Search Results (3,517)

The treatment of gastric ulcers based on antisecretory drugs is often associated with side effects and high recurrence rates, reinforcing the need for new therapeutic alternatives. Medicinal chemistry guided by natural prototypes represents a productive strategy in this context. The antiulcer potential of 2-phenylquinoline (2-PQ), an alkaloid from Conchocarpus longifolius (A.St.-Hil.) Kallunki & Pirani (syn. Galipea longiflora Krause), has been previously reported by our research group. In the present work, four 2-PQ derivatives were synthesized—2,4-diphenylquinoline (1), 2-(4-methoxyphenyl) quinoline (2), 2-phenylquinolin-4-ol (3), and 4-methoxy-2-phenylquinoline (4)—and evaluated for gastroprotective activity in the HCl/ethanol-induced gastric ulcer model in mice. The quinoline derivatives were prepared mainly by trifluoroacetic acid-catalyzed condensations of aminated benzaldehyde or benzophenone precursors with the corresponding ketones under reflux at 100 °C, affording yields of 68–94%. Compound 3 was synthesized via a two-step sequence involving the acylation of 2-aminobenzophenone followed by base-induced cyclization, providing an 85% yield. Compound 4 was obtained by O-methylation of compound 3 using iodomethane (MeI) and potassium carbonate (K₂CO₃) in dimethylformamide (DMF), affording a 95% yield. So, this study provides the first comparative analysis linking structural modifications to gastroprotective activity in synthetic quinoline derivatives inspired by 2-phenylquinoline, a natural alkaloid previously shown to exert gastroprotective effects. Carbenoxolone (200 mg/kg, p.o., positive control) inhibited gastric lesion formation by 94.1%. The synthetic quinoline derivatives also showed significant gastroprotective activity after oral administration (30 mg/kg), reducing ulcer area by 72.4% (compound 1), 76.1% (compound 2), 49.1% (compound 3), and 66.1% (compound 4). Compounds 2, 3, and 4 further retained efficacy following intraperitoneal administration (3 mg/kg), whereas compound 1 was inactivated by this route. Overall, compound 4 exhibited the greatest efficacy, significantly reducing the gastric lesion area, decreasing lipid hydroperoxide (LOOH) and tumor necrosis factor-alpha (TNF-α) levels, and increasing glutathione (GSH) content in ulcerated gastric tissue. These findings suggest that its gastroprotective effects are mediated by antioxidant and anti-inflammatory mechanisms, identifying compound 4 as the most promising candidate for the prevention and treatment of peptic ulcers. Its promising pharmacological profile warrants further investigation to elucidate its molecular mechanisms of action, assess its safety and efficacy in additional preclinical studies, and explore its potential for future therapeutic development. Full article

Background: MSC–hydrogel composite systems were developed to overcome the poor cell retention and limited durability of conventional marrow stimulation and suspension-based MSC delivery. A rigorous synthesis of the clinical evidence is lacking. Objectives: To evaluate the safety and efficacy of MSC–hydrogel composite therapy for focal knee cartilage defects and knee osteoarthritis, and to assess the certainty of evidence using the GRADE framework. Methods: PROSPERO-registered systematic review (CRD420261393525), conducted and reported per PRISMA 2020 and SWiM. Five databases (Embase, PubMed/MEDLINE, Cochrane CENTRAL, Scopus, Web of Science) were searched in May 2026 without date, language, or design restrictions. Adults receiving MSCs co-delivered in a hydrogel carrier for knee cartilage pathology were eligible. Risk of bias was assessed using RoB 2 (RCTs) and ROBINS-I (non-randomized studies). Narrative synthesis following Popay et al. was the primary method; GRADE certainty was assessed per outcome domain. Results: Ten studies (N = 521) were identified. Eight studies fulfilled the predefined eligibility criteria for MSC–hydrogel composite interventions and formed the primary evidence synthesis. Two additional studies were retained as contextual comparators because they evaluated either hydrogel-based therapy without MSC administration or MSC therapy without a structured hydrogel carrier. Surgical MSC–hydrogel implantation was associated with improvements in cartilage repair. Intra-articular injection without a hydrogel scaffold produced synovitis reduction but no detectable structural regeneration at six months. No serious treatment-related adverse events were recorded. Risk of bias was serious or critical in seven of nine assessable studies; GRADE certainty was low to very low across all outcome domains. Conclusions: MSC–hydrogel composite implantation may provide favorable safety signals and directionally positive effects on cartilage repair, pain, and function, with seven-year follow-up data suggesting a possible durability advantage over marrow stimulation. However, adverse-event reporting was inconsistent, and certainty of evidence remains low or very low because most studies were non-randomized, single-center, and concentrated around one commercial platform. These findings are relevant to international cartilage-regeneration research because they identify key methodological limitations and trial-design priorities for translating MSC–hydrogel systems across different clinical and regulatory settings. Full article

Our earlier studies have revealed the beneficial impact of vitamin D3 (VD3) metabolites on the development of pulmonary fibrosis in a murine model of hypersensitivity pneumonitis (HP). Despite the discovery of the great antifibrotic potential of both the bioactive form of VD3, 1,25(OH)₂-VD3 and its direct precursor, 25(OH)-VD3, study designs based on the co-administration of VD3-metabolites and fibrosis-inducers do not reflect the clinical situation. Thus, the presented study aims to examine the effectiveness of therapeutic interventions based on the mentioned inhalations, initiated during the acute phase of HP at the first signs of pulmonary fibrosis. The research was performed using VD3-deficient mice with HP, while VD3-sufficient mice were used as the main control. The data were collected after 28 days of daily exposure of the mice to a fibrosis-inducer (an antigen of Pantoea agglomerans, a well-known etiological factor in HP), with 25(OH)-VD3 or 1,25(OH)₂-VD3 administered daily during the last 14 days of the experiment. The effect of the intervention was monitored by whole-body plethysmography, histological assessment, flow cytometry, RealTime-PCR, and ELISA. Treatment with VD3 metabolites initiated during the acute phase of HP alleviated the disease courses and restored respiratory function, thanks to inhibition of pathological extracellular matrix deposition, immune-cell infiltration of lung parenchyma, profibrotic cytokine production, and EMT progression. Despite the discovery of the beneficial features of the investigated VD3-based therapies, none of them caused full recovery in mice with HP. Nevertheless, after verification in additional animal models and a deeper understanding of the underlying molecular mechanisms, the identified beneficial features of the investigated metabolites have the potential to serve as a foundation for future therapies for HP fibrosis. Full article

Human T-cell lymphotropic virus type 1 (HTLV-1) is a neglected pathogen with a heterogeneous global distribution. In low-prevalence areas, diagnostic testing is challenged by limited clinical awareness and the low positive predictive value of screening tests. We retrospectively analyzed 10,891 HTLV-1/2 test results from 7719 patient samples submitted to a specialized laboratory in Germany between 2004 and 2024. Antibody screening had a positive predictive value (PPV) of 31.7% for the Diasorin Murex HTLV I + II assay (39 of 123 reactive samples confirmed) and 34.5% for the Abbott Architect rHTLV-1/2 assay (67 of 194 reactive samples confirmed). Raising the sample/cutoff (s/co) threshold to ≥5 would have increased the PPV to >80%, with only two missed diagnoses per assay. HTLV-1 infection was confirmed in 124 carriers and HTLV-2 infection in three carriers. The vast majority of carriers originated from countries with higher endemicity. A delayed antibody response was observed in HTLV-1 infections via organ transplantation. In four patients with neurological disease, elevated HTLV-1/2-specific antibody indices showed antibody production in cerebrospinal fluid (CSF). HTLV-1 proviral load was measured in 83 carriers, with a median of 20,000 HTLV-1 DNA copies per 10⁶ cells (interquartile range, 4000–119,600). Seventy-four percent (17/23) of high-dose intravenous immunoglobulin (IVIg) preparations contained HTLV-1/2 antibodies, which can lead to false-positive HTLV-1/2 antibody screening results in recipients without underlying infection. Therefore, HTLV-1/2 testing presents two major pitfalls: false-negative results in immunosuppressed patients and false-positive results following IVIg administration. Full article

Background: The mechanisms underlying central nervous system oxygen toxicity (CNS-OT), which manifests as generalized seizures, remain poorly understood, thereby limiting the utility of hyperbaric oxygen therapy and deep-sea diving. This study investigates the distinct contributions of ionotropic N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors to hyperoxic seizure initiation and hippocampal neurodegeneration. Method: Male Wistar rats were assigned to seizure-monitoring groups (n = 86) exposed to 100% O₂ at 6 ATA until seizure onset: saline control; memantine (1, 5, 25 mg/kg); perampanel (0.2, 1, 5 mg/kg); memantine + perampanel combination (5 + 1 mg/kg); and methionine sulfoximine controls (50, 100 mg/kg). For morphological analysis (NeuN immunohistochemistry, 48 h post-exposure), separate groups (n = 8 per group) were exposed to HBO₂ for a fixed 30 min duration, alongside a normobaric room-air control (n = 8). Seizure latency and progression (Racine scale) were analyzed via one-way ANOVA and Tukey’s test. Results: Paradoxically, NMDA receptor blockade with memantine completely failed to protect animals, significantly accelerating seizure onset (p < 0.05). Conversely, non-competitive AMPA inhibition with perampanel (1, 5 mg/kg) exerted a powerful, dose-dependent anticonvulsant effect and prevented hippocampal CA1/CA3 cell death. Perampanel co-administration completely mitigated the proconvulsant acceleration induced by memantine, demonstrating that AMPA receptor activation, rather than NMDA signaling, serves as the true primary upstream trigger for hyperoxic convulsions. Conclusion: Our findings sharply contrast with the established priority of NMDA glutamate receptors in epileptogenesis, revealing a novel neurochemical mechanism under extreme hyperoxia. We identify fast-acting AMPA receptors as the definitive principal molecular targets for mitigating CNS oxygen toxicity. Full article

Hyperlipidemia (HL) is a major metabolic disorder and a critical risk factor for cardiovascular diseases, closely associated with oxidative stress, inflammation, and disrupted cholesterol homeostasis. Freeze-dried Poecilobdella manillensis powder (FDPMP), a traditional medicinal product, has shown therapeutic potential against hyperlipidemia; however, its underlying mechanisms remain largely unclear. In this study, HL was induced in ApoE⁻/⁻ mice by feeding a high-fat diet (HFD) for eight weeks, during which FDPMP or simvastatin (positive control) was orally administered daily. Concurrently, an in vitro foam cell model was established by exposing RAW264.7 macrophages to oxidized low-density lipoprotein (ox-LDL, 80 μg/mL) for 24 h, with FDPMP pretreatment applied 30 min prior to ox-LDL stimulation. Following intervention, serum lipid profiles, hepatic oxidative stress markers, histopathological changes, and cholesterol metabolism-related gene and protein expression were systematically evaluated. FDPMP administration significantly improved serum lipid profiles by reducing triglycerides, total cholesterol, and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol levels. Additionally, FDPMP alleviated histopathological damage in the liver, kidney, and heart, enhanced antioxidant enzyme activities, and attenuated oxidative stress. Untargeted metabolomic analysis revealed that FDPMP markedly modulated key metabolic pathways, including choline metabolism, glycerophospholipid metabolism, and arachidonic acid metabolism. Mechanistically, FDPMP restored cholesterol homeostasis through dual regulation of cholesterol metabolism, characterized by upregulation of cholesterol 7α-hydroxylase (CYP7A1) to promote bile acid-mediated cholesterol excretion, alongside downregulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and synthase (HMGCS1) to inhibit cholesterol biosynthesis. In vitro, FDPMP effectively suppressed ox-LDL-induced foam cell formation, reduced intracellular lipid accumulation, and mitigated oxidative stress in macrophages. Collectively, these findings demonstrate that FDPMP ameliorates hyperlipidemia through coordinated regulation of cholesterol synthesis and excretion, coupled with systemic metabolic reprogramming and antioxidative effects. This study provides mechanistic insights supporting FDPMP as a promising natural therapeutic candidate for hyperlipidemia and related metabolic disorders. Full article

Background: Hyperuricemia is a well-established risk factor for both chronic kidney disease and gout. Currently available urate-lowering drugs, however, are frequently compromised by hepatorenal toxicity and gastrointestinal adverse effects. Cinnamaldehyde, the principal bioactive constituent of the traditional Chinese medicine cinnamon, has documented renoprotective properties, yet its integrated effects on hyperuricemia-associated renal injury remain incompletely defined. Objectives: This study investigated the therapeutic effects of cinnamaldehyde on hyperuricemia and explored the molecular mechanisms involved. Materials and Methods: An in vivo hyperuricemia model was established in KM mice by co-administration of potassium oxonate and hypoxanthine for 14 consecutive days, and an in vitro injury model was generated by exposing HK-2 human renal tubular epithelial cells to uric acid. For the in vivo study, mice were divided into five groups (control, model, febuxostat, low-dose CA, and high-dose CA; n = 9 per group) and were treated by oral gavage. Serum biochemical indices, renal and intestinal histopathology, inflammatory cytokines, renal urate transporter proteins (OAT1, OCT2, ABCG2, and SLC2A9), and components related to AIF1 and CMPK2/NLRP3 inflammasome signaling (ASC, caspase-1, IL-18, and IL-1β) were examined. Western blotting, qPCR, immunofluorescence, apoptosis analysis, mitochondrial membrane potential assessment, transmission electron microscopy, siRNA-mediated knockdown, and 16S rRNA gene sequencing were used to characterize the relevant mechanisms. Results: CA reduced serum uric acid (p ≤ 0.001 vs. model), creatinine (p ≤ 0.01 vs. model), and blood urea nitrogen (p ≤ 0.01 vs. model), alleviated renal and intestinal histopathological injury, and decreased circulating and renal inflammatory cytokines. Cinnamaldehyde increased ABCG2, OAT1, and OCT2 protein expression and reduced SLC2A9 expression (all p ≤ 0.05 vs. model). In vivo and in vitro, cinnamaldehyde suppressed AIF1- and CMPK2/NLRP3-related inflammatory proteins, reduced uric acid-induced apoptosis, and preserved mitochondrial membrane potential and ultrastructure. Fecal 16S rRNA sequencing suggested changes in selected microbial taxa, although alpha-diversity and BrayCurtis-based PERMANOVA/ANOSIM analyses did not demonstrate significant global community separation. Conclusions: These findings suggest that CA alleviates hyperuricemia-associated renal injury by regulating renal urate transporters, attenuating AIF1- and CMPK2/NLRP3-related inflammatory signaling, accompanied by compositional shifts in selected gut microbial taxa that warrant further mechanistic investigation. The study provides experimental support for further evaluation of cinnamaldehyde as a multi-target candidate for hyperuricemia-related renal injury. Full article

Background: Former and current smokers in lung cancer screening remain at elevated risk for lung cancer despite smoking cessation. We and others have shown that curcumin (CUR) exhibits anti-inflammatory and antiproliferative effects but is limited by poor bioavailability. However, since CUR is lipophilic, co-administration with ω-3 FAs represents a mechanistically rational strategy to enhance delivery and target complementary pathways, including signal transducer and activator of transcription 3 (STAT3) and the transcription factor NF-κB (NF-κB) signaling for lung cancer chemoprevention. Methods: We conducted a randomized, single-blind, placebo-controlled Phase II pilot study evaluating CUR combined with ω-3 FAs in high-risk former and current smokers with CT-detected pulmonary nodules. Participants received intervention agents with active-dose groups (low dose = 3; high dose = 9) or a placebo (n = 7) for 6 months. Primary endpoints included radiologic changes in nodule size, number, and density. Secondary endpoints included safety, adherence to the study agent and exploratory biomarker analyses. Correlation analyses of imaging-derived metrics were performed to assess relationships among LDCT parameters. Results: Nineteen participants were enrolled (intervention, n = 12; placebo, n = 7). Eighteen (11 intervention, 7 placebo) subjects completed post-intervention imaging. One subject was unable to complete follow-up and study-related procedures. Data from the treatment arms were pooled for analysis and comparison with the placebo arm. No statistically significant between-group differences were observed in primary imaging endpoints. The intervention was well tolerated, with predominantly grade 1 adverse events. Exploratory analyses demonstrated consistent positive correlations among established imaging biomarkers, with clustering of size-based metrics (mean diameter, volume, sum of longest diameters) and density-based parameters. Multidimensional scaling supported this structure, indicating internal coherence among imaging-derived endpoints. Conclusions: Although no statistically significant treatment effect on the image biomarkers was observed, this pilot study demonstrates feasibility challenges and identifies coherent imaging biomarkers that may serve as intermediate endpoints in early-phase chemoprevention trials. These results support further investigation of strategies utilizing agent combinations with enhanced bioavailability and safety and refinement of trial design in high-risk lung cancer patient populations. Full article

Objective: To evaluate whether human adipose-derived mesenchymal stem cells (ADSCs) protect against ᴅ-galactose (ᴅ-gal)-induced aging-like testicular injury and to investigate the involvement of the Keap1/Nrf2 pathway and NLRP3-associated pyroptosis. Methods: A mouse model of aging-like testicular injury was established by subcutaneous administration of ᴅ-gal for 8 weeks, followed by tail vein injection of ADSCs. Testicular morphology, blood–testis barrier (BTB) integrity, and senescence-associated markers (p16, p21) were assessed. In vitro, TM4 Sertoli cells were used to establish a senescence model and Tranwell co-cultured with ADSCs. Oxidative stress, inflammatory responses, and pyroptosis-related markers were evaluated using biochemical assays, immunofluorescence, Western blotting, and RT-qPCR. The involvement of the Keap1/Nrf2-NLRP3 axis was further examined using pharmacological inhibitors. Results: ADSC treatment significantly alleviated ᴅ-gal-induced testicular atrophy and histopathological injury, accompanied by reduced expression of the senescence markers p16 and p21 and partial restoration of BTB-related structures. ADSCs also attenuated oxidative stress, as evidenced by decreased ROS and MDA levels, increased SOD activity, and enhanced expression of Nrf2 and its downstream antioxidant targets, including HO-1 and NQO1. In parallel, ADSC administration suppressed NLRP3 activation, reduced caspase-1 cleavage, and lowered the expression of pro-inflammatory cytokines. In TM4 cells, inhibition of Nrf2 weakened the protective effects of ADSCs and was accompanied by reactivation of NLRP3-associated signaling, whereas inhibition of NLRP3 attenuated senescence- and inflammation-related changes without restoring Nrf2 activity. Conclusions: ADSCs alleviate ᴅ-gal-induced aging-like testicular injury, at least in part, by restoring redox balance, preserving BTB-associated structure, and suppressing NLRP3-associated pyroptosis through the Keap1/Nrf2 pathway. These findings suggest that ADSC-based therapy may represent a promising strategy for age-related male reproductive dysfunction, while further studies using genetic models and functional fertility endpoints are needed to confirm causality and translational relevance. Full article

Ulcerative colitis is characterized by inflammation, oxidative stress, and excessive free radical production. This study investigated the antioxidant, anti-inflammatory, and protective effects of N-acetylcysteine (NAC), Tiron, and their fixed-ratio combination in acetic acid-induced colitis. An integrated approach was used, combining ligand–ligand docking, acellular antioxidant and protein-denaturation assays, and an in vivo model in male Wistar rats. Colitis was induced by intrarectal administration of 3% acetic acid after 14 days of intraperitoneal pretreatment with NAC, Tiron, or NAC–Tiron. Docking analysis suggested physicochemical compatibility through non-covalent interactions. In vitro, NAC, Tiron, and their combination showed antioxidant and anti-denaturation activities. NAC–Tiron displayed greater activity than the individual compounds in selected endpoints, particularly 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, but did not consistently outperform them across the other assays. In vivo, NAC, Tiron, and NAC–Tiron attenuated macroscopic and histological colonic damage, reduced inflammatory cell infiltration and edema, decreased lipid peroxidation and protein carbonylation, and helped preserve superoxide dismutase (SOD) activity, reduced glutathione (GSH), and total thiols. The treatments also attenuated increases in C-reactive protein (CRP) and free iron without evident worsening of the measured systemic biochemical parameters. Overall, these findings provide an exploratory proof of concept for fixed-ratio NAC–Tiron co-administration but do not establish pharmacological synergy or superiority over standard therapies. Full article

Ketamine produces clinical states ranging from subanesthetic analgesia and dissociation to anesthetic-dose behavioral unresponsiveness. Its electroencephalographic (EEG) effects differ from the slow-delta and frontal-alpha patterns commonly observed with GABAergic-dominant anesthetics and vary with exposure, administration kinetics, and co-administered agents. After anesthetic bolus dosing, ketamine may produce alternating slow-delta and gamma activity; at lower exposures, spectral and connectivity findings are more heterogeneous. When ketamine is added to propofol or volatile anesthesia, bispectral index and spectral-entropy values may remain elevated or increase, limiting their interpretation as stand-alone measures of hypnotic state. Prior syntheses have largely addressed molecular, cellular, and cortical-circuit mechanisms of dissociation; this narrative review instead synthesizes human EEG, connectivity, imaging, and selected mechanistic evidence using a dose–state framework. We distinguish behavioral responsiveness, environmental connectedness, and conscious experience; assess which network measures are technically derivable from clinical scalp recordings; and consider implications for operating-room and critical-care monitoring. Available evidence supports a cautious interpretation of processed indices and greater attention to the raw EEG, spectrogram, background hypnotic, administration pattern, and clinical context. Validated ketamine-specific EEG biomarkers and prospective monitoring algorithms are not yet available. Potential links between acute EEG effects and antidepressant mechanisms are discussed as shared upstream pathways rather than a single electrophysiological state. Full article

Azelaic acid (AZA) and salicylic acid (SA) are widely used active ingredients in pharmaceutical and cosmetic formulations for the treatment of acne, rosacea, hyperpigmentation, and other dermatological conditions. Despite their frequent co-administration, analytical methods for their simultaneous determination remain limited. In the present study, a capillary electrophoresis (CE) method with indirect UV detection was developed and validated for the simultaneous determination of AZA and SA in pharmaceutical and cosmetic preparations. Preliminary experiments demonstrated that direct UV detection was unsuitable because of the weak UV absorbance of AZA; therefore, indirect UV detection based on a sodium benzoate background electrolyte (BGE) was used. Following an initial one-factor-at-a-time (OFAT) screening, method optimization was performed using a face-centered central composite design (CCD) to evaluate the effects of BGE concentration, BGE pH, and separation voltage on the separation. The optimum separation was achieved using a 30 mM sodium benzoate BGE at pH 6.5 containing 5% (v/v) methanol, a separation voltage of +18 kV, a capillary temperature of 20 °C, and indirect UV detection at 230 nm. Baseline separation of both analytes was achieved within 5 min. The method was validated according to the ICH Q2(R2) guideline and demonstrated satisfactory accuracy, linearity, precision, selectivity, sensitivity, and robustness. The developed procedure was successfully applied to the analysis of commercial cosmetic formulations containing AZA, SA, or both active ingredients, providing assay results consistent with the declared contents. The proposed CE method provides a simple, rapid, cost-effective, and environmentally friendly alternative for the routine quality control of pharmaceutical and cosmetic formulations containing AZA and SA. Full article

Sodium arsenite (SA) is an environmental chemical toxin that induces hepatotoxicity and cellular ferroptosis under exposure. Ferroptosis is characterized by elevated ferrous ion levels and decreased glutathione peroxidase 4 (GPX4) activity. Lentinan (LNT), a bioactive polysaccharide derived from shiitake mushrooms, was investigated for its regulatory effects on SA-induced hepatotoxicity. In vivo experiments demonstrated that LNT ameliorated SA-induced hepatic lipid accumulation, increased GPX4 content and the mRNA levels of AMP-activated protein kinase (AMPK), and decreased ferrous ion concentrations in the livers of mice. However, co-administration of the AMPK inhibitor compound C and LNT negated these protective effects on hepatic lipid accumulation and ferroptosis-related markers. Complementary in vitro studies revealed that LNT activates AMPK signaling, mimicking the antagonistic effects of the AMPK agonist metformin (Met) on lipid accumulation and ferroptosis in hepatocytes exposed to SA. Notably, immunoblotting analyses indicated that treatment with LNT or Met increased the LC3-II/LC3-I ratio and upregulated the expression of ULK1 and the lipophagy receptor oxysterol-binding protein-related protein 8 (ORP8). Furthermore, co-immunoprecipitation assays demonstrated enhanced interaction between ORP8 and ULK1, suggesting activation of the AMPK-mediated ORP8/ULK1 signaling pathway. This pathway appears to play a protective role against SA-induced hepatic lipid accumulation and ferroptosis. Collectively, these findings elucidate the beneficial effects of LNT-mediated AMPK activation in mitigating SA-induced lipid accumulation and ferroptosis in the liver. Full article

Background/Objectives: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved for weight management as both a weekly subcutaneous (s.c.) injection (2.4 mg) and a daily oral tablet (50 mg). Although head-to-head trials are lacking, the oral formulation offers potential advantages in adherence, patient preference, and accessibility. This systematic review critically appraised comparative and formulation-specific evidence to characterise the efficacy, safety, pharmacokinetics, and patient-reported outcomes of oral vs. s.c. semaglutide in adults with obesity or overweight with at least one weight-related comorbidity. Methods: PubMed, Google Scholar, and SciSpace were searched from inception to June 2025, applying PRISMA 2020 guidelines. Eligibility criteria (PICO): adults with BMI ≥ 27 kg/m²; intervention, oral semaglutide (any dose); comparator, s.c. semaglutide or placebo; outcomes, body weight, BMI, cardiometabolic markers, adverse events, adherence. Risk of bias was assessed with RoB 2.0 (RCTs) and AMSTAR-2 (systematic reviews). Results: Thirty studies met inclusion criteria (12 RCTs, nine systematic reviews/meta-analyses, five comparative/observational studies, four pharmacokinetic studies). OASIS 1 demonstrated −15.1% body weight reduction with oral semaglutide 50 mg at 68 weeks, comparable to s.c. semaglutide 2.4 mg (−14.9% in STEP 1). Both formulations significantly improved HbA1c, blood pressure, and lipid profiles. Oral bioavailability (~1%) requires co-administration with the SNAC absorption enhancer; s.c. bioavailability is ~89%. Oral semaglutide showed superior patient preference and equivalent adherence in needle-averse patients. Conclusions: Oral semaglutide 50 mg is a clinically valid alternative to s.c. semaglutide for obesity management, offering equivalent efficacy and an improved patient experience for individuals who prefer needle-free treatment. Robust direct comparative trials are needed. Full article

Background: Hepatocellular carcinoma (HCC) is a highly lethal malignancy and remains a major contributor to global cancer mortality. In situ vaccination (ISV) holds great potential for HCC therapy. Still, its efficacy is severely limited by intrinsic antigen scarcity and the tumor-associated macrophage (TAM)-mediated inhibition of dendritic cell (DC) maturation and T cell activation. In particular, the M2 TAM-HCC cell crosstalk may further aggravate ISV suppression. Moreover, as an internal organ tumor, HCC requires systemic administration of ISV agents, which often cause severe off-target toxicity. Methods: To address these challenges, we developed secretory phospholipase A2 (sPLA₂)-responsive liposomes co-loaded with the TLR7/8 agonist R848 and the ICD inducer doxorubicin (DOX) via a sequential remote loading method, termed sP-Lips@DR. Results: Incorporation of cholesterol (CHOL) significantly improved DOX encapsulation, and the sequential loading method enabled efficient co-encapsulation of both R848 and DOX. sP-Lips@DR responds to an sPLA₂-overexpressed, mildly acidic microenvironment in HCC, enabling selective drug release. In addition, sP-Lips@DR exhibited sPLA₂-responsive cytotoxicity toward H22 cells and macrophage phenotypic shift. Furthermore, sP-Lips@DR could disrupt the crosstalk between M2-like macrophages and H22 cells in an sPLA₂-responsive manner. Conclusions: Overall, the preparation and in vitro evaluation of sP-Lips@DR demonstrate their potential to enhance ISV efficacy in HCC, providing a solid foundation for future in vivo investigations. Full article