Search Results (5,803)

Organophosphate (OP) and carbamate pesticides are widely employed in agriculture to facilitate the production of economically viable crops. However, pesticide contamination of food, water, and air leads to undesired human exposure. Neuronal tissue may be particularly vulnerable to pesticide toxicity during periods of neurodevelopment. Hence, this study aimed to investigate the neurotoxicity of three pesticide compounds, namely chlorpyrifos-oxon (CPO), azamethiphos (AZO), and aldicarb, on human neural progenitor cells (hNPCs) and whether toxicity differed between undifferentiated and differentiated stem cells. Undifferentiated and differentiated hNPCs were exposed to these neurotoxicants at concentrations of 0–200 µM for 24 h, and cell viability was evaluated using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The impact of the neurotoxicants on cellular bioenergetics was determined by quantifying cellular ATP levels and the production of reactive oxygen species (ROS) using a 2′,7′-dichlorofluorescein diacetate (DCFDA) assay. Concentration–response curves were also generated to measure their relative inhibition of AChE. The neurotoxicants induced concentration-dependent reductions in cell viability (p < 0.0001), cellular ATP levels (p < 0.0001), and the inhibition of AChE (p < 0.0001). Notably, differentiated neurons displayed higher sensitivity than undifferentiated neural stem cells (NSCs), with a toxicity threshold of ≥1 µM. ROS levels were significantly increased (p < 0.0001) following neurotoxicant exposures, more so in differentiated cells, with levels that correlated with cytotoxicity, cell death, and the induction of oxidatively damaged proteins in surviving cells. These findings suggest a central role of oxidative stress and protein oxidation in mediating the neurotoxic effects of pesticide compounds on NSCs. Furthermore, the heightened susceptibility of NSCs to pesticide toxicity after differentiation is indicative of human vulnerability during periods of neurodevelopment. Full article

(1) Background: The present study investigated the effects of extracellular vesicles (EVs), derived from adipose tissue stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMMSCs), on atherosclerosis-associated cardiac hypertrophy. (2) Methodology: The experiments were performed on hamsters divided into the following groups: control (C) fed with a standard diet; hypertensive–hyperlipidemic (HH) generated by combining a diet enriched with 3% cholesterol, 15% butter, and by gavage with 8% NaCl on a daily basis; HH groups injected with EVs (ADSCs) or EVs (BMMSCs), either transfected with Smad2/3 siRNAs or not (HH-EVs (ADSCs), HH-EVs (BMMSCs), HH-EVs (ADSCs) + Smad2/3siRNA, HH-EVs (BMMSCs) + Smad2/3siRNA); and HH group injected with Smad2/3 siRNAs (HH-Smad2/3siRNA). (3) Results: In comparison with the HH group, the findings demonstrated that treatment using EVs (ADSCs or BMMSCs), either with or without Smad2/3 siRNAs, resulted in several significant improvements in the following aspects: the plasma levels of cholesterol, LDL, triglycerides, TGF-β1, and Ang II were decreased; the left ventricular structure and function were recovered; inflammatory markers, ROS, COL1A, α-SMA, Cx43, MIF, ANF, and M1/M2 macrophages, were reduced; the level of key protein NF-κB p50 was diminished. (4) Conclusions: These findings underscore the therapeutic potential of mesenchymal stem cell-derived EVs in atherosclerosis-associated cardiac hypertrophy. Full article

The endometrium is a highly dynamic tissue central to female reproductive function, undergoing nearly 500 cycles of proliferation, differentiation, shedding, and regeneration throughout a woman’s reproductive life. This remarkable regenerative capacity is driven by a reservoir of endometrial stem/progenitor cells (ESCs), which are crucial for maintaining tissue homeostasis. Dysregulation of these cells is linked to a variety of clinical disorders, including menstrual abnormalities, infertility, recurrent pregnancy loss, and serious gynecological conditions such as endometriosis and endometrial cancer. Recent advancements in organoid technology and lineage-tracing models have provided insights into the complex cellular hierarchy that underlies endometrial regeneration and differentiation. This review highlights the latest breakthroughs in endometrial stem cell biology, focusing particularly on 3D in vitro platforms that replicate endometrial physiology and disease states. By integrating these cutting-edge approaches, we aim to offer new perspectives on the pathogenesis of endometrial disorders and establish a comprehensive framework for developing precision regenerative therapies. Full article

The puff adder (Bitis arietans) is a clinically relevant viper species found throughout Africa, and it is responsible for a greater incidence of health-related envenomations than all other snake species on the continent combined. Unresolved skeletal muscle damage is a common consequence of B. arietans envenomation that can result in long-term morbidity and even death. Antivenom treatment can mitigate the systemic effects of the venom but offers little protection against local tissue damage. Identifying the mechanisms through which B. arietans venom induces tissue damage and impedes skeletal muscle regeneration could identify possible treatment alternatives that could help alleviate the long-term consequences of envenomation. Skeletal muscle has an innate ability to regenerate, but constituents within the venom can impede multiple stages of this regeneration process. In this study, we employed a combination of biochemical analyses, cell-based assays, and in vivo experiments to assess the toxicological implications of B. arietans envenomation and its impacts on key processes of regeneration. Our findings demonstrate that the pathological characteristics of permanent muscle damage resulting from B. arietans envenomation may be attributed to the venom’s effects on muscle stem cell precursors, the extracellular matrix (ECM), and the influence of blood-borne proteins that promote fibrosis. Full article

Ischemia–reperfusion (I/R) injury is a complex pathological process underlying numerous acute organ failures and is a significant cause of morbidity and mortality in diseases such as myocardial infarction, stroke, thrombosis, and organ transplantation. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have demonstrated considerable therapeutic potential, but their broad tropism and general repair signaling may limit their efficacy. This review addresses the emerging paradigm of using organ-specific EVs for the treatment of I/R injury in the respective organs. We summarize the existing studies performed on experimental animals showing that these native EVs could possess tissue tropism and carry a specialized cargo of proteins, miRNAs, and lipids tailored to the unique regenerative needs of their organ of origin, enabling them to precisely modulate key processes, including inflammation, apoptosis, oxidative stress, and angiogenesis. However, their clinical translation faces challenges related to scalable production, standardization, and the dualistic nature of their effects, which can be either protective or detrimental, depending on the cellular source and pathophysiological context. Future developments need to focus on overcoming these obstacles through rigorous isolation protocols, engineering strategies such as cargo enrichment and hybrid vesicle creation, and validation in large-animal models. Overall, organ-specific EVs offer a novel, cell-free therapeutic strategy with the potential to significantly improve outcomes in I/R injury. Full article

(1) Background: The extracellular matrix (ECM) is a natural scaffold for cells, creating a three-dimensional architecture composed of fibrous proteins (mainly collagen) and proteoglycans, which are synthesized by resident cells. In this study, a physiological hypoxic environment was utilized to enhance ECM production by human mesenchymal stem cells (hMSCs), a process relevant to tissue engineering and regenerative medicine. (2) Methods: hMSCs were treated with deferoxamine (DFO), a pharmaceutical hypoxia-mimetic agent that induces cellular responses similar to low-oxygen conditions through stabilization of hypoxia inducible factor-1α (HIF-1α). The time points 0 h 24 h, 3 h 24 h, and 24 h 24 h refer to DFO being added immediately after cell seeding (before cells adhesion), 3 h after cell seeding (during initial cells attachment), and 24 h after cell seeding (after focal adhesions formation and actin organization), respectively, to evaluate the influence of cell adhesion on ECM deposition. hMSCs incubated in culture media were subsequently exposed to DFO for 24 h. Samples were then subjected to cell viability tests, scanning electron microscopy (SEM), atomic force microscopy (AFM) and laser scanning confocal microscopy (CLSM) assessments. (3) Results: Viability tests indicated that DFO concentrations in the range of 0–300 µM were non-toxic over 24 h. The presence of collagen fibers in the DFO-derived ECM was confirmed with anti-collagen antibodies under CLSM. Increased ECM secretion was observed under the following conditions: 3 μM DFO (24 h 24 h), 100 μM DFO (0 h 24 h) and 300 μM DFO (3 h 24 h). SEM and AFM images revealed the morphology of various stages of collagen formation with both collagen fibrils and fibers identified. (4) Conclusions: Our preliminary study demonstrated enhanced ECM secretion by hMSC treated with DFO at concentrations of 3, 100, and 300 µM within a short cultivation period of 24–48 h without significant affecting cell viability. By mimicking physiological processes, it may be possible to stimulate endogenous tissue regeneration, for example, at an injury site. Full article

Adipose tissue plays a crucial role in the tumor microenvironment (TME), where its secreted extracellular vesicles (EVs) are involved in the complex signaling between tumor cells and surrounding stromal components. This study aims to unravel the mechanisms through which adipocyte-derived EVs influence breast cancer (BC) progression. Human mesenchymal stem cells (hMSCs) were differentiated into adipocytes following a 21-day induction protocol that led to significant accumulation of lipid droplets within the cells. EVs were isolated from the conditioned medium of both hMSC-derived adipocytes and BC cells. Particle size distribution, morphology, and uptake into the recipient cell were investigated via nanoparticle tracking analysis, transmission electron microscopy, and fluorescence microscopy, respectively. Our results show that BC-derived EVs notably impaired cell viability and modulated the expression of key genes involved in apoptosis resistance within stromal cells. On the other hand, stromal-derived EVs significantly altered tumor cell behavior, indicating a dynamic, bidirectional exchange of bioactive signals. These findings underscore the pivotal role of EV-mediated communication in the tumor-stroma interplay, suggesting that adipocyte-cancer cell EV crosstalk contributes to the remodeling of the TME, potentially facilitating tumor progression. Full article

Background: Intervertebral disc degeneration (IVDD) is closely linked to low back pain (LBP), a leading cause of disability worldwide. IVDD is characterized by the loss of proteoglycans (PGs), extracellular matrix (ECM) degradation, and reduced hydration of the nucleus pulposus (NP). Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) exhibit tissue repair and immunomodulatory effects and are emerging as promising cell-free therapeutics. Methods: We established a rat IVDD model via fluoroscopy-guided needle puncture of three consecutive coccygeal discs and confirmed degeneration through Alcian Blue and hematoxylin & eosin (H&E) staining. The gene expression of inflammatory and pain markers (ADRβ2, COMP, CXCL1, COX2, PPTA, MMP13, YKL40) was measured by qPCR. Subsequently, we implanted hUC-MSCs or EVs to evaluate their reparative potential. Results: Upregulation of inflammatory and pain genes in IVDD was associated with an immunomodulatory response. Tracking DiI-labelled hUC-MSCs and EVs revealed enhanced survival of hUC-MSCs, retention of EVs, and dispersion within rat tail discs; EVs showed greater retention than hUC-MSCs. Implanted EVs were internalized by NP cells and remained within degenerative IVDs. EVs passively diffused, accumulated at the injury site, interacted with host cells, and enhanced function, as shown by increased expression of human chondrocyte-related markers (SOX9, TGFβ1, TGFβ2, COL2) compared to hUC-MSC treatment. Histological analysis of two weeks post-transplantation showed NP cellular patterns resembling chondromas in treated discs. EVs integrated into and distributed within degenerated NP regions, with greater glycosaminoglycan (GAG) content. Conclusions: Overall, hUC-MSC EVs demonstrated superior regenerative capacity, supporting a safe, cell-free strategy for disc repair. Full article

Regenerative medicine holds significant promise for addressing diseases and irreversible damage that are challenging to treat with conventional methods, making it a prominent research focus in modern medicine. Research on stem cells, a key area within regenerative medicine due to their self-renewal capabilities, is expanding, positioning them as a novel therapeutic option. Stem cells, utilized in various treatments, are categorized based on their differentiation potential and the source tissue. The term ‘stem cell’ encompasses a broad spectrum of cells, which can be derived from embryonic tissues, adult tissues, or generated by reprogramming differentiated cells. These cells, applied across numerous medical disciplines including cardiovascular, neurological, and hematological disorders, as well as wound healing, demonstrate varying therapeutic applications based on their differentiation capacities, each presenting unique advantages and limitations. Nevertheless, the existing literature lacks a comprehensive synthesis examining stem cell therapy and its cellular subtypes across different medical specialties. This review addresses this lacuna by collectively categorizing contemporary stem cell research according to medical specialty and stem cell classification, offering an exhaustive analysis of their respective benefits and constraints, thereby elucidating multifaceted perspectives on the clinical implementation of this therapeutic modality. Full article

Adipose tissue renewal requires precise coordination of stem/progenitor cell proliferation, preadipocyte commitment, and terminal adipocyte differentiation. T-cadherin (CDH13), an atypical GPI-anchored cadherin, is expressed in adipose tissue and functions as a receptor for high-molecular-weight (HMW) adiponectin—a key adipokine produced by adipose tissue and involved in metabolic regulation. While T-cadherin is implicated in cardiovascular and metabolic homeostasis, its role in adipogenesis still remains poorly understood. In this study, we used the 3T3-L1 preadipocyte model to investigate the function of T-cadherin in adipocyte differentiation. We analyzed T-cadherin expression dynamics during differentiation and assessed how T-cadherin overexpression or knockdown affects lipid accumulation, expression of adipogenic markers, and key signaling pathways including ERK, PI3K–AKT, AMPK, and mTOR. Our findings demonstrate that T-cadherin acts as a negative regulator of adipogenesis. T-cadherin overexpression ensured a proliferative, undifferentiated cell state, delaying early adipogenic differentiation and suppressing both lipid droplet accumulation and the expression of adipogenic markers. In contrast, T-cadherin downregulation accelerated differentiation, enhanced lipid accumulation, and increased insulin responsiveness, as indicated by PI3K–AKT pathway activation at specific stages of adipogenesis. These results position T-cadherin as a key modulator of adipose tissue plasticity, regulating the balance between progenitor expansion and terminal differentiation, with potential relevance to obesity and metabolic disease. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Periodontal disease is a prevalent inflammatory disorder that can lead to severe oral complications. Recent studies increasingly underline the role of endoplasmic reticulum (ER) stress in its pathogenesis. Experimental models using inflammatory agents such as lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), and ligature-induced periodontitis in rodents, as well as chemical hypoxia, have consistently demonstrated the activation of unfolded protein response (UPR) pathways in periodontal cells. Key ER stress markers, including CHOP, GRP78, PERK, and ATF6, were upregulated in periodontal ligament cells, stem cells, and gingival epithelial cells under these conditions. While ER stress in periodontitis is primarily associated with detrimental outcomes such as apoptosis and inflammation, it may also have a physiological role in bone remodeling via the PERK-eIF2α-ATF4 axis. Importantly, several ER stress-modulating agents—such as oridonin, melatonin, and exosomes derived from M2 macrophages—have shown therapeutic potential by reducing stress marker expression and limiting periodontal damage. These findings suggest that targeting ER stress may offer a novel therapeutic strategy. Future human studies are essential to determine whether a combined approach targeting inflammation and ER stress could more effectively halt or reverse periodontal tissue destruction, while also assessing the long-term safety of ER stress modulation. Full article

Radiation-induced intestinal injury (RIII), a severe complication of abdominopelvic radiotherapy, causes intestinal ischemia, ulcers, and necrosis, severely impacting patients’ quality of life. Currently, effective treatments are limited, and a specific cure remains elusive. Our previous research showed that lactoferrin (LF) can promote intestinal stem cell (ISC) proliferation and tissue repair; however, its oral administration is limited by rapid degradation in the gastric environment. In this study, we developed LF-loaded liposomal nanoparticles (Lip-LF) using a simple ethanol injection method. The optimal formulation (cholesterol/egg yolk lecithin ratio 2:8, LF concentration 12.5 mg/mL) achieved a drug-loading capacity of 6.8% and a narrow size distribution (0.2 < PDI < 0.4). In vitro experiments demonstrated that Lip-LF protected LF from pepsin degradation in simulated gastric fluid (SGF), retaining over 80% integrity after 120 min, while releasing in simulated intestinal fluid (SIF). In vivo imaging revealed prolonged gastrointestinal retention of Lip-LF compared to free LF. In a murine model of RIII (12 Gy whole-body irradiation), Lip-LF significantly restored villus counts, increased crypt height, and promoted goblet-cell regeneration. Immunohistochemical and qPCR analyses revealed enhanced ISCs proliferation and upregulation of repair-associated genes, including Pcna and Olfm4. These findings demonstrate that Lip-LF protects LF from gastric degradation and enhances its targeted delivery to the intestine, improving its therapeutic efficacy in repairing RIII. Lip-LF thus offers a promising strategy for managing RIII. Full article

Background: The limited self-repair capacity of nerve tissue requires a new therapeutic approach. Mesenchymal stem cells from the uterine cervix, hUCESC, have shown anti-inflammatory, regenerative, and anti-oxidative stress effects through their secretome, which makes them candidates to evaluate their potential in the context of neuronal damage. In this study, we aimed to determine whether secretome or conditioned medium of hUCESC (hUCESC-CM) has beneficial action in the treatment of PC-12 and HMC3 cells in vitro under conditions of oxidative stress and inflammation. Methods: Differentiated PC-12 cells and HMC3 cells were subjected to oxidative stress and inflammatory conditions in the presence of hUCESC-CM. The expression of factors related to both processes was evaluated by q-RT-PCR. Results: PC-12 cells treated with hUCESC-CM showed a significant increase in the expression of anti-oxidative stress factors (HO-1 and Nrf2) and a significant decrease in the expression of pro-inflammatory factors (IL1β, IL6 and TNFα). In addition, the treatment of HMC3 cells with hUCESC-CM significantly decreased the expression of IL6 and TNFα and enhanced the expression of neuroprotective factors such as BDNF and GDNF. Conclusions: Considering that both oxidative stress and inflammation are interrelated and implicated in several nerve injuries and neurodegenerative disorders, the effects of hUCESC-CM on neuronal cells are very promising. Full article

Wharton’s jelly (WJ), the mucoid connective tissue of the umbilical cord, provides essential protection to the umbilical vessels against mechanical stress. While research into WJ-derived stem cells for regenerative medicine has surged, the clinical significance of its in utero pathologies remains less explored. This review synthesizes the current literature on the pathophysiology of WJ abnormalities and their direct impact on fetal and neonatal outcomes. Pathologies are broadly categorized as quantitative (absence/reduction or excess/edema) and structural (pseudocysts, mucoid degeneration). A reduction or segmental absence of WJ critically compromises cord integrity, leading to vascular compression and is a direct cause of stillbirth, fetal growth restriction (FGR), and intrapartum distress. Conversely, excessive WJ or edema is associated with maternal diabetes and fetal hydrops and can also impair hemodynamics. Umbilical cord pseudocysts, arising from focal WJ degeneration, are significant markers for severe chromosomal abnormalities, particularly Trisomy 18 and 13, and other structural defects, especially when persistent or multiple. Sonographic measurement of WJ area shows promise as a surrogate for placental function, with decreased area correlating with placental pathology and FGR. However, significant diagnostic challenges persist, particularly the prenatal detection of segmental WJ absence, a “silent” pathology often discovered only after a catastrophic event. This review highlights the critical role of WJ integrity in determining perinatal outcomes and underscores the urgent need for improved diagnostic modalities and standardized management protocols to mitigate associated risks. Full article