Pyrrolizidine
alkaloids (PAs) are the most common toxins
of plant
origin, and it is evident that PAs pollute soil, water, nearby plants,
and derived foods. Cases of human poisoning due to ingestion of PA-contaminated
foods have been reported in several countries. Monocrotaline (MCT)
is a pyrrolizidine alkaloid from the plants of Crotalaria genus that causes hepatic and cardiopulmonary toxicities, and the
exhibition of the toxicities requires the metabolic activation by
CYP3A4 to form electrophilic dehydro-monocrotaline (DHM). The present
study demonstrated that myeloperoxidase (MPO) also participated in
the bioactivation of MCT. N-Chloromonocrotaline was
detected in both HClO/MCT incubations and MPO/H2O2/MgCl2/MCT incubations. DHM-derived N-acetylcysteine (NAC) conjugates were detected in the above incubations
fortified with NAC. Lipopolysaccharide-induced inflammation in mice
resulted in an elevated level of hepatic MPO activity, increased metabolic
activation of MCT, and intensified elevation of serum ALT and AST
activity induced by MCT. MPO inhibitor 4-aminobenzoic acid hydrazide
was found to reverse these alterations. Mpo-KO mice
were resistant to the observed potentiating effect of inflammation
on MCT-induced liver injury. In conclusion, inflammation intensified
MCT-induced liver injury. MPO participated in the observed potentiating
effect of inflammation on the hepatotoxicity induced by MCT.
Background: Aidi Injection (ADI), a Chinese herbal preparation with anti-cancer activity, is used for the treatment of hepatocellular carcinoma (HCC). Several clinical studies have shown that co-administration of ADI with doxorubicin (DOX) is associated with reduced toxicity of chemotherapy, enhanced clinical efficacy and improved quality of life for patients. However, limited information is available about the herb-drug interactions between ADI and DOX. The study aimed to investigate the pharmacokinetic mechanism of herb-drug interactions between ADI and DOX in a rat model of HCC.Methods: Experimental HCC was induced in rats by oral administration of diethylnitrosamine. The HCC rats were pretreated with ADI (10 mL/kg, intraperitoneal injection) for 14 consecutive days prior to administration of DOX (7 mg/kg, intravenous injection) to investigate pharmacokinetic interactions. Plasma concentrations of DOX and its major metabolite, doxorubicinol (DOXol), were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).Results: Preadministration of ADI significantly altered the pharmacokinetics of DOX in HCC rats, leading to increased plasma concentrations of both DOX and DOXol. The area under the plasma drug concentration-time curve (AUCs) of DOX and DOXol in rats pretreated with ADI were 3.79-fold and 2.92-fold higher, respectively, than those in control rats that did not receive ADI.Conclusions: Increased levels of DOX and DOXol were found in the plasma of HCC rats pretreated with ADI.
Although Polygonum orientale L. (PO) has a beneficial effect on treatment of myocardial ischemia (MI), its mechanism remains unclear. This study aimed to explore the pharmacological mechanism of PO against MI through MAPK signaling pathways. Firstly, the therapeutic effect of PO was evaluated for treatment of MI mice. Using Western blot and immunohistochemistry, the influence of PO on MAPK signaling pathways and cell apoptosis was investigated. Subsequently, one key pathway (ERK) of MAPK signaling pathways was screened out, on which PO posed the most obvious impact. Finally, an inhibitor of ERK1/2 was utilized to further verify the regulatory effect of PO on the MAPK/ERK signaling pathway. It was found that PO could reduce the elevation of the ST segment; injury of heart tissue; the activity of LDH, CK, NOS, cNOS and iNOS and the levels of NO, BNP, TNF-α and IL-6. It is notable that PO could significantly modulate the protein content of p-ERK/ERK in mice suffering from MI but hardly had an effect on p-JNK/JNK and p-p38/p38. Additionally, the expressions of bax, caspase3 and caspase9 were inhibited in heart tissue in the PO-treated group. To evaluate whether ERK1/2 inhibitor (PD98059) could block the effect of PO on treatment of MI, both PO and PD98059 were given to mice with MI. It was discovered that the inhibitor indeed could significantly reverse the regulatory effects of PO on the above indicators, indicating that PO could regulate p-ERK/ERK. This study provides experimental evidence that PO extenuates MI injury, cardiomyocyte apoptosis and inflammation by activating the MAPK/ERK signaling pathway.
Background: Aidi Injection (ADI), a Chinese herbal preparation with anti-cancer activity, is used for the treatment of hepatocellular carcinoma (HCC). Several clinical studies have shown that co-administration of ADI with doxorubicin (DOX) is associated with reduced toxicity of chemotherapy, enhanced clinical efficacy and improved quality of life for patients. However, limited information is available about the herb-drug interactions between ADI and DOX. The study aimed to investigate the pharmacokinetic mechanism of herb-drug interactions between ADI and DOX in a rat model of HCC. Methods: Experimental HCC was induced in rats by oral administration of diethylnitrosamine. The HCC rats were pretreated with ADI (10 mL/kg, intraperitoneal injection) for 14 consecutive days prior to administration of DOX (7 mg/kg, intravenous injection) to investigate pharmacokinetic interactions. Plasma concentrations of DOX and its major metabolite, doxorubicinol (DOXol), were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Results: Preadministration of ADI significantly altered the pharmacokinetics of DOX in HCC rats, leading to increased plasma concentrations of both DOX and DOXol. The area under the plasma drug concentration-time curve (AUCs) of DOX and DOXol in rats pretreated with ADI were 3.79-fold and 2.92-fold higher, respectively, than those in control rats that did not receive ADI. Conclusions: Increased levels of DOX and DOXol were found in the plasma of HCC rats pretreated with ADI.
Columbin (CLB) is a diterpenoid furanolactone compound
occurring
in some herbal medicines. Administration of CLB has been reported
to induce liver injury. The reported CLB hepatotoxicity is suggested
to require metabolism to a cis-enedial intermediate.
We successfully detected hepatic protein adduction resulting from
the metabolic activation of CLB and found that the intermediate reacted
with lysine residues or lysine/cysteine residues to produce the corresponding
pyrroline derivative or pyrrole derivative. The detection was achieved
by proteolysis- and liquid chromatography–tandem mass spectrometry
(LC–MS/MS)-based methods. Furthermore, we prepared a polyclonal
antibody approach which allowed us to detect the protein adduction
in the forms of protein immunoblot as well as tissue- and cell-based
immunostaining. The antibody technique verified the protein adduction
detected by LC–MS/MS.
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