods: First, we loaded EVs derived from cancer cells 4T1 with AuNPs-antimiR. The AuNPs were also decorated with or without transferrin (Tf) molecules. We examined parental cell-specific delivery of the AuNPs-Tf-antimiR within monocultures as well as co-cultures in vitro. Subsequently, we used autologous EVs containing AuNPs-Tf-antimiR to target tumor cells in a xenograft tumor model in vivo. Efficacy of the antimir transfer was assessed by qPCR and apoptosis assessment. Results: In vitro, EVs loaded with AuNPs-antimiR were internalized only by the parental cells and the AuNPs-antimiR transfer was successful and effective only in EVs that were decorated with Tf. We achieved effective delivery of the antimiR molecule into cancer cells in vivo, which was proved by specific silencing of the target oncogenic miRNA as well as induction of cancer cells apoptosis. Conclusions: EVs represent an interesting and potent way for targeted cargo delivery and personalized medicine. On the other hand, there are various safety and efficacy challenges that remain to be addressed. Full article

The Caco-2 in vitro model of the intestinal barrier is a well-established system for the investigation of the intestinal fate of orally ingested chemicals and drugs, and it has been used for over ten years by pharmaceutical industries as a model for absorption in preclinical studies. The Caco-2 model shows a fair correlation with in vivo drug absorption, though some inherent biases remain unresolved. Its main limitation lies in the lack of structural complexity, as it does not replicate the diverse cell types and mucus layer present in the human intestinal epithelium. Consequently, the development of advanced in vitro models of the intestinal barrier, that more structurally resemble the human intestinal epithelium physiology, has increased the potential applications of these models. Recently, Caco-2-based advanced intestinal models have proven effective in predicting nanomaterial uptake and transport across the intestinal barrier. The aim of this review is to provide a state-of-the-art of human in vitro intestinal barrier models for the study of translocation/uptake of nanoparticles relevant for oral exposure, including inorganic nanomaterials, micro/nano plastic, and fiber nanomaterials. The main effects of the above-mentioned nanomaterials on the intestinal barrier are also reported. Full article

The genus Anisosciadium, belonging to the Apiaceae family, has been traditionally recognized for its anti-inflammatory, antioxidant, and antimicrobial properties. However, scientific research on this genus is still limited, highlighting the need for a comprehensive review of its chemical composition and pharmacological characteristics. A comprehensive compilation of data was conducted using major databases such as Google Scholar, Research Gate, Web of Science, Scopus, and ScienceDirect. In this review, we collected and organized the available information of identified compounds from different species of the genus Anisosciadium, covering the literature from 2003 to 2024. In total, 64 phytoconstituents were detected. The findings suggest that the traditional therapeutic properties of Anisosciadium are well supported by the reported pharmacological activities from previous studies. Notably, these studies highlight its antioxidant, antibacterial, and cytotoxic effects, emphasizing the potential of this genus in the development of new therapeutic agents. Nonetheless, the lack of comparative studies among Anisosciadium species and the scarcity of in vivo studies and clinical trials limit the full realization of its therapeutic potential. Specifically, comparative studies could be crucial in identifying species with unique chemical profiles and understanding how variations in secondary metabolite compositions may influence their pharmacological activities. Full article

Background/Objectives: Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide, with its incidence rising each year. Despite its relatively low incidence, the aggressiveness of pancreatic cancer results in high mortality, with only 12% of patients surviving five years post-diagnosis. Surgical resection remains the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage. The goal of this work is to identify vulnerabilities that can affect the efficacy of treatments and improve the efficacy of therapy. Methods: MAP17 overexpression in pancreatic cancer cell lines, RT-qPCR analysis, xenografts, in vitro and in vivo treatments, analysis of data from pancreatic tumors in transcriptomic patient databases. Results: We studied the prognostic and predictive value of MAP17 (PDZK1IP1) expression in pancreatic cancer, and we found that high MAP17 mRNA expression was associated with poor prognosis. In addition, single-cell analysis revealed that high MAP17 expression was present only in tumor cells. We investigated whether the response to various antitumor agents depended on MAP17 expression. In 2D culture, MAP17-expressing pancreatic cancer cells responded better to gemcitabine and 5-fluorouracil. However, in vivo xenograft tumors with MAP17 expression showed resistance to all treatments. Additionally, MAP17-expressing cells had a high NAD pool, which seems to be effectively depleted in vivo by NAMPT inhibitors, the primary enzyme for NAD biosynthesis. Conclusions: Our findings suggest that MAP17 expression could enhance the prognostic stratification of pancreatic cancer patients. Moreover, the coadministration of NAMPT inhibitors with current treatments may sensitize tumors with high MAP17 expression to chemotherapy and improve the efficacy of chemotherapy. Full article

Background/Objectives: Chemotherapy-induced neuropathic pain (CINP) represents a critical challenge in oncology, emerging as a common and debilitating side effect of widely used chemotherapeutic agents, such as paclitaxel (PTX). Current therapeutic interventions and preventive strategies for CINP are largely insufficient, as they fail to address the underlying peripheral nerve damage, highlighting an urgent need for the development of new drugs. This study aimed to investigate the dual-function effects on normal cell protection and tumor suppression of BMX-001, a redox-active manganese metalloporphyrin that has demonstrated antioxidant and anti-inflammatory properties, which offers potential in protecting central nervous system tissues and treating CINP. Methods: This study assessed BMX-001’s different roles in protecting normal cells while acting as a pro-oxidant and pro-inflammatory molecule in cancer cells in vitro. We also evaluated its neuroprotective effect in preclinical PTX-induced CINP models in vivo. Results: Our results showed significant reductions in mechanical and cold allodynia, decreased pro-inflammatory cytokine levels, and restored antioxidant capacity in peripheral nerves and dorsal root ganglia (DRGs) following BMX-001 treatment. Conclusions: Overall, our study highlights the therapeutic potential of BMX-001 to mitigate CINP and enhance anticancer efficiency. Its dual-selective mechanism supports the future clinical investigation of BMX-001 as a novel adjunct to chemotherapeutic regimens. Full article

The Anti-Müllerian hormone (AMH) is widely recognized for promoting Müllerian duct regression in higher vertebrates and regulating key reproductive functions like steroidogenesis, folliculogenesis, and Leydig cell development. In teleost fish, which lack Müllerian ducts, Amh primarily influences male reproductive functions, including sex determination, testis differentiation, and germ cell proliferation. In adult fish, Amh supports gonad development and spermatogenesis, but its role in teleost gonadal physiology remains largely underexplored. This study reveals a novel steroidogenic function in the European sea bass (Dicentrarchus labrax) using in vitro testis culture, in vivo plasmid injection, and cell-based transactivation assays. The Amh-induced significant increase in androgen levels was also confirmed in Japanese medaka (Oryzias latipes) treated with recombinant sea bass Amh. Beyond activating the canonical Smad pathway, Amh also triggered the cAMP/PKA signalling pathway via its cognate type II receptor, Amhr2. Inhibitors of these pathways independently and synergistically counteracted Amh-induced CRE-Luc activity, indicating pathway crosstalk. Moreover, inhibition of the cAMP pathway suppressed Amh-induced androgen production in testis cultures, emphasizing the crucial role of protein kinase A in mediating Amh steroidogenic action. These findings uncover a novel steroidogenic function of Amh in teleosts and highlight its broader role in male reproductive physiology. Full article

Virgin coconut oil (VCO) has emerged as a functional food oil with considerable health benefits and wide applications in the food, pharmaceutical, and cosmetic industries due to its resident bioactive compounds, including lauric acid (LA). LA is the most abundant saturated medium-chain fatty acid in VCO and has been associated with several pharmacological activities. The literatures show the pharmacological effects of VCO and LA on chronic pathologies, infectious diseases, and metabolic disorders. A robust body of evidence shows that LA and other phenolic compounds are responsible for the VCO protection against toxicities and pharmacological efficacies. This review elucidates the anticancer mechanisms of VCO/LA and their modulation of the chemotherapy-induced side effect toxicity. VCO, LA, and their nanomaterial/encapsulated derivatives promote ROS generation, antiproliferation, apoptosis, cell cycle arrest, the inhibition of metastasis, and the modulation of cancer-related signaling pathways for cancer cell death in vivo and in vitro. VCO mitigates oxidative inflammation and apoptosis to block the underlying mechanisms of the side effect toxicity of chemotherapy. However, the possible beneficial effect of LA on the toxicity of chemotherapy is currently unknown. The available evidence emphasizes the anticancer effect and mechanism of VCO and LA, and the VCO potential to combat adverse side effects of chemotherapy. Thus, VCO and LA are potential adjuvant therapeutic agents in the management of various cancers. Nevertheless, future studies should be targeted at elucidating cancer-related molecular mechanisms to bridge the gap in knowledge. Full article

The MIM1-BH3 mimetic, which inhibits the Mcl-1 antiapoptotic protein, may be an efficacious molecule able to induce apoptosis. Previously, we found that moxifloxacin (MXFL) is able to modulate Mcl-1 protein expression. Therefore, in the current study, we assessed the impact of the MXFL, MIM1, and MXFL/MIM1 mixtures on viability and apoptosis in amelanotic A375 and melanotic G361 melanoma cells. The obtained results showed that MXFL and MIM1 exerted high cytotoxic and proapoptotic potential. In the case of two-component models, we have demonstrated that the use of the MIM1 and MXFL mixtures resulted in a significant intensification of both cytotoxic and proapoptotic activity, shown as a modulatory effect on the early and late phases of apoptosis toward the analyzed melanoma cells when compared with MIM1 or MXFL alone. We report, for the first time, the high proapoptotic activity of MIM1 and MXFL applied in a two-component model toward melanoma cells, pointing to the Mcl-1 protein as an important molecular target. The observed potential synergistic mode of action—expressed as cytotoxic and proapoptotic activity enhancement, detected for MIM1 and MXFL—may represent a new direction for further in vitro and in vivo experiments concerning the role of the Mcl-1 protein in the treatment of melanoma. Moreover, the presented results certainly contribute to expanding the knowledge of the pharmacology of both fluoroquinolones and BH3 mimetics, and also enable a better understanding of melanoma cell biology. Full article