Engineered SPIONs functionalized with endothelin a receptor antagonist ameliorate liver fibrosis by inhibiting hepatic stellate cell activation.

Endothelin-1/endothelin A receptor (ET-1/ETAR) pathway plays an important role in the progression of liver fibrosis by activating hepatic stellate cells (HSCs) - a key cell type involved in the pathogenesis of liver fibrosis. Inactivating HSCs by blocking the ET-1/ETAR pathway using a selective ETAR antagonist (ERA) represents a promising therapeutic approach for liver fibrosis. Unfortunately, small-molecule ERAs possess limited clinical potential due to poor bioavailability, short half-life, and rapid renal clearance. To improve the clinical applicability, we conjugated ERA to superparamagnetic iron-oxide nanoparticles (SPIONs) and investigated the therapeutic efficacy of ERA and ERA-SPIONs in vitro and in vivo and analyzed liver uptake by in vivo and ex vivo magnetic resonance imaging (MRI), HSCs-specific localization, and ET-1/ETAR-pathway antagonism in vivo. In murine and human liver fibrosis/cirrhosis, we observed overexpression of ET-1 and ETAR that correlated with HSC activation, and HSC-specific localization of ETAR. ERA and successfully synthesized ERA-SPIONs demonstrated significant attenuation in TGFß-induced HSC activation, ECM production, migration, and contractility. In an acute CCl4-induced liver fibrosis mouse model, ERA-SPIONs exhibited higher liver uptake, HSC-specific localization, and ET-1/ETAR pathway antagonism. This resulted in significantly reduced liver-to-body weight ratio, plasma ALT levels, and α-SMA and collagen-I expression, indicating attenuation of liver fibrosis. In conclusion, our study demonstrates that the delivery of ERA using SPIONs enhances the therapeutic efficacy of ERA in vivo. This approach holds promise as a theranostic strategy for the MRI-based diagnosis and treatment of liver fibrosis.

A biomechanical study of the effect of weight loading conditions on the mechanical environment of the hip joint endoprosthesis.

BACKGROUND: Total hip arthroplasty is one of the most successful orthopedic surgical procedures aiming to eliminate pain related to several types of hip arthritis and restore mobility. Obesity has been associated with an increased risk of complications after a total hip arthroplasty such as poor wound healing, periprosthetic joint infection, instability, and aseptic loosening. METHODS: This paper presents an in-vitro study on composite femoral models to investigate the impact of different weight loading conditions on the mechanical environment of the hip joint endoprosthesis considering normal-weight and overweight individuals from 70 to 110 kg. The micro strains on the femur during single-leg stance of gait were measured on critical stress points based on the Gruen femoral zones. FINDINGS: The micro strains increase as the weight increases implying that the displacement in the hip joint endoprosthesis is higher for overweight subjects enhancing the risk of failure. The highest increase was measured in Gruen zone 1 by 5.60% indicating that the great trochanter is subjected to higher stress shielding with increasing the weight. Also, the statistically significant increase of the micro strain values with increasing the weight in Gruen Zones 3 (2.91%), 5 (1.56%), and 11 (1.75%) may enhance the risk for a periprosthetic fracture at the lower region of the prosthesis. INTERPRETATION: This is the first biomechanical study which quantifies the effect of increasing weight loading conditions on the mechanical environment of the hip joint endoprosthesis considering different positions of evaluation.