Graphical abstract

It is well‐recognized that glycemic disorders are leading causes of diabetic complications and acute fluctuation of blood glucose and reported more likely being related to oxidative stress, vasculopathy, and other diabetic complications than continuous hyperglycemia in patients with diabetic and animal models. To explore the hypothesis that acute glucose fluctuation (GF) aggravates inflammatory lesions and neuron apoptosis in the hippocampus of diabetic rats. Twenty female GK rats were randomly allocated into a glucose fluctuating group (GK‐GF) and a continuous hyperglycemia group (GK‐CHG) and 10 age‐matched female Wistar rats served as controls. GF was induced in the GK‐GF group by injection with glucose and insulin at different periods of time per day for 6 weeks. Body weight was determined weekly. At the end of the study, blood hemoglobin A1c (HbA1c) and serum lipids were measured. Serum and hippocampus interleukin 1β (IL‐1β), IL‐6, IL‐8, and tumor necrosis factor‐α (TNF‐α) were measured by enzyme‐linked immunosorbent assay and real‐time quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR). Hippocampus Bcl‐2, Bax, Pten, fas, and myc were quantified by qRT‐PCR and Western blot analysis and Mirror Water Maze (MWM) test was performed. We successfully established an animal model with daily GF and a control model with CHG using GK diabetic rats. The GF and CHG rats showed lower weight gain during the 6‐week experimental period with no significant difference in the levels of serum lipids such as total triglyceride, total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol compared with the control rats at the end of the study. Meanwhile, the GF and CHG rats showed higher blood HbA1c levels than that of control rats. MWM trainings tests detected that glucose disorders in GF and CHG rats tend to present longer latencies, more cross times and longer path length compared with those of the control rats, indicating impaired the hippocampus‐regulated behavioral function such as spatial orientating and memory. Importantly, it was found that GF promoted the expression of TNF‐α and IL‐1β in the hippocampus of the GF rats while continuous hyperglycemia in CHG rats had little effect on that. Furthermore, both GF and CHG diabetic rats had abnormal expression of apoptosis‐associated genes in the hippocampus compared with control Wistar rats and neurons apoptosis in GF rats appears to be more severe than CHG rats. Overall, this study confirmed that GF is a more critical factor that would promote the neuron apoptosis and induce inflammation in the hippocampus than continuous hyperglycemia in diabetic animals, which shed new light on the importance of monitoring and administration of blood glucose in the prevention and therapy for diabetes.

No abstract

Isatis indigotica (Ii) is a cruciferous herb that is widely distributed in China, and its roots and leaves have been used in two renowned antipyretic detoxicate crude drugs in Chinese Pharmacopoeia, Radix (R) and Folium (F) Isatidis. However, the pharmacodynamic material basis and underlying mechanisms of the herbal efficacy remained to be elucidated. Methods: Ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was adopted for the chemical profiling of R and F Isatidis. The active ingredients were screened out through the prediction of gastrointestinal absorption and druglikeness analysis using SwissADME. A herb-ingredient-target network was constructed through target prediction of the herbal active ingredients and anti-inflammation or anti-viral properties, followed by protein-protein interaction analysis. Then, the potential relevant signaling pathways were predicted by pathway enrichment. Finally, for verification, RAW 264.7 cell line was adopted to examine the anti-inflammatory and anti-viral activities of 6 representative ingredients in Ii. Results: Seventy-three compounds have been identified from Ii through UPLC-Q-TOF-MS. A total of 17 potential active ingredients were screened through pharmacokinetics and druglikeness evaluation using SwissADME. It was shown that key targets might include TNF, AKT1, SRC, IL2, CASP9, and CASP3 in our herb-ingredient-target network, and isovitexin, a flavonoid, tended to participate in the inflammatory response, indoles were more likely to affect the cell proliferation processes, and lignans might have a broader affinity to key targets than the other active ingredients, such as regulating immune system (targeting IL-2) and PI3K-Akt signaling pathway. In vitro, indigo and secoisolariciresinol diglucoside markedly reduced TNF-α expression in Poly (I: C)-incubated cells. Isovitexin significantly inhibited TNF-α expression, and isatin treatment markedly reduced IL-1β expression in LPS-incubated cells. Conclusion:As the pharmacodynamics material basis of Ii, indoles, lignans, and flavonoids are believed to confer beneficial properties through various cellular aspects with multiple signaling pathways involved.