Search Results (264)

Our Goal is to identify how colorectal cancer (CRC) arises in the single-layered cell epithelium (simple columnar epithelium) that lines the luminal surface of the large intestine. Background: We recently reported that the dynamic organization of cells in colonic epithelium is encoded by five biological rules and conjectured that colon tumorigenesis involves an autocatalytic tissue renewal reaction. Introduction Our objective was to define how altered crypt turnover explains tissue disorganization that leads to adenoma morphogenesis and CRC. Hypothesis: Changes in rate of tissue renewal-based cell polymerization leads to epithelial expansion and tissue disorganization during adenoma histogenesis. Methods: Accordingly, we created a computational model that considers the structure of colonic epithelium to be a polymer of cells and that tissue renewal is autocatalytic. Indeed, self-renewal of stem cells in colonic crypts continuously produces cells that act like monomers to form a polymer of cells (an interconnected, continuous cell sheet) in a polymerization-based process. Our model is a system of nonlinear differential equations that simulates changes in human crypt cell population dynamics. Results: We investigated how changes occur in the proportion of different cell types during adenoma development in FAP patients. The results show premalignant colonic crypts have a decreased rate of tissue renewal due to APC-mutation. Discussion: This slower rate of cell polymerization causes a rate-limiting step in the crypt renewal process that expands the proliferative cell population size. Conclusions: Our findings provide a mechanism that explains how a prolonged rate of crypt renewal leads to tissue disorganization with local epithelial expansion, infolding, and contortion during adenoma morphogenesis.: Full article

Vital pulp therapy (VPT) seeks to preserve pulp vitality by using biocompatible with regenerative potential. This study tested the hypothesis that an injectable gelatin methacryloyl (GelMA) hydrogel containing piezoelectric barium titanate promotes odontogenic differentiation of dental pulp stem cells (DPSC) significantly better than a commercially available tricalcium silicate material used for vital pulp therapy. First, the light-curable, injectable piezoelectric hydrogel was engineered and characterized for its physicomechanical, piezoelectric properties and biocompatibility to DPSCs. The effect of this gel on the odontogenic differentiation of DPSCs was determined by measuring the expression level of key genes, compared to Biodentine XP. The hydrogel exhibited excellent injectability (<1 kgf of force), mechanical stability, and generated physiologically relevant voltages under cyclic loading mimicking mastication. MTT and ROS assays show no cytotoxic or damaging oxidative stress effects. When DPSCs were cultured over the materials under cyclic loading, the piezoelectric hydrogel significantly enhanced cell viability and upregulated COL1A1, DSPP, and DMP1 expression compared to Biodentine XP and non-piezoelectric hydrogel controls. These findings establish piezoelectric hydrogel as a self-powered, bioactive platform that converts physiological forces into regenerative bioelectric cues, offering a promising next-generation material for vital pulp therapy. Full article

Background and Objectives: MGN-3/Biobran (BRM4, Lentin Plus or Ribraxx) is a natural, rice bran-derived arabinoxylan immunoceutical that modulates the adaptive immune response to viral infections. In response to bacterial infections, basophils act as “first responders” and are also associated with modulation of the adaptive immune response. The maturation of pluripotent CD34⁺ stem cells into basophils is supported by the cytokine interleukin-3 (IL-3). The aim was to test the hypothesis that modulation of the adaptive immune response in bacterial infection by MGN-3/Biobran entails a basophilic response. The tick-related disorder Lyme borreliosis was chosen as the disease model; tick bites are associated with cutaneous IL-3-mediated basophil recruitment. Materials and Methods: A three-month randomised double-blind placebo-controlled trial was conducted in patients with a history of borreliosis who were suffering from symptoms attributable to this disorder. The immunoceutical group received oral Biobran; the dosage for both groups was 1 g thrice daily. Both groups were matched for age, sex, and ethnicity. Results: A higher percentage of basophil count occurred in the immunoceutical group (p = 0.038). The final general linear model included the group (immunoceutical/placebo) and change in fatigue assessed by the 11-item Chalder Fatigue Questionnaire (CFQ) (r² = 0.63; p = 0.0066). The change in basophil count was positively correlated with CFQ change (r_s = 0.633; p = 0.020); only the immunoceutical group showed a positive correlation. Conclusions: These results support the hypothesis being tested. Basophils may modulate the adaptive immune response by acting as immunoregulatory cells. They can regulate the functioning of type 2 T-helper lymphocytes, enhance immunological memory, and present antigens to CD8 T lymphocytes. Further studies are needed to clarify potential mechanistic factors and the timing of this basophilic response. Full article

Deep alterations in tumor cell gene profiles resulting in the loss of their specific functions are frequently the cause of resistance to traditional cancer treatments. Therefore, reprogramming the expression pattern of cancer cells toward a differentiated phenotype represents a promising therapeutic strategy. In this study, we investigated whether resveratrol (RSV) and its natural analogs—3,4′,5-trimethoxystilbene (3-MET-OX) and isorhapontigenin (ISOR-H-PG)—can modulate the SOX2/SOX17 balance and promote re-differentiation in anaplastic thyroid cancer (ATC) cells. Two human ATC cell lines (SW1736 and 8505c) and non-tumoral thyroid cells (Nthy-ori 3-1) were cultured in two-dimensional (2D) or three-dimensional (3D) systems and treated with polyphenols at sub-cytotoxic doses. In 2D cultures, cell viability and cell cycle analyses confirmed a cytostatic effect characterized by G1 arrest. In 3D cultures, polyphenol treatment caused morphological disruption of ATC spheroids and significantly modulated the gene expression profile. RSV and 3-MET-OX reduced stemness markers (SOX2, NANOG), increased the thyroid lineage transcription factor (SOX17), and enhanced differentiation genes (TTF-1, TPO, NIS). Overall, these results support our hypothesis that modulation of the SOX2/SOX17 ratio by polyphenols provides a mechanistic basis for re-differentiation, thereby improving therapeutic responsiveness in ATC. Full article

Background and Clinical Significance: This case report describes a 46-year-old male with no prior comorbidities who developed progressive neurological symptoms—ataxia and diplopia—shortly after the second Comirnaty (Pfizer-BioNTech) COVID-19 vaccine dose. The aim is to highlight the diagnostic challenges of central nervous system-dominant hemophagocytic lymphohistiocytosis (HLH) and its overlap with neuroinflammatory disorders. Case Presentation: Initial MRI showed demyelinating lesions in the brain and spinal cord, suggesting acute disseminated encephalomyelitis (ADEM). The patient had only transient improvement with corticosteroids and then multiple relapses with expanding CNS lesions despite cyclophosphamide, plasmapheresis, and rituximab. After 27 months, systemic features appeared, including fever, cytopenias, elevated inflammatory markers, and splenomegaly. Bone marrow analysis revealed hemophagocytosis, fulfilling HLH-2004 criteria, with an H-score of 200 supporting secondary HLH. Given consanguinity and persistent immune activation, next-generation sequencing identified two homozygous PRF1 variants—one pathogenic (p.Arg232His) and one of uncertain significance (p.Ala91Val)—consistent with autosomal recessive familial type 2 HLH. The patient underwent matched unrelated donor hematopoietic stem cell transplantation (HSCT) 11 months after HLH diagnosis, achieving initial stabilization, but ultimately died from infectious complications in March 2025 without evidence of HLH relapse. Conclusions: This case illustrates an atypical adult-onset presentation of familial HLH manifesting primarily with recurrent neuroinflammatory symptoms that initially mimicked ADEM. The diagnostic delay reflects the challenge of recognizing CNS-dominant HLH, especially in adults and in the absence of early systemic features. The identification of biallelic PRF1 variants confirmed an underlying genetic predisposition. This is the first reported case of adult-onset familial HLH presenting predominantly with neurological symptoms following COVID-19 vaccination. The case emphasizes the need to consider genetic forms of HLH in relapsing neuroinflammatory disorders and raises the hypothesis that vaccination may unmask subclinical immune dysregulation in genetically susceptible individuals Full article

Mutations in genes encoding sarcomeric proteins are a common cause of cardiomyopathy and sudden cardiac death in humans. We evaluated the hypothesis that myofilament dysfunction is coupled to morphological and functional alterations of cardiomyocyte nuclei in a Tnnc1-targeted knock-in (Tnnc1-p.A8V) mouse model of hypertrophic cardiomyopathy (HCM). Tnnc1 is the gene that codes for the isoform of the Ca²⁺-regulatory protein troponin C (cTnC) that is expressed in cardiomyocytes and slow skeletal muscle fibers and resides on thin filaments of sarcomeres in those muscles. This pathogenic mutation in a sarcomere gene alters many aspects of cardiomyocyte function, including sarcomere contractility, cytoplasmic Ca²⁺ buffering, and gene expression. Analysis of myocardial histological sections and isolated cardiomyocytes from adult Tnnc1-p.A8V mouse hearts revealed significantly smaller (cross-sectional area and volume) and rounder nuclei compared to those from age-matched, wild-type control mice. Changes in nuclear morphology could not be explained by differences in cardiomyocyte size or ploidy. Isolated wild-type and mutant cardiomyocyte nuclei, which are embedded centrally within myofibrils, undergo compression during contraction of the cardiomyocyte, indicating that during each heartbeat cardiomyocyte nuclei would be mechanically deformed as well as being exposed to elevated cytoplasmic Ca²⁺. Immunoblotting analysis indicated decreased nuclear localization of cardiac troponin C and decreased histone H4 expression in Tnnc1-p.A8V mouse hearts. Next, we investigated the influence of nucleocytoplasmic transport by immunofluorescence microscopy, and we could not confirm nuclear localization of cardiac troponin C in fixed myocardial tissue from adult mice. However, cardiac troponin C could be detected in healthy human-induced pluripotent stem cell-derived cardiomyocyte nuclei. We conclude that pathological myofilament dysfunction due to a pathogenic, cardiomyopathy-associated mutation can be linked to altered protein composition of cardiomyocyte nuclei and aberrant nuclear morphology. Full article

Streptozotocin (STZ) is an alkylating agent that has neurotoxic effects when injected into the cerebral ventricles (ICV) and also models many other features of Alzheimer’s disease. However, the mechanisms of STZ neurotoxicity are not well understood. In this study, we hypothesized that some of the neurotoxic effects of STZ could be due to direct activities on brain endothelial cells and astrocytes, which are key in forming and supporting the functions of the blood–brain barrier (BBB), respectively. To test this hypothesis, we characterized the changes induced by STZ either in cultures of human-induced pluripotent stem cell (iPSC)-derived brain endothelial-like cells (iBECs), which form an in vitro BBB model, or in primary human astrocytes. We found that STZ at a dosage of 5 mM caused a delayed reduction in the transendothelial electrical resistance (TEER) of iBECs at 7–11 days post-treatment, indicating induction of BBB leakage. Additionally, we observed significant increases in albumin leakage across the monolayer, altered iBEC morphology, and reductions in tight junction proteins, suggesting that STZ causes BBB disruption. We further found that the BBB glucose transporter GLUT-1 was reduced in iBECs, as was the total number of iBECs. In astrocytes, the 5 mM dose of STZ reduced the GFAP signal and total number of cells, suggesting that STZ has anti-proliferative and/or toxic effects on astrocytes. Together, these data support that STZ’s neurotoxic effects could be due, in part, to its direct toxic activities on brain endothelial cells and astrocytes. Full article

Periodontitis is a prevalent condition that leads to the destruction of periodontal tissue, making the regeneration of the periodontium a key focus in dental research. In this context, periodontal ligament cells (PDLCs) are particularly interesting due to their stem cell-like properties, including the ability to differentiate into various cell types and further contribute to tissue repair. This study aimed to isolate and characterize primary human PDLCs and examine the effects of both indirect and direct treatment with the blood concentrate platelet-rich fibrin (PRF), with particular focus on how PRF influences cell proliferation and differentiation. PDLCs were treated with PRF prepared using a low relative centrifugal force (600 rpm) either directly through a conditioned medium or indirectly using trans-well filter systems. The impact of PRF on PDLC proliferation and differentiation was assessed through viability assays, alkaline phosphatase assays, gene and protein expression analyses, and immunofluorescence. PDLCs exhibited cellular markers characteristic of stem cell-like cells. In addition, PRF treatment was found to suppress cell proliferation while concurrently promoting osteogenic differentiation and increase factors important for tissue regeneration. These effects were more pronounced when the cells were directly treated with PRF-conditioned medium compared to indirect treatment. Our findings support the hypothesis that PRF serves as a biologically active reservoir of growth factors that modulate PDLC behavior and might create a microenvironment favorable for periodontal repair. Full article

Postnatal stem cells are crucial for tissue homeostasis and repair and are regulated by specialized microenvironmental microterritories known as “stem cell niches”. Proposed by R. Schofield in 1978 for hematopoietic stem cells, niches maintain self-renewal, guide differentiation and maturation, and can even revert progenitor cells to an undifferentiated state. Niches respond to injury, oxygen levels, mechanical cues, and signaling molecules. While the niche concept has advanced regenerative medicine, bioengineering, and 3D bioprinting, further progress is hindered by inconsistent interpretations of its core principles. To address this, we proposed a consensus-building initiative among experts in regenerative medicine and bioengineering. We have developed a questionnaire covering the niche topography, hierarchy, dimension, geometry, composition, regulatory mechanisms, and specifically the mesenchymal stem cell niches. This pilot survey, being conducted under the auspices of the National Society for Regenerative Medicine in the Russian Federation, aims to establish a standardized framework on the eve of the 50th anniversary of Schofield’s hypothesis. The resulting consensus will guide future research and innovation in this pivotal field. Full article

Background and Objectives: Over the past few years, there has been a significant shift in focus from developing better diagnostic tools to detecting Alzheimer’s disease (AD) earlier and initiating treatment interventions. This review will explore four main objectives: (a) the role of biomarkers in enhancing the diagnostic accuracy of AD, highlighting the major strides that have been made in recent years; (b) the role of neuropsychological testing in identifying biomarkers of AD, including the relationship between cognitive performance and neuroimaging biomarkers; (c) the amyloid hypothesis and possible molecular mechanisms of AD; and (d) the innovative AD therapeutics and the challenges and limitations of AD research. Materials and Methods: We have searched PubMed and Scopus databases for peer-reviewed research articles published in English (preclinical and clinical studies as well as relevant reviews and meta-analyses) investigating the molecular mechanisms, biomarkers, and treatments of AD. Results: Genome-wide association studies (GWASs) discovered 37 loci associated with AD risk. Core 1 biomarkers (α-amyloid Aβ42, phosphorylated tau, and amyloid PET) detect early AD phases, identifying both symptomatic and asymptomatic individuals, while core 2 biomarkers inform the short-term progression risk in individuals without symptoms. The recurrent failures of Aβ-targeted clinical studies undermine the amyloid cascade hypothesis and the objectives of AD medication development. The molecular mechanisms of AD include the accumulation of amyloid plaques and tau protein, vascular dysfunction, neuroinflammation, oxidative stress, and lipid metabolism dysregulation. Significant advancements in drug delivery technologies, such as focused Low-Ultrasound Stem, T cells, exosomes, nanoparticles, transferin, nicotinic and acetylcholine receptors, and glutathione transporters, are aimed at overcoming the BBB to enhance treatment efficacy for AD. Aducanumab and Lecanemab are IgG1 monoclonal antibodies that retard the progression of AD. BACE inhibitors have been explored as a therapeutic strategy for AD. Gene therapies targeting APOE using the CRISPR/Cas9 genome-editing system are another therapeutic avenue. Conclusions: Classic neurodegenerative biomarkers have emerged as powerful tools for enhancing the diagnostic accuracy of AD. Despite the supporting evidence, the amyloid hypothesis has several unresolved issues. Novel monoclonal antibodies may halt the AD course. Advances in delivery systems across the BBB are promising for the efficacy of AD treatments. Full article

Lesch–Nyhan disease (LND) is associated with a complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity due to mutations in the HPRT1 gene. Although the physiopathology of LND-related neurological manifestations remains unknown, a defective neuronal developmental process is the most widely accepted hypothesis. We generated an HPRT-deficient line from the pluripotent human embryonic cell line NT2/D1 by CRISPR-Cas9 and induced its differentiation along neuroectodermal lineages by retinoic acid treatment. As levels of folic acid in the culture media may affect results in LND models, we employed physiological levels of folate. The effect of HPRT deficiency on neural development-related gene expression was evaluated using two methodological approaches: a directed qPCR array of genes related to neuronal differentiation, and global gene expression by RNAseq. HPRT-deficient pluripotent cells presented altered expression of genes related to pluripotency in human embryonic stem cells, such as DPPA3 and CFAP95, along with genes of the homeobox gene family. HPRT-deficient pluripotent cells were able to differentiate along neuro-ectodermal lineages but presented consistent dysregulation of several genes from the homeobox gene family, including EN1 and LMX1A. GO enrichment analysis of up- and downregulated genes in HPRT-deficient cells showed that the most significant biological processes affected are related to development and nervous system development. Full article

The review compares the principles of organization of the brain and immune system, two important organs developed over 500 million years in multicellular organisms, including humans. It summarizes the latest results from research in neurosciences and immunology concerning intercellular communication. While in the brain, intercellular communication is primarily based on exchange of electrical signals, this is not the case in the immune system. The question, therefore, arises as to whether nature developed two entirely different systems of organization. It will be demonstrated that a few basic principles of brain and immune responses are organized in a different way. A majority of intercellular communications, however, such as the formation of synapses, are shown to have many similarities. Both systems are intimately interconnected to protect the body from the1 dangers of the outside and the inside world. During homeostasis, all systems are in regulatory balance. A new hypothesis states that the central systems surrounded by bone, namely the central nervous system (CNS) and the central immune system (CIS), are based on three types of stem cells and function in an open but autonomous way. T cell immune responses to antigens from blood and cerebrospinal fluid protect the system and maintain neuroimmune homeostasis. The newly discovered tunneling nanotubes and extracellular vesicles are postulated to play an important role in crosstalk with already known homeostasis regulators and help in cellular repair and the recycling of biologic material. Three examples are selected to illustrate dysfunctions of homeostasis, namely migraine, multiple sclerosis, and brain cancer. The focus on these different conditions provides deep insights into such neurological and/or immunological malfunctions. Technological advances in neurosciences and immunology can enable neuroimmunomodulation and the development of new treatment possibilities. Full article

Respiratory syncytial virus (RSV) represents one of the main respiratory infections found among immunocompromised patients. Objective: The study analyzes the incidence of RSV infection in different populations of immunocompromised patients as organ transplant recipients (lung, other solid organs, hematopoietic stem cells) and oncologic patients (solid organ malignancy and hematological malignancy) compared to a group of non-immunocompromised patients. We also assessed the prevalence of viral, bacterial, and mycotic coinfection. Moreover, we aimed at evaluating the efficacy of ribavirin treatment in terms of mortality reduction. Methods: We conducted a retrospective analysis on a total of 466 transplant patients undergoing bronchoscopy with bronchoalveolar lavage for suspected viral disease or surveillance between 2016 and 2023, compared to 460 controls. Results: The incidence of RSV was significantly higher in immunocompromised patients, particularly in those with lung and bone marrow transplants. Among RSV+ patients, a higher prevalence of viral (influenza virus), bacterial (S. pneumoniae, M. pneumoniae, Nocardia spp.), and fungal (Aspergillus spp.) coinfections were observed. The efficacy of ribavirin in reducing mortality did not show significant differences compared to supportive therapy alone. Conclusions: The results of our exploratory study suggest that immunocompromised patients are particularly vulnerable to RSV infection and coinfections. Our hypothesis-generating data warrant the need for future studies aimed at exploring preventive and therapeutic strategies for RSV infection in these high-risk patient groups. Full article

Eukaryotic cells double their mass and divide at the same rate, allowing cells to maintain a uniform cell size over many cell divisions. We hypothesize that aneuploid cancer cells are more sensitive to forced overgrowth, more than doubling their mass during a single longer-duration cell division cycle, relative to healthy diploid cells. This hypothesis stems from the observation that cancer cells are under proteotoxic stress, during which heat-shock proteins become rate-limiting and the unfolded-protein response network has a growth-suppressive phenotype. Forced overgrowth will lead to the production of more individual proteins per cell division cycle and increase the duration of time during which any mis-folded or aggregated proteins might disrupt the function of properly folded proteins. To induce these potential forced overgrowth effects, we suggest targeting the cell division cycle regulatory enzyme, the anaphase-promoting complex/cyclosome (APC/C), to suppress—but not inhibit—its activity. We conclude by proposing experiments to test this hypothesis in which an APC/C inhibitor, such as a low level of proTAME, is combined with the clinically approved heat-shock protein 90 (HSP90)-inhibitor pimitespib (TAS-116) or the pre-clinical molecule tanespimycin, which, to the best of our knowledge, are combinations that have not been investigated before. Full article

MiaA is responsible for the addition of the isopentyl modification to adenine 37 in the anticodon stem loop of specific tRNAs in Escherichia coli. Mutants in miaA have pleotropic effects on the cell in E. coli and play a role in virulence gene regulation. In addition, MiaA is necessary for stress response gene expression by promoting efficient decoding of UUX-leucine codons, and genes with elevated UUX-leucine codons may be a regulatory target for i⁶A-modified tRNAs. Understanding the temporal nature of the i⁶A modification status of tRNAs would help us determine the regulatory potential of MiaA and its potential interplay with leucine codon frequency. In this work, we set out to uncover additional information about the synthesis of the MiaA. MiaA synthesis is primarily driven at the transcriptional level from multiple promoters in a complex operon. However, very little is known about the post-transcriptional regulation of MiaA, including the role of sRNAs in its synthesis. To determine the role of small RNAs (sRNAs) in the regulation of miaA, we constructed a chromosomal miaA-lacZ translational fusion driven by the arabinose-responsive P_BAD promoter and used it to screen against an Escherichia coli sRNA library (containing sRNAs driven by the IPTG-inducible P_Lac promoter). Our genetic screen and quantitative β-galactosidase assays identified CsrB and its cognate protein CsrA as potential regulators of miaA expression in E. coli. Consistent with our hypothesis that CsrA regulates miaA post-transcriptional gene expression through binding to the miaA mRNA 5′ UTR, and CsrB binds and regulates miaA post-transcriptional gene expression through sequestration of CsrA levels, a deletion of csrA significantly reduced expression of the reporter fusion as well as reducing miaA mRNA levels. These results suggest that under conditions where CsrA is inhibited, miaA mRNA translation and thus MiaA-dependent tRNA modification may be limited. Full article