Search Results (992)

Background: Alzheimer’s disease (AD) features progressive cognitive decline and amyloid-beta (Aβ) accumulation. Insulin resistance in type 2 diabetes mellitus (T2DM) is increasingly recognised as a mechanistic link between metabolic dysfunction and neurodegeneration. Although sodium–glucose cotransporter-2 inhibitors (SGLT2is) have established glycaemic and cardioprotective benefits, their neuroprotective role remains less well defined. Objectives: This systematic review examines animal studies on the neuroprotective effects of SGLT2i in T2DM and AD models. Methods: A literature search was conducted across the Web of Science, Scopus, and PubMed databases, covering January 2014 to November 2024. Heterogeneity was assessed with I², and data were pooled using fixed-effects models, reported as standardised mean differences with 95% confidence intervals. We focus on spatial memory performance as measured by the Morris Water Maze (MWM) test, including escape latency and time spent in the target quadrant, as the primary endpoints. The secondary endpoints of Aβ accumulation, oxidative stress, and inflammatory markers were also analysed and summarised. Results: Twelve studies met the inclusion criteria for this review. A meta-analysis showed that SGLT2i treatment significantly improved spatial memory by reducing the escape latency in both T2DM and AD models. In addition, SGLT2i yielded a significant improvement in spatial memory, as indicated by an increased target quadrant time for both T2DM and AD. Furthermore, SGLT2i reduced Aβ accumulation in the hippocampus and cortex, which met the secondary endpoint; the treatment also lessened oxidative stress and inflammatory markers in animal brains. Conclusions: Our findings indicate that SGLT2is confer consistent neuroprotective benefits in experimental T2DM and AD models. Full article

Background: Oral insulin improves compliance and convenience in patients with diabetes who require regular needle injections. However, the clinical application of oral insulin preparations has been limited due to instability and inefficient permeation through the gastrointestinal tract. In this study, a novel cationic polysaccharide nanodrug delivery platform was designed for efficient oral insulin delivery. Methods: The innovative thiolated trimethyl chitosan-grafted β-cyclodextrin (NCT) was synthesized by utilizing N-trimethyl chitosan (TMC) as the polymer backbone. This involved modifying TMC with thiol group-containing N-acetylcysteine and carboxymethyl-β-cyclodextrin that possesses hydrophobic cavities via an amide condensation reaction. Subsequently, this polymer was employed to construct the NCT nanoparticle system using an ionic cross-linking method. The physicochemical properties of the NCT nanoparticles were systematically analyzed, and their therapeutic efficacy was comprehensively evaluated in streptozotocin (STZ)-induced animal models. Results: The NCT nanoparticles demonstrated mucus adhesion, permeability, and pH sensitivity, which facilitated a slow and controlled release within the gastrointestinal microenvironment due to both ionic electrostatic interactions and disulfide bonding interactions. The experiments revealed in vivo that insulin/NCT nanoparticles extended the retention time of insulin in the small intestine. Blood glucose levels decreased to approximately 39% of the initial level at 5 h post-administration while exhibiting smooth hypoglycemic efficacy. Simultaneously, insulin bioavailability increased to 12.58%. Conclusions: The NCT nanoparticles effectively protect insulin from degradation in the gastrointestinal microenvironment while overcoming intestinal barriers, thereby providing a promising approach to oral biomolecule delivery. Full article

Background: Depression and diabetic neuropathy (DN) commonly complicate diabetes and impair glycemic control and quality of life. Ketamine and its S-enantiomer, esketamine, provide rapid antidepressant and analgesic effects, yet diabetes-related pathophysiology and co-therapies may modify exposure, response, and safety. Methods: We conducted a scoping review following PRISMA-ScR. MEDLINE/PubMed, CINAHL, and APA PsycInfo were searched (January 2020–31 May 2025). Eligible human and animal studies evaluated ketamine, esketamine, or norketamine in the context of diabetes (type 1 [T1DM], type 2 [T2DM], gestational [GDM]), or DN, and reported psychiatric, analgesic, metabolic, or mechanistic outcomes. Two reviewers independently screened and charted data; no formal risk-of-bias assessment was performed. Results: Eleven studies met inclusion criteria: four human case reports/series (three T1DM, one T2DM), one randomized trial in GDM, two narrative reviews of topical ketamine for DN, and four preclinical rodent studies using streptozotocin- or diet-induced diabetes models. Short-term improvements were reported for treatment-resistant depression and neuropathic pain, including opioid-sparing postoperative analgesia in GDM. Glycemic effects varied across settings, with both hyperglycemia and hypoglycemia reported. Mechanistic and clinical drug–drug and drug-disease interactions (particularly involving metformin, GLP-1 receptor agonists, SGLT2 inhibitors, and CYP3A4/CYP2B6 modulators) remain insufficiently studied. We outline a forward-looking population pharmacokinetic (popPK) and pharmacokinetic-pharmacodynamic (PK-PD) research agenda, including priority covariates (eGFR, hepatic function, inflammatory status, HbA1c, genotype, co-medications) and sparse-sampling windows for future model-informed precision dosing. Conclusions: Current evidence supports cautious, selective use of ketamine for refractory depression and DN within multidisciplinary diabetes care. Purpose-built popPK/PK-PD studies in both human and preclinical diabetic models cohorts are needed to quantify variability, define drug–disease–drug interactions and glycemic risk, and inform individualized dosing strategies. Full article

Diabetes mellitus (DM) is a chronic disease characterised by chronic hyperglycaemia due to a defect in the production of or cell insensitivity to insulin. If left untreated, it might result in severe side effects such retinal, nephropathy, neuropathy, and cardiovascular disease. Extensive research has been made to develop more effective and less expensive alternatives to existing treatment regimes. This review aims to evaluate research done thus far to test the effect of Saccharomyces boulardii (S. boulardii or Sb) in treating DM and its complications. Searches were conducted using Scopus, Web of Science, PubMed and Google Scholar on 26 July 2025. Overall, 227 articles were identified, and 5 fulfilled the inclusion criteria. Results extracted were from two models of diabetes (type 1 and 2) and two strains of Sb. In type 1 diabetes models, a significant reduction in glycaemia was observed, while in type 2 diabetes models, a non-significant effect was noted, depending on the strain used. Furthermore, an improvement in cardiac function was observed through reduced heart rate variability, a decrease in blood pressure, an increase in C-peptide and hepatic glycogen stores, enhanced liver healing, a nephroprotective effect, as well as a reduction in oxidative stress, blood triglyceride levels, and the inflammatory response. Administration of Sb induced positive modulation of the intestinal microbiota, with a decrease in pathobionts in the stools. Overall, the few studies evaluated indicate that the use of Sb appears to be a promising approach to improve the management of diabetes and its associated metabolic and related complications. The protocol of this review is registered in PROSPERO under ID CRD420251012919. Full article

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin hormone identified, best known for promoting glucose-stimulated insulin secretion. Increasing evidence has expanded its physiological relevance beyond glucose metabolism, revealing a significant role for GIP in the gut–bone axis. In vitro studies demonstrate that GIP inhibits osteoclast differentiation and activity while promoting osteoblastic bone formation. Findings from genetic animal models and human variant analyses further support the essential role of endogenous GIP signaling in maintaining bone mass and quality. Exogenous administration of GIP suppresses the bone-resorption marker C-terminal telopeptide of type I collagen (CTX) and increases the bone-formation marker procollagen type I N-terminal propeptide (P1NP) in healthy individuals, reflecting an acute shift toward reduced bone resorption and enhanced bone formation. Moreover, GIP confers protection against bone deterioration in multiple pathological conditions, including postmenopausal osteoporosis, inflammatory bone loss, obesity, and diabetes, etc., suggesting therapeutic potential beyond physiological contexts. Recent evidence also shows that GIP attenuates orthodontic tooth movement by limiting mechanically induced osteoclast activity, highlighting its broader skeletal actions. In this review, we summarize recent advances regarding the role of GIP in bone metabolism, integrating evidence from cellular studies, animal models and human investigations, and discuss future directions for GIP-based interventions. Full article

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have revolutionized the management of type 2 diabetes mellitus, heart failure, and chronic kidney disease (CKD), providing cardiorenal and metabolic benefits that extend beyond glycemic control. While their clinical efficacy is well established, the underlying molecular mechanisms remain only partially understood. This review focuses on current knowledge of SGLT2 expression and regulation in health and metabolic diseases, as well as transcriptional and epigenetic consequences of pharmacological SGLT2 inhibition. Human and experimental studies demonstrate that SGLT2 expression is confined to proximal tubular cells and regulated by insulin, the renin–angiotensin–aldosterone system, the sympathetic nervous system, oxidative stress, and transcriptional and epigenetic pathways. SGLT2 expression follows a biphasic pattern in metabolic disorder-associated CKD: upregulation in early phases and reduction in advanced stages. Evidence from animal models and single-cell transcriptomic studies indicates that SGLT2is normalize metabolic and inflammatory gene networks. To our knowledge, a recent single-cell RNA sequencing study provides the only currently available human dataset linking SGLT2i therapy with tubular metabolic rewiring and suppression of the energy-sensitive mechanistic target of rapamycin complex 1. Collectively, these findings support a model in which SGLT2 inhibition mitigates metabolic stress by restoring energy homeostasis across multiple nephron segments. Full article

Type 2 diabetes mellitus (T2DM) is a highly prevalent disease characterized by chronic hyperglycemia, commonly associated with intake of a high-calorie diet (HCD). Although numerous T2DM murine models have been developed using C57BL/6 mice, BALB/c mice typically fail to develop the disease under the same conditions. We hypothesized that diets optimized for C57BL/6 mice may be insufficient to induce T2DM in BALB/c mice. Female BALB/c and C57BL/6 mice (n = 48 each) were fed either a specific high-calorie diet (HCD) or a standard diet (SD) for ten weeks. BALB/c mice fed a specific HCD exhibited developed persistent hyperglycemia (112.6 mg/dL ± 3.4) from week 1 through week 10, while SD-fed controls maintained normal glucose levels (84.2 mg/dL ± 2.8). HCD-fed BALB/c mice showed elevated serum insulin (39.09 pg/dL ± 25.94), triglycerides (290.8 mg/dL ± 139.5), HOMA index (7.68 ± 1.49) and high post-challenge glucose along with visceral adiposity, hepatic steatosis, and pancreatic alterations. SD-fed BALB/c mice showed no such changes. Similar findings were observed in C57BL/6 mice, used as a positive disease-control group. This model demonstrates that a properly formulated HCD can induce T2DM in BALB/c mice, enabling the study of genes and molecules associated with diabetes susceptibility without requiring genetic or chemical manipulation. Full article

Overactivation of the renin–angiotensin–aldosterone system (RAAS) promotes haemodynamic overload, inflammation, and fibrosis in the heart and kidneys. Recently, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone therapy in cardiorenal protection. Emerging data indicate that adding SGLT2 inhibitors to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or angiotensin receptor–neprilysin inhibitors confers additional cardiorenal protection, yet their mechanistic basis and optimal clinical use in cardiovascular (CV) disease remain unclear. This review will integrate pre-clinical and clinical evidence on dual RAAS/SGLT2 modulation in CV disease, providing mechanistic insight into dual therapy. The review will finally outline priorities for future translational and outcome studies. Clinically, adding SGLT2 inhibitors to RAAS-based therapy reduces heart failure hospitalizations and slows kidney disease progression without new safety liabilities in type 2 diabetes, heart failure, and chronic kidney disease. Mechanistically, SGLT2 inhibition restores tubuloglomerular feedback and constricts the afferent arteriole; RAAS blockade dilates the efferent arteriole, and together, they lower intraglomerular pressure. Both classes also reduce oxidative stress, inflammatory signalling, and pro-fibrotic pathways, with SGLT2 inhibitors in several settings shifting RAAS balance toward the protective ACE2/angiotensin-(1–7)/Mas receptor axis. Key gaps include the scarcity of adequately powered trials designed to test combination therapy versus either component alone, limited evidence on timing and sequencing, incomplete characterization in high-risk groups, and mechanistic insight limited by study design in animal and cell models. Collectively, current data support layering SGLT2 inhibitors onto RAAS-based therapy, while definitive evidence from dedicated clinical trials is awaited. Full article

Interspecies variability in diabetes mellitus (DM) represents a critical challenge for translational medicine, as metabolic pathways, pancreatic architecture, and therapeutic responses differ substantially across animal models. This systematic review, conducted according to PRISMA 2020 guidelines, synthesized evidence from 86 eligible studies published between 2001 and 2025. Comparative data from rodents, dogs, cats, pigs, non-human primates, and humans were analyzed to identify species-specific patterns in insulin secretion, insulin resistance (IR), β-cell dysfunction, microbiota–metabolism interactions, and susceptibility to diabetic complications. Results indicate that spontaneous diabetes in dogs closely mirrors human type 1 diabetes (T1DM), whereas feline obesity-associated diabetes reflects key features of human type 2 diabetes (T2DM). Rodent models remain essential for mechanistic and genetic studies but show limited chronicity and lower predictive fidelity for long-term outcomes. Non-human primates exhibit the highest physiological similarity to humans, especially regarding β-cell structure and incretin response, supporting their role in advanced translational studies. Major limitations included methodological heterogeneity and inconsistent molecular reporting. Integrating spontaneous models with standardized protocols and multi-omics approaches enhances translational relevance and supports more accurate model selection in diabetes research. Full article

Background: Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful analytical tool in metabolomics, but it is often hindered by the high cost and technical complexity of the machines, limiting its clinical and point-of-care applications. Recent advances in benchtop NMR technology have sought to overcome these barriers by providing more compact, affordable, and user-friendly instruments. This systematic review aims to assess the potential of benchtop NMR in clinical metabolomics, highlighting its practical advantages, current applications, and technological challenges relative to high-field systems. Methods: For this systematic review we searched Web of Science and PubMed databases to identify studies employing benchtop NMR spectroscopy in clinical and biomedical applications. The review focuses on works that evaluated metabolic profiling in human and animal disease contexts, compared benchtop and high-field performance, and utilized advanced data analysis methods, including multivariate and machine learning approaches. Results: Among the 74 records identified, 15 research articles were eligible, including 11 studies involving human biospecimens and 4 studies concerning animal samples. The selected works were published between 2018 and 2025. These studies demonstrated the potential clinical utility of low-field NMR in differentiating disease states such as tuberculosis, type 2 diabetes, neonatal sepsis, and chronic kidney disease, achieving diagnostic accuracies comparable to high-field instruments. Conclusions: Although limited by lower sensitivity and spectral resolution, benchtop NMR represents a significant step toward the democratization of NMR-based metabolomics. Continued hardware development, improved pulse sequences, and the integration of artificial intelligence for spectral processing and modeling are expected to enhance its analytical power and accelerate its clinical adoption. Full article

Traumatic brain injury (TBI) represents a significant health concern, with an estimated 70 million annual cases worldwide. Mild brain trauma (concussions) is the most common TBI (81%), followed by moderate (11%) and severe (8%). Cytokine release and neuroinflammation after TBI may cause blood–brain barrier and tissue damage, triggering unfavorable outcomes, including disabilities and mortality. Current TBI treatments, focused on preventing secondary injury, are limited and insufficient. Therefore, new therapeutic approaches are necessary. A growing body of recent literature supports the potential use of incretins: glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and glucagon receptor agonists, as potent neurotrophic/neuroprotective agents. Experiments performed in cellular and animal models, and a limited number of clinical studies, provide evidence that incretins might be a novel and effective treatment for TBI. Incretin-based compounds have already been shown to be safe and efficacious for the treatment of type 2 diabetes mellitus in humans. Therefore, incretins are ideal candidates for rapid evaluation in clinical trials of TBI and might become a novel therapeutic tool for a condition that has very few disease modifying treatments available. Well-designed human clinical trials are urgently needed to determine optimal dosing, timing, and patient selection for effective incretin use in concussion and TBI. Full article

Diabetic retinopathy (DR), a leading cause of vision loss in diabetic patients, involves complex pathological mechanisms including neurodegeneration, microvascular damage, inflammation, and oxidative stress. Recent studies have identified ferroptosis—a ferrodependent cell death mechanism—as playing a pivotal role in DR development. Existing evidence indicates that oxidative stress and mitochondrial dysfunction induced by hyperglycemia may contribute to retinal damage through the ferroptosis pathway in DR. Ferroptosis inhibitors such as Ferostatin-1 have demonstrated protective effects against DR in animal models. The core mechanisms of ferroptosis involve iron homeostasis imbalance and lipid peroxidation, with key regulatory pathways including GPX4-dependent and non-dependent mechanisms (such as FSP1-CoQ10). Within the signaling network, Nrf2 inhibits ferroptosis, p53 promotes it, while Hippo/YAP functions are environment-dependent. Non-coding RNAs and epigenetic modifications (e.g., DNA methylation and histone modifications) also participate in regulation. In DR, iron overload, GPX4 dysfunction, and p53 upregulation collectively induce ferroptosis in various types of retinal cells, making these pathways potential therapeutic targets. This review not only elaborates the role of iron metabolism imbalance and ferroptosis pathway in the occurrence and development of DR but also summarizes the new therapeutic approaches of DR targeting ferroptosis pathway. Investigating the relationship between ferroptosis and DR not only helps unravel its core pathophysiological mechanisms but also provides theoretical foundations for developing novel therapeutic approaches. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity due to their metabolic effects. Emerging evidence suggests they may also have neuroprotective effects, indicating their potential as disease-modifying therapies in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Preclinical studies in animal models have demonstrated that GLP-1RAs can reduce neuroinflammation, oxidative stress, neuronal apoptosis, and pathological protein aggregation, while enhancing glucose metabolism and mitochondrial function. This narrative review analyzed results from human clinical trials evaluating GLP-1RAs in AD and PD, based on a search of four databases (Web of Science, Medline, Embase, and Clinical Trials). The analysis included eleven studies. In AD, clinical trials suggest that GLP-1RAs such as liraglutide and semaglutide may enhance brain glucose metabolism, facilitate glucose transport across the blood–brain barrier, and benefit neuronal networks. However, most studies did not demonstrate improvements in cognitive functions or radiological markers. Short-term clinical trials of GLP-1RAs, including exenatide and lixisenatide, demonstrated promising effects on motor and selected non-motor symptoms in patients with PD, but their disease-modifying effects remain unproven. GLP-1RAs showed a favorable safety profile. Despite promising findings, small study populations, heterogeneous protocols, and short observation periods limit definitive conclusions. Further larger, long-term studies are needed, particularly to clarify the risk–benefit balance, weight control, and long-term outcomes. Full article

Redox unbalance, a molecular trait common to neurodegenerative conditions and para-physiological processes like aging, is a critical factor in disease development and in exacerbating progression. The mechanism by which redox imbalance perturbs cellular homeostasis is strongly linked to the activity and function of the ubiquitin–proteasome system (UPS). The UPS, along with autophagy, is the primary intracellular proteolytic system, regulating targeted proteolysis and removing damaged proteins. Consequently, the UPS serves also as the first line of defense for cellular recovery following exposure to redox stressors. Paradoxically, the composition and function of the UPS can also be negatively targeted by redox unbalance through a vicious cycle. The alterations in redox balance and UPS biological mechanisms are involved in the etiopathogenesis of chronic eye disorders. These disorders encompass a diverse repertoire of pathologies affecting the retinal layers (e.g., age-related macular degeneration, diabetic retinopathy) and the optic nerve (e.g., glaucoma). Nowadays, the comprehension of the interplay between proteostasis and oxidative redox status remains pivotal for identifying new therapeutic approaches. Encouragingly, a number of anti-oxidant compounds have been reported to modulate proteasome activity against redox insults in vitro and in vivo. Furthermore, these compounds provide cytoprotective roles in both in vitro and animal models of eye diseases. Therefore, this review highlights recent research on the interplay of the UPS with oxidative stress in physio-pathological conditions, focusing on the onset and progression of ocular diseases, thereby providing new insights into UPS-oxidative stress interaction. Full article

In the pathological process of acute kidney injury (AKI) and its transition to chronic kidney disease, the uric acid (UA) metabolic pathway plays a significant role. UA is produced as the last oxidative product in the metabolism of purine nucleotides. Prolonged organ ischemia promotes the breakdown of nucleotides into adenosine, hypoxanthine, xanthine, and UA. In this study, animal models of ischemia–reperfusion-induced AKI and renal tubular epithelial cells subjected to hypoxia–reoxygenation injury exhibited significantly reduced ATP levels, along with elevated concentrations of purine catabolites, including AMP, hypoxanthine, xanthine, and UA. Concurrently, the expression of xanthine oxidase (XO), a key enzyme in purine catabolism, was upregulated, peaking at 3 h after reoxygenation, accompanied by increased reactive oxygen species (ROS) production. Treatment with the XO inhibitor febuxostat in hypoxia–reoxygenated HK-2 cells led to a marked reduction in UA, inflammatory cytokines, and ROS levels, along with decreased apoptosis and enhanced proliferative capacity. Clinical data analysis revealed that 59.4% of AKI patients presented with hyperuricemia. UA levels demonstrated a linear correlation with the estimated glomerular filtration rate (eGFR) and the tissue necrosis marker lactate dehydrogenase (LDH). A random forest model constructed based on UA, LDH, age, diabetes, and hypertension accurately predicted the eGFR. These findings indicate that patients with I/R-induced AKI exhibit enhanced purine catabolism, and purine metabolic breakdown products are closely associated with the severity of renal injury in I/R AKI. For high-risk AKI populations or patients diagnosed with AKI with significantly elevated UA levels, febuxostat may be considered to prevent AKI onset and improve renal function. Furthermore, in AKI patients where creatinine data are unavailable or not significantly elevated despite markedly increased UA levels, a comprehensive assessment incorporating relevant indicators of glomerular filtration function is recommended. Full article