Search Results (2,614)

Opioid analgesics are essential in the management of severe and chronic pain; however, their prolonged use is limited by the onset of analgesic tolerance and opioid-induced hyperalgesia (OIH). Recent studies increasingly implicate both synaptic functional and structural plasticity within nociceptive pathways as crucial mechanisms in OIH and tolerance. This review integrates current mechanistic understanding of how opioids alter synaptic transmission throughout the dorsal root ganglia (DRG), spinal dorsal horn, and supraspinal nociceptive networks. Peripherally, μ-opioid receptor (MOR) activation on TRPV1-positive nociceptors initiates presynaptic long-term potentiation (LTP), forming an early substrate for central sensitization. In the spinal dorsal horn, chronic opioid exposure drives NMDAR-dependent LTP, TRPC-mediated calcium influx, and actin cytoskeleton remodeling, leading to persistent increases in synaptic strength and excitatory connectivity. In supraspinal regions—including the ventral hippocampus, prefrontal cortex, and amygdala—opioids promote experience-dependent plasticity and predictive coding, which link environmental cues to reduced analgesic effectiveness. In addition to synaptic functional plasticity, opioid-induced synaptic structural plasticity within nociceptive pathways has been shown to underlie the long-term nature of opioid analgesic tolerance. Collectively, these data define a distributed network of opioid-responsive synapses whose pathological potentiation underpins the development of tolerance and hyperalgesia. Elucidating these mechanisms underlying OIH and tolerance paves the way for targeted therapeutic strategies that maintain analgesic efficacy while minimizing adverse synaptic remodeling and negative outcomes. Full article

Eating behavior requires a balance between metabolic and hedonic components. Anxiety and dietary type may influence the quantity, patterns, and other aspects of food intake. Modern diets, especially in Western societies, often contain high levels of calories from fat and simple sugars (e.g., cafeteria-style diets). This type of diet may promote overweight and/or obesity in some, although many consumers remain at a normal weight. The mechanisms underlying susceptibility or resistance to weight gain remain unclear. Here, Sprague-Dawley male rats were fed a cafeteria diet for 10 weeks and then classified into quartiles based on body mass. We evaluated locomotor activity and anxiety-like behaviors and analyzed hypothalamic proteomics in overweight (Q4) rats compared with underweight (Q1) rats. Our results showed that locomotor activity and anxiety-like behaviors did not differ across quartiles (p > 0.05). Nevertheless, the expression of several hypothalamic proteins differed between Q4 and Q1 rats. Functional enrichment analysis of these differentially expressed proteins (p ≤ 0.05) revealed changes in cytoskeleton dynamics, synaptic communication, energy production and utilization, biosynthesis of cellular components (including nucleotides and carbohydrates), and regulation of metabolism between Q1 and Q4 rats. Neuro-humoral hypothalamic output regulates metabolism and food intake. Therefore, these functional changes in the hypothalamus may be associated with rats’ susceptibility/resistance to weight gain. Full article

Background/Objectives: Variants of MYPN, encoding a sarcomeric protein myopalladin, are associated with different types of cardiomyopathies and myopathies. However, the molecular mechanisms of MYPN-associated pathologies are still poorly understood. Methods: In this study, we generated induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient carrying a novel p.N989I (c.2966A>T) variant of MYPN and used iPSC-derived cardiomyocytes to examine the impact of the variant on biophysical characteristics and transcriptomic profile. Results: No significant changes in parameters of calcium transients, sodium current and action potential were found in iPSC-derived cardiomyocytes with the p.N989I (c.2966A>T) variant of MYPN compared to non-isogenic cells from an unrelated healthy donor. At the transcriptomic level, MYPN-N989I cardiomyocytes demonstrated an upregulation of genes linked to cell cycle, mitotic spindle, microtubule cytoskeleton organization, and myogenic program genes. Downregulation of sarcomeric, Z-disc- and cell junction-associated genes, as well as genes involved in ATP synthesis, oxidative phosphorylation, and the SRF-signaling pathway, was also revealed. Conclusions: Our data suggest that the p.N989I (c.2966A>T) variant of MYPN plays a dual role in hypertrophic cardiomyopathy pathogenesis, disrupting not only sarcomeric and cytoskeletal organization but also the regulation of the muscle gene program. Full article

Fruit branch length in cotton is a key trait influencing plant architecture and suitability for mechanisation; elucidating its molecular regulatory mechanisms is crucial for breeding varieties with desirable plant architecture. In this study, an F₂ segregating population was established using the long-fruit-branch upland cotton line L16 and the short-fruit-branch line S14 as parents. By integrating morphological, cytological, and omics approaches, we systematically analysed the underlying mechanisms of variation in fruit branch length. Phenotypic analysis indicated that the inter-node elongation rate of the first fruit branch in L16 was significantly higher than that in S14. Tissue section observations revealed that the length of cortical parenchyma cells in L16 was significantly greater than that in S14, suggesting that the difference in fruit branch length primarily stems from variations in the extent of cortical parenchyma cell elongation. BSA-Seq analysis identified five QTL regions significantly associated with fruit branch length, encompassing 82 coding genes. Further RNA-Seq analysis of the fruit branch initiation stage (T0) and rapid elongation stage (T1) identified 3106 differentially expressed genes common to both stages. GO and KEGG enrichment analyses revealed that these genes were significantly enriched in pathways related to plant hormone signalling, the cytoskeleton, and microtubule organisation. By integrating BSA-Seq and RNA-Seq data, three candidate genes were screened that simultaneously harboured non-synonymous mutations and were significantly highly expressed in the short fruit branch line S14. Combined with bioinformatics analysis, GH_D02G0744 was predicted to be the most likely key candidate gene regulating cotton fruit branch length. This study provides important genetic resources to elucidate the molecular regulatory mechanisms of cotton fruit branch length and lays a theoretical foundation for molecular breeding to improve cotton plant architecture. Full article

Long non-coding RNAs (lncRNAs) and RNA–protein complexes (RNPs) are increasingly recognized as central to the regulatory complexity of modern eukaryotes. This review proposes that the remarkable diversity of eukaryotic systems arises from the long-term integration of ancient RNA/RNP mechanisms, layered with innovations introduced by successive symbioses. We outline four interconnected levels of symbiosis contributing to this process: (1) molecular symbiosis, involving dynamic assemblies of RNAs, proteins, and membraneless organelles (MLOs); (2) genome symbiosis, driven by the expansion of non-coding and repetitive DNA; (3) intracellular symbiosis, initiated by mitochondria acquisition; and (4) intercellular symbiosis, rooted in the cellular cooperation that enables multicellularity. We highlight lncRNAs and intrinsically disordered proteins (IDPs) as versatile mediators that interweave interactions across scales, predominantly within phase-separated condensates. Building upon these multi-level processes, we propose the framework of integrated symbiotic pleiotropy—a concept where molecular components acquire layered functional roles as a direct consequence of successive symbiotic acquisitions. This paradigm unites information layering, functional moonlighting, molecular tinkering, and exaptation into a coherent trajectory for eukaryotic evolution. Full article

K-Rev Interaction Trapped protein-1 (KRIT1) is a scaffold protein that forms functional protein complexes involved in physiologically important signaling networks. While it is primarily recognized for its association with Cerebral Cavernous Malformations (CCMs), KRIT1 may also play critical roles in tumor formation and the acquisition of malignant phenotypes, regulating cell adhesion, cytoskeletal dynamics, and angiogenesis. In this study, we investigated the role of KRIT1 in cancer cell migration and metastasis, with a focus on identifying novel interacting proteins and characterizing the intracellular signaling pathways activated upon its loss. By using a yeast two-hybrid screening, we identified Kinesin Family Member 1C (KIF1C), a protein involved in regulating podosome and invadopodium elongation, as a novel binding partner of KRIT1, and the interaction was confirmed in melanoma and epithelial cancer cells. In silico docking and interaction interface analyses supported the KRIT1–KIF1C interaction, providing structural insight into the binding mode as shown experimentally. We also found that SRC and focal adhesion kinase (FAK) phosphorylation, as well as Ras homolog family member A (RhoA) expression, represent additional pathways affected by the loss of KRIT1. This study confirms our earlier hypothesis that KRIT1 functions as a tumor suppressor and uncovers a compelling link between its loss and enhanced cancer aggressiveness. Full article

This study compared the wound-healing response and osteogenic gene expression profile of osteoblasts exposed to pediatric-equivalent concentrations of dexmedetomidine (DXMT) and propofol (POF). Human osteoblast-like SAOS-2 cells were assigned to control, low- and high-dose DXMT and POF groups based on pharmacokinetically derived free-drug levels. Scratch-wound closure was quantified over 24 h, and expression of osteogenesis- and cytoskeleton-related genes (RANKL, RUNX2, SP7, BMP2, VIM, VCL, OCN, ALP) was measured by SYBR Green quantitative Polymerase Chain Reaction (qPCR). Normality was assessed using the Shapiro–Wilk test, and group differences were analyzed with two-way ANOVA followed by Tukey’s multiple comparisons test (p < 0.05). All groups demonstrated complete scratch closure by 24 h, with no differences at 6 h. At 18 h, POF did not differ from the control, whereas DXMT significantly accelerated closure at both doses in a dose-dependent fashion. High-dose DXMT significantly increased VIM (3.95 ± 3.12, p = 0.0144) and BMP2 (2.28 ± 0.70, p = 0.0002) expression, while RUNX2, SP7, and RANKL remained comparable to controls. ALP (1.68 ± 0.40, p = 0.0005) and OCN (3.31 ± 0.35, p = 0.0108) were significantly elevated only in the high-dose DXMT group, whereas POF showed no significant effects. At clinically relevant concentrations, DXMT was associated with enhanced scratch closure and increased expression of selected osteogenesis- and cytoskeleton-related genes in SAOS-2 cells, whereas POF showed limited effects under the tested conditions. These findings suggest that DXMT may influence early in vitro cellular responses relevant to bone healing and should be further validated in functional differentiation models and in vivo studies. Full article

Background/Objectives: Diabetic small fiber neuropathy and related sensory and epidermal problems affect up to 70% of all patients with diabetes. Long-term hyperglycemia disrupts cytoskeletal organization and axonal transport; however, molecular changes within human diabetic epidermis remain understudied. Diaph1 and its cytoskeletal ligands, including β-Actin and Profilin, are key regulators of cytoskeletal dynamics and may be associated with diabetes-related alterations in skin structure and innervation. Methods: Sixteen patients with type 2 diabetes, aged 43.3 ± 9.6 years (disease duration 18.9 ± 8.7 years), and twelve non-diabetic controls, aged 43.9 ± 8.9 years, were enrolled in the study. All participants provided informed consent. Skin punch biopsies were obtained under local anesthesia and processed for staining of PGP 9.5, Diaph1, β-Actin, and Profilin. Quantitative image analysis was performed to assess stained area fraction, signal intensity, and intraepidermal nerve fiber density. Statistical comparisons and Spearman’s rank correlation analyses were used to evaluate group differences and associations between staining parameters. Results: Diabetic skin samples exhibited a significant reduction in PGP 9.5-positive intraepidermal nerve fibers, indicating reduced cutaneous innervation. In contrast, Diaph1 and Profilin showed broader and more diffuse epidermal staining, while β-Actin displayed altered staining patterns and intensity. Significant correlations between Diaph1- and β-Actin-related staining measures indicated an association consistent with altered cytoskeletal organization under chronic hyperglycemic conditions. Conclusions: Long-standing type 2 diabetes was associated with reduced PGP 9.5-positive intraepidermal nerve fibers, together with altered epidermal staining patterns of Diaph1, Profilin and β-Actin. These findings indicate coexisting cutaneous denervation and cytoskeletal alterations in diabetic skin. Full article

Life evolved under a persistent 1 g field that is continuous, ubiquitous, and directionally structured. Here, we synthesize evidence across evolutionary biology, mechanobiology, and genome architecture to propose gravity as a mechanical boundary condition that helped canalize the emergence of complex multicellularity. Order-of-magnitude considerations indicate that gravity-derived hydrostatic loads can fall within force/pressure regimes relevant to nuclear and chromatin mechanosensitivity when transmitted through adhesion–cytoskeleton–LINC–lamina coupling. Comparative genomic and imaging frameworks suggest that complex animals increasingly rely on volumetric genome organization (packing domains and higher-order 3D architectures) that supports durable transcriptional memory and stable differentiated cell identities. Integrating these concepts with altered-gravity experiments, we argue that microgravity and hypergravity perturb chromatin topology and region-level transcription in rapid, largely reversible patterns consistent with a mechanically defined 1 g reference state. We advance a boundary-condition thesis: gravity is not a sole driver but a stable reference that likely contributed to the evolvability and long-term robustness of mechanogenomic architectures required for high-dimensional differentiation and tissue homeostasis. Full article

Actin is a key component of the cytoskeleton and plays diverse roles in cellular processes. Autophagy regulates homeostasis through various mechanisms that recycle nutrients and degrade unnecessary or harmful cellular components and aggregates. These two processes are engaged in a highly conserved crosstalk through which they regulate each other, including autophagolysosomal formation and regulation of actin dynamics. The regulation of autophagy is involved in cancer, neurodegeneration, infectious diseases, and inflammation, providing possible avenues for treatments for these diseases. In this review, we summarize current knowledge of the actin–autophagy interplay and regulation, and explore the possible implications for disease progression and therapies. Although more research is necessary to strengthen the effectiveness of therapies that target the regulation of autophagy and actin dynamics, significant strides have already been made, clearly indicating the potential benefit of targeting these processes. Full article

Background/Objectives: Osteoarthritis has been increasingly described as associated with systemic inflammation, raising the question of how it would affect fertility in young women with or without reproductive hormone administration. We studied oogenesis in mice with collagenase-induced osteoarthritis (CIOA) as a model system with fewer ethical limitations after estradiol (E2) or follicle-stimulating hormone (FSH) treatment. Methods: Oocytes have been isolated from mice subjected to various treatment regimens. The meiotic spindle, the chromatin, and the actin cap were fluorescently labeled and analyzed. Results: In addition to reduced maturation rates, specific oocyte abnormalities were registered when CIOA, FSH, or E2 were applied in isolation. Combined treatments showed that the spindle, chromatin, and actin cytoskeleton parameters were differently affected in oocytes from groups with CIOA treated by estradiol and those treated with FSH. Enlarged spindles, ooplasmic tubulin asters, aligned metaphases, and predominantly normal actin caps, often with an actin halo, were typical for groups with CIOA combined with estradiol. The groups with CIOA and FSH had slightly enlarged spindles, unaligned metaphases with degenerated chromatin surrounded by a cloud of depolymerized tubulin, and small actin caps. Conclusions: Our results show that experimental osteoarthritis with or without exogenous reproductive hormones negatively affects oogenesis, presumably due to systemic inflammatory factors making the ovarian microenvironment less capable of supporting oocyte maturation. Estradiol supplementation does not benefit oogenesis. FSH treatment induced cytoskeletal and chromatin abnormalities that presumably disturb the fertilization and development potential of affected oocytes. These data can have implications for assisted reproduction in cases of patients with osteoarthritis. Full article

The fall armyworm (Spodoptera frugiperda) is a major global migratory pest. Its increasing insecticide resistance poses a severe threat to food security. Developing biopesticides such as SfMNPV is critical for sustainable control. Nevertheless, the early molecular mechanisms underlying the S. frugiperda midgut response to oral SfMNPV challenge remain poorly understood. This study utilized high-throughput transcriptome sequencing to systematically characterize the dynamic transcriptional profiles of the larval midgut at 1, 12, and 24 h after oral SfMNPV inoculation. Results showed that the midgut transcriptional response to SfMNPV is time and stage-specific. During this period, the physical midgut barrier underwent remodeling, with core components of the peritrophic matrix downregulated at 1 h, followed by the basal lamina at 12 h, alongside the activation of cytoskeleton genes during 12–24 h. Concurrently, sustained endoplasmic reticulum stress, autophagy, and ubiquitin system responses occurred from 12 to 24 h. At the metabolic level, the defense system exhibited a functional succession, shifting from ABC transporters and UDP-glycosyltransferases at 1 h to glutathione S-transferases and superoxide dismutase at 12–24 h. Additionally, the midgut tissue exhibited a cascade transition from pro-apoptotic signaling at 1 h to compensatory regenerative repair mediated by the Wnt, mTOR, and Hippo pathways at 12–24 h. This study elucidates the molecular process of barrier damage, homeostatic imbalance, and tissue remodeling during early oral SfMNPV challenge. These findings provide a global perspective on baculovirus-host interactions and establish a theoretical foundation for designing novel biopesticides targeting the midgut interaction. Full article

Nuclear lamins are the core molecular bridge linking the extracellular mechanical microenvironment to intranuclear gene regulation, and play a central regulatory role in cellular mechanosensation and mechanotransduction. Here, we systematically integrate the latest global research progress on nuclear lamins, delineating the cascade regulatory mechanism by which lamins mediate the transmission of mechanical signals across the nuclear envelope and the subsequent regulation of chromatin remodeling and epigenetic modification, with a focus on the molecular characteristics and functional specificity of distinct nuclear lamin subtypes and their interaction modes with the Linker of Nucleoskeleton and Cytoskeleton complex (LINC complex) and chromatin. Existing studies have established that nuclear lamins are mainly divided into three categories: A-type lamins (Lamin A/C), B-type lamins (Lamin B1, B2), and germ cell-specific subtypes. Among these, A-type lamins directly determine the mechanical stiffness of the nucleus and serve as the core mediators of intranuclear mechanical signal transduction. Each subtype of B-type nuclear lamins has a well-defined, non-redundant functional division: Lamin B1 and Lamin B2 indirectly maintain nuclear structural stability and regulate epigenetic status by anchoring facultative heterochromatin and constitutive heterochromatin, respectively. Notably, Lamin A/C distributed in the nucleoplasm also bears significant mechanical tension, which challenges the long-standing view that the mechanical functions of nuclear lamins are restricted to the nuclear envelope region. After mechanical force is transmitted across the nuclear envelope to nuclear lamins via the LINC complex, it can regulate the spatial conformation of chromatin and epigenetic modifications, thereby determining core cellular life activities including proliferation, differentiation, and migration. Dysregulation of this pathway is closely associated with a wide spectrum of human diseases, including cardiovascular diseases, progeria, muscular dystrophy, and neurodevelopmental disorders. Taken together, this review systematically delineates the hierarchical regulatory network of the “LINC complex–nuclear lamina–chromatin” axis, advances our understanding of the fundamental principles of cellular mechanobiology, and provides a theoretical framework for deciphering the pathological mechanisms and developing targeted therapeutic drugs for related diseases. Full article

Embryo and organ shapes emerge from the interplay between genetic programs and physical forces. In recent years, there has been a growing appreciation of the role of mechanical forces in morphogenesis. Here, we review how the integration of advanced genetic approaches with high-resolution imaging, biophysics, and modeling has begun to yield new insights into C. elegans embryonic morphogenesis. Building on past reviews in the field, we analyze dorsal intercalation, ventral enclosure, and axis extension, with a focus on how forces impinge on cellular processes and serve to coordinate morphogenesis across adjacent tissues through mechanotransduction. We also discuss how different forms of cellular rosettes contribute to ventral patterning and head morphogenesis, which had not been discussed in previous reviews. Throughout, we highlight how the reciprocal feedback mechanisms between molecular processes and mechanical forces, as well as cell material properties, shape the embryo. Full article

Background/Objectives. The actin-binding protein EPLIN (epithelial protein lost in neoplasm), also known as LIMA1, contributes to the maintenance of cytoskeleton structure and dynamic. This protein, which interacts with multiple partners to regulate cell adhesion and migration, has been implicated in the progression of solid tumors and in tumor metastasis. Consequently, small molecules binding to EPLIN are actively searched. EPLIN has been characterized as a molecular target for the antitumor antibiotic albacarcin V which affects the cytoskeletal structure and induces cell growth arrest. Methods. We have modeled the binding of albacarcin and naturally occurring derivatives to EPLIN conformers, in order to locate the drug-binding site and to identify additional EPLIN binders. Nineteen compounds were studied, including albacarcins V (vinyl) and M (methyl), five gilvocarcins, four ravidomycins, two chrysomycins, and six related products (including polycarcin and fucomycin). Results. The modeling analysis confirmed the capacity of albacarcin V to bind to EPLIN and identified a few better binders. In particular, ravidomycin V bearing a dimethylamino sugar unit were identified as the best binders in the series, along with the two related anticancer natural products FE35A-B. Structure-binding relationships are discussed. The drug-binding site has been localized near the central residue Asn34 in the conformationally constrained domain between the two zinc-binding regions. Conclusions. This study provides guidance to the design of EPLIN inhibitors based on the ravidomycin core structure. Full article