A substantial knowledge on the pathogenesis of diabetes mellitus (DM) by oxidative stress and inflammation is available. Berberine is a biologically active botanical that can combat oxidative stress and inflammation and thus ameliorate DM, especially type 2 DM. This article describes the potential of berberine against oxidative stress and inflammation with special emphasis on its mechanistic aspects. In diabetic animal studies, the modified levels of proinflammatory cytokines and oxidative stress markers were observed after administering berberine. In renal, fat, hepatic, pancreatic and several others tissues, berberine-mediated suppression of oxidative stress and inflammation was noted. Berberine acted against oxidative stress and inflammation through a very complex mechanism consisting of several kinases and signaling pathways involving various factors, including NF-κB (nuclear factor-κB) and AMPK (AMP-activated protein kinases). Moreover, MAPKs (mitogen-activated protein kinases) and Nrf2 (nuclear factor erythroid-2 related factor 2) also have mechanistic involvement in oxidative stress and inflammation. In spite of above advancements, the mechanistic aspects of the inhibitory role of berberine against oxidative stress and inflammation in diabetes mellitus still necessitate additional molecular studies. These studies will be useful to examine the new prospects of natural moieties against DM.
A new fluorenone alkaloid (caulophine) was isolated from the radix of Caulophyllum robustum Maxim. (collected from the Qinling mountains) using cell membrane chromatography as the screening method. Caulophine was identified as 3-(2-(dimethylamino)ethyl)-4,5-dihydroxy-1,6-dimethoxy-9H-fluoren-9-one based on physicochemic and spectroscopic analyses, particularly by NMR spectroscopic data (i.e., COSY, HMQC, HMBC, NOESY). Caulophine possessed anti-myocardial ischemia activity.
Nuciferine is an aporphine alkaloid monomer that is extracted from the leaves of the lotus species Nymphaea caerulea and Nelumbo nucifera Gaertn. Nuciferine was reported to treat cerebrovascular diseases. However, the potential mechanism of the neuroprotective effects of nuciferine at the metabolomics level is still not unclear. The present research used neurological score, infarct volume, cerebral water content, and ultraperformance liquid chromatography to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based serum metabolomics to elucidate the anti-ischemic stroke effect and mechanisms of nuciferine. The results showed that nuciferine significantly improved neurological deficit scores and ameliorated cerebral edema and infarction. Multivariate data analysis methods were used to examine the differences in serum endogenous metabolism between groups, and the biomarkers of nuciferine on ischemic stroke were identified. Approximately 19 metabolites and 7 metabolic pathways associated with nuciferine on treatment of stroke were found, which indicated that nuciferine exerted a positive therapeutic action on cerebral ischemic by regulating metabolism. These results provided some data support for the study of anti-stroke effect of nuciferine from the perspective of metabolomics.
The adverse effects of Polygonum (P.) multiflorum, including abnormal bilirubin metabolism, are a serious public health issue. As uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) is the only enzyme responsible for bilirubin metabolism, we investigated the inhibitory effect of a P. multiflorum extract and 10 anthraquinone and dianthrone compounds on UGT1A1 in rat liver microsomes in vitro. The P. multiflorum extract exhibited the strongest inhibitory effect on UGT1A1 activity (inhibition constant [Ki] = 0.3257 μM, 1422 μg of material/mL), followed by cis-emodin dianthrones (Ki = 0.8630 μM), trans-emodin dianthrones (Ki = 1.083 μM), emodin-8-O-glc (Ki = 3.425 μM), and polygonumnolide C2 (Ki = 4.291 μM). Analysis of the structure–activity relationships of these compounds suggested that the spatial orientation of the molecules and the presence of particular functional groups affect UGT1A1 inhibition. A mechanistic analysis showed that all the tested compounds docked into two of the nine active sites of UGT1A1 and suggested that hydrophobic interactions and hydrogen bonds are important for the affinity of the tested compounds for UGT1A1; moreover, their interaction energies were generally in agreement with the Ki values. These findings provide insight into adverse reactions to P. multiflorum and identify the pharmacophores involved in inhibition of UGT1A1.
Polygonum multiflorum Thunb. (PM)
is one of the most frequently used natural products in China. Its
hepatotoxicity has been proven and reported. However, chronic PM toxicity
is a dynamic process, and a few studies have reported the long-term
hepatotoxic mechanism of PM or its nephrotoxicity. To elucidate the
mechanism of hepatotoxicity and nephrotoxicity induced by PM after
different administration times, different samples from rats were systematically
investigated by traditional biochemical analysis, histopathological
observation, and nontargeted metabolomics. The concentrations of direct
bilirubin (DBIL) at 4 weeks and total bile acid, DBIL, uric acid,
and blood urea nitrogen at 8 weeks were significantly increased in
the treatment group compared with those in the control group. Approximately,
12 metabolites and 24 proteins were considered as unique toxic biomarkers
and targets. Metabolic pathway analysis showed that the primary pathways
disrupted by PM were phenylalanine and tyrosine metabolism, which
resulted in liver injury, accompanied by chronic kidney injury. As
the administration time increased, the toxicity of PM gradually affected
vitamin B6, bile acid, and bilirubin metabolism, leading to aggravated
liver injury, abnormal biochemical indicators, and marked nephrotoxicity.
Our results suggest that the hepatotoxicity and nephrotoxicity caused
by PM are both dynamic processes that affect different metabolic pathways
at different administration times, which indicated that PM-induced
liver and kidney injury should be treated differently in the clinic
according to the degree of injury.
Estimating the extent to which drugs inhibit uridine 5′-diphosphate-glucuronosyltransferases1A1 (UGT1A1) enzyme activity is important for predicting hepatotoxicity and neurotoxicity. UGT1A1 enzyme activity is commonly evaluated by detecting the elimination of bilirubin substrate or the generation of bilirubin glucuronides. However, the present methods are inadequate for accurately assessing bilirubin metabolism, selecting incubation conditions, and comparing different systems. Therefore, in our study, we first established a ultra-performance liquid chromatography (UPLC)-MS/MS method to identify bilirubin and bilirubin glucuronides. To ensure the reaction was linear, we performed assays to optimize the protein concentration and incubation time. Finally, we measured UGT1A1 activity using three different systems. Data revealed the optimum incubation conditions were 10 min with 0.5 mg/mL human liver microsomes (HLM), recombinant human UGT1A1 (rUGT1A1), and rat liver microsomes (RLM). Bilirubin glucuronidation obeyed Michaelis-Menten kinetics in all three systems. The diversity in bilirubin metabolism among species was revealed. rUGT1A1 had the strongest binding affinity for bilirubin, but the lowest metabolism velocity. Compared with the other systems, RLM exhibited a significant difference. It has the lowest CL int and the highest K m . The difference in parameters between three systems may be attributable to the species differences. In conclusion, these in vitro studies provide useful information regarding drug interactions and the prediction of toxicity for future studies.
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