Disease Status–Dependent Drug–Herb Interactions: NASH Lowered the Risk of Hepatotoxicity in Rats Coadministered With Simvastatin and Gardenia jasminoides J. Ellis

Concurrent use of simvastatin (SV) and Gardenia jasminoides J. Ellis (GJ) was adopted in patients with multi-morbidity, such as stroke rehabilitation patients with NASH. Although hepatotoxicity has been reported in both of them and NASH could alter the pharmacokinetics of drugs/herbs, the interaction between SV and GJ and the related hepatotoxicity remained uninvestigated under neither healthy nor NASH condition. The current study aimed to evaluate the potential hepatotoxicity resulted from the interactions between SV and GJ in both healthy and NASH rats. Both healthy and NASH rats received two-week SV (p. o., 8.66 mg/kg, once daily) and/or GJ (p.o., 325 mg/kg, twice daily). Pharmacokinetic profiles of SV, simvastatin acid (SVA, active metabolite of SV), and geniposide (major component in GJ); hepatic Cyp2c11/Oatp1b2/P-gp expression; and biomarker levels of liver function, lipid levels, and liver histology were compared to demonstrate the interactions in rats. To explore the mechanism of the interaction-mediated hepatotoxicity, hepatic genipin-protein adduct content and iNOS/COX-1/COX-2 expressions from related groups were compared. Moreover, liver histology of healthy/NASH rats at 90 days after discontinuation of two-week GJ in the absence and presence of SV was evaluated to estimate the long-term impact of the interactions. GJ reduced the systemic exposures of SV and SVA by up-regulating the hepatic P-gp expression in healthy but not NASH rats. Meanwhile, SV increased the systemic exposure of geniposide via inhibiting the activity of P-gp in both healthy and NASH rats. Although neither SV nor GJ induced hepatotoxicity in healthy rats, their co-treatment elevated serum ALT and AST levels, which may attribute to the aggravated genipin-protein adduct formation, inflammation infiltration, and iNOS/COX-1 expressions in the liver. In NASH rats, SV and/or GJ reduced serum ALT, AST, LDL/vLDL, and TC levels via alleviating hepatic inflammation infiltration and iNOS/COX-1 expressions. Moreover, in comparison to NASH rats, more severe fibrosis was observed in the livers of healthy rats at 90 days after discontinuation of two-week SV and GJ coadministration. Although interactions between SV and GJ induced short-term and long-term liver injuries in healthy rats, NASH condition in rats could lower such risk.

The first step of arsenoplatin-1 aggregation in solution unveiled by solving the crystal structure of its protein adduct

AP-1 spontaneously aggregates in aqueous solutions. The structure of the adduct formed by an AP-1 trimer with lysozyme offers insight into the process of the oligomer's growth.

Interaction of Platinum-based Drugs with Proteins: An Overview of Representative Crystallographic Studies

: Pt-based drugs are widely used in clinics for the treatment of cancer. The mechanism of action of these molecules rely on their interaction with DNA. However, the recognition of these metal compounds by proteins plays an important role in defining pharmacokinetics, side effects and their overall pharmacological profiles. Single crystal X-ray diffraction studies provided important information on the molecular mechanisms at the basis of this process. Here, the molecular structures of representative adducts obtained upon reaction with proteins of selected Pt-based drugs, including cisplatin, carboplatin and oxaliplatin, were briefly described and comparatively examined. Data indicate that metal ligands play a significant role in driving the reaction of Pt compounds with proteins; non-covalent interactions that are formed in the early steps of Pt compound/protein recognition process play a crucial role in defining the structure of the final Pt-protein adduct. In the metalated protein structures, Pt centers coordinate few protein side chains, such as His, Met, Cys, Asp, Glu and Lys residues upon releasing of labile ligands.

Isoleucine 44 Hydrophobic Patch Controls Toxicity of Unanchored, Linear Ubiquitin Chains through NF-κB Signaling

Ubiquitination is a post-translational modification that regulates cellular processes by altering the interactions of proteins to which ubiquitin, a small protein adduct, is conjugated. Ubiquitination yields various products, including mono- and poly-ubiquitinated substrates, as well as unanchored poly-ubiquitin chains whose accumulation is considered toxic. We previously showed that transgenic, unanchored poly-ubiquitin is not problematic in Drosophila melanogaster. In the fruit fly, free chains exist in various lengths and topologies and are degraded by the proteasome; they are also conjugated onto other proteins as one unit, eliminating them from the free ubiquitin chain pool. Here, to further explore the notion of unanchored chain toxicity, we examined when free poly-ubiquitin might become problematic. We found that unanchored chains can be highly toxic if they resemble linear poly-ubiquitin that cannot be modified into other topologies. These species upregulate NF-κB signaling, and modulation of the levels of NF-κB components reduces toxicity. In additional studies, we show that toxicity from untethered, linear chains is regulated by isoleucine 44, which anchors a key interaction site for ubiquitin. We conclude that free ubiquitin chains can be toxic, but only in uncommon circumstances, such as when the ability of cells to modify and regulate them is markedly restricted.

CKD Increases Carbonylation of HDL and Is Associated with Impaired Antiaggregant Properties

BackgroundCKD is associated with increased oxidative stress that correlates with occurrence of cardiovascular events. Modifications induced by increased oxidative stress particularly affect circulating lipoproteins such as HDL that exhibit antiatheromatous and antithrombotic properties in vitro.MethodsTo explore the specific role of oxidative modifications of HDL in CKD and their effect on the platelet-targeting antiaggregant properties of HDL, we used a CKD (5/6 nephrectomy) rabbit model. For ex vivo assessment of the antiaggregant properties of HDL, we collected blood samples from 15 healthy volunteers, 25 patients on hemodialysis, and 20 on peritoneal dialysis. We analyzed malondialdehyde, 4-hydroxynonenal (HNE), and 4-hydroxy-2-hexenal protein adduct levels. Platelet aggregation and activation were assessed by aggregometry, thromboxane B2 assay, or FACS. We modified HDL from controls by incubating it overnight at 37°C with 100 µM of HNE.ResultsHDL from CKD rabbits and patients on hemodialysis had HNE adducts. The percentage of platelet aggregation or activation induced by collagen was significantly higher when platelets were incubated with HDL from CKD rabbit and hemodialysis groups than with HDL from the control group. In both rabbits and humans, platelet aggregation and activation were significantly higher in the presence of HNE-modified HDL than with HDL from their respective controls. Incubation of platelets with a blocking antibody directed against CD36 or with a pharmacologic inhibitor of SRC kinases restored the antiaggregative phenotype in the presence of HDL from CKD rabbits, patients on hemodialysis and peritoneal dialysis, and HNE-modified HDL.ConclusionsHDL from CKD rabbits and patients on hemodialysis exhibited an impaired ability to inhibit platelet aggregation, suggesting that altered HDL properties may contribute to the increased cardiovascular risk in this population.