Diabetes mellitus is a global healthcare issue of epidemic proportions. At the root of these disorders, characterized by poor glucose regulation and insulin deficiencies, is the pancreatic beta cell and insufficient insulin signal transduction in peripheral tissues. Residual c-peptide secretion and persisting beta cells have been found in patients who have been living with type 1 diabetes for over 50 years. Thus, beta cell regeneration has been vastly studied in rodents, and many agents to expand beta cell mass are under rigorous investigation for the treatment of diabetes. Multipotent stromal cells (MSC), isolated from human bone marrow, have an immunomodulatory and pro-regenerative secretome that can aid in repairing damaged tissues, including pancreatic islets. MSC transplantation has been shown to reduce hyperglycemia and orchestrate islet repair in experimental diabetes models and is currently being assessed in clinical trials. While the immunomodulatory mechanisms of MSC are well-studied, the beta-cell-regenerative mechanisms are unknown. MSC likely play a regenerative role by signaling to resident progenitor or precursor cells in the pancreas; however, the decades-long controversy surrounding the origin of regenerated adult beta cells remains unresolved. Herein, we take a deep dive into the role of MSC in the treatment of diabetes and the potential cellular mechanisms behind the MSC stimulation of beta cell regeneration.

Osteoarthritis (OA) is a multifactorial disease characterized by inflammation, extracellular matrix remodeling, and joint degeneration, and it still lacks disease-modifying treatments. Here, we applied an ex vivo OA model based on transwell co-cultures of cartilage and synovial membrane explants harvested from OA patients to compare the effects of adipose-derived stem/stromal cell (ASC) conditioned medium (CM) with dexamethasone (DEX), a clinically used corticosteroid. Explants were treated for 48 h with 100 nM DEX, CM derived from 5 × 105 ASCs, or left untreated. Outcomes included gene and protein expression of key mediators, metalloprotease and aggrecanase activities, and nitric oxide release. DEX significantly reduced inflammatory markers (e.g., PTGS, IL-1β, and IDO) and VEGF expression in both tissues, while CM did not elicit consistent anti-inflammatory effects. Regarding matrix remodeling, both treatments reduced metalloprotease activity, with DEX modulating MMP3 and MMP13 expression in both tissues and CM reducing only MMP3 expression in cartilage while presenting high levels of TIMP-1. These results confirm the robustness of the model, demonstrated by reproducible responses to DEX and its high-throughput potential, and underscore the need for mechanistic studies to optimize novel biotherapeutics.

The therapeutic potential of prodigiosin as a hydrophobic anticancer agent can be enhanced by various approaches, one of which is the loading of PG into extracellular vesicles. Drug distribution and stability in aqueous media play a crucial role in targeting and accumulation, thereby enabling the attainment of therapeutically effective drug concentrations. Extracellular vesicles are nano-sized, cell-derived vesicles with a lipid bilayer membrane. Extracellular vesicles can be utilized as drug carriers for both water-soluble and non-water-soluble therapeutic agents. We hypothesized that microvesicles could effectively address the current challenges of prodigiosin delivery. Several different techniques have been developed for fabricating extracellular vesicles. These include microvesicles induction by cytochalasin B treatment as well as cell cultivation in serum depleted media. In our study, prodigiosin, like cytochalasin B, demonstrated efficacy in microvesicles formation based on protein quantification and Nanoparticle Tracking Analysis. In addition, Nanoparticle Tracking Analysis showed that vesicles from mesenchymal stem cells are more stable under ultrasound exposure. Microvesicles encapsulating prodigiosin, compared to unmodified naïve ones, demonstrated slightly increased zeta potentials and hydrodynamic diameters, which probably contributed to better stability. We demonstrated that ultrasonic treatment for the loading of prodigiosin does not significantly increase the proportion of prodigiosin-positive microvesicles in comparison with microvesicles induced with prodigiosin; moreover, this method cannot be considered as optimal due to its disadvantages, such as particle aggregation. Prodigiosin-induced and prodigiosin-loaded microvesicles from mesenchymal stem cells were significantly smaller and less polydisperse in size. Overall, prodigiosin encapsulated in extracellular vesicles might be more suitable for medical and clinical applications compared to pure forms of PG due to their cell membrane compatibility.

Background: Chronic liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition and architectural remodeling, which may ultimately lead to cirrhosis and liver failure. Although mesenchymal stem cells (MSCs) exhibit antifibrotic and immunomodulatory properties, their therapeutic effects in established chronic liver fibrosis remain incompletely defined. This study aimed to evaluate the biochemical, hematological, and histopathological effects of MSC therapy in a chronic thioacetamide-induced liver fibrosis model. Methods: A controlled preclinical experimental study was conducted using rats with liver fibrosis induced by intraperitoneal thioacetamide administration for 24 weeks. Animals were allocated into three groups: control, untreated fibrosis, and fibrosis treated with MSCs derived from human umbilical cord tissue after fibrosis establishment. Serum biochemical markers, hematological parameters, and liver histopathology were assessed. Fibrosis severity was evaluated using hematoxylin-eosin and Masson's trichrome staining and graded according to the METAVIR scoring system. Results: Thioacetamide exposure induced chronic liver injury characterized by marked elevations in serum transaminases, reduced albumin and total protein levels, hematological alterations, and early-to-intermediate fibrosis stages (METAVIR F1-F2). MSC-treated animals exhibited approximately 40-45% reductions in transaminase levels, partial recovery of hepatic synthetic function, and attenuation of hematological alterations. Histopathological analysis demonstrated a reduction in fibrotic burden and limitation of fibrogenic progression within METAVIR F1-F2 stages. Conclusions: MSC therapy partially mitigates biochemical, hematological, and histopathological alterations associated with chronic thioacetamide-induced liver fibrosis, supporting its potential as a modulatory strategy to attenuate fibrogenic progression and stabilize liver function rather than as a curative intervention.

Metaplastic breast carcinoma (MBC) is a heterogenous group of invasive breast cancer with distinct morphological patterns and negativity for hormone receptors and HER2. The pathogenesis of MBC is unknown but tumour cells exhibit epithelial-mesenchymal transition and breast cancer stem cell-like characteristics. Genomic characterisation of these tumours can lead to identification of targetable mutations which may help in improving the overall treatment outcome. Sixty-seven retrospective cases of MBC were sub-classified morphologically. Cytoplasmic expression of ALDH1 was evaluated using IHC to estimate the stemness. Alteration in PI3K/AKT/PTEN/MAPK pathway was studied using next generation sequencing (n = 47). Histological subtypes were squamous cell carcinoma (n = 25), Metaplastic carcinoma with heterologous mesenchymal differentiation (n = 19), spindle cell carcinoma (n = 19), Fibromatosis like metaplastic carcinoma (n = 3), and Mixed metaplastic carcinoma (n = 1). ALDH1 was positive in 31.3% cases. PI3K was the most frequently altered gene followed by PTEN, TP53 and MAPK1 gene. PI3K alterations were more frequent in Spindle cell carcinoma and squamous carcinoma This study identified high frequency of stem cell marker and targetable genetic alterations in the PI3K signalling pathway. Thus, Inhibitors of the PI3K signalling pathway are ideal candidates for targeted therapy for MBC irrespective of histological subtype.

The present study evaluated and compared the anti‑inflammatory and osteogenic effects of extracellular vesicles (EVs) derived from tonsil‑derived mesenchymal stem cells (T‑MSC‑EVs) in a lipopolysaccharide (LPS)‑induced in vitro model of periodontitis using human periodontal ligament fibroblasts (hPDLFs). hPDLFs were treated with LPS to induce inflammation, followed by treatment with T‑MSC‑EVs. Cell viability was assessed using a 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay. The expression levels of inflammatory cytokines (IL‑1β, IL‑6, IL‑8 and IFN‑γ) and osteogenic markers [alkaline phosphatase (ALP), bone sialoprotein, osteopontin, osteocalcin and sclerostin] were evaluated using reverse transcription‑quantitative PCR. Inflammatory signaling proteins (phosphorylated ERK, phosphorylated JNK, c‑Fos, c‑Jun and NF‑κB) were analyzed by western blotting. Osteogenic activity was assessed using an ALP activity assay and alizarin red staining over 21 days. Treatment with T‑MSC‑EVs significantly protected hPDLFs from LPS‑induced growth suppression. T‑MSC‑EVs exhibited selective immunomodulation, reducing IL‑8 and IFN‑γ expression, while preserving IL‑6 and IL‑1β expression, which was accompanied by inhibited MAPK‑activator protein 1 and NF‑κB signaling. Finally, T‑MSC‑EVs restored the osteogenic potential by recovering ALP activity, mineral deposition and expression of osteogenic marker genes repressed by LPS. These findings underscore the therapeutic potential of EVs as next‑generation biologics for periodontitis and emphasize the importance of selecting appropriate EV sources to achieve targeted immune modulation and tissue regeneration.

Type 1 diabetes (T1D) is a T cell‑mediated autoimmune disorder characterized by the destruction of insulin‑producing β‑cells. Sialic acid‑binding Ig‑like lectin 15 (Siglec‑15) could inhibit T‑cell activation and suppress immune responses. However, the association between Siglec‑15 expression levels and T1D is largely unknown. Serum concentrations of soluble Siglec‑15 were quantified in a cohort comprising 34 individuals newly diagnosed with T1D and 21 healthy control subjects. A murine mesenchymal stem cell (MSC) line, C3H10 T1/2, was genetically engineered to stably express SIGLEC15 through lentiviral transduction. Non‑obese diabetic (NOD) mice were administered treatments with Siglec15‑expressing MSCs, control MSCs, or phosphate‑buffered saline. The present study evaluated diabetes incidence, blood glucose concentrations, the severity of insulitis and the composition of immune cell populations in the pancreatic lymph nodes and spleens. In the present study, measurement of human serum specimens by ELISA revealed a positive association between new‑onset T1D and soluble Siglec‑15 levels. In NOD mice, treatment with Siglec15‑MSCs resulted in a significant reduction in diabetes incidence, preservation of insulin‑positive islets and mitigation of insulitis. Flow cytometric analysis demonstrated an increase in CD4+effector memory T cells within the pancreatic‑draining lymph nodes of mice treated with Siglec15‑MSCs, while no significant alterations were observed in splenic T cell populations or the frequencies of regulatory T cells. The findings of this study underscore the potential of Siglec‑15‑overexpressing MSCs as a promising cell‑based therapeutic approach for T1D, primarily through the localized modulation of memory T cells within the pancreatic lymph nodes.

CD8+ T cell exhaustion represents a major obstacle to effective cancer immunotherapy. While stem-like progenitor exhausted T (TPEX) cells can differentiate into intermediate (Int-TEX) and terminally exhausted (TEX) subsets, the epigenetic regulation of this process is unclear. We identify the RNA methyltransferase Mettl8 as a critical regulator, with expression significantly higher in TPEX than in TEX subsets. In anti-PD-1 responding non-small cell lung cancer patients, Mettl8 and the stemness factor TCF7 were downregulated. In murine models, Mettl8 deletion restrained tumor progression by driving TPEX differentiation into effective Int-TEX cells. Mechanistically, Mettl8 stabilizes Tcf7 mRNA via m3C modification and enhances Tcf1 protein expression. Additionally, Mettl8 interacts with Tcf1 to facilitate chromatin looping at the Tox locus, maintaining TPEX stemness. Pharmacological Mettl8 inhibition promoted TPEX-to-Int-TEX differentiation and tumor control. Combining this inhibition with anti-PD-1 therapy yielded synergistic efficacy. Our findings establish Mettl8 as a pivotal regulator of TPEX fate and a promising therapeutic target for enhancing immunotherapy.

Spinal cord injury (SCI) creates a hostile microenvironment characterized by persistent inflammation and glial scarring, which severely limits endogenous neural regeneration. To address these multifactorial barriers, we developed a targeted nanotherapeutic system comprising glutathione-functionalized Schwann cell-derived exosomes loaded with metformin (Exos-GSH@Met). In vitro and in vivo evaluations showed that GSH functionalization enabled the exosomes to effectively cross the blood-spinal cord barrier and selectively accumulate in macrophages at the injury site. Transcriptomic sequencing identified the PI3K/AKT pathway as a critical target activated by Exos-GSH@Met. Mechanistically, the treatment reprogrammed macrophages from a pro-inflammatory M1 phenotype to a reparative M2 phenotype via PI3K/AKT activation. This immunomodulatory shift subsequently orchestrated the differentiation of neural stem cells (NSCs) into functional neurons while suppressing astrocytic differentiation. Crucially, in vivo blockade of the PI3K pathway using the inhibitor LY294002 negated these regenerative effects, confirming the pathway's centrality. Furthermore, Exos-GSH@Met not only reduced the density of the glial scar but also significantly inhibited the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) by reactive astrocytes. Functionally, the treatment significantly improved motor recovery, restored electrophysiological conduction, and ameliorated bladder dysfunction in SCI mice. Collectively, these findings establish Exos-GSH@Met as a dual-action platform that coordinates immune microenvironment remodeling and neurogenesis through the PI3K/AKT axis, offering a promising strategy for SCI repair.

Psilocybin is studied as innovative medication in anxiety, substance abuse and treatment-resistant depression. Animal studies show that psychedelics promote neuronal plasticity by strengthening synaptic responses and protein synthesis. However, the exact molecular and cellular changes induced by psilocybin in the human brain are not known. Here, we treated human cortical neurons derived from induced pluripotent stem cells with the 5-HT2A receptor agonist psilocin - the psychoactive metabolite of psilocybin. We analyzed how exposure to psilocin affects gene expression, neuronal morphology, synaptic markers and neuronal function. Psilocin provoked a 5-HT2A-R-mediated augmentation of BDNF abundance. Transcriptomic profiling identified gene expression signatures priming neurons to neuroplasticity. On a morphological level, psilocin induced enhanced neuronal complexity and increased expression of synaptic proteins, in particular in the postsynaptic compartment. Consistently, we observed an increased excitability and enhanced synaptic network activity in neurons treated with psilocin. In conclusion, exposure of human neurons to psilocin might induce a state of enhanced neuronal plasticity, which could explain why psilocin is beneficial in the treatment of neuropsychiatric disorders where synaptic dysfunctions are discussed.

Brain metastases from breast cancer (BCBM) are fatal and lack effective treatments. Their cellular and molecular drivers remain poorly understood, partly due to limited preclinical models that fail to capture patient tumor heterogeneity. Cancer stem-like cells (CSCs) are implicated in metastatic dissemination; however, their specific role in brain metastasis remains unclear. In this study, CSCs are isolated from human BCBM specimens and characterized for stem-like properties, including CD44 and ALDH1 expression, sphere formation, tumorigenicity, and in vitro and in vivo self-renewal. Intra-nipple and intra-cardiac xenograft models demonstrate CSC ability to generate brain and bone metastases that recapitulate patient-specific dissemination patterns. Transcriptomic and functional analyses reveal cellular heterogeneity and identify a metastasis-initiating cell (MIC) subpopulation enriched in stemness and adhesion-related pathways. These MICs exhibit enhanced adhesion to brain endothelium and undergo brain-specific transcriptomic reprogramming that enables vascular co-option, resistance to stromal stress, and survival-promoting interactions with brain-resident cells. High-throughput drug screening indicates broad therapeutic resistance within the CSC compartment. Through the comprehensive characterization of BCBM-derived CSCs, this study establishes a clinically relevant model that identifies CSCs and the MIC subpopulation as key drivers of brain metastatic progression and as promising targets for the development of effective therapeutic strategies.

Significant progress has been made in research on chronic pancreatitis (CP). It is essential to analyze recent trends in this field to guide future clinical investigations.

The rational design, sustainable synthesis, and comprehensive biological evaluation of a new family of gold(I)-indomethacin complexes bearing N-heterocyclic carbene (NHC) ligands are reported. The mild, scalable synthetic protocol affords the first reported examples of well-defined [Au(NHC)(indomethacin)] complexes that display robust chemical and thermal stability and exhibit potent antiproliferative activity across a panel of human cancer cell lines, frequently outperforming cisplatin, including in cisplatin-resistant models. Notably, these gold(I)-indomethacin derivatives retain strong cytotoxicity against breast cancer stem cells (CSCs)-like populations and demonstrate superior efficacy in physiologically relevant 3D spheroid models. Mechanistic investigations reveal that their anticancer activity correlates with efficient inhibition of thioredoxin reductase, disruption of intracellular thiol homeostasis, and induction of oxidative stress through reactive oxygen species generation.

Intrauterine adhesion (IUA) is an important cause of infertility and poses a challenge to women's reproductive health. However, conventional clinical treatments fail to fundamentally repair the function of the endometrium. While stem cell therapy is a promising breakthrough in IUA treatment, its clinical application remains limited. Recent studies have highlighted the pivotal roles of oxidative stress and inflammatory immune responses in IUA pathogenesis, underlining the requirement for excessive reactive oxygen species (ROS)-scavenging ability, where nanozymes demonstrated distinctive advantages. Herein, we report the preparation of a nanozyme-powered injectable hydrogel (HME) by integrating hollow estradiol-loaded MnO2 nanoparticles (MnO2@E2 NPs) with a hyaluronic acid-based hydrogel to explore its therapeutic effect in IUA. In vitro studies demonstrated that MnO2@E2 NPs exhibited catalase (CAT)-like and superoxide dismutase (SOD)-like enzymatic activities, effectively scavenging ROS. The HME possessed optimal mechanical properties, biocompatibility, robust antioxidant activities and regulatory properties on macrophages, thereby protecting human endometrial stromal cells (HESCs) and enhancing their proliferation. In a rat endometrial injury model, HME treatment regulated the uterine inflammatory microenvironment, suppressed M1 macrophage expression and further promoted endometrial repair. In conclusion, the HME offers a novel and effective therapeutic approach for IUA, with potential clinical implications for women of reproductive age.

A systematic investigation of various surface coatings on iron oxide nanoparticles (IONPs) was conducted to understand their influence on interfacial interactions, colloidal stability, and magnetic performance. The surface-modified IONPs were synthesized via in situ and physical coating routes using synthetic polymers (polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethene glycol (PEG), polyethylenimine (PEI)), natural polymers (chitosan (CS), carboxymethyl cellulose (CMC), hyaluronic acid (HA)), small molecules (citric acid (CA), and oleic acid (OA)), and a silane coupling agent (3-aminopropyltriethoxysilane (APTES)). Face-centred cubic spinel-structured magnetite (Fe3O4) nanoparticles were synthesized with a lattice parameter of 8.356 Å, a particle size of 62 nm, and a saturation magnetization (Ms) of 67.95 A m2 kg-1. The coating of IONPs was confirmed by X-ray Photoelectron Spectroscopy (XPS) and Fourier Transform Infrared (FTIR) spectroscopy, indicating the formation of coordination bonds, hydrogen bonds, and electrostatic interactions between the NPs and the polymeric shell. The coatings substantially reduced agglomeration, thereby decreasing the particle size to 19-30 nm, while maintaining nearly superparamagnetic behavior at room temperature. The magnetic behavior was governed by Néel relaxation for NPs with a size less than 25 nm, whereas larger particles exhibited Brownian relaxation dominance. The relaxation mechanism is responsible for the heating output, measured as the Specific absorption rate (SAR), which provides a useful metric for comparing the heating efficiency of NPs. Induction heating studies carried out under the alternating magnetic field strength of 12.89 kA m-1 and frequency of 336 kHz revealed that coated IONPs exhibited superior heating performance with improved SAR of 112 to 225 W g-1. PEG, CMC, PEI, and APTES-coated IONPs achieved the hyperthermia temperature range of 42-46°C. However, PEG, CMC, and PEI-coated IONPs exhibited Néel relaxation dominance, which is desirable for in vivo hyperthermia applications. Furthermore, all the coated IONPs (except PEI-IONPs) demonstrated excellent in vitro cytocompatibility (> 80%) with the human embryonic kidney (HEK293) cell line at 2 mg mL-1 for 72 h. Simulated hyperthermic conditions led to cancer cell lethality, with normal cells being largely viable, suggesting the efficacy of hyperthermia for cancer treatment.

Thoracic aortic aneurysms and dissections (TAAD) are life-threatening vascular disorders affecting the medial layer of the aortic wall, associated with high mortality when a rupture or dissection occurs. Though numerous genes are associated with familial TAAD (FTAAD), pathogenic variants in MYH11, encoding smooth muscle cell specific myosin heavy chain (SM-MHC), represent a rare but interesting subgroup as many gaps remain in the knowledge of disease mechanisms, phenotype presentation and gene-environmental interactions. No reliable therapy exists in halting aneurysm growth in affected individuals.

Stem cell biology has rapidly expanded into an interdisciplinary field with potential for next-generation cell-based therapies. However, a critical gap remains in our understanding of how physical forces influence stem cell behavior. Recent studies in mechanotransduction, the process by which cells sense and convert mechanical cues into biochemical signals, have revealed that biomechanical regulation is fundamental for stem cell fate, proliferation, and therapeutic efficacy. This review synthesizes recent findings on the intrinsic and extrinsic parameters of physical cues that govern mechanotransduction and shape stem cell biology, highlights the mechanosensitive responses, and explores how biomedical engineering (BME) can be employed to manipulate these processes to improve translational outcomes in clinical settings. By integrating insights from cell biology, mechanobiology, and engineering, this interdisciplinary field offers strategies to translate benchside discoveries into clinical applications, advancing the development of precise and effective stem cell-based therapies.

After a stroke, many survivors experience post-stroke cognitive impairment (PSCI), a frequent clinical problem that might continue for an extended timeframe. Nerve regeneration is a crucial aspect of the body's self-repair mechanism following a stroke. While Sodium Pyruvate (SP) exhibits notable neuroprotective properties, its potential role in facilitating nerve regeneration requires further investigation.

Human fetal neural stem cells (hfNSCs) from the subventricular zone (SVZ) are employed in clinical trials for neurodegenerative diseases, yet their bioelectrical properties remain largely unexplored. Molecular markers alone do not reliably correlate with functional state, highlighting the need for complementary functional descriptors.