Search Results (259)

Background/Objectives: Metabolic syndrome (MetS) is a multifactorial condition characterized by abdominal obesity, dyslipidemia, insulin resistance, hypertension, and chronic inflammation. As its global prevalence rises, there is increasing interest in natural, multi-targeted approaches to manage MetS. Curcuma longa Linn. (turmeric), especially its active compound curcumin, has shown therapeutic promise in preclinical studies. This systematic review and meta-analysis evaluated the effects of Curcuma longa and its derivatives on MetS-related outcomes in rodent models. Methods: A comprehensive search was conducted across six databases (PubMed, Scopus, AMED, LILACS, MDPI, and Google Scholar), yielding 47 eligible in vivo studies. Data were extracted on key metabolic, inflammatory, and oxidative stress markers and analyzed using random-effects models. Results were presented as mean differences (MD) with 95% confidence intervals (CI). Results: Meta-analysis showed that curcumin significantly reduced body weight (rats: MD = −42.10; mice: MD = −2.91), blood glucose (rats: MD = −55.59; mice: MD = −28.69), triglycerides (rats: MD = −70.17; mice: MD = −24.57), total cholesterol (rats: MD = −35.77; mice: MD = −52.61), and LDL cholesterol (rats: MD = −69.34; mice: MD = −42.93). HDL cholesterol increased significantly in rats but not in mice. Inflammatory cytokines were markedly reduced, while oxidative stress improved via decreased malondialdehyde (MDA) and elevated superoxide dismutase (SOD) and catalase (CAT) levels. Heterogeneity was moderate to high, primarily due to variations in curcumin dosage (ranging from 10 to 500 mg/kg) and treatment duration (2 to 16 weeks) across studies. Conclusions: This preclinical evidence supports Curcuma longa as a promising functional food component for preventing and managing MetS. Its multi-faceted effects warrant further clinical studies to validate its translational potential. Full article

Background: A high-fat diet has been shown to have an impact on metabolism resulting in changes in arterial wall thickness and degeneration of surviving neural cells of the hippocampus. The present review focuses on the various animal models used to induce high-fat diet conditions for studying obesity-induced atherosclerosis, along with the associated changes observed in surviving neural cells of the hippocampus. It also highlights the limitations of rodent models and discusses their implications for human research. Methods: The sources for the literature search were Scopus, PubMed, Medline and Google Scholar. Both animal and human studies published were considered and are cited. Results: High-fat-diet-induced vascular changes, mainly in the tunica media, has been shown to have more impact on medium-sized arteries and on the Cornu Ammonis three subregions and outer dentatae gyrus of the hippocampus. Conclusions: High-fat-diet-induced neurovascular changes have been studied radically in animal models, and more supporting studies representing preclinical research should be advanced to humans. Full article

Background: The reproducibility of research findings continues to be a challenge in many fields, including neurosciences. It is now required that biological variables such as sex and age be considered in preclinical and clinical research. Rodents are frequently used to model clinical conditions; however, litter information is rarely presented. Some studies utilize entire litters with each animal treated as an independent sample, while others equally assign animals from each litter to different groups/treatments, and others use averaged data. These methods can yield different results. Methods: This study used different analysis methods to evaluate embryo and placenta weights from E17.5 acid-sensing ion channel 2a (ASIC2a) mice with or without seizure exposure. Results: When each embryo was treated as an individual sample, fetal and placental weight significantly differed following seizures in the ASIC2a heterozygous (+/−) and homozygous (−/−) groups. Differences in fetal weight were driven by females in the ASIC2a+/− group and both sexes in the ASIC2a−/− group. These differences were lost when an average per sex/genotype/litter was used. There was no difference in placental weight when treated individually; however, female ASIC2a−/− placentas weighed less following seizures. This difference was lost with averaged data. ASIC2a−/− fetuses from −/− dams had reduced weights post-seizure exposure. Position on the uterine horn influenced embryo and placental weight. Conclusions: Our results indicate that using full litters analyzed as individual data points should be avoided, as it can lead to Type I errors. Furthermore, studies should account for litter effects and be transparent in their methods and results. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

Dementia is marked by progressive cognitive decline linked to oxidative stress, neuroinflammation, and synaptic dysfunction. Curcumin, a natural compound from Curcuma longa, has shown promising neuroprotective effects. This systematic review analyzed 29 preclinical studies using rodent models of dementia induced by chemical, genetic, or dietary methods. The review focused on curcumin’s effects on oxidative stress, inflammation, and cognitive outcomes. All studies assessing malondialdehyde (MDA) reported significant reductions, indicating reduced oxidative stress. Superoxide dismutase (SOD) activity increased in all measured cases, while glutathione (GSH) levels rose in about one-third of studies. A literature search was comprehensively conducted using PubMed, Scopus, AMED, and LILACS databases through April 2024. Curcumin also demonstrated anti-inflammatory properties, with over 80% of studies showing reduced levels of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. Additionally, 40% of studies noted increases in anti-inflammatory markers like IL-4 and IGF-1. Cognitive performance improved in around 80% of studies, especially in spatial learning and memory. Some studies also reported behavioral improvements, including reduced anxiety and enhanced locomotion. Curcumin demonstrated potent antioxidative, anti-inflammatory, and cognitive-enhancing effects across diverse dementia models. Its ability to modulate multiple pathological pathways highlights its potential as a bioactive compound for mitigating cognitive decline associated with neurodegenerative diseases. However, variability in study design and curcumin formulations suggests the need for standardized protocols and further high-quality research to facilitate clinical translation. Full article

Retinal ischemia is implicated in ocular diseases involving aberrant neovessel proliferation that characterizes proliferative retinopathies. Their therapy still remains confined to the intravitreal administration of anti-vascular endothelial growth factor (VEGF) medication, which is limited by side effects and progressive reduction in efficacy. Mimicking neovascular diseases in rodents, although of great help for translating fundamental mechanistic findings and assessing therapeutic potential in humans, is limited by the rodent’s short life span, which prevents retinal vessel proliferation over time. However, the oxygen-induced retinopathy (OIR) model, which mimics retinopathy of prematurity, seems to meet some criteria that are common to proliferative retinopathies. The present review provides insight into preclinical models and their suitability to mimic proliferative retinopathies. Further considerations will be applied to emerging approaches and advanced methodologies for the management of proliferative retinopathies, leading to the identification of new therapeutic targets, including our contribution in the field. Major emphasis is given to the possibility of using systemic therapies either alone or in combination with intravitreal anti-VEGF administration to maximize clinical benefits by combining drugs with different modes of action. This review is concluded by an in-depth discussion on future advancements and a critical view of preclinical finding translatability. Despite the major effort of preclinical and clinical research to develop novel therapies, the blockade of VEGF activity still remains the only treatment for proliferative retinopathies for more than twenty years since its first therapeutic application. Full article

Background/Objectives: Substance use disorders, particularly opioid addiction, continue to pose a major global health and toxicological challenge. Morphine dependence represents a significant problem in both clinical practice and preclinical research, particularly in modeling the pharmacodynamics of withdrawal. Rodent models remain indispensable for investigating the neurotoxicological effects of chronic opioid exposure and withdrawal. However, conventional behavioral assessments rely on manual observation, limiting objectivity, reproducibility, and scalability—critical constraints in modern drug toxicity evaluation. This study introduces MWB_Analyzer, an automated and high-throughput system designed to quantitatively and objectively assess morphine withdrawal behaviors in rats. The goal is to enhance toxicological assessments of CNS-active substances through robust, scalable behavioral phenotyping. Methods: MWB_Analyzer integrates optimized multi-angle video capture, real-time signal processing, and machine learning-driven behavioral classification. An improved YOLO-based architecture was developed for the accurate detection and categorization of withdrawal-associated behaviors in video frames, while a parallel pipeline processed audio signals. The system incorporates behavior-specific duration thresholds to isolate pharmacologically and toxicologically relevant behavioral events. Experimental animals were assigned to high-dose, low-dose, and control groups. Withdrawal was induced and monitored under standardized toxicological protocols. Results: MWB_Analyzer achieved over 95% reduction in redundant frame processing, markedly improving computational efficiency. It demonstrated high classification accuracy: >94% for video-based behaviors (93% on edge devices) and >92% for audio-based events. The use of behavioral thresholds enabled sensitive differentiation between dosage groups, revealing clear dose–response relationships and supporting its application in neuropharmacological and neurotoxicological profiling. Conclusions: MWB_Analyzer offers a robust, reproducible, and objective platform for the automated evaluation of opioid withdrawal syndromes in rodent models. It enhances throughput, precision, and standardization in addiction research. Importantly, this tool supports toxicological investigations of CNS drug effects, preclinical pharmacokinetic and pharmacodynamic evaluations, drug safety profiling, and regulatory assessment of novel opioid and CNS-active therapeutics. Full article

Diabetic neuropathy (DN) remains a major clinical burden, characterized by progressive sensory dysfunction, pain, and impaired quality of life. Despite the available symptomatic treatments, there is a pressing need for disease-modifying therapies. In recent years, preclinical research has highlighted the potential of repurposed pharmacological agents, originally developed for other indications, to target key mechanisms of DN. This narrative review examines the main pathophysiological pathways involved in DN, including metabolic imbalance, oxidative stress, neuroinflammation, ion channel dysfunction, and mitochondrial impairment. A wide array of repurposed drugs—including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)—have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN. Full article

Schwann cells (SCs) play a crucial role in peripheral nerve repair by supporting axonal regeneration and remyelination. While extensive research has been conducted using rodent SCs, increasing attention is being directed toward human SCs due to species-specific differences in phenotypical and functional properties, and accessibility of human SCs derived from diverse sources. A major challenge in translating SC-based therapies for nerve repair lies in the inability to replicate human SC myelination in vitro, posing a significant obstacle to drug discovery and preclinical research. In this study, we compared the myelination capacity of human, rodent, and porcine SCs in various co-culture conditions, including species-matched and cross-species neuronal environments in a serum-free medium. Our results confirmed that rodent and porcine SCs readily myelinate neurites under standard culture conditions after treatment with ascorbic acid for two weeks, whereas human SCs, at least within the four-week observation period, failed to show myelin staining in all co-cultures. Furthermore, we investigated whether cell culture manipulation impairs human SC myelination by transplanting freshly harvested and predegenerated human nerve segments into NOD-SCID mice for four weeks. Despite supporting host axonal regeneration into the grafts, human SCs exhibited very limited myelination, suggesting an intrinsic species-specific restriction rather than a cell culture-induced defect. These observations suggest fundamental differences between human and rodent SCs and highlight the need for human-specific models and protocols to advance our understanding of SC myelination. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor impairments resulting from dopaminergic neuron degeneration in the substantia nigra. However, PD is increasingly recognized as a multisystem disorder, where non-motor symptoms such as cognitive impairment, mood disturbances, sleep disorders, and autonomic dysfunction significantly impact patients’ quality of life. These non-motor symptoms often exhibit poor responsiveness to traditional dopaminergic therapies, underscoring a critical gap in current treatment strategies. Our systematic review investigates established methods of PD induction in rodent models and evaluates the methodologies used to assess non-motor symptoms. The review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Cochrane handbook. Thirty-two studies from 832 articles were included. The studies were characterized by MPTP, 6-OHDA, and rotenone. Our results indicate that there was considerable heterogeneity in behavioral and motor tests, which poses challenges for data comparability and highlights the lack of consensus regarding the most appropriate modeling strategies for specific PD-related behavioral outcomes. All three models demonstrated behavioral changes consistent with dopaminergic impairment when compared to control groups. MPTP-induced models showed significant non-motor deficits across various tests, except in social recognition and novelty-suppressed feeding. The 6-OHDA model consistently produced non-motor impairments, supporting its utility in replicating PD-like neurotoxicity. Rotenone-treated animals exhibited reduced social interaction, decreased sucrose preference, and increased immobility in behavioral assays, further supporting its validity. Overall, our findings indicate that these neurotoxin-based models are effective in reproducing non-motor symptoms of PD, though methodological heterogeneity highlights the need for greater standardization in future preclinical research. Full article

Animal models are indispensable in biomedical research, offering critical insights into disease mechanisms and therapeutic strategies. However, existing models often inadequately replicate human pathophysiology, leading to discrepancies between preclinical and clinical outcomes. Despite their contributions, many models exhibit significant limitations, especially concerning cancer and infectious diseases. Inaccurate modeling of human biological responses can result in failed clinical trials, escalated research costs, and delays in developing effective treatments. The golden hamster (Mesocricetus auratus) has emerged as a viable model, particularly in cancer and infectious disease research. Sharing physiological and immunological profiles similar to humans, the golden hamster offers distinct advantages over other rodent models, such as mice and rats. This review explores the benefits of using golden hamsters in cancer research, highlighting their contributions to scientific advancements while also addressing the limitations due to incomplete immunological and molecular knowledge about this species. Full article

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1–3% of the population globally. Owing to its multifactorial origin, complex genetics, and heterogeneity in clinical phenotypes, it is difficult to faithfully model ASD. In essence, ASD is an umbrella term for a group of individually rare disorders, each risk gene accounting for <1% of cases, threaded by a set of overlapping behavioral or molecular phenotypes. Validated behavioral tests are considered a gold standard for ASD diagnosis, and several animal models (rodents, pigs, and non-human primates) have traditionally been used to study its molecular basis. These models recapitulate the human phenotype to a varying degree and have been indispensable to preclinical research, but they cannot be used to study human-specific features such as protracted neuronal maturation and cell-intrinsic attributes, posing serious limitations to translatability. Human stem cell-based models, both as monolayer 2D cultures and 3D organoids and assembloids, can circumvent these limitations. Generated from a patient’s own reprogrammed cells, these can be used for testing therapeutic interventions that are more condition and patient relevant, targeting developmental windows where the intervention would be most effective. We discuss some of these advancements by comparing traditional and recent models of ASD. Full article

Metabolic syndrome (MetS) is a complex condition defined by central obesity, insulin resistance, dyslipidemia, and systemic inflammation. Kefir, a fermented beverage rich in probiotics and beneficial compounds, has emerged as a functional food that may offer metabolic advantages. Nevertheless, preclinical results have been variable. This systematic review and meta-analysis aimed to assess the influence of kefir and its derived compositions on parameters associated with MetS, inflammation, and oxidative stress in rodent studies. A comprehensive literature search was conducted in PubMed, Scopus, AMED, and LILACS through June 2024. Eligible studies involving kefir interventions in rodent MetS models were included. Data extraction followed PRISMA guidelines, with the risk of bias assessed using the CAMARADES and SYRCLE tools. Meta-analyses were performed with a random effects model. Thirty-eight studies involving 1462 rodents (mice and rats) were analyzed. Kefir significantly reduced body weight gain in both mice (MD = –3.33; 95% CI: –4.89 to –1.77) and rats (MD = –41.53; 95% CI: –54.33 to –28.72). In mice, triglycerides and LDL-C levels decreased significantly; in rats, kefir lowered total cholesterol and triglycerides. Insulin levels were reduced (MD = –0.69; 95% CI: –1.16 to –0.22), suggesting improved insulin sensitivity. Several studies also reported reductions in TNF-α, IL-1β, and IL-6. Despite promising results, the high heterogeneity and methodological variability emphasize the need for standardized preclinical protocols and clinical validation. These findings support the role of kefir as a functional food for metabolic health promotion. Full article

Alkylating agents, historically employed as chemical warfare agents and currently used as chemotherapeutic drugs, are known to induce significant pulmonary toxicity. Current clinical interventions often fail to fully prevent or reverse these pathological changes, highlighting the urgent need for safe, broad-spectrum therapeutic agents that are effective across diverse exposure scenarios. Melatonin has emerged as a promising protective agent due to its antioxidant, anti-inflammatory, and immunomodulatory properties, along with a well-established safety profile. This systematic review evaluates the potential of melatonin in mitigating vesicant-induced pulmonary damage, synthesizing and critically analyzing preclinical evidence in accordance with the PRISMA guidelines. Three in vivo rodent studies met the inclusion criteria and were analyzed. In all cases, melatonin demonstrated protective effects against alkylating agents such as mechlorethamine (HN2) and cyclophosphamide (CP). These effects were dose-dependent and observed across various animal models, administration protocols, and dosages (ranging from 2.5 to 100 mg/kg), highlighting the importance of context-specific considerations. The human equivalent doses (HEDs) ranged from 12 to 973 mg per day, suggesting that the effective doses may exceed those typically used in clinical trials for other conditions. Melatonin’s pleiotropic mechanisms, including a reduction in oxidative stress, the modulation of inflammatory pathways, and support for tissue repair, reinforce its therapeutic potential in both prophylactic and treatment settings for alkylating agent exposure. Nonetheless, this review underscores the critical need for further randomized clinical trials to establish the optimal dosing strategies, refine treatment protocols, and fully elucidate melatonin’s role in managing alkylating-agent-induced pulmonary toxicity. Full article