Search Results (483)

Several genetic diseases affecting the human nervous system are incurable and insufficiently understood. Among them, nine rare diseases form the polyglutamine (polyQ) family: Huntington’s disease (HD), spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and spinal and bulbar muscular atrophy. In most patients, these diseases progress over decades to cause severe movement incoordination and neurodegeneration. Although their inherited genes with tandem-repeat elongations and the encoded polyQ-containing proteins have been extensively studied, the neuronal-type-specific pathologies and their long pre-symptomatic latency await further investigations. However, recent advances in detecting the single-nucleus transcriptome, alongside the length of tandem repeats in HD post-mortem brains, have enabled the identification of very high CAG repeat sizes that trigger transcriptional dysregulation and cell death in specific projection neurons. One challenge is to better understand the complexity of movement coordination circuits, including the basal ganglia and cerebellum neurons, which are most vulnerable to the high CAG expansion in each disease. Another challenge is to detect dynamic changes in CAG repeat length and their effects in vulnerable neurons at single-cell resolution. This will offer a platform for identifying pathological events in vulnerable long projection neurons and developing targeted therapies for all tandem-repeat expansions affecting the CNS projection neurons. Full article

Cancer metastasis is responsible for most cancer-related deaths. Migration and invasion, key steps in the metastatic cascade, require nuclear pliability to traverse the physical barriers of the extracellular matrix and cell–cell junctions. The nuclear envelope (NE) contains LINC complex proteins, including nesprin-4, which regulate nuclear integrity, stiffness, and cell movement. We report that nesprin-4 expression is generally upregulated in breast cancer samples but is reduced in triple-negative breast cancer (TNBC) samples compared to other subtypes. A nesprin-4 expression analysis in 62 breast cancer cell lines showed that nesprin-4 expression correlates positively with cell lines representing less aggressive tumors, while TNBC cell lines have low or no nesprin-4 expression. To determine the role of nesprin-4, we modulated nesprin-4 expression levels in three breast cancer cell lines: MCF7, T47D (luminal A and nesprin-4-positive), and MDA-MB-231 (TNBC and nesprin-4-negative). We found that nesprin-4 promotes migration and invasion by driving cell polarization. However, we also found that nesprin-4 impedes intravasation into endothelial microvessels. Thus, we propose that nesprin-4 plays a dual role in breast cancer, promoting efficient migration and invasion, but blocking intravasation. Full article

Blocking the MAPK pathway is a strategy to stop cancer cells proliferation. Despite all the successes, the acquisition of drug resistance by cells, as well as the mutational status of the downstream protein KRAS, reduces the tumor response to therapy. Ribonuclease binase from Bacillus pumilus is among the agents that block this pathway through direct interaction with EGFR and RAS. The present study is aimed at the design, optimization, and characterization of a novel complex based on antitumor binase immobilized on microgranular clinoptilolite-containing rock to ensure its prolonged release in the gastrointestinal tract. A set of modern methods including transmission electron microscopy, scanning electron microscopy, and computed tomography was used to characterize the granularity, porosity and elemental composition of the carrier. The size of binase particles, measured by atomic force microscopy at 7 nm, allows enzyme penetration into meso- and macropores of the carrier. Calorimetric results confirm that binase is stable at high temperatures, even exceeding those in the body, and retains catalytic activity in the model fluids of the gastrointestinal tract. The parameters for processing a natural clinoptilolite-containing rock and the conditions for binase sorption were selected. The gradual release of the enzyme from the carrier lasts over 20 h, which provides cytotoxicity towards human adenocarcinoma cells during movement through the gastrointestinal tract. Thus, for the first time a promising long-acting complex with antitumor and detoxifying properties was successfully created. Full article

Aquaglyceroporins, including human AQP7, AQP10, and E. coli GlpF, are known to facilitate movements of glycerol, water, and some other uncharged molecules across the cell membrane. In this study we focused on the transport of water molecules in the absence of glycerol for AQP7, AQP10 and GlpF using the Transition State Theory for the novel application of permeability and kinetics studies. We conducted around 500 ns of in silico simulations of the aquaglyceroporins embedded in lipid bilayer membranes with intracellular-extracellular asymmetries in leaflet lipid compositions. For the water permeability analysis, we computed the transition rate constant with correction for recrossing events where the water molecules do not completely traverse the protein channel from one side of the membrane to the other side. We also studied the hydrogen bond distributions of the single-file waters and channel residues and linear water densities along the pores of the aquaglyceroporins. Interestingly, we found that there was an inverse correlation between the number of single-file water molecules in the channel and osmotic permeability. Full article

Spinal health depends on the dynamic interplay between mechanical forces, biochemical signaling, and cellular behavior. This review explores how key molecular pathways, including integrin, yeas-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), Piezo, and Wingless/Integrated (Wnt) with β-catenin, actively shape the structural and functional integrity of spinal tissues. These signaling mechanisms respond to physical cues and interact with inflammatory mediators such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), driving changes that lead to disc degeneration, vertebral fractures, spinal cord injury, and ligament failure. New research is emerging that shows scaffold designs that can directly harness these pathways. Further, new stem cell-based therapies have been shown to promote disc regeneration through targeted differentiation and paracrine signaling. Interestingly, many novel bone and ligament scaffolds are modulating anti-inflammatory signals to enhance tissue repair and integration, as well as prevent scaffold degradation. Neural scaffolds are also arising. These mimic spinal biomechanics and activate Piezo signaling to guide axonal growth and restore motor function. Scientists have begun combining these biological platforms with brain–computer interface technology to restore movement and sensory feedback in patients with severe spinal damage. Although this technology is not fully clinically ready, this field is advancing rapidly. As implantable technology can now mimic physiological processes, molecular signaling, biomechanical design, and neurotechnology opens new possibilities for restoring spinal function and improving the quality of life for individuals with spinal disorders. Full article

Pain following orthodontic treatment is the chief complaint of patients undergoing this form of treatment. Although the use of diode lasers has been suggested for pain reduction, the mechanism of laser-induced analgesic effects remains unclear. Neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), contribute to the transmission and maintenance of inflammatory pain. Heat shock protein (HSP) 70 plays a protective role against various stresses, including orthodontic forces. This study aimed to examine the effects of diode laser irradiation on neuropeptides and HSP 70 expression in periodontal tissues induced by experimental tooth movement (ETM). For inducing ETM for 24 h, 50 g of orthodontic force was applied using a nickel–titanium closed-coil spring to the upper left first molar and the incisors of 20 male Sprague Dawley rats (7 weeks old). The right side without ETM treatment was considered the untreated control group. In 10 rats, diode laser irradiation was performed on the buccal and palatal sides of the first molar for 90 s with a total energy of 100.8 J/cm². A near-infrared (NIR) laser with a 808 nm wavelength, 7 W peak power, 560 W average power, and 20 ms pulse width was used for the experiment. We measured the number of facial groomings and vacuous chewing movements (VCMs) in the ETM and ETM + laser groups. Immunohistochemical staining of the periodontal tissue with SP, CGRP, and HSP 70 was performed. The number of facial grooming and VCM periods significantly decreased in the ETM + laser group compared to the ETM group. Moreover, the ETM + laser group demonstrated significant suppression of SP, CGRP, and HSP 70 expression. These results suggest that the diode laser demonstrated analgesic effects on ETM-induced pain by inhibiting SP and CGRP expression, and decreased HSP 70 expression shows alleviation of cell damage. Thus, although further validation is warranted for human applications, an NIR diode laser can be used for reducing pain and neuropeptide markers during orthodontic tooth movement. Full article

Background: Cancer vaccines represent a groundbreaking advancement in cancer immunotherapy, utilizing tumor antigens to induce tumor-specific immune responses. However, challenges like tumor-induced immune resistance and technical barriers limit the widespread application of predefined antigen vaccines. Here, we investigated the potential of viral protein R (Vpr) peptides as effective candidates for constructing anonymous antigen vaccines in situ by directly injecting at the tumor site and releasing whole-tumor antigens, inducing robust anti-tumor immune responses to overcome the limitations of predefined antigen vaccines. Methods: The cytotoxic effects of Vpr peptides were evaluated using the CCK8 reagent kit. Membrane penetration ability of Vpr peptides was observed using a confocal laser scanning microscope and quantitatively analyzed using flow cytometry. EGFR levels in the cell culture supernatants of cells treated with Vpr peptides were evaluated using an ELISA. Surface exposure of CRT on the tumor cell surface was observed using a confocal laser scanning microscope and quantitatively analyzed using flow cytometry. The secretion levels of ATP from tumor cells were evaluated using an ATP assay kit. HMGB1 release was evaluated using an ELISA. Mouse (Male C57BL/6 mice aged 4 weeks) MC38 and LLC bilateral subcutaneous tumor models were established to evaluate the therapeutic effects of Vpr peptides through in situ vaccination. Proteomic analysis was performed to explore the mechanism of anti-tumor activity of Vpr peptides. Results: Four Vpr peptides were designed and synthesized, with P1 and P4 exhibiting cytotoxic effects on tumor cells, inducing apoptosis and immunogenic cell death. In mouse tumor models, in situ vaccination with Vpr peptide significantly inhibited tumor growth and activated various immune cells. High-dose P1 monotherapy demonstrated potent anti-tumor effects, activating DCs, T cells, and macrophages. Combining ISV of P1 with a CD47 inhibitor SIRPαFc fusion protein showed potent distant tumor suppression effects. Proteomic analysis suggested that Vpr peptides exerted anti-tumor effects by disrupting tumor cell morphology, movement, and adhesion, and promoting immune cell infiltration. Conclusions: The designed Vpr peptides show promise as candidates for in situ vaccination, with significant anti-tumor effects, immune activation, and favorable safety profiles observed in mouse models. In situ vaccination with Vpr-derived peptides represents a potential approach for cancer immunotherapy. Full article

This study investigates the biochemical and physiological responses of the economically important fish Barbonymus gonionotus to acute temperature fluctuations. Focusing on malondialdehyde (MDA) levels in serum and visceral organs, serum biochemical indices, hematological parameters, cortisol levels, and operculum movement, this research assessed the impacts of thermal stress. Experimental conditions involved two thermal regimes: heat shock at 25–29 °C and 25–37 °C; as well as cold shock at 25–21 °C and 25–13 °C sustained over 24 (D1), 48 (D2), and 72 (D3) h. Serum MDA levels increased significantly. Notably, MDA in the gills, brain, and liver fluctuated under cold stress, particularly at 13 °C. Serum parameters showed significant alterations except for AST, total protein, and cholesterol, which remained unaffected by heat shock. Red blood cell (RBC) counts dropped to their lowest at 13 °C, while white blood cell (WBC) counts diminished significantly when temperatures dropped to 21 °C and then stabilized. Cortisol surged with temperature changes, peaking at 13 °C and 29 °C for cold and heat shock, respectively. Operculum movement was inversely affected by thermal changes, decreasing with cold and increasing with heat. These findings underscore the sensitivity of silver barb to thermal extremes, providing insights for optimized aquaculture management and enhanced resilience to environmental stressors. Full article

During mouse pregnancy, the pubic symphysis (PS) undergoes a gradual transitioning into an interpubic ligament (IpL) for a successful delivery. After birth, this IpL is rapidly remodeled, returning to the non-pregnant morphology. The PS fibrocartilaginous cells acquire a myofibroblast-like phenotype, characterized by extracellular matrix (ECM) secretion, expression of α-smooth muscle actin (α-SMA), and vimentin. While the presence of myofibroblast-like cells during the IpL remodeling is well described, cell–cell interactions and how this might contribute to the delivery remains poorly understood. This study uses ultrastructure and molecular approaches to investigate cell–cell and cell–ECM junctions during mouse pregnancy and postpartum. Our findings reveal that the intercellular contacts between adjacent IpL myofibroblast-like cells, particularly at late pregnancy stages, are characterized as adherens and GAP junctions. The acquisition of contractile elements by IpL cells, coupled with neighboring cells and the surrounding ECM via junctional complexes, suggests an important role in supporting changes in the mechanical forces generated by pubic bone movements during mouse pregnancy and also in tying the pelvic bones together, which may help the birth canal closure after delivery. Further studies in PS biology may investigate fibroblast to myofibroblast differentiation signaling cascades, which regulate the expression of pro-fibrotic proteins and may provide new insights for preterm labor. Full article

Para-coumaric acid (p-CA) is a phenolic compound that has antioxidant, anti-inflammatory, and anticancer properties which make it potential for cancer treatment. However, its effectiveness has been limited by poor solubility, rapid metabolism, and poor absorptivity. Nonthermal biocompatible pressure plasma (NBP) has gained attention as a cancer treatment due to its ability to generate reactive oxygen and nitrogen species (RONS), inducing oxidative stress that damages cancer cells. This study aimed to investigate the combined effect of NBP and p-CA on the induction of ferroptosis in lung adenocarcinoma via the GPX4, xCT, and NRF2 pathways. H460 and A549 lung adenocarcinoma cells as well as normal lung cells (MRC5) were treated with p-CA, NBP, and their combination. Cell movement, intracellular RONS levels, and lipid peroxidation, along with apoptosis and ferroptosis-related gene expression, were evaluated by co-treatment. Co-treatment also significantly elevated NO₂⁻, NO₃⁻, and H₂O₂ levels and reduced cancer cell (H460, A549) viability (26, 31%) without affecting normal cells MRC5 (7%). Elevated MDA levels and changed expression of ferroptotic proteins indicated mitochondrial dysfunction, oxidative damage, lipid peroxidation, and DNA damage, which resulted in the induction of ferroptosis. These findings reveal a novel ferroptosis mechanism, emphasizing co-treatment for delivering bioavailable natural anticancer drugs. Full article

Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial–mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal–epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival. Full article

CD99 is a membrane protein critical for various immunological functions, including T-cell activation, protein trafficking, cell apoptosis, and leukocyte movement. It is also highly expressed in certain malignant tumors, contributing to the development, invasion, immune evasion, and adaptation of tumor cells to stress stimuli, including drug resistance. CD99 is crucial at the intersection of normal biological processes and pathological conditions like cancer. While research indicates that CD99 may interact homotypically, there is evidence of some heterotypic ligands that align with its roles. The development of multiple anti-CD99 antibodies has shed light on its functions, particularly regarding interactions between tumor cells that overexpress CD99 and immune cells expressing the same protein within the microenvironment. Anti-CD99 antibodies effectively eliminate tumors and attract immune cells to the tumor area. Additionally, CD99 influences the expression of specific immune checkpoint molecules, such as CD47, paving the way for potential combinations of anti-CD99 with immune checkpoint inhibitors. This review explores CD99’s role in normal physiology and cancer biology, focusing on how monoclonal antibodies affect CD99 expression and activity, thereby influencing cancer cells’ interactions with their microenvironment. It summarizes key findings about how these changes impact cancer cell behavior and the effectiveness of treatments. Full article

More than half of Crohn’s disease patients eventually develop intestinal strictures. Intestinal fibrosis is the excessive deposition of the extracellular matrix that obstructs intestinal movement. There is no approved medication to treat intestinal stricture. The roles of serum exosomal miRNAs in intestinal fibrosis are unknown. Serum exosomal miRNA sequencing was performed on samples of healthy donors and stricturing CD (CDS) patients. CDS patient-derived primary intestinal fibroblasts (CD-HIFs), CDS patient-derived serum exosomes (CDSE), human peripheral blood mononuclear cells (PBMCs), human colonic tissues, and mouse models of intestinal fibrosis were used. CDS patients had significantly lower serum exosomal miR205-5p levels than non-CDS patients and healthy donors. CDS patients had reduced miR205-5p expression in PBMCs. miR205-5p reduced its target Zinc finger E-box-binding homeobox 1 (ZEB1) and collagen protein expression in CDSE-treated CD-HIFs. In mouse models of intestinal fibrosis, overexpression of miR205-5p inhibited intestinal fibrosis, which was overcome by Zeb1 overexpression. Elafin, a human anti-fibrogenic protein, induced miR205-5p in intestinal fibroblasts. Inhibition of miR205-5p reversed the anti-fibrogenic effects of elafin in mice. Low serum exosomal anti-fibrogenic miR205-5p levels were associated with intestinal strictures in CD patients. miR205-5p can mediate the anti-fibrogenic effect of elafin by inhibiting ZEB1 and collagen expression. Full article

Calcium movement and concentration in the cell plays significant roles in normal physiology and in diseases such as cancer. The significance of this ion in oncogenesis suggests that membrane-relevant proteins are involved in its regulation and are deregulated in various cancers. These channels and transporters could be targets for therapeutic interventions. An evaluation of the expression of transient receptor potential (TRP) channels in prostate cancer was performed using publicly available genomic and proteome data. Two TRP family members with high expression in prostate cancers, TRPML2 and TRPM4, were chosen for further analysis the uncover the associations of their level of expression with clinical and pathologic prostate cancer characteristics. Several TRP channels were expressed in prostate cancers at the protein level including TRPM4, TRPML1, TRPML2, TRPC1 and TRPP3. At the mRNA level, MCOLN2 and TRPM4 were strongly expressed in a sub-set of prostate cancers. Cases with high MCOLN2 mRNA expression were associated with frequent ERG fusions and a trend for better survival outcomes. In contrast, prostate cancer cases with high TRPM4 mRNA expression were associated with lower ERG fusion frequency than cases with low TRPM4 mRNA expression. The prognosis of prostate cancers with high TRPM4 expression was not different from the prognosis with counterparts having low TRPM4 mRNA expression. TRP channels were expressed in sub-sets of prostate cancers. The two well-expressed channels of the super family, TRPML2 and TRPM4, have divergent associations with the most prevalent prostate cancer molecular aberrations, ERG fusions. These results imply diverse regulations of the TRP channels that would have to be taken into consideration when devising therapeutic interventions targeting individual channels. Full article

Low birth weight (LBW) in various species leads to a pronounced skeletal muscle phenotype and can serve as a model to study muscle formation and draw conclusions for normal and pathological development. We aimed to elucidate in detail how the differentiation of muscular stem cells and their progeny are disturbed in piglets born with LBW. We isolated primary muscle cells from LBW piglets and their normal siblings with two different approaches: (1) single cells from two functionally divergent subpopulations (previously named “fast” and “slow”) and (2) cells derived from isolated, intact myofibers. Subsequently, we analyzed their proliferative and differentiative capacity by determining proliferation rate, migration behavior, myotube formation, and myogenic gene and protein expression. LBW led to a decreased proliferation rate and migration potential in cells from the subpopulation fast group. Cells from LBW piglets were generally able to differentiate, but they formed smaller myotubes with less incorporated nuclei, leading to a diminished fusion rate. Myogenic gene expression was also significantly altered due to pig birth weight. Overall, early postnatal muscle development in LBW was disturbed at several crucial steps involving the establishment of a reserve stem cell pool, movement of cells towards existing myofibers, and the ability to form nascent myofibers. Full article