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GCKR genetic variants and circulating FGF21 identify a metabolic risk signature in metabolic dysfunction-associated steatotic liver disease.
BMC Gastroenterol
Asmaa Mohamed Fteah, Doaa Mamdouh Aly, Mohamed A Elrefaiy +1 more
BACKGROUND & AIMS: Interindividual variability in metabolic dysfunction–associated steatotic liver disease (MASLD) onset and its progressive inflammatory stage, metabolic dysfunction–associated steatohepatitis (MASH), reflects a complex interplay between metabolic burden and inherited susceptibility. We investigated the combined impact of genetic variants in the glucokinase regulatory protein gene (GCKR) and fibroblast growth factor 21 (FGF21), together with circulating FGF21 concentrations, on susceptibility to MASLD and its progression to MASH. METHODS: This case-control study enrolled 150 patients with MASLD, 150 patients with clinically suspected MASH, and 150 age- and sex-matched healthy controls. Genotyping of GCKR rs1260326 and FGF21 rs838133 polymorphisms was performed using DNA extracted from peripheral blood samples by real-time polymerase chain reaction, while serum FGF21 levels were quantified by enzyme-linked immunosorbent assay. Associations with metabolic characteristics, liver function indices, and fibrosis severity were examined using correlation analyses and multivariate logistic regression models. RESULTS: The GCKR rs1260326 TT genotype and T allele carriers had an increased risk of MASH progression versus MASLD (AOR for TT genotype: 16.875; 95% CI: 6.339–44.921, P = 0.001), adjusted for age, sex, BMI, HOMA-IR and triglycerides level. Moreover, the TT genotype was associated with higher alanine aminotransferase levels and reduced markers of hepatic synthetic capacity. In parallel, carriers of AG genotype of FGF21 rs838133 exhibited a higher propensity for progression to MASLD (AOR: 18.622; 95% CI: 1.619-214.169, P = 0.019) and G allele accompanied by greater insulin resistance and unfavorable lipid profiles. Circulating FGF21 concentrations demonstrated a stepwise increase from controls to MASLD and MASH groups and showed good discriminatory performance in differentiating MASLD from controls (AUC = 0.821) and excellent accuracy in identifying MASH among healthy individuals (AUC = 0.929). CONCLUSIONS: Genetic variation in GCKR and FGF21, together with altered hepatokine signaling, contributes substantially to metabolic dysregulation and liver disease severity. Integrating genetic profiling with circulating biomarkers may offer a refined strategy for identifying individuals at high risk of MASLD progression and advancing precision-based approaches in metabolic liver disease.
Recombinant Human Thymosin β4 Attenuates Endotoxemia-Induced ALI and EAE by Suppressing Inflammatory and Oxidative Responses.
Biomolecules
Yumeng Ye, Xuefeng Yang, Ying Liu +6 more
Endotoxemia represents a life-threatening clinical disorder driven by an aberrant host immune response to pathogenic infection, often resulting in severe multiple organ dysfunction. Among its most devastating complications are acute lung injury (ALI) and endotoxemia-associated encephalopathy (EAE), both of which are associated with elevated mortality and currently lack effective targeted interventions. This study evaluated the therapeutic efficacy and underlying molecular mechanisms of recombinant human thymosin β4 (rhTβ4) in a murine model of lipopolysaccharide (LPS)-induced endotoxemia. Our results showed that treatment with rhTβ4 markedly enhanced survival rates and diminished the systemic overproduction of diverse proinflammatory cytokines and chemokines in endotoxemic mice. These systemic protective actions were achieved through the inhibition of the TLR4/NF-κB signaling cascade, the reduction in M1 macrophage polarization, and the simultaneous alleviation of mitochondrial impairment and oxidative stress. Moreover, rhTβ4 treatment significantly rescued EAE-related cognitive deficits and attenuated neuronal damage, primarily through the suppression of neuroinflammation and microglial overactivation. Integrative transcriptomic profiling and functional assays identified lysophosphatidic acid receptor 3 (LPAR3) as an important contributor, suggesting that rhTβ4 suppresses microglial-mediated neurotoxicity at least in part through LPAR3 downregulation. In conclusion, rhTβ4 confers robust multi-organ protection against endotoxemic injury by orchestrating the inhibition of systemic and central neuroinflammatory cascades, positioning it as a promising candidate for the treatment of endotoxemia-induced ALI and EAE.
MALAT1 promotes autophagy via the mir-28-5p/IGF1R axis in nasopharyngeal carcinoma.
Med Oncol
Xiaopeng Huang, Yunxiu Luo, Jiawei Chen +1 more
The long non-coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is implicated in cancer progression, yet its precise mechanism in nasopharyngeal carcinoma (NPC), particularly its interaction with microRNAs and its role in regulating autophagy, remains to be fully elucidated. We analyzed MALAT1 and miR-28-5p expression in NPC clinical tissues and assessed their correlation with autophagy markers. The direct binding between MALAT1 and miR-28-5p, and between miR-28-5p and Insulin-like Growth Factor 1 Receptor (IGF1R), was validated using dual-luciferase reporter and RNA immunoprecipitation assays. Functional roles in proliferation, apoptosis, migration, and invasion were determined using Cell Counting Kit-8, flow cytometry, Transwell, and wound healing assays. Autophagic activity was evaluated by measuring microtubule-associated protein 1 A/1B-light chain 3 (LC3)-II/I ratio and p62 levels and observing autophagosome formation. In vivo tumor growth and autophagy were assessed in a xenograft mouse model. We found MALAT1 was significantly upregulated, and miR-28-5p was downregulated in NPC tissues, showing a significant correlation with autophagic activity. MALAT1 functioned as a competitive endogenous RNA by directly binding to and sequestering miR-28-5p. Subsequently, miR-28-5p was shown to directly target and suppress IGF1R. Overexpression of miR-28-5p curbed NPC cell growth, migration, and invasion and promoted apoptosis, whereas MALAT1 overexpression or IGF1R restoration counteracted these effects. The MALAT1/miR-28-5p/IGF1R axis increased the LC3-II/I ratio, decreased p62, and elevated autophagosome formation. These pro-tumorigenic and pro-autophagic effects were consistently observed in vivo. In conclusion, MALAT1 promotes autophagy by sequestering miR-28-5p to upregulate IGF1R in NPC, providing a novel mechanistic insight and a potential therapeutic target.
β-Amyloid (Aβ) and Human Cathelicidin LL-37: Two Sides of the Same Coin?
Int J Mol Sci
Anna Lia Asti
Physiologically produced circulating β-amyloid (Aβ) exerts critical physiological functions. Although Aβ is a key player in Alzheimer's disease (AD), it may initially be beneficial at the onset of infection. As an evolutionary conserved antimicrobial peptide (AMP), Aβ contributes to innate immune defense against pathogens. Host defense peptides such as Aβ and human cathelicidin (LL-37) not only kill pathogens through their antimicrobial activity but also exhibit high affinity for bacterial lipopolysaccharides (LPSs) and membrane receptors. LL-37, which is upregulated in the brain, binds to Aβ, modulating its aggregation; Aβ and LL-37 are protective under physiological conditions, but during chronic infection or dysregulation, their interaction becomes toxic and contributes to AD pathology. Similarly to Aβ, LL-37 can induce neuroinflammation by stimulating human microglia to release inflammatory cytokines, such as TNF-α and IL-6. Neuroinflammation is essential for protecting the brain from pathogens-when prolonged, it drives pathological processes underlying AD, Parkinson's disease (PD), and other neurodegenerative disorders.
Immunomodulatory effects of synthetic antimicrobial peptides on LPS-induced inflammatory responses in THP-1 macrophages.
Front Immunol
Ilayda Akbulut, Ziyun Zhang, Tracy Hussell +2 more
Macrophage polarization is critical for maintaining health and for recognizing and eliminating a diverse array of antigens. These disparate roles require distinct macrophage responses, and the induction of inappropriate macrophage responses is intimately associated with disease. It is therefore important to understand how macrophages respond to new biomedicines and to harness those with immune modulatory properties for therapeutic use. This study defines the effects of rationally designed antimicrobial peptides (AMPs) on macrophage polarization and function, compared with natural host-defense peptides (natural AMP LL-37 and antibiotic polymyxin B). Using an in vitro model system, our results show that the designed AMPs suppress pro-inflammatory cytokine production while enhancing anti-inflammatory responses, with potency comparable to LL-37, and mitigate the impact of LPS-induced inflammation. Furthermore, AMPs influence key molecular pathways, such as IRF3/IRF4 and PPAR-γ, favoring M2 polarization. These results highlight the amphiphilic, sequence-engineered design of the peptides, which enables controlled membrane interaction, low cytotoxicity, and structural adaptability, properties central to next-generation immune-active biomaterials. By coupling antimicrobial function with immune reprogramming, these synthetic AMPs act as dual-function agents capable of alleviating inflammatory conditions such as cytokine storm and promoting reparative macrophage phenotypes. This work identifies a new design framework for bioinspired, immunomodulatory peptide materials with potential applications in infection control, inflammatory disease management, and wound healing.
High-yield recombinant production of the semaglutide main chain P29 intermediate using SNAC-tagged enterokinase-cleavable fusion peptides.
PLoS One
Qingyu Qi, Ge Gao, Guodong Li +1 more
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insufficient insulin secretion or impaired cellular response to insulin, resulting in increased blood sugar levels and persistent hyperglycemia. The diabetes-related health expenditure worldwide is estimated to have surpassed 1,000 billion USD according to the new data from the International Diabetes Federation. Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated high efficacy in glycemic control and body weight loss, is approved for T2DM and obesity treatment. However, up to now, industrial production of semaglutide remains constrained by limited yield and high cost associated with conventional approaches. Therefore, improving production efficiency while reducing manufacturing cost remains a challenge. In this study, we report a new strategy for obtaining semaglutide main chain P29, also known as Arg34GLP-1 (9-37), which is a key intermediate precursor in semaglutide synthesis. The method employs a series of semaglutide-derived helical fusion pro-peptides containing the sequence GSHHWHHHSSGDDDDK, which could be cleaved by a 2-step processing via sequence-specific nickel-assisted chemical protein cleavage followed by enterokinase cleavage. Using this strategy, semaglutide main chain P29 was highly expressed and purified to 98% purity, with yields exceeding 5 grams per liter of broth. This process provides improved productivity compared with previously reported strategies. The work establishes an efficient and scalable platform for semaglutide intermediate production and shows potential for large-scale industrial production.
From evidence to practice: Identifying candidates for semaglutide in chronic atherosclerotic disease.
Int J Cardiol
Aldo P Maggioni, Francesco Orso, Donata Lucci +2 more
Randomised clinical trials (SELECT and SOUL) demonstrated that semaglutide, a GLP-1 receptor agonist, reduces the combined outcome measure of atherothrombotic events or cardiovascular mortality in patients with coronary artery disease, both with and without diabetes. Because real-world populations may differ from trial cohorts, we assessed the proportion of patients potentially eligible for semaglutide using the criteria set out by the regulatory authorities based on the SELECT and SOUL results.
Heart Failure Etiology and 6-Month Cardiorenal Recovery Patterns After Early In-Hospital SGLT2 Inhibitor Initiation in HFrEF: A Prospective Real-World Cohort.
Medicina (Kaunas)
Marija Radić, Ivana Jurin, Fran Rode +10 more
Background: SGLT2 inhibitors improve outcomes in heart failure with reduced ejection fraction (HFrEF), but whether early recovery patterns after initiation differ according to HF etiology in real-world practice remains uncertain. Objective: To evaluate whether ischemic versus non-ischemic etiology is associated with different 6-month cardiac, renal, biomarker, and exploratory metabolic trajectories after early in-hospital SGLT2 inhibitor initiation in HFrEF. Materials and Methods: In this prospective single-center observational cohort (2022-2025), consecutive adults hospitalized with first-presentation acute HFrEF who initiated empagliflozin or dapagliflozin within 48 h of admission were enrolled. Patients were classified as having ischemic cardiomyopathy (ICM) or non-ischemic cardiomyopathy (NICM). The primary analytic cohort included patients with paired baseline and 6-month echocardiography. The primary outcome was change in left ventricular ejection fraction (LVEF); eGFR and NT-proBNP were secondary outcomes. Exploratory metabolic/laboratory variables were summarized descriptively using paired available-case follow-up. The study was approved by the institutional ethics committee and registered in ClinicalTrials.gov under the CaRD registry framework (NCT06090591). Results: The paired 6-month echocardiographic analytic cohort comprised 241 patients who survived to reassessment (ICM n = 90; NICM n = 151). NICM showed greater improvement in LVEF than ICM (ΔLVEF +10% [IQR 0-18] vs. +5% [IQR 0-12]; p = 0.049) and a more favorable eGFR trajectory (ΔeGFR 0.30 [IQR -5.90 to 6.60] vs. -2.70 [IQR -12.60 to 3.40] mL/min/1.73 m2; p = 0.038). NT-proBNP declined substantially in both groups, with no between-group difference in change magnitude (p = 0.845), although 6-month values remained higher in ICM (p = 0.034). However, after multivariable adjustment, ischemic etiology was no longer independently associated with 6-month LVEF or eGFR outcomes. Exploratory metabolic findings varied descriptively by etiology but should be interpreted cautiously because follow-up completeness and background treatment intensity varied across variables. Conclusions: In this real-world cohort of patients with HFrEF who initiated SGLT2 inhibitors during hospitalization, HF etiology was associated with different short-term cardiorenal recovery patterns, whereas NT-proBNP reduction was similar across groups. These findings characterize etiology-related recovery within a treated cohort rather than differential SGLT2 inhibitor efficacy and should therefore be considered as hypothesis-generating.
Differential Associations of Oxidative Biomarkers with Symptomatic and Systolic Severity in Heart Failure.
Medicina (Kaunas)
Aleksandra Arsić, Bojana Kisić, Vladan Perić +8 more
Background and Objectives: Oxidative stress is recognized as an important contributor to heart failure (HF) pathophysiology, but the relationships of individual oxidative and antioxidant biomarkers with symptomatic severity and systolic dysfunction remain insufficiently defined. This study examined circulating oxidative and nitrosative stress markers across New York Heart Association (NYHA) classes and left ventricular ejection fraction (LVEF) categories in HF and their associations with HF severity. Materials and Methods: In this case-control study, 85 patients with HF and 33 healthy controls were included. Malondialdehyde (MDA), nitrates and nitrites (NOx), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), sulfhydryl (SH) groups, and NT-proBNP were measured. Group differences were analyzed using the Kruskal-Wallis test with post hoc comparisons. Adjusted ordinal logistic regression models examined associations with NYHA class and LVEF category, and receiver operating characteristic (ROC) analysis evaluated discriminatory performance. Results: Compared with controls, all biomarkers differed significantly across NYHA classes and LVEF categories (all p < 0.001). In separate adjusted models, higher NOx, MDA, and NT-proBNP were associated with worse NYHA class and more impaired LVEF, whereas higher antioxidant marker levels were associated with lower odds of severe HF. In combined models, NOx remained independently associated with worse NYHA class (OR 1.07, 95% CI 1.04-1.11; p < 0.001), while MDA remained independently associated with more impaired LVEF (OR 1.02, 95% CI 1.00-1.03; p = 0.022). NT-proBNP showed the best discrimination for NYHA III/IV versus I/II (AUC 0.966), while among oxidative biomarkers NOx performed best for symptomatic severity (AUC 0.782) and MDA for LVEF ≤ 40% (AUC 0.751). Conclusions: HF is characterized by increased oxidative and nitrosative stress together with reduced antioxidant defense. NOx appears more closely related to symptomatic severity, whereas MDA appears more closely related to systolic dysfunction. However, NT-proBNP remained the strongest overall discriminator. NOx and MDA may provide complementary mechanistic information on redox imbalance across HF severity categories.
Intermittent Levosimendan Administration for Advanced Heart Failure Treatment in Adults with Congenital Heart Disease (Levo-ACHD Study).
Medicina (Kaunas)
Flavia Fusco, Ippolita Altobelli, Vito Casale +11 more
Background and Objective: Heart failure (HF) is a major cause of morbidity in adults with congenital heart disease (ACHD), who may also have limited access to transplant. Intermittent levosimendan administration has shown benefit in advanced HF due to acquired heart disease, but currently, there are no data on ACHD. We aimed to evaluate the effects of this treatment in ACHD patients with advanced heart failure, focusing on both clinical status and objective outcome measures. Materials and Methods: We conducted a single-center retrospective analysis of ACHD patients aged >18 years with advanced HF who received ≥ three intermittent levosimendan infusions (either 12.5 mg once monthly or 6.25 mg every two weeks over a 6 h infusion) between March 2020 and January 2025 at a tertiary ACHD center. Clinical outcomes during follow-up were compared with those in the year preceding treatment. Primary endpoints included safety and HF-related adverse events, particularly HF hospitalizations. Secondary endpoints included changes in New York Heart Association (NYHA) class, nt-pro-B-natriuretic peptide (nt-proBNP) values, and ventricular systolic function assessed by echocardiography. Results: Twelve patients (median age 44.6 years, 25% female) were included, with heterogeneous congenital diagnoses and advanced HF. Five patients had a systemic right ventricle (sRV) and one had a single ventricle with previous Fontan palliation. During a median follow-up of 1.3 years, intermittent levosimendan was well-tolerated, with no treatment-limiting adverse events. Two patients (16%) required hospitalization for HF during follow-up compared with 8 (66%) in the year preceding treatment. The incidence of HF hospitalizations decreased from 0.83 to 0.20 events per person-year during follow-up (p = 0.03), although findings should be interpreted cautiously given the small sample size and retrospective design. NYHA functional class improved significantly (p = 0.005). While no significant changes were observed in NT-proBNP or left ventricular ejection fraction, patients with a systemic right ventricle (sRV) showed an increase in right ventricular fractional area change (27 ± 7.4% to 30.6 ± 7%, p = 0.02); however, this observation should be regarded as exploratory given the limited sample size. Two deaths occurred, consistent with the severity of the underlying disease and not directly attributable to levosimendan and the Fontan patient received a successful heart and liver transplant. Conclusions: In a small, real-world cohort of ACHD and advanced HF, intermittent levosimendan administration was safe and associated with improved symptoms, reduced HF hospitalizations, and signals of enhanced systemic right ventricular function. These hypothesis-generating findings may help inform future multicenter studies in ACHD patients with advanced HF, suggesting a potential role for intermittent levosimendan in selected patients, while highlighting the need for prospective, adequately powered studies to confirm its efficacy and better define optimal patient selection.
Heart Failure Medication Withdrawal in Patients With Improved Cardiac Function After Atrial Fibrillation Ablation: The DEFINITION-AF Pilot Randomized Clinical Trial.
JAMA Netw Open
Sitong Li, Yidan Sun, Yiwei Lai +20 more
Withdrawal of guideline-directed medical therapy (GDMT) for heart failure (HF) is common after atrial fibrillation (AF) catheter ablation and recovery of cardiac function, but safety remains uncertain.
Cardiac remodelling and functional status after cardiac resynchronisation therapy: comparison between de-novo implantation and upgrade from right ventricular pacing.
ESC Heart Fail
Henrik Laurits Bjerre, Emil Anton Frandsen, Anders Sommer +5 more
Patients with heart failure induced by chronic right ventricular (RV) pacing commonly undergo upgrade to cardiac resynchronization therapy (CRT). We aimed to compare the effect size of improvement in cardiac function and functional capacity between patients with RV pacing and intrinsic conduction at baseline.
HMB and Liraglutide Confer Complementary Protection Against Lipotoxic and Atrophic Alterations in High-Glucose Plus Free Fatty Acid-Treated C2C12 Myotubes.
Nutrients
Li-Yuan Chen, Shao-Hsing Weng, Hsin-Hua Li +7 more
Type 2 diabetes (T2D)-associated sarcopenia is characterized by impaired insulin signaling, lipotoxicity, oxidative stress, and progressive muscle loss. Although liraglutide improves glucose control and reduces lipid burden, its ability to preserve muscle integrity under diabetic lipotoxic conditions remains limited. This study investigated whether β-hydroxy-β-methylbutyrate (HMB) could enhance liraglutide-mediated protection against high-glucose plus free fatty acid (HG+FFA)-induced injury in skeletal muscle cells.
Targeting the GLP-1 receptor pathways for dual management of obesity and depression.
Drug Discov Today
Ruchi Keswani, Shvetank Bhatt
Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), initially developed for the treatment of diabetes mellitus, are now widely used in obesity management. Obesity and depression are interconnected and share common biological pathways, including inflammation, oxidative stress, neurotransmitter imbalance, mitochondrial dysfunction, adipocytokine alterations, as well as gut-brain and HPA-axis dysregulation. These mechanisms are mediated by the signaling pathways that involve the GLP-1 receptor and provide a therapeutic target in comorbid disorders. GLP-1RAs have an impact on glycemic levels, weight reduction, insulin sensitivity, appetite and satiety control. Recent studies also highlight their neuroprotective effects, including modulation of dopaminergic pathways, enhanced hippocampal neurogenesis and neuroinflammation reduction. Hence, this review focuses on the therapeutic potential of using GLP-1 receptor pathways in the dual treatment of obesity and depression.
Efficacy of GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists in managing MALFD: a meta-analysis of randomized controlled trials.
BMC Gastroenterol
Surtika Tamilwanan, Zoriah Aziz, Lim Yan Rong +3 more
BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) affects up to 30% of the global population, yet effective pharmacological treatments remain limited. This systematic review and meta-analysis evaluated the efficacy of GLP-1 receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists in managing MAFLD. METHODS: We systematically searched PubMed/MEDLINE, Cochrane CENTRAL, Web of Science, and Scopus, through July 2025. Randomised controlled trials (RCTs) assessing GLP-1 receptor agonists or dual GLP-1/GIP GIP receptor Agonists in managing MAFLD patients were included. Primary outcomes included liver fat content, liver enzymes, and glycemic parameters. Meta-analyses were performed with subgroup analyses by receptor target, treatment duration, control type, and age. In addition, implementing a formal GRADE evaluation framework. RESULTS: Twenty-six trials involving 3,453 participants were included. GLP-1 receptor agonists significantly reduced liver fat content (MD: -3.37%, 95% CI: -4.98 to -1.76, p < 0.001), ALT levels (SMD: -0.47, 95% CI: -0.73 to -0.22, p < 0.001), and AST levels (SMD: -0.29, 95% CI: -0.53 to -0.05, p < 0.05). Significant improvements were observed in HbA1c (SMD: -0.67, 95% CI: -0.99 to -0.34, p < 0.001), fasting glucose (MD: -0.60 mmol/L, 95% CI: -0.92 to -0.27, p < 0.001), HOMA-IR (SMD: -0.34, 95% CI: -0.66 to -0.02, p < 0.05), and total cholesterol (MD: -0.23 mmol/L, 95% CI: -0.30 to -0.15, p < 0.001). Liver stiffness showed no significant improvement (MD: -0.12 kPa, 95% CI: -0.75 to 0.50, p = 0.70). Dual GLP-1/GIP agonists demonstrated superior efficacy compared to mono GLP-1 agonists for reducing liver fat (MD: -7.15, 95% CI: -10.23 to -4.07, p < 0.001 versus MD: -2.44, 95% CI: -4.18 to -0.71, p < 0.01), representing a 2.9-fold greater effect. Long-term treatment (lasting over 48 weeks) demonstrated enhanced benefits across all outcomes. Overall, changes in body weight were not significant (MD: -1.51 kg, 95% CI: -4.07 to 1.06, p = 0.25). CONCLUSIONS: This meta-analysis provides evidence for the effectiveness of GLP-1 receptor agonists in managing MAFLD, with dual GLP-1/GIP agonists demonstrating superior hepatic benefits. Long-term therapy (lasting more than 48 weeks) is necessary for optimal outcomes. These findings support clinical implementation, particularly for patients with concurrent diabetes or obesity, positioning dual agonists as promising advancements in treatment.
Emerging Therapeutic Perspectives in Obese Patients with MASLD Leading to Compensated Advanced Chronic Liver Disease.
Biomolecules
Roberta Chianetta, Lydia Giannitrapani, Alessio Giuseppe Lipari +9 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognized as the principal hepatic manifestation of obesity and metabolic dysfunction. Its pathogenesis is complex and multifactorial, driven by insulin resistance, low-grade chronic inflammation, oxidative stress, gut microbiota alterations, and abnormalities in lipid metabolism; together, these promote steatosis, lipotoxicity, and progression to fibrosis which can lead to compensated advanced chronic liver disease (cACLD). MASLD is also a multisystem condition closely associated with an increased risk of major adverse cardiovascular events such as myocardial infarction, ischemic stroke, atrial fibrillation, and other extrahepatic complications. In this context, emerging metabolic therapies show significant potential for modifying the natural history of the disease. Glucagon-like peptide (GLP)-1 receptor agonists induce substantial weight loss and improve steatosis and necro-inflammatory activity. Sodium-glucose cotransporter 2 inhibitors (SGLT-2I) reduce glucotoxicity, promote modest weight loss, and lower hepatic fat content by improving insulin sensitivity and inflammatory signaling. Even more promising are dual GLP-1/GIP receptor agonists, which have demonstrated superior efficacy in metabolic control, reducing hepatic steatosis, and potentially modulating fibrotic processes, although definitive histological confirmation is still lacking. Overall, in this review, we discuss the physiopathological mechanisms of MASLD leading to cACLD along with the emerging therapies, such GLP1 receptor agonists, SGLT-2I, and GLP1/GIP which, when combined with structured lifestyle interventions, may attenuate progression toward steatohepatitis (MASH), fibrosis, and, thus, cirrhosis.
SHLP2 restores pre-osteoblastic cells against oxidative stress-induced inflammaging.
Sci Rep
Jeong-Hyun Ryu, Utkarsh Mangal, Jae-Hyung Kim +6 more
This study aimed to evaluate the cytoprotective effects of the mitochondrial-derived peptide, Small Humanin-Like Peptide-2 (SHLP2), on pre-osteoblastic cells exposed to sub-toxic oxidative stress, with the aim of preserving bone homeostasis under conditions of inflammaging. Pre-osteoblastic MC3T3-E1 cells were cultured under sub-toxic oxidative stress induced by 600 µM H2O2. The study evaluated the effects of SHLP2 (at 10 µM concentration) through assays for mitochondrial activity, reactive oxygen species (ROS) generation, apoptosis markers, and osteogenic differentiation. Quantitative polymerase chain reaction, alkaline phosphatase (ALP) staining, and Alizarin Red S biomineralization assays were performed to assess gene expression, osteogenic activity, and biomineralization. Oxidatively stressed but untreated cells served as the positive control (PC), while oxidative stress-free cells were used as the mock control. Statistical analyses were performed using one-way ANOVA and t-tests. SHLP2 treatment significantly (p < 0.001) improved cell viability and reduced ROS activity in oxidatively stressed cells. A significant (p < 0.001) decrease in apoptotic markers, including p53 and BAX, and an increase in anti-apoptotic BCL-2 levels, were observed. Additionally, SHLP2 treatment upregulated key osteogenic markers, including RUNX2, OSX, and ALP, compared to PC. When compared to the mock group, SHLP2 restored ALP activity to 95.6% by day 14. By day 21, the biomineralization assay demonstrated 94.92% activity following SHLP2 treatment. SHLP2 treatment effectively mitigates oxidative stress in pre-osteoblastic cells, providing apoptosis protection and preserving osteogenic activity. These findings underscore the potential of SHLP2 as an adjuvant therapeutic agent for enhancing the tissue microenvironment in conditions such as periodontitis and inflammaging.
Unilateral Adrenalectomy, and the Stable Pentadecapeptide BPC 157 as Therapy in Rats-A Cytoprotection Approach.
Pharmaceuticals (Basel)
Ivan Maria Smoday, Vlasta Vukovic, Katarina Oroz +19 more
Background. This rat study reveals a new point: the considerable impact of unilateral adrenalectomy, severe vascular and multiorgan failure, occlusion/occlusion-like syndrome, and the stable gastric pentadecapeptide BPC 157 therapy. Based on the recent Fourier transform infrared (FTIR) spectroscopy vascular disturbance studies, particularly those after unilateral adrenalectomy in rats, the noted cytoprotective vascular recovery effect of the BPC 157 therapy may be useful. Methods. In rats, unilateral adrenalectomy (at 15 min, 5 h, 24 h) leads to integrated gross and morphological changes, vascular alterations, oxidative stress parameters, molecular markers and occlusion/occlusion-like syndrome and BPC 157 as useful therapy (/kg ig) (10 µg, 10 ng). Results. Peripherally and centrally, counteraction includes the lesions (adrenal, brain, heart, lung, liver, kidney, gastrointestinal tract), organ hemorrhage, and thrombosis. Attenuated/eliminated were arrhythmias, intracranial (superior sagittal sinus), portal, caval hypertension, and aortic hypotension. Significant resolution occurred via activation of collateral pathways, the azygos vein (direct blood flow delivery), and the recovered peduncle of the inferior suprarenal artery and superior suprarenal vein. Virchow's triad circumstances were reversed. Occlusion/occlusion-like syndrome was counteracted as a whole. Also, BPC 157 counteracted adrenal lesions (lipid depletion, congestion). There were higher cortisol values, but still very low, and a shift toward the left of the adrenal compensatory weight increase. For the indicative conclusion along with previous studies, mechanistically, BPC 157 therapy exhibits the NO-system modulation/oxidative stress balance, increases NO-level, counteracts oxidative stress (malondialdehyde (MDA)), upregulates NOS1-3, and VEGF-A expression. Conclusions. These effects of BPC 157 therapy and its easy applicability deserve further consideration.
Redox-Responsive GHK-Conjugated Sponge Spicules for Sustained Dermal Delivery and Enhanced Collagen Synthesis.
Micromachines (Basel)
Won-Kyu Hong, Patrick Po-Han Huang, Diane Duncan +3 more
Sponge spicules have emerged as promising biomaterial scaffolds due to their biocompatibility and unique structural properties; however, achieving stable and bioactive functionalization remains a key challenge. The tripeptide GHK is known to promote collagen synthesis and wound repair, yet its therapeutic efficacy is often limited by rapid diffusion and instability. Here, we report ALTUM, a thiol-functionalized sponge spicule composite in which GHK is covalently conjugated via disulfide linkage to enable controlled and redox-responsive peptide delivery. ALTUM exhibited sustained GHK retention under physiological and storage conditions, while exposure to reduced glutathione (GSH) selectively accelerated peptide release through disulfide bond cleavage. This dual release behavior-long-term stability combined with reduction-triggered activation-distinguishes ALTUM from conventional delivery systems. The composite also demonstrated structural stability under thermal, cyclic, and photostability conditions. In an artificial human skin model, ALTUM enhanced dermal penetration of GHK and significantly increased collagen deposition in the dermal layer, demonstrating its capacity to promote collagen production within deeper skin tissue, compared to simple spicule-peptide mixtures. ALTUM was fabricated at an optimized spicule-to-peptide ratio of 3% (w/w), preserving the needle-shaped spicule morphology after surface modification. In vitro, ALTUM exhibited a sustained release profile, with GHK release markedly accelerated in the presence of 10 mM glutathione (GSH) compared with non-reductive conditions, reaching approximately 60% cumulative release over 35 days. In the bioprinted artificial human skin model, ALTUM delivered 9.72 ng/cm2 of GHK, more than five-fold higher than the physical mixture of spicules and free GHK (1.9 ng/cm2), and significantly increased type I collagen expression in human dermal fibroblasts. Mechanistically, ALTUM-mediated delivery was associated with increased TGF-β expression and engagement of the SMAD signaling pathway, as indicated by increased phosphorylation of SMAD2/3, consistent with involvement of the TGF-β-SMAD axis in the observed collagen induction. Collectively, these findings establish ALTUM as a structurally stable, redox-responsive dermal delivery platform that enhances collagen synthesis and skin regeneration.
The Ghrelin/GHSR-1a Axis Attenuates Preeclampsia-like Features with Decidual Macrophage Reprogramming and Improved Placental Remodeling.
Biomolecules
Lingling Zhang, Jiani Yuan, Ningning Hu +4 more
Preeclampsia (PE) is a severe pregnancy-specific hypertensive disorder characterized by immune microenvironment dysregulation at the maternal-fetal interface, with decidual macrophage phenotypic imbalance being a key pathological feature. The Ghrelin/growth hormone secretagogue receptor-1a (GHSR-1a) axis exerts immunomodulatory and anti-inflammatory effects, but its role in regulating decidual macrophage infiltration and phenotypic marker expression in PE remains unclear. In this study, we first detected the expression of the Ghrelin/GHSR-1a axis in decidual tissues from 10 healthy pregnant women and 12 PE patients via immunohistochemistry (IHC). We then established a lipopolysaccharide (LPS)-induced PE-like rat model to investigate the axis's functional role and underlying mechanisms. Intriguingly, clinical analysis revealed a severity-dependent compensatory escalation of the Ghrelin/GHSR-1a axis in PE decidual tissues, potentially representing an endogenous antagonistic response to pregnancy-associated pathological stress. In the animal model, exogenous Ghrelin supplementation reversed LPS-induced PE-like phenotypes, including hypertension, proteinuria, fetal growth restriction (FGR), and placental dysfunction, and alleviated pathological damage to the maternal liver, kidney, and placenta. Mechanistically, Ghrelin modulated decidual macrophage phenotypic marker expression by downregulating the M1 marker CD86 and upregulating the M2 marker CD163 and promoted trophoblast invasion and spiral artery remodeling by restoring laminin, α-cytokeratin 7 (α-CK7), and α-smooth muscle actin (α-SMA) expression in placental tissue. All protective effects of Ghrelin were abrogated by co-administration of D-lys-3-GHRP-6, a specific GHSR-1a antagonist, confirming the dependence on the Ghrelin/GHSR-1a axis. Collectively, our findings suggest that the Ghrelin/GHSR-1a axis is compensatorily upregulated in PE and may exert a protective role by regulating decidual macrophage phenotypic marker expression and improving placental function, providing preliminary evidence that this axis merits further investigation as a potential research target for PE.