Mangiferin, a C-glucosyl xanthone from Mangifera indica, has known antidiabetic activity, but the specific protein target underlying this activity, and its compatibility with existing antidiabetic drugs such as Atorvastatin, were not defined. In this work, machine learning, network pharmacology, molecular dynamics simulations, and experimental validation identified and validated TGFBR1 as a novel molecular target of Mangiferin and evaluated a Mangiferin-Atorvastatin combination for diabetes therapy. A curated collection of TGFBR1 inhibitors from BindingDB was used to train several supervised learning models, with the best performance from Random Forest (94.68% accuracy, κ = 0.8981) and robust external validation (79.35%) on 868 unseen compounds. Screening of 545 M. indica phytochemicals with this model identified Mangiferin, Fisetin, Isochinomin, Mangiferolic acid, and Astragalin as high-confidence TGFBR1 inhibitors. Network pharmacology identified TGF-β as the most central protein in the interaction network (cumulative score 350), and molecular docking showed that Mangiferin forms stable hydrogen bonds with SER-287, ILE-211, and GLU-208 at the TGFBR1 binding site, together with hydrophobic contacts. This binding pose remained structurally stable (RMSD 1.50-1.75 Å) over 100 nanoseconds of molecular dynamics simulation, with ligand-residue occupancy > 85%. ADMET profiling showed favorable drug-likeness (Lipinski compliance, low predicted toxicity) with a moderate permeability limitation (TPSA 201.28 Å[2]), and DFT analysis showed a HOMO-LUMO gap of 2.85937 eV, supporting antioxidant activity. In cultured cells, Atorvastatin combined with Mangiferin increased apoptosis through the mitochondrial pathway (Bcl-xL downregulation, BAK upregulation, cytochrome c release, caspase-7/8 activation) and enhanced insulin sensitivity, shown by increased glucose uptake (2-NBDG assay) and higher GLUT-4 and pIRS-1(Tyr896) expression. In high-fat diet-fed rats, Atorvastatin plus Mangiferin given for 24 weeks significantly improved glucose tolerance and reduced HbA1c, total cholesterol, triglycerides, and random blood sugar relative to untreated high-fat diet controls, with preserved pancreatic architecture and increased muscle GLUT-4 expression. These findings identify TGFBR1 as a plausible molecular target of Mangiferin and provide a mechanistic rationale for the Mangiferin-Atorvastatin combination as a candidate antidiabetic therapy.

This study aimed to investigate the effect of quercetin on atherosclerosis(AS) in apolipoprotein E knockout(ApoE~(-/-))mice and the mechanism underlying the regulation of cholesterol efflux mediated by adenosine triphosphate-binding cassette transporter A1/G1(ABCA1/G1) pathway and neutrophil extracellular traps(NETs) formation. An AS model was established by feeding Apo E~(-/-)mice with a high-fat diet. The mice were divided into a blank control group, a model group, an atorvastatin calcium group, and lowand high-dose quercetin groups. Serum levels of total cholesterol(TC), triglyceride(TG), low-density lipoprotein cholesterol(LDLC), high-density lipoprotein cholesterol(HDL-C), interleukin(IL)-6, tumor necrosis factor-α(TNF-α), and IL-1β were measured using biochemical methods. Biliary cholesterol excretion rate was determined by acute bile duct cannulation. Hepatic pathology and aortic plaque area were observed by hematoxylin-eosin(HE) and oil red O staining. Collagen and elastic fiber changes in plaques were evaluated by Masson and Verhoeff's Van Gieson(VVG) staining. CD3 and CD68 protein expressions in the aortic root and the colocalization of citrullinated histone H3(Cit-H3) and myeloperoxidase(MPO) were detected by immunohistochemistry and immunofluorescence double staining, respectively. ABCA1 and ABCG1 protein expressions in liver and aortic tissues were detected by Western blot. The results showed that in the model group, serum levels of TC, TG, LDL-C, IL-6, TNF-α, and IL-1β were significantly elevated, hepatic lipid deposition was pronounced, aortic plaque area was enlarged, collagen deposition and elastic fiber rupture were aggravated, inflammatory cell infiltration and NET formation in plaques were enhanced, whereas serum HDL-C level,biliary cholesterol excretion rate, and ABCA1 and ABCG1 protein expressions decreased. Following quercetin intervention, all these abnormal indicators were significantly improved, as evidenced by reduced blood lipid and inflammatory cytokine levels, alleviated hepatic lipid deposition, decreased aortic plaque area, stabilized collagen and elastic fiber architecuture in plaques, suppressed inflammatory cell infiltration and NET formation, accelerated biliary cholesterol excretion, and upregulated ABCA1 and ABCG1 protein expressions. The effects of quercetin were dose-dependent, and the high-dose group showed comparable efficacy to atorvastatin calcium. In conclusion, quercetin may effectively attenuate the progression of AS in Apo E~(-/-)mice by upregulating ABCA1/G1-mediated cholesterol efflux, inhibiting NET formation, and alleviating inflammatory responses.

Atorvastatin is a well-established first-line medication for treating dyslipidemia, but has significant drawbacks of low aqueous solubility, extensive first-pass metabolism, and limited oral bioavailability. Over recent years, lipid-based nanocarriers have emerged as a viable platform to improve atorvastatin's pharmacokinetic profile by enhancing solubility, facilitating absorption via the lymphatic system, and providing a controlled drug release profile. This review provides a comprehensive overview of four primary lipid-based delivery systems: solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), liposomes, and self-nanoemulsifying drug delivery systems (SNEDDS), and their specific application to atorvastatin. Each type of delivery system is reviewed in detail, including composition, drug loading and release mechanisms, encapsulation efficiency, physical characteristics (particle size, surface charge), and in vivo performance. Comparative evaluations indicate that NLCs and SNEDDS achieve the highest bioavailability enhancements (up to five-fold) via improved solubilization and lymphatic transport, whereas SLNs provide superior stability and controlled release, and liposomes offer versatile encapsulation yet limited shelf stability. Additionally, this review integrates current competitive patent opportunities, formulation optimization strategies, and translational research findings from both preclinical and clinical studies. Collectively, these findings show that thoughtful lipid-carrier design can significantly improve atorvastatin's pharmacokinetic profile and ultimately enable the development of large-scale, patient-focused oral lipid formulations.

ObjectiveTo evaluate the effects of early evolocumab plus atorvastatin on lipid metabolism, circulating endothelial biomarkers, and inflammation in STEMI patients undergoing primary percutaneous coronary intervention (PPCI).MethodsIn this single-center, open-label trial, 90 patients were randomized 1:1 to atorvastatin 20 mg/day (control, n=45) or atorvastatin 20 mg/day plus evolocumab 140 mg biweekly (combination, n=45) for 12 weeks. One patient withdrew from the combination group at day 28; last-observation-carried-forward (LOCF) was applied to impute missing 12-week endpoints for the withdrawn participant. All 90 randomized patients were included in the intention-to-treat (ITT) analytic population. Lipid profiles, endothelial biomarkers, inflammatory cytokines, and safety outcomes were assessed at baseline and 12 weeks. Standard Analysis of Covariance (ANCOVA) with 12-week value as dependent variable and corresponding baseline level as covariate was used to compare between-group treatment effects for normally distributed outcomes; non-parametric tests were applied for non-normally distributed data. All secondary biomarker, cardiac function and safety analyses were predefined as exploratory without multiplicity adjustment.ResultsBaseline characteristics were well-balanced. The primary endpoint-change in LDL-C from baseline-was significantly greater in the combination group (adjusted mean difference: -0.31 mmol/L, 95% CI: -0.60 to -0.02, P=0.037). A significantly higher proportion achieved the guideline-recommended LDL-C target of <1.4 mmol/L (48.89% vs. 22.2%, P=0.007). Secondary endpoints showed favorable changes in nitric oxide, endothelin-1, and sICAM-1 (all P<0.05), and a significant reduction in IL-6 by non-parametric testing (P=0.005). No significant between-group differences were observed for other biomarkers, cardiac function indices, or adverse events (all P>0.05).ConclusionsIn this small, single-center trial, early evolocumab added to moderate-intensity atorvastatin was associated with additional LDL-C reduction and favorable changes in selected circulating endothelial biomarkers and IL-6 over 12 weeks in STEMI patients post-PPCI, no major safety signal was observed in this short-term study. These findings are preliminary and require confirmation in larger, adequately powered trials using guideline-directed high-intensity statin therapy as the standard of care. Chinese Clinical Trial Register submission ID: PID343553 (application currently under administrative review, not publicly released).

Tissue-resident long-lived plasma cells, whose current therapies fail to effectively eliminate them, are now recognized as key factors in refractory and relapsed autoimmune diseases such as systemic lupus erythematosus (SLE). In this study, we discovered that the most commonly used cholesterol-lowering drugs in clinical practice, particularly lipophilic statins, can deplete antibody-secreting cells (ASCs) by triggering endoplasmic reticulum stress (ERS)-mediated apoptosis. Supplementation with geranylgeranyl pyrophosphate (GGPP) completely counteracted the effects of statins on ASCs. Targeting geranylgeranyltransferase type II (GGTase Ⅱ) downstream of GGPP through the use of 3-PEHPC, a chemical inhibitor of GGTase Ⅱ, replicated the destructive effects of statins on ASCs. Additionally, by generating mice with B-cell-specific deletion of Rabggta, which encodes RABGGTA, the specific subunit of GGTase II, we further demonstrated that GGTase II is critical for antibody responses, as well as for the generation of germinal centers, memory B cells, and bone marrow plasma cells. Mechanistically, GGTase II is essential for B-cell activation and proliferation and for protecting B cells from cell death triggered by mitogenic signals. Furthermore, GGTase Ⅱ deficiency in B cells impeded disease progression in lupus-like mice. Both 3-PEHPC and atorvastatin were effective at alleviating disease activity in these lupus-like models, resulting in significant depletion of ASCs. In conclusion, our study highlights GGTase II as a potential therapeutic target for autoimmune diseases and highlights the promising role of statins in their treatment.

Gut dysbiosis is associated with chronic immune activation in people with HIV (PWH), but is not well-characterized in elite controllers (ECs) or PWH receiving aspirin or statins. We analyzed gut microbiota among 22 virally-suppressed PWH and 12 ECs before and 9-months after randomization to aspirin or atorvastatin. There were no differences in microbiota between PWH and EC at baseline. There was a significant change in beta diversity after aspirin administration, but no difference in microbiota after atorvastatin. These findings suggest that ECs have gut microbiota resembling virally-suppressed PWH, and aspirin but not atorvastatin may impact gut microbiota diversity in PWH.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed, and two additional oral products received US approval in 2025 and 2026. All eleven US labels examined describe delayed gastric emptying as potentially affecting the absorption of co-administered oral medications. Since the exenatide program, no study has evaluated a narrow therapeutic index victim across more than one administration schedule; the original warfarin and digoxin studies each used a single schedule. The omission may reflect an interaction paradigm built around enzymes and transporters. Current frameworks do not routinely trigger motility-specific studies because the standard in vitro screening cascade does not address gastric emptying. Total area under the concentration-time curve (AUC) may also fail to characterize rate-dependent effects in some victim drugs. Once a class warning is established, further study may receive less priority, and interactions managed by routine dose adjustment may go unreported. Of eleven US prescribing-information documents screened, six contributed quantitative data showing that the direction of effect is not uniform: thyroxine, atorvastatin and ramipril exposures have all been reported to increase under specific conditions, so a reduction in exposure should not be assumed. The class is also pharmacologically heterogeneous; ICH M12 places absorption-mediated interactions outside its scope, and the European Medicines Agency has adopted a concept paper proposing guidance covering them. I propose an evaluation framework built on biopharmaceutically stratified probe panels, timing- and titration-explicit designs, selective use of prespecified partial AUC endpoints for rate-sensitive victims, and physiologically based pharmacokinetic models qualified against human gastric emptying data.

Tumors exhibit the Warburg effect, characterized by elevated glucose metabolism through both oxidative phosphorylation and glycolysis to produce energy. To maintain intracellular pH and metabolic homeostasis, cancer cells depend on monocarboxylate transporters (MCTs) to export the glycolytic end product, l-lactate. Similar to other cancers, glucose metabolism is enhanced in T-cell acute lymphoblastic leukemia (T-ALL), supporting rapid cell proliferation. Although MCT1 expression and its sensitivity to inhibition have been reported in certain T-ALL models, the relative contributions of other co-expressed MCT isoforms (MCT2 and MCT4) to l-lactate transport are unclear. This study aimed to evaluate the functional contribution of MCT isoforms to l-lactate transport in human T-ALL cell lines. We examined the expression and function of MCTs in Jurkat E6-1 and MOLT-3 cells. RT-PCR and Western blot analyses confirmed mRNA and protein expression of MCT1, MCT2, and MCT4 in both cell lines. Treatment with AZD3965, an MCT1 and MCT2 inhibitor, significantly increased intracellular l-lactate levels in T-ALL cells. In contrast, selective inhibition of MCT2 with atorvastatin or MCT4 with AZD0095 and VB124 did not alter intracellular l-lactate levels. Consistent with these pharmacological findings, MCT1 knockdown using small interfering RNA led to significant intracellular l-lactate accumulation. Collectively, these findings indicate that MCT1 is the principal transporter responsible for l-lactate transport in T-ALL cell lines, despite the co-expression of MCT2 and MCT4. Of all the multiple co-expressed isoforms, MCT1 is the primary mediator of l-lactate transport and is a promising therapeutic target for T-ALL treatment.