Search Results (1,991)

Sepsis is a life-threatening syndrome marked by a dysregulated host response to infection, resulting in systemic inflammation, organ dysfunction, and high mortality globally. Despite advancements in supportive care, effective immunomodulatory therapies remain elusive, necessitating exploration of novel biological pathways and subsequent therapeutic development. The endocannabinoid system (ECS), which regulates immune function and homeostasis, has emerged as a key modulator of immunological and metabolic pathways central to sepsis pathophysiology. The ECS mediates its effects through endogenous ligands, G-protein-coupled cannabinoid receptors (CB1 and CB1), and regulatory enzymes that control its synthesis and degradation. Following PRISMA-ScR guidelines, this scoping review synthesizes current evidence on the mechanistic roles of ECS components in experimental and clinical models of sepsis, identifies knowledge gaps, and delineates future areas of work. A comprehensive literature search across multiple databases without restrictions on date or publication type was executed to ensure broad coverage of original studies investigating ECS mechanisms and their intersection with sepsis and septic shock. Across 53 studies, CB2 receptor activation was consistently associated with anti-inflammatory process, organ-protective outcomes, and increased survival rates against septic challenges in preclinical rodent models. CB1 receptor activation trends, however, showed context dependent outcomes. Central antagonism improved hemodynamics and survival rate, but peripheral effects varied with cell type and timing. Non-canonical ECS components (TRPV1, GPR55, PPAR-α, FAAH, MAGL) also contributed to neuroimmune and metabolic regulation. Limited clinical data linked ECS lipid profiles and gene expression with sepsis severity and outcomes. Collectively, ECS modulation, particularly CB2 agonism, TRPV1 activation, and FAAH/MAGL inhibition, shows promise in mitigating sepsis-induced inflammation and organ dysfunction. However, complex, context-dependent effects, especially involving CB1, highlight the need for precision-targeted therapeutic approaches. Further preclinical research is needed to expand generalizable trends to allow translational research to refine ECS-based interventions for sepsis management. Full article

Chronic exposure to pesticides poses significant hepatorenal toxicity risks, yet a systematic comparison of their effects across species and tissues is lacking. In this study, we systematically evaluated the cytotoxicity of eight pesticides using human (CCC-HEL-1 hepatocytes; 293T renal cells) and rodent (IAR hepatocytes; NRK renal cells) cellular models. Our results showed substantial variations in potency, with chlorothalonil exhibiting the highest toxicity (IC50 = 32.55 mg/L in 293T cells) and chlorpyrifos the lowest (IC50 = 444.5 mg/L in 293T cells). Principal component analysis revealed distinct species- and tissue-specific response patterns, highlighting the unique resistance of NRK cells. Mechanistic investigations demonstrated organ-specific biomarker alterations, such as elevated hepatic ALP and suppressed renal KIM-1. Remarkably, the MRP2 transporter exhibited tissue-specific divergence, being significantly downregulated in renal cells (all 8 pesticides, p < 0.005) and most hepatic cells (7/8 pesticides, p < 0.05), while propiconazole uniquely upregulated it in hepatocytes (1.5-fold, p < 0.05). Collectively, these findings offer critical mechanistic insights into pesticide-specific toxicity and cross-species susceptibility, providing valuable data to improve human health risk assessment in food safety and toxicology. Full article

Background. The dense hyaluronan (HA)-rich stroma in solid tumors can prevent effective tumor growth inhibition by hindering drug delivery and immune cell infiltration. However, the degradation of HA alone by systemic delivery of hyaluronidase has not shown significant improvement of tumor growth inhibition. Objectives/Methods. In this study, we targeted hyaluronan degradation by using antibody–enzyme (AbEn) molecules by fusing antibodies to a recombinant human hyaluronidase (HYAL). Results. The AbEn molecules were stable, retained both antigen-binding and enzymatic activities, and demonstrated a prolonged serum half-life of 132 h in rodent models. In the HA-rich colorectal cancer model, the cancer-associated fibroblast (CAF)-directed AbEn, TAVO423 (FAP × LRRC15 × HYAL trispecific antibody) achieved greater intratumoral HA depletion resulting in superior tumor growth inhibition compared to untargeted HYAL. Furthermore, the combination of TAVO423 in combination with other solid tumor cell targeting modalities such as 5-fluorouracil (5-FU), anti-PD-L1 monoclonal antibody, a PD-L1 × CD3 bispecific T-cell engager (TCE), and a CD318-targeting antibody–drug conjugate (ADC) all demonstrated enhanced tumor growth inhibition (TGI) values of 49–67% as compared to the respective monotherapy TGI values of 1–28%. In addition, TAVO423 improved the antitumor response of a 5T4 × CD3 TCE with an increase in TGI from 73% to 92% in an in vivo HA-rich pancreatic cancer model. The CAF-targeted HA degradation mediated by TAVO423 also reversed immune exclusion by increasing the density of CD8⁺ tumor-infiltrating lymphocytes (TILs) by 6–9-fold and synergized with PD-1 blockade to enhance TGI from 33% to 51% in an in vivo immunocompetent EMT-6 breast cancer model. Conclusions. These findings demonstrated the broad potential of the modular AbEn platform for targeted HA degradation to overcome barrier entry in stromal HA-rich solid tumors. Full article

Objectives: This study investigates psychedelic drugs to treat substance use disorder (SUD). Researchers have recently begun conducting clinical trials of psychedelic treatment for SUD. The current meta-analysis investigates the extent of efficacy in alleviating SM behaviours (P) using psychedelic therapy (I), concurrent with determining which psychedelic enables the greatest effect (C) as a treatment tool for reducing SUD (O). Methods: The inclusion criteria in this study include evaluating the efficacy of LSD, psilocybin, ketamine, or ibogaine in human beings with an SUD. The exclusion criteria include studies on rodents, patients with schizophrenia, case studies, incomplete or ongoing trials, and studies with insufficient quantitative data. The search criteria obtained 1278 articles, acquired through PubMed and PsycINFO. After excluding literature, 30 papers were kept in the final meta-analysis. A random-effects model analysis was applied to investigate individual psychedelic interventions, with a corresponding combined psychedelic intervention analysis. Results: The results favoured psychedelics as an SM treatment, with ibogaine evidencing the most prominent. We also found a non-significant difference between the effectiveness of psychedelic treatment paired with psychotherapy and psychedelic treatment alone. This study aims to contribute knowledge to future clinical research on the psychedelic treatment of SUD. Full article

Glaucoma represents a social and economic burden due to both its increasing incidence and the lack of knowledge about its physiopathology and treatment strategies. The main factor hindering progress in glaucoma research is the disease’s heterogeneity, which depends on both genetic and environmental factors. This limitation directly affects glaucoma research, posing obstacles to the elucidation of risk factors, disease mechanisms, and treatment strategies. Therefore, the need emerges to integrate pre-clinical experimental observations from different experimental models to recapitulate different aspects of the disease and achieve a successful translation to clinics. Here, we reviewed the glaucoma models that are currently available for basic and translational research, with a specific focus on models based on rodents. Regarding genetic glaucoma models, we considered the main hallmarks and limitations of DBA/2J, glutamate/aspartate transporter/excitatory amino acid carrier 1, myocilin, connective tissue growth factor, optineurin, purinergic receptor 2Y, caveolin 1, and endothelin-1 mice. Regarding other glaucoma models, we considered rodent models based on intraocular pressure elevation via perturbation of aqueous humor dynamics or on direct degeneration of retinal ganglion cells via physical or chemical damage. Full article

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent aminopeptidase that is found in several places and is thought to be a cytosolic enzyme that helps break down peptides. Recent studies, however, have revealed its extensive therapeutic relevance upon release into circulation, functioning not only as a biomarker for cellular injury but also as an active modulator of cardiovascular homeostasis and critical disease. High levels of circulating DPP3 (cDPP3) have been linked to the causes of cardiogenic shock, septic shock, acute coronary syndromes, heart failure, and serious viral diseases like COVID-19. Its enzymatic breakdown of angiotensin II disrupts vascular tone and myocardial contractility, leading to hemodynamic instability and multi-organ failure. In numerous cohorts, cDPP3 levels reliably correspond with disease severity, acute renal damage, and death, but dynamic trajectories yield superior predictive information relative to single assessments. In addition to risk stratification, translational studies utilizing rodent and porcine models illustrate that antibody-mediated inhibition of cDPP3 with the humanized monoclonal antibody Procizumab reinstates cardiac function, stabilizes renal perfusion, diminishes oxidative stress and inflammation, and enhances survival. First-in-human experiences in patients with refractory septic cardiomyopathy have further emphasized its therapeutic promise. DPP3 is a good example of a biomarker and a mediator in cardiovascular and critical care. Its growing clinical and translational profile makes cDPP3 a strong predictor of bad outcomes and a prospective target for treatment. Ongoing clinical trials using Procizumab will determine if neutralizing cDPP3 can lead to enhanced outcomes in individuals with cardiogenic and septic shock. This review outlines the physiological mechanisms, clinical implications, and emerging therapeutic potential of DPP3 in cardiovascular and critical care. Ongoing trials with Procizumab will clarify whether neutralizing cDPP3 can improve outcomes in patients with cardiogenic and septic shock. Full article

Background/Objectives: The Eustachian tube (ET) is a physiological channel connecting the middle ear with the external atmosphere. The ET plays a role in maintaining the pressure balance of the middle ear, protecting it from pathogen invasion, and cleaning secretions. Eustachian tube dysfunction (ETD) can lead to middle ear diseases in animals. The ET morphological structure are different across species. Therefore, we aim to compare the anatomical and morphological of ET across species. Methods: The combined skull base–nasal approach was used to anatomy ET. Hematoxylin-eosin, luxol fast blue myelin and immunohistochemical Staining were used to observe the morphology of ET. Results: There were significant differences in the size and structure of ET among species: the rodents ET (mouse: 1.152 ± 0.084 mm; rat: 3.738 ± 0.04355 mm) is characterized by cartilage and obvious bubbles; while the miniature pigs ET (32.34 ± 2.157 mm) has a chondroid conical structure similar to that of humans. ET inflammation model was built by intro-tympanic injection of lipopolysaccharide (LPS). NADPH oxidase 2 (NOX2) significantly increased by 38.6% in inflamed mice, causing ET oxidative stress. The expressions of inflammatory factors interleukin-1β (IL-1β) and cyclooxygenase-2 (COX2) increased by 28.4% and 30.8%, resulting in thickening of the ET mucosa and infiltration of inflammatory cells. Conclusions: The combined skull base–nasal approach was an effective method to anatomy ET across species. The morphology of ET varied across species and NOX2 might play an important role in ET inflammation. Full article

Background/Objectives: Acute spinal cord injury (ASCI) often leads to pulmonary complications, yet reliable, non-invasive assessment tools are limited. This study aimed to evaluate the utility of lung ultrasound (LUS) in assessing lung injury following ASCI in a rat model. Methods: Fifty-four female Sprague Dawley rats were randomized into sham (n = 27) or ASCI (n = 27) groups. LUS was performed at 12 h, 48 h, and 1 week post-injury, with lung injury quantified using a modified B-line score (BLS). Pulmonary function was assessed non-invasively, and histopathological evaluation and wet-to-dry (W/D) weight ratios were conducted post-mortem. Correlations between BLS and functional and pathological parameters were analyzed. Results: Histological analysis revealed progressive pulmonary hemorrhage, edema, and inflammatory infiltration peaking at 48 h post-injury, with residual hemorrhage and fibroplasia at 1 week. LUS findings evolved from narrow-based B-lines at 12 h to confluent B-lines with pleural abnormalities by 1 week. ASCI rats showed significant reductions in respiratory frequency, peak inspiratory and expiratory flow, and EF₅₀ at all time points (p < 0.05). Tidal volume and minute volume decreased initially, with partial recovery at 1 week. BLS negatively correlated with all pulmonary function parameters and positively with the histological score and W/D ratio (p < 0.001). Conclusions: LUS reliably detects and tracks lung injury after ASCI, correlating well with physiological and pathological indicators. These findings support its potential as a non-invasive monitoring tool. Future refinement of ultrasound scoring may improve clinical applicability in ASCI-related pulmonary assessment. Full article

Polycystic ovary syndrome (PCOS) represents one of the most prevalent endocrine–metabolic disorder in women of reproductive age, which includes but not restricted to reproductive disruptions, insulin resistance (IR), hyperandrogenism, and chronic low-grade inflammation. Its heterogeneous pathophysiology arises from the interplay of metabolic, endocrine, and immune factors, including dysregulated adipokine secretion, cytokine-mediated inflammation, oxidative stress (OS), and mitochondrial dysfunction. Current pharmacological therapies, such as metformin, clomiphene, and oral contraceptives, often provide partial benefits and are limited by side effects, necessitating the exploration of safer, multi-target strategies. Flavonoids, a structurally diverse class of plant-derived polyphenols, have gained attention as promising therapeutic candidates in PCOS due to their antioxidant, anti-inflammatory, insulin-sensitizing, and hormone-modulating properties. Preclinical studies in rodent PCOS models consistently demonstrate improvements in insulin sensitivity, normalization of ovarian morphology, restoration of ovulation, and reduction in hyperandrogenism. Human clinical studies, though limited in scale and heterogeneity, report favorable effects of flavonoids such as quercetin, isoflavones, and catechins on glucose metabolism, adipokine balance, inflammatory markers, and reproductive functions. This evidence-based study critically synthesizes mechanistic insights into how flavonoids modulate insulin signaling, adipokine–cytokine crosstalk, OS, and androgen excess, while highlighting translational evidence and emerging delivery systems aimed at overcoming bioavailability barriers. Collectively, flavonoids represent a promising class of nutraceuticals and adjuncts to conventional therapies, offering an integrative strategy for the management of PCOS. Full article

Human early embryogenesis remains unexplored due to limited access to human embryos for research purposes. Meanwhile, the number of natural early pregnancy terminations remains significant, and solving the problem requires a deep understanding of the developmental mechanisms of this period. Although assisted reproductive technologies (ART) utilize up-to-date approaches in culturing human embryos in vitro, characterization of the embryos is still based on visual evaluation and subjective assessment. In addition, embryonic development in animal models, such as rodents and cattle, correlates poorly with human embryonic development. Synthetic embryology presents a promising new approach for studying human embryos involving the creation of embryos without the use of haploid germ cells. Instead, diploid pluripotent stem cells (PSCs) in a given state of pluripotency, which is maintained under conditions of induction and/or inhibition of certain signaling pathways, are used. Synthetic embryo systems (SES) may become a successful alternative model for studying fundamental processes of human early preimplantation embryogenesis, exploring new methods of objective embryo qualification, and personalized approaches in ART. However, the question of whether SES models can be considered as full-fledged mimics of the embryo remains open. This review examines human blastocyst-like structures known as blastoids. It discusses their use as models, as well as the parameters that need to be modified to more accurately simulate the human blastocyst. Full article

Silymarin, a flavonolignan-rich extract of Silybum marianum, is widely recognized for its hepatoprotective potential. While rodent studies predominate, pigs (Sus scrofa) offer a more translationally relevant model due to their hepatic architecture, bile acid composition, and transporter expression, which closely resemble those of humans. This narrative review synthesises current evidence on the chemistry, pharmacokinetics, biodistribution, and hepatoprotective activity of silymarin in porcine models. Available studies demonstrate that when adequate intrahepatic exposure is achieved, particularly through optimised formulations, silymarin can attenuate oxidative stress, suppress inflammatory signalling, stabilise mitochondria, and modulate fibrogenic pathways. Protective effects have been reported across diverse porcine injury paradigms, including toxin-induced necrosis, ethanol- and diet-associated steatosis, metabolic dysfunction, ischemia–reperfusion injury, and partial hepatectomy. However, the evidence base remains limited, with few long-term studies addressing fibrosis or regeneration, and methodological heterogeneity complicates the comparison of data across studies. Current knowledge gaps in silymarin research include inconsistent chemotype characterization among plant sources, limited reporting of unbound pharmacokinetic parameters, and variability in histological scoring criteria across studies, which collectively hinder cross-study comparability and mechanistic interpretation. Advances in analytical chemistry, transporter biology, and formulation design are beginning to refine the interpretation of exposure–response relationships. Advances in analytical chemistry, transporter biology, and formulation design are beginning to refine the interpretation of exposure–response relationships. In parallel, emerging computational approaches, including machine-learning-assisted chemotype fingerprinting, automated histology scoring, and Bayesian exposure modeling, are being explored as supportive tools to enhance reproducibility and translational relevance; however, these frameworks remain exploratory and require empirical validation, particularly in modeling enterohepatic recirculation. Collectively, current porcine evidence supports silymarin as a context-dependent yet credible hepatoprotective agent, highlighting priorities for future research to better define its therapeutic potential in clinical nutrition and veterinary practice. Full article

This study, for the first time, explored the preventive effects of a novel pectic polysaccharide from Premna microphylla Turcz leaves (PMTL) on experimental constipation. Diphenoxylate-induced constipation model (CM) rats were fed a standard rodent chow supplemented with or without PMTL (5%, 10%, and 20%) for 6 weeks. Supplementation of PMTL was shown to accelerate intestinal peristalsis, increase fecal water content, improve intestinal morphology, and suppress gut inflammation by facilitating the secretion of excitatory neurotransmitters (MTL, ACH, and SP) and decreasing the secretion of inhibitory neurotransexcitatory neurotransmittersmitters (SS and NO) in the CM rats. PMTL also reduced the expressions of the colonic aquaporins AQP3 and AQP4 in the CM rats to normalize the colonic water transport system. 16S rRNA gene sequencing revealed that PMTL relieved the gut microbiota disorder of the CM rats and promoted the proliferation of several beneficial bacteria, resulting in an increase in fecal short-chain fatty acids. These findings demonstrate that dietary PMTL consumption can ameliorate the development of constipation and PMTL can be considered as a great promising dietary supplement for alleviating constipation. Full article

Background/Objectives: Obesity and insulin resistance are increasing globally. Emerging evidence suggests that not only the quantity but also the source of dietary protein may improve metabolic health outcomes. This study evaluated the effects of high-protein diets (HPDs) containing animal or plant protein sources on obesity and obesity-related metabolic markers in a rodent model of genetic obesity. Methods: Obese male fa/fa Zucker rats were fed HPDs (35% of energy) containing protein from different sources (casein, egg white protein, soy + pea protein, mixture of egg white + soy + pea proteins) or a normal protein diet (15% of energy) containing casein over 8 weeks. Oral glucose tolerance, weight gain, fat depots, serum biochemistry, adipocyte and pancreatic islet size, and markers of adipose tissue lipolysis, insulin signaling, and immune cells were assessed. Results: Consumption of HPDs containing egg white protein, soy + pea, or their mixture resulted in smaller adipocytes compared to the casein diets, despite greater weight gain, elevated serum NEFA, and more total visceral fat in the HPD plant group. These HPD groups had reduced fasting insulin and no compensatory pancreatic islet enlargement. CD3 levels were elevated in adipose tissue without changes in F4/80, and no differences were observed in ATGL, HSL, Akt or AS160. Conclusions: The source of dietary protein in HPDs significantly influences metabolic outcomes in obese rats, impacting adipocyte and pancreatic islet size, insulinemia, and immune cell markers in adipose tissue. These findings support the potential of employing targeted dietary protein interventions for managing obesity-related metabolic disorders. Full article

Parkinson’s disease (PD) is a progressive neurological disorder marked by the gradual loss of dopamine-producing neurons in the brain. This neuronal degradation causes motor symptoms such as tremors, stiffness, and slowness of movement. Despite decades of research, current treatments remain limited to symptom management, highlighting the urgent need for deeper insights into PD mechanisms and new therapeutic approaches. Among model organisms, zebrafish (Danio rerio) have emerged as a valuable tool for PD research due to the possibility of genetic manipulation. Zebrafish can be engineered to carry human PD-associated mutations, such as those in α-synuclein, LRRK2, and Parkin, enabling researchers to study the molecular and cellular basis of the disease. Additionally, exposure to neurotoxins like MPTP and paraquat allows scientists to replicate PD-like symptoms in zebrafish, supporting drug screening and behavioural analysis. This review summarises the key advantages and limitations of zebrafish as a model for PD, compares it with rodent models, and discusses recent advances and future directions that may improve translational outcomes in PD therapy and personalised medicine. Full article

Early postnatal stress is a critical factor in metabolic programming. Maternal separation (MS) in rodents, a widely validated model, has been linked to pancreatic alterations. This systematic review and meta-analysis aimed to evaluate the effect of MS on pancreatic morphology and function in rodents. This review followed the PRISMA and SYRCLE guidelines, with a protocol registered in PROSPERO (CRD420251004633). Experimental studies in rodents comparing MS with standard rearing, which reported pancreatic morphofunctional and metabolic parameters, were included. A comprehensive search was performed in the Web of Science, Embase, Medline, Scopus, BIREME-BVS, and SciELO databases until March 2025, without language restrictions. Extracted data included glucose, insulin, insulin sensitivity indices (QUICKI, HOMA), and glucose tolerance tests (GTTs). Meta-analyses were performed using random-effects models, and subgroup analyses were applied to explore sources of heterogeneity. Of 491 references, 25 studies were included in the meta-analysis, which showed that MS was associated with significantly higher glucose levels (SMD −0.41; 95% CI: −0.71 to −0.11) and worse GTT response (SMD −1.02; 95% CI: −1.23 to −0.82). Furthermore, the QUICKI index was significantly decreased (SMD 0.75; 95% CI: 0.14 to 1.35), indicating insulin resistance. MS in rodents induces pancreatic alterations associated with insulin resistance and glucose intolerance, suggesting that early stress could program long-term metabolic vulnerability. Full article