Skeletal muscle toxicity has often been a critical concern in drug development, particularly with statins, which can cause adverse effects ranging from mild myalgia to fatal rhabdomyolysis. Traditional plasma biomarkers such as creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) have limitations in specificity and sensitivity. This study investigates urinary N-terminal titin fragment (N-titin) as a non-invasive biomarker for simvastatin-induced skeletal muscle toxicity in rats. Female Wistar Hannover rats were administered simvastatin at varying doses, and urine, blood, and muscle samples were collected for analysis. Histopathological examination revealed muscle fiber degeneration and inflammation in the fast-twitch muscles (gastrocnemius and biceps femoris) in high-dose rats. Correspondingly, urinary N-titin/creatinine (CRN) levels showed a marked increase, while plasma CPK and LDH levels remained unchanged. These findings suggest that urinary N-titin/CRN is a sensitive and practical biomarker for detecting skeletal muscle injury, potentially offering advantages over traditional blood-based markers.

The liver plays a central role in xenobiotic metabolism, and its activity is strongly influenced by physiological interactions with the gut. However, the molecular signals mediating this gut-liver crosstalk and their impact on drug-metabolizing enzymes remain poorly understood. Here, we used a human-derived gut-liver microphysiological system (MPS) to investigate how bile acid transport and arachidonic acid (ARA) metabolism regulate hepatic cytochrome P450 (CYP) activity under normal physiological conditions. Intestinal expression of the bile acid transporter ASBT was elevated in coculture, suggesting active bile acid uptake and signaling. Inhibition of ASBT significantly reduced ARA levels in the circulating medium and selectively decreased hepatic CYP activity, particularly CYP2D6. These findings indicate that bile acid transport can influence lipid mediator balance, which in turn modulates CYP activity. Our results highlight a potential mechanism by which gut-liver communication contributes to drug metabolism and may inform the development of improved models for toxicological evaluation.

The purpose of this study was to examine the molecular mechanisms by which silica micro/nanoparticles (SiPs) with different sizes and surface functional groups cause cytotoxicity in the murine RAW-Blue macrophages and N18 neuroblastoma cells. The possibility that these materials may act via macropinocytosis, clathrin-mediated endocytosis (CME), or caveolae-mediated endocytosis (CvME) was focused. Three types of SiPs, 3 μm-plain (3 μm diameter particles without surface modification), 50 nm-plain (50 nm diameter particles without surface modification) and 50 nm-NH₂ (50 nm diameter particles with an amine functional group as surface modification) were tested. Cytotoxicity in the presence of 50 nm-plain in RAW-Blue macrophages was seen but N18 neuroblastoma cells did not exhibit evident cytotoxicity in the presence of 50 nm-plain at the 24-hr time point. In the presence of 50 nm-plain, cell proliferation was significantly inhibited and cell death was significantly induced in RAW-Blue macrophages. These macrophages incorporated particles of 50 nm-plain and 50 nm-NH₂ via the CME and macropinocytosis pathways. When the macrophages were treated with 50 nm-plain plus chlorpromazine, a CME inhibitor, the NF-κB-inducible secreted embryonic alkaline phosphatase (SEAP) activity significantly decreased compared to the control. When the macrophages were treated with 50 nm-plain plus imipramine, a macropinocytosis inhibitor, cell death significantly decreased compared to the control. Collectively, these results demonstrate that the size and surface properties of SiPs are critical in modulating endocytosis-mediated cellular responses including cytotoxicity and regulation of the SEAP activity; thus enhancing the safe and effective design of SiPs and a reliable standard for biomedical applications.