Bai-Mi-Decoction (BMD), which is composed of Eugenia caryophyllata, Myristica fragrans, Moschus berezovskii, and Crocus sativu, is a characteristic TCM multi-herb formula for brain disease. However, the mechanism of protective effects of BMD on ischemic stroke (IS) still has not been clarified. Our study is designed to elucidate the protective effects and underlying mechanisms of BMD on IS by employing pharmacodynamic and serum and brain metabolomic methods. In this experiment, 90 adult male Sprague–Dawley rats were randomly divided into the sham operation group (SHAM, vehicle), middle cerebral artery occlusion–reperfusion injury model group (MCAO/R, vehicle), positive control group (NMDP, 36 mg/kg/day nimodipine), and low (BMDL, 0.805 g/kg/day), moderate (BMDM, 1.61 g/kg/day), and high (BMDH, 3.22 g/kg/day) dosage of BMD prophylactic administration groups. The drugs were dissolved in 0.5% CMC-Na and orally administered to rats with equal volumes (100 g/ml body weight) once a day for 14 consecutive days. Neurological deficit score, cerebral infarct volume, change in body weight, and serum NO, SOD, MDA, GSH, and GSSG levels were determined. Pathological abnormalities using hematoxylin and eosin staining and the expression of VEGF, caspase-3, and NF-κB were analyzed. Furthermore, serum and brain metabolic profiles were explored to reveal the underlying mechanism using UHPLC-QTOF-MS/MS technology. BMD exhibited significant neuroprotective effects on MCAO/R rats. As compared to the MCAO/R model group, it could reduce the neurological deficit score and cerebral infarct volume, increase body weight, enhance GSH, SOD, and GSSG activities, and decrease NO and MDA contents of MCAO/R rats. Meanwhile, BMD could ameliorate pathological abnormalities of MCAO/R rats through reducing neuronal loss, vacuolated spaces, shrunken neurons, and destructed neuron structure, as well as regulating the expression of VEGF, caspase-3, and NF-κB. UHPLC-QTOF-MS/MS-based serum and brain metabolomics analysis found a total of 53 differential metabolites between MCAO/R and SHAM groups, of which 30 were significantly regulated by BMD intervention, and further metabolic pathway analysis implied that the protective effects were mainly associated with amino acid and glycerophospholipid metabolisms. Our pharmacodynamic and metabolomic results revealed the neuroprotective effects of BMD on MCAO/R rats, and the underlying mechanisms were probably related to amino acid and glycerophospholipid metabolisms.
Mi-Jian-Chang-Pu formula (MJCPF), composed of Crocus sativus L. and Acorus tatarinowii Schott, is a well-known TCM for treatment of hemiplegia, facial paralysis as well as language dysfunction caused by stroke both in ancient and modern times. By using pharmacodynamics, pharmacokinetics, and metabolomics, our present study discusses whether the combination of individual herbs or major active components of MJCPF possess synergistic neuroprotective effects against ischemic stroke (IS). 108 adult male Sprague-Dawley rats were randomly and equally divided into 9 groups, including sham group (N, vehicle), middle cerebral artery occlusion (MCAO) model group (M, vehicle), positive group (P, 36 mg/kg/day nimodipine), crocin I (A1, 40 mg/kg/day), β-asarone (B1, 15 mg/kg/day), crocin I + β-asarone (A1B1, 55 mg/kg/day), C. sativus (A, 580 mg/kg/day), A. tatarinowii (B, 480 mg/kg/day), and C. sativus + A. tatarinowii, also named MJCPF (AB, 1060 mg/kg/day) groups. All drugs were orally administered to rats once a day for 14 consecutive days. Neurological deficit score, cerebral infarct volume, body weight change, TTC, HE and IHC staining, behavioral evaluation, metabolic profiles, and pharmacokinetic parameters were determined. MCAO led to severe brain damage including large infarct volume, more severe brain tissue injury, and worse neurological function as compared to the sham rats. All treatment groups showed a significant neuroprotective effect on MCAO rats. Furthermore, the pharmacodynamics’ results demonstrated that MJCPF had a synergistic effect evidenced by small infarct volume, more regular arrangement of neuronal cells, and more improved neural function, and the levels of inflammatory factors were closer to normality. A total of 53 differential metabolites between MCAO and sham groups were screened by integration of serum and brain metabolisms, all of which were restored at varying degrees in treatment. PCA and PLS-DA analysis showed that the levels of differential metabolites treated with MJCPF were closer to the sham group than the individual herb and single compound alone or A1B1 combination. The pharmacokinetic parameters further verified the above results that MJCPF could synergistically promote drug absorption greater than others. Our integrated pharmacodynamics, metabolomics, and pharmacokinetic approach reveals the synergistic effect of MJCPF on treatment of IS, which powerfully contribute to the understanding of scientific connotation of TMC formula.
Chronic kidney disease, including renal failure (RF), is a global public health problem. The clinical diagnosis mainly depends on the change of estimated glomerular filtration rate, which usually lags behind disease progression and likely has limited clinical utility for the early detection of this health problem. Now, we employed Q-Exactive HFX Orbitrap LC-MS/MS based metabolomics to reveal the metabolic profile and potential biomarkers for RF screening. 27 RF patients and 27 healthy controls were included as the testing groups, and comparative analysis of results using different techniques, such as multivariate pattern recognition and univariate statistical analysis, was applied to screen and elucidate the differential metabolites. The dot plots and receiver operating characteristics curves of identified different metabolites were established to discover the potential biomarkers of RF. The results exhibited a clear separation between the two groups, and a total of 216 different metabolites corresponding to 13 metabolic pathways were discovered to be associated with RF; and 44 metabolites showed high levels of sensitivity and specificity under curve values of close to 1, thus might be used as serum biomarkers for RF. In summary, for the first time, our untargeted metabolomics study revealed the distinct metabolic profile of RF, and 44 metabolites with high sensitivity and specificity were discovered, 3 of which have been reported and were consistent with our observations. The other metabolites were first reported by us. Our findings might provide a feasible diagnostic tool for identifying populations at risk for RF through detection of serum metabolites.
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