Pharmaceuticals

Background: Combining natural products with conventional antidiabetic agents to inhibit α-glucosidase activity is an effective strategy for preventing postprandial hyperglycemia. Baicalein, a natural flavonoid with well-documented low toxicity, showed potential synergistic effect with acarbose in diabetic models; however, the synergistic performance and mechanisms of the two agents targeting human maltase–glucoamylase (MGAM) remain unclear. Methods: Recombinant human MGAM-C and MGAM-N were expressed in Pichia pastoris for in vitro inhibition assays. Maltose-loaded mice were used to assess the in vivo hypoglycemic activity and intestinal maltase inhibition. Inhibitor–enzyme interactions were investigated by fluorescence spectroscopy, circular dichroism (CD), multiple molecular docking, and molecular dynamics (MD) simulations. Results: Baicalein potently inhibited MGAM-C and MGAM-N with IC₅₀ values of 20.41 ± 4.80 μM and 14.04 ± 0.94 μM, respectively, and demonstrated a synergistic effect when combined with acarbose. In vivo, co-administration significantly reduced blood glucose levels and suppressed small intestinal maltase activity in maltose-loaded mice. Mechanistic studies revealed that baicalein functions as a non-competitive inhibitor by binding to the allosteric site of MGAM-C via stable hydrogen bonds with residues Ile1716 and Trp1749. This interaction induces conformational changes in the enzyme’s secondary structure and optimizes the hydrophobic microenvironment of the active site, thereby enhancing the binding affinity and hydrogen bond stability of acarbose. These molecular events collectively contribute to the synergistic inhibition of MGAM-C hydrolytic activity. Conclusions: This research revealed the synergistic inhibitory effect of baicalein and acarbose on MGAM and the underlying mechanisms, thereby providing a theoretical basis for developing pharmaceutical formulations to enhance acarbose efficacy.

Objectives: The purpose of this study was to investigate the protective effects and underlying mechanisms of fucoidan on contrast-induced acute kidney injury (CI-AKI) in mice, focusing on the TLR4/NF-κB and Nrf2/GPX4 pathways. Methods: Five-week-old male ICR mice were randomly divided into normal control, contrast model, low-dose (100 mg/kg), and high-dose (300 mg/kg) fucoidan groups. Renal index, biochemical markers, histopathology, oxidative stress indicators, inflammatory cytokine levels, and the expression of TLR4/NF-κB, Nrf2/HO-1, and ferroptosis-related proteins were assessed. Untargeted metabolomics followed by KEGG pathway enrichment was also performed. Results: Our results showed that contrast successfully established the CI-AKI model, as evidenced by an increased kidney index, abnormal biochemical parameters, severe renal pathological damage, oxidative stress imbalance, inflammatory activation, ferroptosis, and metabolic disturbances. Fucoidan dose-dependently improved kidney index and biochemical markers, alleviated pathological injury, enhanced antioxidant capacity, suppressed inflammation and ferroptosis, and reversed metabolic pathway disorders (e.g., purine and glycerophospholipid metabolism), with the high dose showing more pronounced effects. Conclusions: Fucoidan could effectively ameliorate CI-AKI, and its effects are closely associated with the inhibition of the TLR4/NF-κB pathway, activation of the Nrf2/HO-1 pathway, regulation of ferroptosis-related proteins, and improvement of key metabolic disturbances, suggesting a new research direction for the prevention of CI-AKI.

Background/Objectives: The four androgen-receptor pathway inhibitors (ARPIs) for advanced prostate cancer are broadly comparable in efficacy, so the choice between them depends on tolerability and, in elderly patients, on central nervous system (CNS) safety. CNS signals from the FDA Adverse Event Reporting System (FAERS) now inform that choice, yet they rest on uncalibrated disproportionality, which cannot separate pharmacology from reporting. Methods: Across the full FAERS database (20,328,575 reports), we computed reporting odds ratios (ROR) for enzalutamide, apalutamide, darolutamide, and abiraterone over 32 drug–event pairs, recalibrated every estimate against a drug-specific empirical null from 18 negative controls, and corrected for multiplicity. The null was fitted two ways and validated against twelve label-established positive controls. Results: Uncalibrated analysis flagged 22 of 32 pairs, and also 41 of 72 control pairs on events judged to carry no true effect, so its null does not hold. Calibration removes that bias, but the verdict then depends on how the null is fitted: with its dispersion taken as the sample standard deviation of the control estimates, no pair reached q < 0.05, while under the maximum-likelihood fit the framework prescribes six did, three of them being CNS pairs. Positive controls confirmed that calibration retains genuine agent-specific effects, and the detection floor lay above every CNS estimate for the same agent. Conclusions: Comparative ARPI CNS signals in FAERS are not identifiable; the verdict is set by the calibration design rather than by the drugs, so such signals should not stand alone in agent selection. The firmer safety axis remains fall and fracture risk, the class’s dominant serious harm in trials and guidelines.