Search Results (20,897)

Copper (Cu)–zinc (Zn) imbalance has been implicated in colorectal cancer (CRC). Exchangeable copper (exCu), the labile circulating Cu fraction, may better reflect functionally relevant metal dysregulation than total Cu. We investigated sex-specific associations between systemic Cu–Zn indices, tumor burden, and epithelial–mesenchymal transition (EMT)-related tissue remodeling in CRC. We studied 152 CRC patients and 140 healthy controls. Serum Cu, Zn, and exCu were measured using validated analytical methods; circulating gonadotropins, sex steroids, and carcinoembryonic antigen were also assessed. EMT-related proteins (E-cadherin, vimentin, fibronectin, vinculin, MEMO1) were quantified by Western blot in paired tumor and adjacent mucosa. Analyses were sex-stratified and age-adjusted. CRC patients exhibited higher serum Cu and exCu and lower Zn than controls, resulting in a marked increase in the exCu:Zn ratio in both sexes. In patients, exCu:Zn was associated with tumor burden and pathological stage, with stronger associations with tumor size and pT stage in women and with metastatic status in men. Serum exCu:Zn was associated with tumor − normal differences in EMT-related proteins, particularly ΔE-cadherin, in both sexes. Systemic Cu–Zn disequilibrium, summarized by the exCu:Zn ratio, was associated with tumor burden and epithelial remodeling in CRC in a sex-specific manner, suggesting its potential as a biologically informative biomarker warranting further validation. Full article

The molecular coordination between the central nervous system and peripheral organs is fundamental to euryhalinity. This study elucidates the distinct adaptive strategies of the brain and gills in the four-finger threadfin (Eleutheronema tetradactylum), an aquaculture species of growing importance, during long-term (30-day) acclimation to low salinity (5 versus 25 control). A profound dichotomy in tissue-specific plasticity was uncovered: while the brain maintained remarkable transcriptional stability with only 10 differentially expressed genes (DEGs), the gills underwent extensive remodeling with 702 DEGs. Gill DEGs were functionally enriched in ion transport and metabolic remodeling, highlighted by the significant upregulation of the Na⁺-Cl⁻ cotransporter (slc12a10) and the prolactin receptor (prlr), coupled with a profound downregulation (log2FC = −5.97) of aquaporin-1 (aqp1). This indicates a concerted strategy to enhance ion uptake while minimizing water permeability. In contrast, the brain’s subtle response was dominated by the upregulation of key neuroendocrine hormones, including growth hormone (gh), prolactin (prl), and pro-opiomelanocortin (pomc). This suggests a top-down regulatory cascade. Integrative pathway analysis identified the PI3K-Akt and JAK-STAT signaling pathways as the primary conduits linking central hormonal signals to peripheral physiological adjustments. These results demonstrate that the euryhalinity of E. tetradactylum is achieved through a highly efficient strategy: a transcriptionally stable brain provides precise endocrine commands that orchestrate robust peripheral remodeling in the gills. This study deciphers the molecular basis of the brain–gill axis in osmoregulation and provides a rich repository of candidate genes for the genetic improvement of low salinity tolerance in aquaculture. Full article

Hypothyroidism is associated with metabolic, neurobehavioral, and reproductive alterations that may involve neuroendocrine regulatory peptides. Spexin, a neuropeptide implicated in energy homeostasis, has recently attracted attention for its possible role in thyroid and reproductive axis regulation. Therefore, this study aimed to investigate the effects of spexin on neurobehavioral responses and the tissue-specific expression of irisin and KISS-1 in the cerebral cortex and testis under hypothyroid conditions. Thirty-two male Wistar albino rats were randomly divided into four groups: Control, Hypothyroid (methimazole, 0.03% in drinking water for 35 days), Hypothyroid + Spexin (methimazole plus spexin, 25 µg/kg, intraperitoneally), and Spexin (25 µg/kg, intraperitoneally). Behavioral assessments were performed using the Open Field Test and Forced Swim Test. Serum thyroid hormone levels were analyzed, and brain and testis tissues were evaluated immunohistochemically for irisin and KISS-1 expression. Hypothyroid rats showed increased thyroid-stimulating hormone levels, decreased thyroxine concentrations. Spexin administration significantly reduced TSH levels and increased T4 concentrations. Spexin treatment reduced thigmotaxis compared to controls. No significant differences were found among groups in overall locomotor activity, time spent in the central zone, or FST parameters. Immunohistochemical analyses demonstrated reduced irisin and KISS-1 expression in hypothyroid rats, which was restored following spexin treatment. In conclusion, spexin exerted TSH-suppressive and T4-enhancing effects in experimental hypothyroidism. Its effects on irisin and KISS-1 expression suggest potential involvement in neuroendocrine and reproductive axis regulation. Full article

Background/Objectives: Hyalinizing clear cell carcinoma (HCCC) and clear cell odontogenic carcinoma (CCOC) are rare clear cell neoplasms with overlapping histopathological features. This study aimed to compare their clinicopathological characteristics, particularly in anatomically challenging sites such as the palate and maxilla. Methods: Three analyses were performed. First, an unpublished series of five HCCC and three CCOC cases was evaluated for diagnostic histopathological features. Second, a PRISMA-ScR-guided literature review of 58 HCCCs and 45 CCOCs restricted to tumours arising in intraoral minor salivary glands, major salivary glands and gnathic bones published between 2000 and 2025 was conducted using PubMed. Third, a sub-analysis compared palatal HCCC and maxillary CCOC (25 vs. 14 cases), integrating literature and unpublished cases. Results: The case series and overall literature review showed that HCCC and CCOC predominantly occurred in adults (mean age, case series: 50.8 years; literature: 56.33 years for HCCC and 61 vs. 54.11 years for CCOC) with a female predilection (case series: 60%; literature: 68%) and generally exhibited clinically indolent behaviour. The site of occurrence, soft tissue (HCCC) versus intraosseous location (CCOC), was the principal distinguishing feature. No marked differences were observed between the two tumours in either the overall literature analysis or the site-specific sub-analysis. However, CCOC at maxillary/palatal sites presented with a higher number of larger lesions and higher number of cases with nodal metastasis compared with HCCC, most probably indicating delayed clinical detection rather than intrinsic aggressiveness of CCOC. Histopathological overlap was considerable; however, diffuse dense hyalinization (4/5), focal glandular differentiation (2/5), mucous-secreting cells (4/5) and salivary gland association (5/5) favoured HCCC, whereas patchy hyalinization (3/3), larger tumour lobules (3/3) and peripheral palisading (2/3) favoured CCOC. Conclusions: HCCC and CCOC demonstrate clinicopathological similarities and shared EWSR1 rearrangement, supporting a close biological relationship. The considerable overlap between these tumours support the hypothesis that CCOC may represent the intraosseous counterpart of HCCC and highlight the importance of integrated clinicopathological assessment and further clarification in future WHO classifications. Full article

Background/Objectives: Ganglion cells are the projection neurons of the retina, and there are multiple types that differ in their morphology, light responses and central projections. Parasol cells are one of the major retinal ganglion cell types in primates. The presynaptic bipolar cells have been well-characterized, but less is known about the amacrine cells that provide the majority of their inputs. The goal of this study was to identify the amacrine cells presynaptic to the OFF subtype of parasol cells. Methods: Central retinal tissue from an adult macaque was processed for serial block-face scanning EM, and a volume of images of the inner retina located 2 mm temporal to the center of the fovea was analyzed. Results: All the OFF parasol cells in the volume were reconstructed. All the synaptic inputs of two OFF parasol cells were analyzed. They received 80% or more of their input from amacrine cells and the remainder from bipolar cells, almost entirely from the Off diffuse type. Many of the presynaptic amacrine cells were reconstructed sufficiently to be classified as wide-field or narrow-field, and the latter type predominated. Five specific types of presynaptic amacrine cells were identified as AII, A4, knotty bistratified type 1, A13 and wiry type 1. Notably, the same types of amacrine cells are also presynaptic to OFF midget ganglion cells, another major type. Conclusions: These findings suggest that differences between the light responses of midget and parasol ganglion cells likely arise from differences in the presynaptic bipolar cell types. Full article

Background/Objectives: Pelvic organ prolapse (POP) management requires precise patient selection for surgical techniques to balance clinical efficacy and safety. The primary aim of this study was to evaluate the role of preoperative 3D/4D transperineal ultrasound in the risk stratification of POP recurrence. We analyzed the impact of levator ani muscle (LAM) injuries, specifically avulsion and ballooning, as identified by ultrasound, on both anatomical and subjective success rates, comparing native tissue repair versus mesh-augmented surgery. Methods: A prospective, multicenter observational study was conducted over a five-year period, January 2021 to December 2024 (recruitment), with follow-up completed in December 2025, ensuring a minimum follow-up of 12 months for all participants. The cohort included 276 women scheduled for primary surgery for symptomatic POP stage ≥ 2. Prior to intervention (116 underwent native tissue repair and 160 received mesh), all patients underwent 3D/4D transperineal ultrasound for standardized volume acquisition. Using this preoperative functional imaging technique, we measured the hiatal area and diagnosed the presence of hiatal ballooning (≥25.0 cm²) or levator muscle avulsion. Results: Ultrasound assessment revealed significant differences in surgical success based on the diagnosed baseline site-specific defects. Hiatal ballooning was the sonographic finding that demonstrated the greatest impact on risk stratification. Among patients with preoperative ballooning, mesh use significantly reduced both subjective recurrence (5.7% vs. 21.4%, p = 0.001) and objective recurrence (21.4% vs. 35.7%, p = 0.040) compared to native tissue repair. Furthermore, in women without ultrasound-documented avulsion, mesh also decreased objective recurrence (17.9% vs. 33.0%, p = 0.024). Multivariate analysis, adjusted for age, BMI, menopausal status, and parity, confirmed that, after stratifying by these preoperative ultrasound findings, a native tissue approach remains the primary independent predictor of surgical failure (OR 1.752 for objective recurrence; p = 0.041). Conclusions: In conclusion, native tissue repair was identified as the primary independent predictor of surgical failure. While 3D/4D transperineal ultrasound helps identify high-risk phenotypes such as hiatal ballooning, these sonographic findings did not maintain independent significance in the multivariate model. Therefore, ultrasound should be considered a complementary tool for surgical planning rather than a definitive predictor of recurrence. Full article

Cardiovascular diseases remain the leading cause of mortality worldwide, highlighting the urgent need for more effective therapeutic strategies. Despite substantial advances in conventional biomaterials, their limited ability to support functional integration and dynamically interact with the biological microenvironment continues to hinder therapeutic outcomes. Native cardiovascular tissues rely on tightly regulated bioelectrical signaling to coordinate cellular communication, tissue homeostasis, and functional repair. Consequently, recreating these bioelectrical cues has emerged as a key design principle in cardiovascular tissue engineering. Electroactive biomaterials have gained increasing attention as a promising platform to address this challenge by enabling electrical modulation of cellular behavior and tissue function. In this review, we summarize the intrinsic bioelectrical properties of cardiovascular tissues and discuss the roles of electrical stimulation in regulating disease-relevant cellular responses. We further highlight recent advances in the development of conductive, piezoelectric, and other electroactive biomaterials for cardiovascular tissue engineering applications. Finally, we critically discuss the major challenges and future opportunities in the field, including tissue-specific responses, stimulation parameter optimization, long-term safety, and clinical translation. Collectively, electroactive biomaterials represent a promising and rapidly evolving frontier for the development of dynamic, responsive, and next-generation therapies for cardiovascular diseases. Full article

Adipose tissue expansion in obesity is accompanied by extracellular matrix (ECM) remodeling, regulated by matrix metalloproteinases (MMPs). Visceral adipose tissue (VAT) is metabolically more active than subcutaneous adipose tissue (SAT). However, depot-specific differences in proteolytic activity and protein glycooxidation remain incompletely characterized. In this case–control study, we assessed the activity of six matrix metalloproteinases (MMP-1, -2, -7, -9, -11, and -13) using a fluorescence resonance energy transfer (FRET) assay and quantified advanced glycation- and glycooxidation-related markers in paired VAT, SAT, and plasma samples obtained from 40 patients with obesity and 21 non-obese controls. The activities of all assessed MMPs were greater in patients with obesity than in the control group (p < 0.01 for all MMPs). Direct tissue-compartment comparisons showed that MMP activity and glycooxidation-related markers were most pronounced in VAT, with markedly higher values in obese individuals compared with controls. In VAT of obese individuals, median MMP activity was approximately 50–60% higher compared with controls. Amyloid cross-β-structure, vesperlysine, and pentosidine were significantly elevated in VAT in obesity, whereas plasma levels were markedly lower and showed limited group differences. No significant differences were observed between obese participants with and without metabolic syndrome. Obesity is associated with a depot-specific molecular profile characterized by enhanced proteolytic and glycooxidative activity predominantly within visceral adipose tissue. These findings highlight the importance of tissue-compartment-specific assessment in obesity. Full article

Basonuclin 2 (BNC2) is a highly conserved cysteine–histidine (C2H2)-type zinc-finger nuclear regulatory protein characterized by three pairs of zinc-finger domains, a putative nuclear localization signal, a serine-rich region, broad tissue distribution, and remarkable transcript diversity generated through alternative promoter usage, alternative splicing, and polyadenylation. Increasing evidence from human genetics, animal models, functional genomics, and transcriptomic studies indicates that BNC2 links nuclear regulatory mechanisms to tissue-specific developmental and disease phenotypes. In the nervous system, BNC2-positive neuronal populations and BNC2-derived circular RNAs have been implicated in energy-balance circuits and neuroinflammatory regulation. In the skeletal system, BNC2 contributes to osteochondral development, periosteal stem-cell activation, chromatin remodeling, fracture repair, and genetic susceptibility to adolescent idiopathic scoliosis. BNC2 variants have also been associated with congenital lower urinary tract obstruction, whereas its expression and regulatory landscape are closely related to germ-cell development, epithelial ovarian cancer susceptibility, pigmentation traits, fibrosis, and several tumor contexts. Mechanistically, BNC2-associated phenotypes appear to involve cysteine–histidine zinc-finger-mediated transcriptional regulation, non-coding enhancer activity, epigenetic alterations, RNA-processing-associated nuclear functions, and chromatin-remodeling-dependent control of cell proliferation, differentiation, and stromal activation. This review integrates current evidence on the molecular architecture and regulatory functions of BNC2, critically discusses its context-dependent roles across development and disease, and highlights unresolved questions regarding isoform-specific activity, cell-type-specific regulation, downstream target networks, and clinical translation. A clearer understanding of these mechanisms may support the future evaluation of BNC2 as a biomarker, genetic susceptibility locus, molecular stratification factor, and potential therapeutic regulatory node. Full article

Cathepsin C (CTSC), also known as dipeptidyl peptidase I, is an upstream activator of serine protease networks that may promote metastatic progression through inflammatory amplification and microenvironmental remodeling. Increasing evidence suggests that CTSC contributes to cancer progression not simply as an overexpressed lysosomal protease, but as a context-dependent regulator of metastatic traits. This review summarizes the structure, maturation, and biological functions of CTSC, with emphasis on its protease-activating capacity and its links to tumor-associated inflammation. Current evidence connecting CTSC to epithelial–mesenchymal transition, extracellular matrix remodeling, neutrophil extracellular trap formation, and immune microenvironment reprogramming is then synthesized across hepatocellular carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, non-small-cell lung cancer, and glioma. Available data most strongly support a pro-metastatic role for CTSC in breast cancer and colorectal cancer, whereas evidence in several other malignancies remains predominantly preclinical and mechanistically incomplete. Importantly, CTSC is better viewed as a targetable protease network hub than as a universal pan-cancer metastatic driver. The biomarker potential and therapeutic relevance of CTSC are also evaluated, with particular attention to the opportunities and limitations of current DPP-1/CTSC inhibitors and the need for tumor-specific translational strategies. Overall, CTSC represents a promising but still incompletely validated target in oncology, and future work should prioritize tissue-specific dependency, biomarker qualification, and rational combination approaches. Full article

Salivary aldehyde dehydrogenases (ALDHs), particularly ALDH3A1, are increasingly recognized as potential contributors to oral defense against aldehyde-associated stress at the oral–environment interface. Unlike freely secreted salivary enzymes, measurable salivary ALDH activity primarily reflects intracellular and vesicle-associated enzymes derived from salivary gland epithelial cells, oral mucosal cells, immune cells, and exfoliated cellular components. Within the oral exposome, ALDHs expressed in oral epithelial and salivary gland tissues participate in the detoxification of reactive aldehydes, while salivary ALDH activity may serve as an indicator of local aldehyde-detoxification capacity and tissue redox status. Beyond aldehyde metabolism, emerging evidence suggests that ALDH-associated pathways are linked to redox regulation, epithelial stress adaptation, inflammatory signaling, and tissue repair through NAD(P)⁺-dependent processes and stress-responsive networks such as Nrf2 and SIRT1. This review provides a saliva-focused synthesis of ALDH biology, emphasizing isoform-specific functions and the potential importance of ALDH3A1 in oral epithelial defense. Altered salivary ALDH activity has been reported in association with oral conditions including periodontitis, oral lichen planus, radiation-induced salivary dysfunction, and oral squamous cell carcinoma (OSCC). Genetic factors, particularly ALDH2 polymorphisms, together with environmental exposures and microbial dysbiosis, may further influence aldehyde burden and oral disease susceptibility. Although current evidence supports the biological relevance of salivary ALDHs, their utility as clinical biomarkers or therapeutic targets remains investigational and requires further mechanistic and clinical validation. Full article

Introduction: Lymph nodes (LN) in the anterior periprostatic fat (APPF) may harbour metastatic disease in patients with Prostate Cancer (PCa). We investigated the incidence and significance of LN in APPF tissue removed during robotic and laparoscopic radical prostatectomy (RP). Patients and Methods: We retrospectively analysed RP performed by a single surgeon from 2013 to 2023. A total of 670 patients underwent RP, with 407 procedures conducted laparoscopically and 263 robotically. Histological results were available for 509 patients, who were examined for the presence of LN and any evidence of metastatic involvement. Results: LN were detected in the periprostatic fat of eighty patients; however, only twelve had lymph node metastasis. Seven of the twelve patients presented with prostate-specific antigen (PSA) levels greater than 10 ug/L. All LN-positive patients had a Gleason score of seven or higher. On MRI, all patients had a PIRADS score of four or higher, and eleven were staged at T3 or higher. Additionally, all twelve patients had a Briganti score exceeding twenty. Conclusions: Our series indicates that the APPF contains LN that can harbour metastatic disease. Patients can have LN involved in APPF without the involvement of pelvic LN. Therefore, our study suggests that routine excision of APPF should be considered for appropriate LN staging and to avoid missing any metastasis, and that scoring systems like Briganti should be used to help identify this high-risk group. Full article

Background/Objectives: Cardiac regenerative ability varies in vertebrates. Adult mammals cannot mount a regenerative response, while fetal mammals and some salamanders and teleosts fully regenerate the heart after a cryoinjury mimicking a myocardial infarction. This contrast is suggested to be regulated in part by metabolism, with high regenerative capacity correlating with a comparatively lower mass-specific metabolic rate, ectothermy rather than endothermy and a metabolic phenotype favoring glycolysis in cardiac muscle. Methods: In this physiological study on axolotl salamanders, we altered the housing temperatures from the standard 20 °C to 10 °C, 25 °C and 30 °C and assayed key metabolic parameters as well as cardiac function, survival and regenerative capacity. Results: Our study demonstrated that while axolotls could be housed at temperatures ranging from 10 °C to 30 °C in an uninjured state, signs of a pathological response involving cardiac and metabolic insufficiency and mortality, especially after cryoinjury, increased progressively with increasing temperatures. We observed several metabolic effects, including differences in oxygen consumption, plasma metabolites and cardiac function. Cardiac regeneration after cryoinjury progressed as expected with only a small remaining injury after 60 days at the standard housing temperature of 20 °C. Regeneration was highly reduced in a reversible manner at 10 °C while regenerative rate was not affected at 25 °C. At 30 °C, cardiac regeneration could not be evaluated as the majority of animals (five out of six) did not survive the injury, likely reflecting insufficient cardiac reserve capacity to simultaneously sustain thermal metabolic effects and support tissue repair. Conclusions: The ectothermic axolotl undergoes several metabolic changes when exposed to different housing temperatures, with heart regeneration showing a narrower permissive temperature range than survival of the axolotl in an uninjured state. Full article

Nanofiber scaffolds play a crucial role in bioengineering by providing structural support for tissue and organoid growth. For composite nanofibers, optimizing their properties for specific applications often requires analyzing the spatial distribution of their chemical structure. This review focuses on the applications of Raman hyperspectral imaging to the mapping of the chemical composition of nanofibers. While the technique is diffraction-limited to the size of the scanning beam, it is possible to decipher the nanoscale features of these fibers by employing oversampling during scanning. Subsequently, these oversampled data can be analyzed by a singular-value decomposition (SVD) analysis and classical least-squares (CLS) decomposition. In many cases, this technique is essential for verifying the spatial distribution of different chemical components within multi-component nanofibers. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) belongs to the group of killer human cancers. Its ferocity is sustained by an unusual mix of genetic changes—primarily in KRAS and TP53—a hypoxic as well as desmoplastic tumor microenvironment, plus metabolic and redox adaptations that allow tumor life amidst intense stress situations. Content: This paper will discuss the molecular networks of wild-type and mutant p53, wild-type and mutant KRAS, PUMA, TIGAR, PRMT5, NRF2, oxygen tension, reactive oxygen species (ROS), and oxidative stress pathways that contribute to pancreatic cancer. It will describe how these factors help set the tumor’s redox state and control apoptosis and therapeutic resistance. This shall therefore specifically discuss what role oxygen gradients play in pancreatic tissues, as well as retinoic acid, together with redox-targeted therapies that are specific to vulnerabilities within such types of networks. Summary and Outlook: An understanding of the crosstalk of these molecular pathways will be critical in designing rational therapeutic strategies. Genetics, metabolism, and microenvironmental integration may open a path toward combinatorial therapies that would resensitize PDAC to apoptosis and overcome resistance to current treatments. Full article