Objective: To investigate whether TAK1 regulates lipid-induced macrophage polarization and contributes to inflammatory progression in obesity cardiomyopathy (OCM). Background: OCM is characterized by lipid overload, chronic low-grade inflammation, macrophage polarization imbalance, and myocardial remodeling. Preliminary internal RNA-Seq data suggested that TAK1 may be involved in obesity-related cardiac pathological remodeling. However, its regulatory role in lipid-induced macrophage polarization remains unclear. Methods: Network pharmacology was performed to determine whether TAK1 was located within an OCM-related metabolic-inflammatory target network. OCM-related targets and compound-intervention-related targets were retrieved from public databases, followed by overlap analysis, protein–protein interaction analysis, and GO/KEGG enrichment. A high-fat diet-induced rat model was used to assess cardiac function, myocardial remodeling, TAK1 expression, and cardiac macrophage polarization. In vitro, NR8383 macrophages were exposed to palmitic acid (PA, 400 μM, 24 h), followed by TAK1 overexpression or knockdown. Macrophage polarization and inflammatory signaling were evaluated by RT-qPCR and Western blotting. Results: Network pharmacology identified 125 overlapping targets within the OCM-related intervention target space. The PPI network contained 108 nodes and 486 edges. AKT1, STAT3, IL6, TP53, and TNF were the top hub genes. TAK1 showed a degree value of 20 and interacted directly with NFKB1, IL1B, and TNF. Enrichment analysis indicated involvement of glucose homeostasis, cardiac contraction, protein serine/threonine kinase activity, insulin signaling, AGE-RAGE signaling, and HIF-1 signaling. In vivo, high-fat diet-induced obesity and OCM were accompanied by increased TAK1 expression and altered cardiac macrophage polarization. In vitro, PA increased TAK1 and CD86 expression and decreased CD163 expression. TAK1 overexpression enhanced iNOS, NF-κB, and IL-12 expression and suppressed Arg1 and IL-10 expression. TAK1 knockdown reversed these changes. Conclusions: TAK1 is positioned within an OCM-related metabolic-inflammatory network and is upregulated during OCM progression. Functional validation suggests that TAK1 contributes to lipid-induced M1 macrophage polarization, in association with NF-κB-related inflammatory signaling.
Background: Diabetes management in patients with hematologic malignancies is challenging because of advanced age, multimorbidity, and cancer-related therapies. However, real-world evidence regarding glycemic control in this population remains limited. We aimed to evaluate glycemic control, glucose-lowering treatment patterns, and factors associated with tight glycemic control in patients with type 2 diabetes and hematologic malignancies. Methods: This retrospective cross-sectional study included 86 adults treated at a tertiary university hematology department. Demographic, clinical, laboratory, and treatment data were extracted from medical records. Low measured glycated hemoglobin (HbA1c) was defined as HbA1c <6.5%. Associated factors were examined using exploratory multivariable logistic regression. Results: The mean age was 75.0 ± 11.6 years; 48 patients (55.8%) were men. Among the 80 patients with available HbA1c measurements, the median HbA1c was 6.6% (interquartile range 6.0–7.2), and 37 (46.3%) had HbA1c <6.5%. Exploratory regression analyses suggested higher odds of HbA1c <6.5% with higher estimated glomerular filtration rate (adjusted odds ratio [OR], 1.03; 95% confidence interval [CI], 1.002–1.055; p = 0.035) and lower odds with diabetic vascular complications (adjusted OR, 0.30; 95% CI, 0.09–0.99; p = 0.048). At the alternative HbA1c threshold of <7.0%, corticosteroid exposure was associated with lower odds (adjusted OR, 0.35; 95% CI, 0.13–0.98; p = 0.046). Fifteen patients (18.8%) had HbA1c <6.5% while receiving insulin and/or a sulfonylurea. Conclusions: Low HbA1c values were common in this cohort, including among patients receiving insulin and/or sulfonylureas. These findings describe low measured HbA1c and associated treatment patterns but do not establish unnecessarily intensive treatment, clinical inappropriateness, hypoglycemia, or treatment-related harm. Prospective studies incorporating individualized treatment targets and documented hypoglycemia are needed to clarify their clinical significance.
Background: Niemann–Pick disease type C (NPC) is a rare, progressive lysosomal storage disorder characterized by impaired intracellular lipid trafficking, leading to systemic, neurological, and psychiatric manifestations. Although supportive care was historically the main treatment approach, several disease-modifying and symptomatic therapies have recently emerged. This systematic review aimed to evaluate the efficacy and safety of current therapeutic strategies for NPC. Methods: A systematic literature search was conducted in PubMed, Scopus, and ClinicalTrials.gov from inception to 1 August 2026. Eligible studies included randomized controlled trials and interventional clinical studies involving patients with NPC of any age or sex. Interventions included miglustat, arimoclomol, N-acetyl-L-leucine (NALL), hydroxypropyl-β-cyclodextrin (HPβCD), vorinostat, N-acetylcysteine (NAC), efavirenz, nizubaglustat and other therapeutic strategies. Outcomes included neurological progression, clinical severity scores, ataxia measures, quality of life, biomarkers, cognition, and adverse events. Due to heterogeneity in study designs and outcome measures, findings were synthesized narratively. Results: Twenty-four studies representing approximately 475 participants, after removal of documented cohort overlap, were included. Miglustat showed evidence of neurological stabilization, particularly when initiated early, with mainly gastrointestinal adverse effects. Arimoclomol demonstrated evidence of slowing neurological progression and was generally well tolerated, although longer-term safety and effectiveness data remain necessary. NALL improved ataxia-related symptoms and was generally well tolerated. HPβCD demonstrated biological target engagement, including changes in cholesterol-related biomarkers, but clinical findings were mixed: uncontrolled intrathecal and intravenous studies suggested stabilization or improvement, whereas controlled evidence was less supportive. Hearing impairment remained an important safety concern. Evidence for vorinostat, NAC, efavirenz, and nizubaglustat was limited by small samples and early-phase or uncontrolled designs. Conclusions: The available evidence most consistently supports miglustat, arimoclomol, and NALL for stabilizing neurological progression or improving functional outcomes in NPC. However, differences in study design, outcome measures, and follow-up preclude direct comparison between therapies. HPβCD remains investigational because its biological activity has not translated into consistent controlled clinical benefit and requires careful safety monitoring. Larger controlled studies using standardized clinical outcomes and reliable biomarkers are needed to define long-term effectiveness and optimize treatment selection.
Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options. Although Fagopyrum cymosum exhibits anti-inflammatory and antioxidant activities, its efficacy in UC and the underlying mechanisms are not well defined. Here, we evaluate whether Fagopyrum cymosum extract (RFC) alleviates DSS-induced colitis in mice and investigate the involvement of the PI3K/Akt/FOXO3A pathway. Methods: C57BL/6 mice received 2% DSS for 14 days, followed by 7-day intragastric RFC (low: 234 mg/kg; medium: 468 mg/kg; high: 936 mg/kg) with 5-ASA (200 mg/kg) as a control. Disease activity index (DAI), colon length, histopathology, bacterial translocation, and organ indices were assessed. Colonic mitochondrial membrane potential (JC-1), ATP, oxidative markers (SOD, GSH-px, MDA), and cytokines (IL-6, IL-1β, TNF-α) were measured. Network pharmacology, qPCR, and Western blotting were performed, alongside a PI3K agonist (740Y-P) rescue experiment. Results: RFC dose-dependently improved weight loss, DAI, colon shortening, mucosal damage, bacterial loads, and immune organ indices. It restored mitochondrial function, reduced MDA, elevated SOD/GSH-px, and suppressed inflammatory cytokines. Mechanistically, RFC inhibited PI3K/Akt phosphorylation and upregulated FOXO3A, effects reversed by 740Y-P, which also abolished RFC’s protective, antioxidant, and anti-inflammatory actions. Conclusions: RFC ameliorates DSS-induced colitis by suppressing PI3K/Akt signaling and upregulated FOXO3A expression, thereby preserving mitochondrial function, reducing oxidative stress, and alleviating colonic inflammation. The PI3K/Akt/FOXO3A axis emerges as a promising therapeutic node, and RFC merits further evaluation for UC treatment.
The present paper is based on a long personal experience of research on the retina. Over almost forty years, questions that were originally pursued as curiosity-driven physiology progressively acquired unexpected translational implications. The retina provides a particularly instructive setting in which to examine translational potential because its accessible and highly organized neural and vascular architecture has allowed mechanisms identified in experimental models to be tested as potential therapeutic targets. Three research trajectories from our laboratory are discussed as examples of different translational outcomes. Studies of the somatostatinergic system illustrate how a strong mechanistic rationale and convincing preclinical efficacy may not necessarily translate into comparable clinical benefit. Investigations of the uPA/uPAR system and its pharmacological inhibition show how a candidate that does not reach clinical application may nevertheless provide durable insight into disease mechanisms and identify biologically relevant pathways. Conversely, studies of β-adrenoceptor signaling and propranolol in retinopathy of prematurity illustrate how drug repurposing can shorten the distance between experimental evidence and clinical investigation, while still leaving important questions about dose, safety, and delivery. These experiences also highlight model selection, disease stage, pharmacokinetics, tissue exposure, reproducibility and patient heterogeneity as critical determinants of translational success. Taken together, my experience of research on the retina suggests that translation should be viewed not as a one-way progression from bench to bedside, but as an iterative process in which experimental findings, clinical outcomes and even unsuccessful therapeutic attempts continuously reshape biological questions.
