Search Results (9,421)

Cryotherapy involves flash freezing of tissue and removing unwanted tissue. Mechanism of injury is causing cell membrane rupture by rapid multiple freeze–thaw cycles, while reserving tissue architecture and the collagen matrix. This promotes favorable wound healing. In recent years, it has gained increasing attention as a treatment option for upper gastrointestinal diseases (Barrett’s Esophagus and early cancer). Currently, two FDA-approved delivery methods are available in the GI tract: Cryoballoon and spray cryotherapy, which will be discussed. In this review, we also propose to examine the expanding role of cryotherapy in gastrointestinal practice, drawing from both clinical studies and illustrative vignettes. In addition, we will highlight its established role in eradicating Barrett’s with low and high-grade dysplasia and compare its outcomes and safety profile with radiofrequency ablation (RFA). We will also discuss the application and safety of spray cryotherapy in the palliation of malignant esophageal strictures when compared with Esophageal stent placement. Cryotherapy may have immunological potential, and it may shrink both primary and metastatic diseases. Ongoing research in this field of Cryo-immunology will be highlighted. Beyond esophageal neoplasia, cryotherapy is increasingly utilized in other upper gastrointestinal precancerous conditions. Through this synthesis, our goal is to provide a timely and comprehensive overview of advancements in cryotherapy and its potential to reshape novel therapeutic approaches in upper gastrointestinal cancers. Finally, we highlight the evolution of a novel platform using nitrous oxide delivered by a handheld device, a contact balloon, and a small replaceable cartridge. This approach may make delivery of cryogen application favorable and a first-line approach in the management of Barrett’s esophagus and early cancer. In addition, Cryoballoon therapy for dysphagia palliation for malignant esophageal strictures may become a preferred approach as more data evolves. Full article

Pulmonary vascular proliferative lesions are rarely reported and poorly characterized in animals. In this study, we describe 13 cases identified in wild Korean raccoon dogs (Nyctereutes procyonoides), suggesting a higher-than-expected incidence in this species. Gross examination revealed villous projections within the lumina of pulmonary vessels, sometimes accompanied by pneumonia, hemorrhage, or Dirofilaria immitis (heartworm) infection. Most affected animals also presented with thick, dark gray cutaneous crusts associated with scabies infestation. Histopathologically, the lesions consisted of papillary proliferations within thickened vascular lumens. Special stains (Masson’s trichrome and Elastic Verhoeff–Van Gieson) demonstrated a single layer of endothelial cells lining fibromuscular and collagenous thick cores. Immunohistochemistry confirmed endothelial origin and benign proliferative nature, with positive expression of CD31, collagen types I, III, and IV, and proliferating cell nuclear antigen (PCNA). To date, pulmonary vascular proliferative lesions have not been well documented in N. procyonoides, and baseline pathological data, including findings from special stains, are lacking. These findings indicate that pulmonary vascular proliferative lesions may be underrecognized in raccoon dogs and suggest a likely association with chronic vascular injury related to parasitic infections. Further studies are warranted to elucidate the underlying mechanisms and contributing factors. Full article

Adverse pregnancy outcomes (APOs) such as prematurity, low birth weight, stillbirth, and birth defects remain significant global health challenges. While many risk factors are known, APOs encompass a wide range of outcomes with diverse, sometimes poorly understood etiologies. Pregnancy-related acute kidney injury (PR-AKI) and liver injury are particularly associated with increased maternal and fetal mortality. This study investigated the association between hematological parameters, kidney and liver injury markers and adverse pregnancy outcomes. This cross-sectional study involved 714 pregnant women aged 18–40 years, conducted between August 2021 and August 2022. Maternal blood samples were collected before and after delivery to compare hematological parameters. Kidney and liver injury markers were measured using standard methods. The study analysed the association of these parameters with adverse pregnancy outcomes. The median age of participants was 24 years (Q1, Q3: 21, 26). Women with adverse pregnancy outcomes had statistically significant serum creatinine levels [0.52 mg/dL (0.45, 0.58)] compared to those without [0.50 mg/dL (0.44, 0.56)], although the difference was not clinically significant. Elevated Aspartate Transaminase (AST) levels (>90th percentile) were statistically associated with adverse pregnancy outcomes. Pairwise comparisons with Bonferroni corrections revealed significant differences in Hemoglobin (Hb), White Blood Cell (WBC), Red Blood Cell (RBC), platelet, and Packed Cell Volume (PCV) levels before and after delivery (p < 0.05) in both groups. Elevated AST levels, but not other hematological or biochemical parameters, were independently associated with adverse pregnancy outcomes, whereas creatinine differences lacked clinical impact. Full article

Cigarette smoking is the leading preventable cause of chronic diseases (e.g., COPD, cardiovascular disease, cancer), largely driven by persistent immune-inflammatory mechanisms. This review synthesizes the molecular and cellular cascades linking cigarette smoke (CS) exposure to chronic pathology. CS constituents, particularly ROS/RNS, induce rapid oxidative stress that overwhelms antioxidant defenses and generates damage-associated molecular patterns (DAMPs). These DAMPs activate pattern recognition receptors (PRRs) and the NLRP3 inflammasome, initiating NF-κB signaling and the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). CS exposure causes profound innate immune dysregulation, including airway epithelial barrier disruption, hyperactivated neutrophils, and dysfunctional alveolar macrophages (AMs) that release destructive proteases (e.g., MMP-12) and acquire foam-cell–like characteristics. Furthermore, CS drives adaptive immunity toward a Th1/Th17-dominant phenotype while suppressing regulatory T-cell (Treg) function, thereby promoting autoimmunity and chronic tissue injury. Critically, CS induces epigenetic reprogramming (e.g., DNA methylation, miRNA dysregulation), locking immune cells into a persistent pro-inflammatory state. This convergence of oxidative stress, innate and adaptive immune dysregulation, and epigenetic alterations underlies the systemic low-grade inflammation that fuels smoking-related chronic diseases, highlighting key targets for novel therapeutic interventions. Full article

Dental pain often arises from the compromised integrity of the tooth pulp due to dental injury or caries. The dentin–pulp complex has long been considered to be central to the unique biology of dental pain. Most trigeminal ganglion afferents projecting into tooth pulp are myelinated neurons, which lose their myelination at the site of peripheral dentin innervation. The pulpal afferents likely combine multiple internal and external stimuli to mediate nociception and maintain pulp homeostasis. Transient receptor potential (TRP) ion channels in neurons and odontoblasts, along with mechanosensitive ion channels such as Piezo, form a key molecular hub for pulpal nociception by sensing thermal, chemical, and hydrodynamic stimuli. Among these, TRP vanilloid 1 (TRPV1) mediates nociception and the release of calcitonin-gene-related peptides (CGRPs), while TRP canonical 5 (TRPC5) mediates cold pain. TRP melastatin 8 (TRPM8) mediates the transduction of hyperosmotic stimuli. Pulpitis elevates endogenous TRPV1 and TRPA1 agonists, while inflammatory mediators sensitize TRP channels, amplifying pain. CGRP recruits immune cells and promotes bacterial clearance and reparative dentinogenesis, yet the roles of TRP channels in these processes remain unclear. Future studies should use advanced multi-omics and in vivo or organotypic models in animal and human teeth to define TRP channel contributions to pain, immune responses, and regeneration. Understanding neuronal and non-neuronal TRP channel interactions and their integration with other ion channels may enable novel analgesic and regenerative strategies in dentistry. Full article

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with heart failure (HF) representing a major contributor to hospitalizations, healthcare costs, and death. Effective management of HF is hindered by the limitations of current biomarkers and diagnostic tools. Conventional biomarkers, such as natriuretic peptides, primarily reflect downstream hemodynamic stress and often lack specificity, particularly in HF with preserved ejection fraction or multiple comorbidities. While imaging provides valuable structural and functional information, it is resource-intensive, costly, and unsuitable for frequent longitudinal monitoring. As a result, these conventional approaches are inadequate to capture the dynamic and heterogeneous nature of HF pathophysiology. Circulating cell-free nucleic acids (cfNAs), including cell-free DNA (cfDNA) and RNA (cfRNA), have emerged as promising noninvasive liquid biopsy biomarkers capable of providing real-time insight into upstream pathological events, such as cardiomyocyte injury, immune activation, inflammation, and maladaptive remodeling. Importantly, cfNAs also act as active mediators of CVD pathology. When released under stress or injury, cfNAs interact with pattern recognition receptors (PRRs) that trigger sterile inflammation, cardiovascular cell dysfunction, and adverse cardiac remodeling. This review summarizes the origins, mechanistic roles, and clinical significance of cfNAs in HF and related CVD, highlighting their dual roles as diagnostic biomarkers and mechanistic effectors of disease. Finally, we discuss emerging cfNA-targeted therapeutic strategies, challenges, and future opportunities for precision medicine in HF and HF-associated CVD. Full article

Background/Objectives: Burn injuries pose a significant challenge due to tissue damage and impaired healing. Cell-based therapies offer promise by delivering therapeutic cells to the wound site. However, effective cell delivery remains a critical hurdle. This study investigates the potential of non-crosslinked hyaluronic acid (HA) as a simple, versatile carrier for delivering autologous keratinocytes and fibroblasts to treat early burn wounds. Methods: Primary keratinocytes and fibroblasts were isolated from uninjured adult skin. In addition, fibroblasts and adipose stem cells (ASC) from polydactyly and progenitor fibroblasts were used. Non-cross-linked HA Redensity 1^® (RD1) solutions of varying concentrations were prepared and applied to various in vitro models. Cell viability, proliferation, migration, and collagen stimulation were assessed using standard assays. Additionally, cells were suspended in Redensity 1 and applied to an in vitro de-epidemalized dermis (DED) wound model to examine cell delivery and tissue reformation. Results: Preliminary data demonstrated the feasibility of using non-cross-linked HA RD1 gel as a cell carrier. RD1 gel enhanced cell viability, retention, migration, and collagen deposition. Histological analysis revealed improved cell adhesion and migration. Conclusions: This study provides valuable insight into the potential of non-cross-linked HA RD1 as a simple and effective delivery vehicle for cell therapies in early burn care. Successful translation of this approach could significantly improve clinical outcomes for burn patients. Full article

Goose astrovirus 2 (GAstV-2) infection leads to visceral gout and swollen kidneys in goslings, causing a 5–50% mortality rate and significant economic losses for goose flocks. While most studies on the virus’s pathological damage have focused on the kidneys, few reports have examined the effects of this fecal-oral pathogen on the digestive system. This study investigated GAstV-2 localization, cellular targets, and its impact on intestinal structure and homeostasis in orally infected goslings. Twenty 1-day-old goslings were randomly assigned to the infected and control groups. Clinical signs, organ lesions, viral distribution, histopathology, and alterations in intestinal cell populations, cytokine expression, and signaling pathways were assessed at 7 days post-infection. GAstV-2 was detected in the duodenum, jejunum, ileum, cecum, and rectum, with the highest viral load in duodenal crypt cells. Infection induced crypt cell necrosis, reduced villus height, decreased villus-to-crypt ratio, and lowered numbers of goblet cells and Lgr5+ intestinal stem cells. In contrast, Paneth cell abundance, Bmi1+ stem cells, and tight junction-related gene expression increased. Inhibition of stem cell differentiation into goblet cells was observed, mediated by modulation of the Notch signaling pathway. Proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-22, and TNF-α, were markedly upregulated, indicating a strong inflammatory response. These results demonstrate that GAstV-2 preferentially targets duodenal crypt cells, disrupts epithelial renewal, and impairs mucosal barrier function, while triggering compensatory regenerative and immune mechanisms. This study provides new insights into the intestinal pathogenesis of GAstV-2 and identifies potential targets for interventions to mitigate intestinal injury and economic losses in gosling production. Full article

Background/Objectives: Facial nerve injury from conditions such as Bell’s palsy, trauma, surgery, and infection leads to facial asymmetry and motor deficits. Axotomy models reproduce peripheral nerve disruption and consequent motor impairment. To compare the effects of forward versus reverse autologous nerve suturing on neural regeneration and motor recovery within the facial nucleus after axotomy. Methods: In rats subjected to facial nerve axotomy, motor recovery was assessed at 8 weeks using whisker movement and blink reflex tests. Immunohistochemistry quantified choline acetyltransferase (ChAT), sirtuin 1 (SIRT1), and Iba-1 as indices of cholinergic function, cellular stress/inflammation modulation, and microglial activation in the facial nucleus. Results: Axotomy significantly reduced whisker and blink scores compared with sham. Both forward and reverse suturing significantly improved these behavioral outcomes versus axotomy. Within the facial nucleus, axotomy decreased ChAT- and SIRT1-positive cells and increased Iba-1 expression, while both suturing techniques increased ChAT and SIRT1 and reduced Iba-1. These changes suggest enhanced cholinergic function, mitigation of stress/inflammatory responses, and attenuation of microglial activation following repair. Conclusions: Forward and reverse suturing were each associated with improved motor function and favorable molecular and cellular changes in the facial nucleus after facial nerve axotomy. These findings support the utility of surgical repair irrespective of graft orientation and highlight involvement of key pathways—cholinergic signaling, SIRT1-related regulation, and microglial activity—in nerve restoration. This work extends our previous study, which focused on peripheral nerve regeneration after forward and reverse suturing, by elucidating how graft orientation affects central facial nucleus responses. By integrating behavioral outcomes with ChAT, Iba-1, and SIRT1 expression, the present study provides novel insight into the central mechanisms underlying motor recovery after facial nerve repair and helps explain why comparable functional outcomes are achieved regardless of graft polarity. Full article

Background: Postoperative abdominal adhesions are a common and serious complication following abdominal surgery, often leading to chronic pain, bowel obstruction, or infertility. This study aimed to evaluate the efficacy of the new starch-based absorbable hemostatic agent and dressing, BioSight, in comparison with a predicate device (4DryField^® PH) for the prevention of abdominal adhesions in a rat model. Methods: A total of 90 Sprague–Dawley rats were used to establish an intra-abdominal adhesion model and assigned to the BioSight, 4DryField^® PH, or control group. Standardized injuries were created on the cecum and parietal peritoneum, followed by application of the designated materials. Animals were sacrificed at 2, 4, and 12 weeks for macroscopic adhesion scoring and histopathological evaluation. Adhesion area, adhesion strength, and tissue thickness were assessed using established scoring systems, and local healing was examined by H&E staining. All quantitative data were analyzed using one-way ANOVA. Conclusions: In a rat peritoneal adhesion model, BioSight exhibited pronounced anti-adhesion efficacy comparable to 4DryField^® PH. Macroscopic evaluation showed consistently low adhesion scores (≤0.4) across all time points up to 12 weeks, while histological analysis confirmed reduced adhesion thickness, with BioSight displaying numerically lower values, particularly at early stages (251.3 ± 137.4 µm vs. 323.2 ± 174.6 µm at Week 2). This performance is attributed to rapid in situ hydrogel formation that provides effective temporary tissue separation, limits early fibrin deposition and inflammatory cell infiltration, and supports hemostasis. Importantly, the starch-based hydrogel exhibits a balanced biodegradation profile—persisting long enough to protect injured tissues during the critical inflammatory and fibroproliferative phases, yet undergoing complete enzymatic resorption thereafter without adverse tissue reactions. Collectively, these results highlight the anti-adhesion functionality of BioSight and support the clinical potential of plant-derived starch-based bioresorbable surgical adjuncts. Full article

Oxidative stress (OS) is increasingly recognized as a dynamic disturbance of cellular redox networks rather than a simple imbalance between oxidants and antioxidants. In this context, ferroptosis and cuproptosis—two regulated and metal-dependent forms of cell death—emerge as key mechanisms linking OS to metabolic dysfunction, inflammation, and tissue injury. This review integrates findings from biochemical, lipidomic and metallomic studies to describe how lipid peroxidation (LPO), glutathione (GSH)–Glutathione Peroxidase 4 (GPX4) activity, ferritinophagy, copper-induced mitochondrial protein lipoylation, and altered communication between organelles generate distinct redox signatures across diseases. By examining cutaneous, metabolic, cardiovascular, infectious, neurodegenerative, and oncologic conditions, we outline the shared redox pathways that connect iron- and copper-dependent cell death to systemic inflammation, immune dysregulation, and chronic tissue damage. Common oxidative markers—such as oxidized phospholipids, lipid aldehydes including 4-Hydroxynonenal (4-HNE) and malondialdehyde (MDA), and systemic metal imbalance—are highlighted as potential indicators of disease severity and as emerging therapeutic targets. We also discuss innovative analytical tools, including redox lipidomics, metallomic profiling and artificial-intelligence (AI)-based classification approaches, which improve the characterization of redox vulnerability and may guide the development of precision redox therapies. Overall, ferroptosis and cuproptosis represent unifying mechanisms that connect OS to multisystem disease and provide new opportunities for diagnostic refinement and targeted antioxidant-based interventions. Full article

Cognitive deterioration and the transition to neurodegenerative disease does not develop through simple, linear regression; it develops as rapid and global transitions from one state to another within the neural network. Developing understanding and control over these events is among the largest tasks facing contemporary neuroscience. This paper will discuss a conceptual reframing of cognitive decline as a transitional phase of the functional state of complex neural networks resulting from the intertwining of molecular degradation, vascular dysfunction and systemic disarray. The paper will integrate the latest findings that have demonstrated how the disruptive changes in glymphatic clearance mechanisms, aquaporin-4 polarity, venous output, and neuroimmune signaling increasingly correlate with the neurophysiologic homeostasis landscape, ultimately leading to the destabilization of the network attraction sites of memory, consciousness, and cognitive resilience. Furthermore, the destabilizing processes are exacerbated by epigenetic silencing; neurovascular decoupling; remodeling of the extracellular matrix; and metabolic collapse that result in accelerating the trajectory of neural circuits towards the pathological tipping point of various neurodegenerative diseases including Alzheimer’s disease; Parkinson’s disease; traumatic brain injury; and intracranial hypertension. New paradigms in systems neuroscience (connectomics; network neuroscience; and critical transition theory) provide an intellectual toolkit to describe and predict these state changes at the systems level. With artificial intelligence and machine learning combined with single cell multi-omics; radiogenomic profiling; and digital twin modeling, the predictive biomarkers and early warnings of impending collapse of the system are beginning to emerge. In terms of therapeutic intervention, the possibility of reprogramming the circuitry of the brain into stable attractor states using precision neurointervention (CRISPR-based neural circuit reprogramming; RNA guided modulation of transcription; lineage switching of glia to neurons; and adaptive neuromodulation) represents an opportunity to prevent further progression of neurodegenerative disease. The paper will address the ethical and regulatory implications of this revolutionary technology, e.g., algorithmic transparency; genomic and other structural safety; and equity of access to advanced neurointervention. We do not intend to present a list of the many vertices through which the mechanisms listed above instigate, exacerbate, or maintain the neurodegenerative disease state. Instead, we aim to present a unified model where the phenomena of molecular pathology; circuit behavior; and computational intelligence converge in describing cognitive decline as a translatable change of state, rather than an irreversible succumbing to degeneration. Thus, we provide a framework for precision neurointervention, regenerative brain medicine, and adaptive intervention, to modulate the trajectory of neurodegeneration. Full article

The blood–brain barrier (BBB) is essential for maintaining cerebral homeostasis, and its dysfunction is increasingly recognized as an active driver of epilepsy. This review explores the mechanisms by which BBB disruption contributes to seizures and the development of chronic epilepsy. Potentially epileptogenic insults, including traumatic brain injury, stroke, and status epilepticus, induce acute and often persistent BBB leakage. This breach permits the extravasation of serum albumin, which activates transforming growth factor-beta (TGF-β) signaling in astrocytes. This cascade leads to astrocytic dysfunction, impaired potassium buffering, neuroinflammation, and synaptic remodeling, collectively fostering neuronal hyperexcitability. Furthermore, BBB disruption facilitates the infiltration of peripheral immune cells, amplifying neuroinflammation and propagating a pathologic cycle of BBB damage and seizure activity. BBB damage is mediated by multiple processes, including the activation of the plasminogen activation (PA) system. Furthermore, these processes of BBB disruption and neuroinflammation provide a shared pathological basis for neuropsychiatric disorders like depression and anxiety, which are common comorbidities of epilepsy, through shared mechanisms of neuroinflammation and neurovascular unit (NVU) dysregulation. BBB dysfunction can also contribute to the resistance to antiepileptic drugs. Finally, we discuss the therapeutic potential of stabilizing the BBB as a viable strategy for developing disease-modifying therapies for epilepsy. Full article

Backgrounds: While the conditionally essential amino acid taurine is known to confer hepatoprotection against injury through anti-inflammatory and antioxidant mechanisms, it remains unclear whether it plays an active role in the process of hepatocarcinogenesis. Emerging research portrays taurine as a double-edged sword in oncology, with its capacity to either inhibit or facilitate carcinogenesis being contingent upon the specific tumor microenvironment. Objectives: Investigating the effect of taurine on hepatocellular carcinoma progression and its underlying mechanisms. Methods: A hydrodynamic tail vein injection (HDT) model of primary hepatocellular carcinoma was established in mice to validate the effects of taurine and its downstream bile acid synthesis pathway on liver cancer progression. Subsequent RNA sequencing analysis was performed to investigate the molecular pathways through which taurine exerts its functions. Results: Supplementation of taurine or overexpression of its transporter SLC6A6 significantly accelerated HCC development in vivo. Inhibition of taurine transporter abrogated the tumor-promoting effects of the bile acid synthesis enzymes CYP7A1 and BAAT. This suppression may be mediated through the blockade of the cell cycle, p53 signaling pathway and metabolic pathways. Conclusions: Our findings demonstrate that taurine plays a vital role in the tumor-promoting activities of HCC. Full article

Background: Gastrointestinal (GI) mucosal injury is a frequent complication of long-term nonsteroidal anti-inflammatory drug (NSAID) use. Effective mucosal healing requires coordinated epithelial migration, proliferation, and angiogenesis, which may be influenced by focal adhesion kinase (FAK). This study aimed to determine whether our newly developed FAK activators promote intestinal mucosal healing by enhancing angiogenesis and whether FAK activation increases resistance to reinjury. Methods: Ischemic jejunal ulcers were induced in C57BL/6 mice. After 24 h, mice received intraperitoneal injections of the FAK activator ZINC40099027 (ZN27, 900 µg/kg every 6 h) or vehicle for 2, 4, or 14 days. Ulcer areas were quantified, and liver and kidney function were assessed. Ulcer and adjacent tissues were analyzed by immunofluorescence staining for angiogenesis and proliferation markers. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with ZN27 to evaluate proliferation, migration, angiogenesis, and intracellular signaling. In a reinjury model, male C57BL/6J mice received continuous infusion of the FAK activator M64HCl (25 mg/kg/day) or vehicle for 7 days, with a single subcutaneous injection of indomethacin (10 mg/kg) on day 1 to induce GI injury. Fourteen days after the first dose of indomethacin, the mice received a second indomethacin challenge, and one day later, total ulcer areas in the pyloric opening and small intestine were quantified. Results: Ulcer areas were significantly smaller in ZN27-treated mice compared with vehicle-treated controls at 3 and 5 days, accompanied by increased expression of angiogenesis and proliferation markers. In vitro, ZN27 enhanced HUVEC migration via FAK activation in an ERK1/2-dependent manner and increased the number of angiogenic sprouts. In the reinjury model, treatment with M64HCl during the initial indomethacin-induced injury resulted in significantly smaller ulcer areas in both the pyloric opening and small intestine after the second indomethacin challenge compared with controls. Conclusions: FAK activation accelerates ischemic ulcer healing, in part by enhancing angiogenesis. Moreover, FAK activation during an initial injury reduces susceptibility to recurrent NSAID-induced intestinal injury, perhaps because it promotes initial higher-quality ulcer repair. Full article