Journal: Journal of Nanobiotechnology

Article Title: Bidirectional regulation of liver sinusoidal clearance by amino acid nanofibers and IGFBP4 complex: effects on HbA1c

doi: 10.1186/s12951-025-03943-5

Figure Lengend Snippet: Combination of apo-hIGFBP4 with electropositive AAC2 nanofibers enhances glucose uptake and attenuates the proinflammatory effects of MGO. ( a ) Schematic representation of hIGFBP4 structure highlighting domains susceptible to interaction with charged, hydrophobic, and oxidant molecules. ( b ) AAC structure: a dilysine backbone modified with a hydrophobic coumarin side group, enabling self-assembly into positively charged nanofibers. ( c ) Schematic of methylglyoxal (MGO) production under hyperglycemic stress, showing its role as a precursor of electronegative AGEs and driver of diabetic inflammation. ( d ) FD-glucose uptake in human subcutaneous SVF preadipocytes isolated from obese patients ( n = 6) with and without diabetes. Confluent cells were glucose- and serum-deprived (starved) for 40 min and treated with vehicle (Veh, PBS) or designated concentrations of insulin (Ins), leptin (Lep), and hIGFBP4. Statistical analysis was performed using unpaired t-test. * P = 0.05–0.01; ** P = 0.01–0.001; *** P < 0.001. ( e ) Dose-dependent FD-glucose uptake in 3T3-L1 preadipocytes ( n = 4) starved for 50 min and treated for 90 min with hIGFBP4 alone or with AAC2 (0.1 µM). ( f ) IL-11 reporter activity in HEK293 cells ( n = 4) after 24 h stimulation with recombinant human IL-11 (1 ng/mL), MGO (10 µM), or their combination. Data is expressed as a percentage relative to unstimulated control. ( g ) HEK293 cells ( n = 4) were stimulated for 24 h with IL-11 and MGO (as in panel f) in the presence or absence of AAC2 (1 µM), hIGFBP4 (50 ng/mL), or their combination

Article Snippet: HEK293 IL-11 reporter cells (Invivogen, hkb-hil11rv2) were cultured in T-150 flasks using complete growth medium consisting of high-glucose DMEM (Gibco) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Gibco, A5268-01), 1% penicillin-streptomycin, and 5 mM L-glutamine.

Techniques: Modification, Isolation, Activity Assay, Recombinant, Control

Journal: Journal of Nanobiotechnology

Article Title: Bidirectional regulation of liver sinusoidal clearance by amino acid nanofibers and IGFBP4 complex: effects on HbA1c

doi: 10.1186/s12951-025-03943-5

Figure Lengend Snippet: Expression of Cluster II genes in LSECs and Cluster I genes in other hepatic cell populations supports the scavenging input hypothesis underlying AAC2 and AAC2–hIGFBP4 regulation of capillarized and fenestrated LSEC phenotypes. ( a–g ) Correlation and mechanistic modeling support the scavenging input hypothesis underlying AAC2 and AAC2–hIGFBP4 regulation of LSEC phenotypes. ( a–b ) Cluster II genes expressed in LSECs significantly correlate with Cluster I genes expressed in other hepatic cell populations ( n = 12, R² > 0.33, P < 0.05; Pearson correlation). Specifically, Oit3 correlates positively with Klf9 ( a ), while Klf9 shows an inverse correlation with genes expressed in the hepatocyte-associated Cluster I ( b ). ( c ) Eng expression correlates with receptors of the TGFβ pathway and with Tgfb1 . ( d ) Fcgr2b expression is positively correlated with Adgrf5 . ( e ) Eng correlates with Smad family transcription factors. ( f ) Cdh5 expression is positively associated with Tgfb1 . ( g ) The proposed scavenging input hypothesis suggests that TGFβ production is stimulated by AGE uptake via stabilin 2 ( Stab2 ), which activates the canonical ALK5 pathway underlying the capillarized LSEC phenotype and induces transcription of Eng and other Cluster II genes. Translation of Eng mRNA to protein endoglin defines the transition to ALK1 signaling, which, in conjunction with Cluster II proteins, promotes the fenestrated LSEC phenotype. Endoglin mediates endocytosis that terminates the ALK1 state. This physiological cycle is sustained by renewed scavenger activity, leptin receptor ( Lepr ), and VEGFR2/VE-cadherin signaling, which reinforce TGFβ production adapted for amount of waste in circulation. Binding of positively charged AGEs with AAC2 may reduce scavenger receptor input and suppress the fenestrated LSEC state, whereas the AAC2–hIGFBP4 complex promotes the transition toward a fenestrated phenotype. Inflammatory conditions disrupt this physiological TGFβ cycle in LSEC through cytokines (e.g., IL-11), accumulation of toxic waste, or TGFβ derived from damaged or immune cells that drive a pathological process toward fibrosis

Article Snippet: HEK293 IL-11 reporter cells (Invivogen, hkb-hil11rv2) were cultured in T-150 flasks using complete growth medium consisting of high-glucose DMEM (Gibco) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Gibco, A5268-01), 1% penicillin-streptomycin, and 5 mM L-glutamine.

Techniques: Expressing, Activity Assay, Binding Assay, Derivative Assay