Liraglutide alleviates postoperative cognitive impairment via NRF2/NLRP3 signal pathway in aged mice.

Dental pulp stem cells (DPSCs) are critical for periodontal tissue regeneration, yet their therapeutic potential is limited by suboptimal osteogenic differentiation. Liraglutide (LIRA), a glucagon-like peptide-1 receptor agonist, exhibits anti-inflammatory and bone-protective properties. This study aimed to investigate the modulatory effects of LIRA on DPSCs proliferation and osteogenic differentiation. DPSCs were treated with LIRA to assess proliferation and osteogenic differentiation using Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine staining, alkaline phosphatase (ALP), and alizarin red S (ARS) assays. Histone lactylation levels (total lactylation and H3K18la) were quantified by Western blot. Chromatin immunoprecipitation (ChIP) and dual-luciferase assays evaluated H3K18la enrichment at the dentin sialophosphoprotein (DSPP) promoter. DSPP overexpression was used in rescue experiments to validate the role of the H3K18la-DSPP axis. LIRA significantly enhanced DPSC proliferation and osteogenic differentiation, as evidenced by increased ALP activity, mineralization nodules, and upregulated osteogenic markers (DMP1, DSPP, RUNX2, OCN, OPN). LIRA elevated global lactylation and H3K18la levels, with ChIP assays showing H3K18la enrichment specifically at the DSPP promoter. Dual-luciferase and RT-qPCR confirmed LIRA-induced DSPP transcriptional activation. Oxamate reversed LIRA's effects, while Nala amplified them. DSPP overexpression rescued oxamate-mediated suppression of osteogenesis, confirming the H3K18la-DSPP regulatory mechanism. This study demonstrates that LIRA promotes DPSC osteogenesis via histone lactylation-mediated DSPP transcriptional activation. The H3K18la-DSPP axis represents a novel metabolic-epigenetic pathway for enhancing periodontal regeneration.

Background: Type-2 diabetes mellitus (T2DM)posesa formidable global health challenge, characterized by persistenthyperglycemia resulting from insulin resistance and progressive β-celldysfunction. Liraglutide (LIRA), a GLP-1 receptor agonist, and dapagliflozin(DAPA), an SGLT2 inhibitor, are established therapies with complementarymechanisms. However, the potential synergy of their combination, particularlythrough modulation of the gut microbiota and host metabolism, remainsincompletely understood. To elucidate the gut microbiota–metaboliteaxis underlying the therapeutic effects of combination therapy inT2DM, we explored the interplay between β-cell function, fecalmicrobiota composition, and microbial metabolites. Methods: A T2DM mouse model was induced by a high-fat diet and streptozotocin.Mice were treated for 4 weeks with LIRA, DAPA, or their combination(COM). We assessed glycemic control, insulin sensitivity, pancreaticislet morphology, serum biochemistry, gut microbiota (shotgun metagenomicsequencing), and plasma metabolome (nontargeted metabolomics). Integratedmultiomics analysis was performed to elucidate microbiota–metaboliteinteractions. Results: Combination treatment demonstratedsuperior efficacy compared to monotherapies, resulting in significantlygreater improvements in body weight, glucose tolerance, insulin sensitivity,lipid profiles, and liver function. Histologically, COM most effectivelyrestored pancreatic islet architecture, increased β-cell mass,and normalized α/β-cell ratio. Metagenomic analysis revealedthat COM induced a unique and restorative remodeling of the gut microbiota,distinct from monotherapies. This was characterized by suppressionof pathobionts (e.g., Klebsiella and Enterorhabdus) and enrichment of beneficial taxa (e.g., Akkermansia, Lactobacillus, and Faecalibaculum). Metabolomics profiling showed that COM extensively normalizedthe diabetic plasma metabolome. Key altered pathways included tryptophanmetabolism, sphingolipid metabolism, and branched-chain amino aciddegradation. Integrated correlation analysis unveiled significantassociations between specific microbial genera and host metabolites,suggesting a functional gut microbiota–metabolite axis underpinningthe synergistic benefits. Conclusions: The combinationof liraglutide and dapagliflozin exerts synergistic antidiabetic effectsthat extend beyond glycemic control to encompass pancreatic protectionand systemic metabolic improvement. This synergy is mechanisticallylinked to collaborative remodeling of the gut ecosystem and consequentnormalization of host metabolic pathways. Our findings provide a novelrationale for this combination therapy and highlight the gut microbiotaas a pivotal target for T2DM management.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by joint inflammation and systemic symptoms. This study evaluates the efficacy of liraglutide (LIRA), a glucagon-like peptide-1 receptor agonist, in RA management, particularly in conjunction with methotrexate (MTX), a standard RA therapy on complete Freund's adjuvant (CFA)-induced arthritis. Rats were injected with 0.12 mL of CFA (10 mg/1 mL) intradermally on day 1. Rats were divided into 6 groups, Normal group, Model group, MTX group (methotrexate 1 mg/kg/wk/i.p.), LIRA protection group (liraglutide 75 μg/kg/day/i.p. from day 1 to day 56), LIRA group (liraglutide 75 μg/kg/day/i.p. from day 15 to day 56), LIRA + MTX group (liraglutide 75 μg/kg/day/i.p. + methotrexate 1 mg/kg/wk/i.p. from day 15 to day 56). The arthritic rats developed significant joint destruction accompanied by alterations in metabolic parameters, elevated inflammatory cytokines, and enhanced apoptosis and autophagy. Liraglutide treatment and protection significantly showed metabolic hexokinase 2-succinate-hypoxia-inducible factor 1α axis modulation, inflammasome NOD-like receptor family, pyrin domain containing 3 suppression, apoptosis and autophagy flux normalization and joint pathology improvement. Liraglutide produced more pronounced effects when administered in combination with methotrexate. In conclusion, liraglutide demonstrated significant therapeutic and protective efficacy in a CFA-induced rat model of RA. The mechanism involves metabolic reprogramming where liraglutide downregulated the hexokinase 2-succinate-hypoxia-inducible factor 1αaxis, correcting disease-associated metabolic dysregulation. Similarly, liraglutide inhibited key proinflammatory signaling cascades, specifically the nuclear factor κB/NOD-like receptor family, pyrin domain containing 3/interleukin-1β and tumor necrosis factor-α/P38 mitogen-activated protein kinase pathways. SIGNIFICANCE STATEMENT: Rheumatoid arthritis is a chronic immuno-inflammatory disorder causing joint damage. Liraglutide presents opportunities for repurposing metabolic agents in the treatment of autoimmune illnesses. Liraglutide modulates metabolic dysfunction, normalizes autophagy markers, inflammatory pathways, and lower apoptotic signals in complete Freund's adjuvant-induced arthritis in rats.

Injectable Schiff base-engineered hydrogel for spatiotemporal liraglutide delivery orchestrates diabetic periodontitis regression via multimodal microenvironment reprogramming.

Liraglutide Ameliorates Gamma Radiation-Induced Hepatic Damage in Rats: The Role of an Autophagy Flux Activation Via LKB1/AMPK/mTOR Axis.

Psychiatric patients have a high risk of obesity, frequently due to psychotropic medication-induced weight gain. However, real-world comparative data on antiobesity medications (AOMs) in this population remain rare. To compare short-term weight-loss efficacy, adverse events (AEs), and early discontinuation (ED) among psychiatric outpatients taking liraglutide (LIRA), naltrexone/bupropion, phentermine-topiramate (PT), or metformin (MET). Retrospective observational cohort study. We conducted a 12-week retrospective chart review of 117 psychiatric outpatients with International Classification of Diseases, 10th Revision, F01-F99 diagnoses. Percent weight change over time was analyzed using linear mixed-effects models. AEs and ED were compared across treatment groups. Compared with MET, LIRA was associated with a greater percent weight reduction (estimate -3.45%, 95% confidence interval (CI) -5.35 to -1.55, p < 0.001), with a significant treatment-by-time interaction at 12 weeks (p = 0.019). Female sex and full-time employment were associated with attenuated weight loss, and the number of concomitant psychotropic medications with moderate weight-gain risk showed a trend toward greater weight reduction (p = 0.066). No significant differences were observed in AE incidence across AOMs. ED rates differed by drug type (p = 0.017), being lowest in the MET group (39.1%) and highest in the PT group (72.2%). In this real-world psychiatric cohort, LIRA was associated with greater short-term weight loss than MET without an increased observed frequency of AEs. ED rates varied across AOMs. These findings should be interpreted cautiously, given the observational design and short follow-up period, and require confirmation in larger, long-term studies.

Pulmonary delivery provides a noninvasive route for systemic administration of biologics, yet efficient lung deposition and permeation across pulmonary barriers remain major challenges. In this study, morphology-engineered zinc oxide (ZO) biointeractive carriers were fabricated and evaluated as inhalable carriers for liraglutide (LG). Three distinct morphologies were obtained: smooth spherical ZO-1 (5–7 μm), spiky sea-urchin-like ZO-2 (5–8 μm with elongated ~ 3.5 μm tips), and compact spiky ZO-3 (1–3 μm with short ~ 1.3 μm tips). Particle image velocimetry (PIV) revealed morphology-dependent aerodynamic behaviors, where ZO-3 exhibited turbulence-driven dispersion favoring distal lung deposition. At the cellular level, ZO-3 demonstrated enhanced mucus penetration and reduced macrophage uptake, maintaining prolonged contact with the epithelial surface. Following intratracheal administration, LG@ZO-3 achieved bioavailability of ~ 60% relative to subcutaneous injection in healthy rats and ~ 51% in diabetic rats, far exceeding the < 2% oral bioavailability of semaglutide. These results suggest that morphology-controlled modulation of aerodynamic and biological interactions can overcome multiple pulmonary barriers, offering a promising strategy for effective inhalable delivery of peptide therapeutics.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12951-026-04085-y.

Vascular endothelial cells (ECs) are pivotal in maintaining vascular homeostasis. Liraglutide (LIR) can prevent and reverse hyperglycemia-induced cell dysfunction. However, the mechanism by which it improves hyperglycemia-induced EC senescence remains unclear. This study investigates whether the La Ribonucleoprotein 7/Sirutin 1 (LARP7/SIRT1) signaling axis is essential for LIR efficacy in mitigating EC senescence and dysfunction. We treated senescent human umbilical vein ECs induced by high glucose levels with LIR and evaluated cell viability cell counting kit-8 (CCK-8 assay), senescence (SA-β-gal staining), and SASP alterations (qPCR). We also investigated the expression of senescence-related proteins and changes in the LARP7/SIRT1 signaling pathway using Western blot analysis. Additionally, reactive oxygen species levels were measured with 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), and changes in oxidative stress-related factors were assessed using specific assay kits. The effect of LIR on endothelial dysfunction was examined by cellular tube-forming assay and transwell assay after LARP7 knockdown/overexpression. LIR markedly improved cell vitality and the senescence phenotype while reducing oxidative stress. The LARP7/SIRT1 pathway emerged as crucial for its effectiveness. Following LARP7 knockdown, the therapeutic efficacy of LIR was notably attenuated. The overexpression of LARP7 enhanced the therapeutic efficacy of LIR. The tube formation and transwell assays further supported the hypothesis that LIR's beneficial impact on endothelial dysfunction depends on the LARP7/SIRT1 signaling axis. Our study reveals a novel aspect of LIR as an antidiabetic agent in delaying vascular aging driven by high glucose through targeting the LARP7/SIRT1 pathway. This discovery enhances the therapeutic value of LIR and proposes a new strategy for addressing vascular aging in treatments for elderly patients with diabetes.

Methotrexate (MTX) is mostly used to treat different types of malignancies, but unfortunately, it also has fatal cytotoxic effects on many organs, including the heart. Liraglutide (LIR) is known to exhibit anti-inflammatory and cardioprotective effects. Therefore, our study aimed to explore the possible cardioameliorative effects of two different dosages of LIR on MTX-induced cardiotoxicity in rats. Four groups of rats were divided into a control group, a group that received a single dose of 20 mg/kg of MTX by intraperitoneal injection (ip) (MTX-alone group), a group that received a subcutaneous (sc) dosage of 0.2 mg/kg/day of LIR for 2 weeks (low-dose LIR group), and a group that received a sc dosage of 0.4 mg/kg/day of LIR for 2 weeks (high-dose LIR group). The latter two groups were given MTX on day 10. After 2 weeks, each group was assessed by an electrocardiography (ECG) and by measuring serum levels of cardiac enzymes and histopathological and caspase-3 immunohistochemical levels in heart tissues. In addition, cardiac tissue was evaluated for oxidative stress and inflammatory and apoptotic markers. When compared with the MTX-alone group, the LIR-treated groups had improved ECG results and significantly decreased levels of the cardiac enzyme malondialdehyde (creatine kinase (CK) and troponin), autophagy markers (including the microtubule-associated proteins 1 A/1B light chain 3B [MAP1LC3B] and Beclin-1), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β). The LIR-treated groups also had significantly increased superoxide dismutase activity compared with the MTX-alone group. In addition, the LIR-treated groups had much less cardiac tissue destruction and had mitigated the increased caspase-3 immunoexpression that had been produced by MTX. These improvements were greater in the group that received the higher dosage of LIR than in the group that received the lower dosage of LIR. In conclusion, LIR improved MTX-induced cardiotoxicity more significantly at a dosage of 0.4 mg/kg/day, probably through the interruption of oxidative stress and autophagy pathways and the activation alleviation of inflammatory cytokines.

Background/Objectives: Thermoregulation is essential for survival, with the hypothalamic preoptic area integrating peripheral signals to maintain core body temperature. While fever enhances immune responses, excessive hyperthermia causes cellular damage. Previous work has shown that central glucagon-like peptide-1 (GLP-1) receptor antagonism intensifies lipopolysaccharide (LPS)-induced fever, suggesting a role for GLP-1 signaling in temperature regulation. However, the direct effects of GLP-1 receptor agonists on fever remained unexplored. This study investigated the effects of liraglutide (LIRA), a GLP-1 analog used to treat diabetes and obesity, on temperature regulation and fever in rats, with a focus on sex-dependent mechanisms. Methods: Male and female Wistar rats received lipopolysaccharide (LPS, i.p.) to induce fever, followed by LIRA treatment (0.3 mg/kg, i.p.) one hour later. Body temperature was monitored for up to six hours post-LPS injection. Results: LIRA reduced body temperature in both euthermic and febrile rats of both sexes. LPS increased PGE2 concentration in both sexes, with males showing a twofold increase compared to females. LIRA treatment reduced PGE2 levels in LPS-challenged males (62%, p < 0.01) but not in female rats. LPS elevated interleukin (IL)-6 levels in both sexes, while LIRA treatment decreased IL-6 only in females (45%, p < 0.05). In males, LPS reduced hypothalamic serotonin (5-HT) levels, and LIRA further decreased 5-HT in saline-treated animals. In females, LIRA increased 5-HT levels (84%, p < 0.01) in LPS-challenged animals. Additionally, LIRA exhibited sex-specific effects on hypothalamic JNK phosphorylation, increasing activation in LPS-treated males and reducing it in LPS-treated females. Conclusions: LIRA demonstrates antipyretic properties through distinct, sex-specific mechanisms. In males, temperature reduction correlates with decreased hypothalamic PGE2, whereas in females, antipyretic effects are associated with reduced IL-6, decreased JNK phosphorylation, and increased 5-HT. These findings reveal sexually dimorphic GLP-1R-mediated thermoregulatory pathways during inflammation. However, the causal relationships between these molecular changes and temperature regulation require further investigation, particularly regarding whether observed biochemical alterations represent primary mechanisms or secondary consequences of temperature modulation. Future studies should investigate the functional significance of the apparent contradiction in serotonergic responses between sexes.

Effects of liraglutide on progenitor cell lineage and maturation in cd34+ hematopoietic stem cells: a single-cell rna sequencing analysis

Liraglutide attenuates high glucose-induced 'trained immunity' in cd34+ hematopoietic stem cells

Liraglutide suppresses ferroptosis by upregulation NRF2 in type 2 diabetic cardiomyopathy.

Treatment of obesity with GLP-1 receptor agonist after bariatric surgery: Real-world evidence.

This study evaluated the neuroprotective potential of a combination therapy using liraglutide (LIRA), an antidiabetic agent, and rivastigmine (RIVA), a standard treatment for Alzheimer's disease (AD), in a rat model of aluminum chloride (AlCl₃)-induced AD. Male rats were divided into five groups: control, AD (AlCl₃,75 mg/kg for 60 days), RIVA-treated (1 mg/kg daily for 6 weeks), LIRA-treated (300 µg/kg daily for 6 weeks), and combination-treated (LIRA + RIVA). Cognitive function was assessed behaviorally, and hippocampal biomarkers related to AD-such as microtubule-associated protein Tau (MAPt), Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), Sequestosome 1 (SQSTM1/p62), and acetylcholinesterase (AChE) activity-were evaluated. Histopathological changes, immunohistochemistry, and transmission electron microscopy were also assessed. The levels of MAPt, BACE1, SQSTM1/p62, and AChE in the LIRA + RIVA group were 11.32 ± 0.467 ng/mL, 1069 ± 80.1 pg/mL, 408.7 ± 19.41 pg/mL, and 0.805 ± 0.342 µmol of acetylthiocholine iodide hydrolyzed/min/g of tissue, respectively. These levels were significant (p < 0.01) when compared with the AlCl3 group. Histological findings supported these biochemical data, indicating enhanced neuroprotection. LIRA may have a potential neuroprotective effect due to the rise in AChE, BACE1, (SQSTM1/p62) amyloid beta (Aβ), and caspase-3 levels induced by AlCl3. Co-administration of LIRA and RIVA provided superior neuroprotective effects compared with RIVA alone, suggesting a promising therapeutic strategy for preserving cognitive function in AD.

High salt (NaCl) intake has been associated with visceral adipose tissue (VAT) dysfunction independently of its impact on blood pressure. Liraglutide (LGT), a GLP-1 agonist, could be a potential therapeutic option. We investigated the impact of a chronic high-salt diet (HSD) on VAT homeostasis and evaluated the potential protective effects of LGT, a GLP-1 receptor agonist. Male C57BL/6 mice were fed a standard diet (Control, C) or 8% NaCl (HSD) for 15 weeks and subsequently treated with LGT or vehicle for 5 weeks. In VAT, histological characteristics, collagen deposition, vascular density, mitochondrial dynamics, oxidative stress, and adipokine expression were evaluated. The HSD significantly decreased body weight, VAT mass, and adipocyte size (p < 0.05). Moreover, it impaired vascular density and induced interstitial fibrosis (p < 0.01). LGT treatment improved vascularization and VEGF expression and reduced fibrosis (p < 0.05 vs. the HSD). The HSD induced oxidative stress and mitochondrial fragmentation, which were attenuated by LGT (p < 0.001). Leptin levels were elevated by the HSD (p < 0.05) and normalized with LGT, while adiponectin levels increased. In conclusion, excessive salt consumption induces structural and metabolic dysfunction in VAT. LGT therapy mitigates several of these adverse effects, supporting its potential as a novel strategy for managing salt-sensitive adipose tissue dysfunction.

Liraglutide (LGT), a synthetic glucagon-like peptide-1 (GLP-1) analogue, is widely used in the treatment of Type 2 diabetes and obesity. Due to its peptide-based nature, it is prone to degradation, particularly under improper storage or handling conditions. Environmental stressors, such as heat and light, can lead to the formation of impurities that may compromise the quality and safety of the drug. In this study, we have investigated the impact of thermal and photolytic stress on LGT stability using reverse-phase liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). This method enabled the separation, identification, and characterization of intact LGT and its degradation products (DPs). Ten impurities were identified, including four DPs that have not been reported so far. Further, MS/MS fragmentation analysis was employed to elucidate the sequences of LGT and its impurities, pinpointing the modifications and their respective sites. The formation mechanisms of these impurities were also proposed, providing critical insights into the degradation pathways. This study offers a comprehensive analytical approach for assessing the stability of peptide drugs, contributing to enhanced quality control and safer pharmaceutical formulations.

The goal of this effort was to create mesoporous nanoparticles (MSNs) decorated with amine groups and loaded with liraglutide (LRT) for oral delivery. Amine-decorated MSNs were helpful for peptide entrapment and prolonged release of liraglutide, a GLP-1 analog. Liraglutide-loaded MSNs were made by using acetonitrile and water sol-gel techniques. Over the course of 24h, the particles provided consistent drug release, with cumulative release reaching up to 90% in vitro. Differential dynamic light scattering, scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, Brunauer-Emmett-Teller (BET) analysis and differential scanning calorimetry (DSC) were used to characterize the synthesized formulation. The MTT assay was used to evaluate cell viability along with the hemolysis assay and was found to be safe. Particle size determination was performed by a zeta sizer; the size was 286nm [Formula: see text], and the PDI and zeta potential were 0.29 and +8.89 mV, respectively. The drug entrapment efficiency was also very good at 56% ± 9%, and the drug release was more than 90.0% ± 9 within 24h at all pH values tested. The efficacy of the particles was examined in a rat model of diabetes and contrasted with that of a group that received daily injections of liraglutide. Between 0 and 5 days after the start of treatment, lower blood sugar levels were observed in the particle treatment groups than in the injection groups. Overall, the liraglutide-loaded MSNs created in this work are effective in a rat model of diabetes, and as a result, we believe that they have great potential for clinical application.

Ameliorative effect of GLP1 agonist on vascular calcification in normoglycemic aged rat aorta via miR34a/SIRT6/NRF2/HO-1 signalling pathway.