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As people's living standards improve， the development trend of diabetes has gradually become severe. Diabetes is a chronic inflammatory disease associated with abnormal expression of nuclear factor-kappa B （NF-κB） in patients. NF-κB exists in various tissue cells and participates in the regulation of a variety of genes related to immune function and inflammation. Varieties of factors can activate NF-κB when the body is stimulated by external factors， so as to produce inflammation and other reactions. Previous studies on NF-κB mainly focus on cancer， and the pathological mechanism of the treatment of diabetes by related signaling pathways and the progress of traditional Chinese medicine （TCM） treatment have not been systematically elaborated on. By referring to the relevant literature in China and abroad， it was found that NF-κB is not isolated in the development and progression of diabetes but is associated with signal molecules related to inflammation， oxidative stress， and energy metabolism， and it is involved in mediating inflammation， pancreatic β cell apoptosis， insulin signal transduction， and other physiological functions. Therefore， blocking the transmission of NF-κB signaling pathway is beneficial to the treatment of diabetes. At present， Western medicine for the treatment of diabetes mainly includes oral hypoglycemic drugs and insulin injections， but the adverse reactions are obvious. TCM has been characterized by multi-target， extensive action， and excellent curative effects in the treatment of diabetes. TCM and its compounds with functions of tonifying Qi and promoting blood circulation， regulating qi and eliminating phlegm， clearing heat and detoxifying， and nourishing Yin and moistening dryness can effectively intervene in the abnormal expression of NF-κB signaling pathway in vivo through anti-inflammatory effects. In this paper， the association between NF-κB signaling pathway and diabetes was summarized， and the modern research progress of TCM intervention of NF-κB signaling pathway in the treatment of diabetes in the past five years was reviewed， so as to lay a laboratory foundation for the study of a new pathological mechanism of diabetes based on NF-κB signaling pathway and provide new targets and research direction for the prevention and treatment of diabetes and development of related TCM.
RÉSUMÉ
ObjectiveTo observe the effect of water extract of Mori Folium （MLE） on oxidative stress in adipose tissue of type 2 diabetes mellitus （T2DM） mice and explore its mechanism. MethodTwenty-four male db/db mice were randomly divided into model group， metformin group， low-dose MLE （MLE-L） group， and high-dose MLE （MLE-H） group according to their body weight and blood glucose， with six mice in each group， and other six C57BLKS/JGpt wild littermate mice were selected as normal group. The mice in the metformin group were given 200 mg·kg-1 metformin suspension， and the mice in the MLE-L and MLE-H groups were respectively given 2 g·kg-1 and 4 g·kg-1 MLE， while the mice in the normal group and model group were given the same dose of deionized water by daily gavage for eight weeks. Body weight， subcutaneous fat index， fasting blood glucose （FBG）， and oral glucose tolerance level （OGTT） of the mice were detected， and serum superoxide dismutase （SOD）， glutathione peroxidase （GSH-Px）， and malondialdehyde （MDA） were measured. The expression levels of silent information regulator 1 （SIRT1） and NADPH oxidase type 4 （NOX4） protein in subcutaneous adipose tissue of the mice were detected by Western blot. ResultThe FBG level， OGTT， and subcutaneous fat index of T2DM mice were significantly decreased （P<0.05， P<0.01） after administration of MLE compared with the blank group. The contents of serum SOD and GSH were significantly increased， while the level of oxidative stress damage marker MDA was significantly decreased （P<0.05， P<0.01）. The expression of SIRT1 protein in adipose tissue was significantly increased， while the expression of NOX4 protein was significantly decreased （P<0.05， P<0.01）. ConclusionMLE can ameliorate T2DM by alleviating oxidative stress in adipose tissue of T2DM mice and reducing blood glucose.
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ObjectiveTo investigate the protective effects of Mori Folium extract （MLE） on the kidney of db/db diabetic mice and its mechanism. MethodTwenty-four male C57BLKS/JGpt-Leprdb/Leprdb （db/db） mice were randomly divided into model group， metformin group， low-dose group of MLE （MLE-L）， and high-dose group of MLE （MLE-H） according to their fasting blood glucose （FBG）， with six mice in each group， and other six C57BLKS/JGpt wild littermate （m/m） mice were selected as normal group. The mice in the drug administration groups were given corresponding drugs by gavage， and the mice in the normal group and model group were given the same dose of deionized water by gavage once a day for continuous eight weeks. Body weight， bilateral kidney weight， and FBG were measured， and an oral glucose tolerance test （OGTT） was performed. The pathological changes in the kidney tissue of mice were observed by hematoxylin-eosin （HE） and periodic acid-silver （PAS） staining， and serum creatinine （SCr） and blood urea nitrogen （BUN） levels were detected. Enzyme-linked immunosorbent assay （ELISA） was used to detect the levels of tumor necrosis factor-alpha （TNF-α） and interleukin-6 （IL-6） in serum and urinary microalbumin （U-mAlb） of mice. The expression levels of toll-like receptor 4 （TLR4）， myeloid differentiation factor 88 （MyD88）， and nuclear factor-kappa B p65 （NF-κB p65） protein in kidney tissue of mice were tested by Western blot. ResultCompared with the normal group， the body weight， absolute renal weight， FBG， and the area under the curve （AUC） of OGTT of mice in the model group were significantly increased （P<0.01）， and the levels of SCr， BUN， and U-mAlb， as well as TNF-α and IL-6 in serum were significantly increased （P<0.01）. The glomerular basement membrane in the kidney tissue of mice was thicker， with obvious inflammatory cell infiltration. The protein expression levels of TLR4， MyD88， and NF-κB p65 in the kidney tissue of mice were increased significantly （P<0.01）. Compared with the model group， there was no statistical difference in the body weight of mice in each drug administration group. The absolute renal weight of mice in the MLE-H and metformin groups was significantly reduced （P<0.05， P<0.01）. The FBG levels of mice in the metformin， MLE-L， and MLE-H groups started to decrease after treatment for four to eight weeks （P<0.05， P<0.01）. The AUC of mice in the MLE-H and metformin groups was significantly decreased （P<0.01）. The levels of SCr， BUN， and U-mAlb of mice in the MLE-H and metformin groups were significantly decreased （P<0.01）， and those of SCr and U-mAlb of mice in the MLE-L group were significantly decreased （P<0.01）. The levels of TNF-α and IL-6 in the serum of mice in the MLE-H and metformin groups were significantly decreased （P<0.01）. The renal tissue pathology of mice in each drug administration group was improved to varying degrees， and the protein expression levels of TLR4， MyD88， and NF-κB p65 in the MLE-H group were decreased significantly （P<0.05， P<0.01）. ConclusionMLE can improve the renal structure and function of db/db diabetic mice， and its mechanism may be related to the inhibition of the TLR4/MyD88/NF-κB signaling pathway.
RÉSUMÉ
Mori Folium， the dried leaves of Morus alba， is widely used in clinical practice for dispersing wind and heat， clearing the lung and moistening dryness， soothing the liver and improving vision， and cooling blood and stopping bleeding. It has been used to regulate blood glucose since ancient times， and modern studies have shown that the active components of Mori Folium for lowering blood glucose mainly include flavonoids， alkaloids， polysaccharides， and phenols. These components are mainly extracted by solvents such as water and alcohols with the assistance of ultrasound and microwave. In addition， new extraction methods are emerging， such as CO2 supercritical fluid extraction， enzymatic hydrolysis， and cloud point extraction. Mori Folium lowers blood glucose via multiple components， pathways， and targets. Specifically， it can improve glucose and lipid metabolism， protect pancreatic β cells， and alleviate insulin resistance to reduce the damage caused by hyperglycemia and restore normal physiological functions. Although a large number of studies have been carried out on diabetes， the causes and radical treatment methods remain to be explored， and diabetes is still a major disease that endangers human health and needs to be solved urgently. The articles about extraction process and mechanism of active components in Mori Folium for lowering blood glucose were retrieved from the China National Knowledge Infrastructure （CNKI）， Web of Science， and PubMed. We analyzed the applicable extraction methods for the blood glucose-lowering components such as flavonoids， polysaccharides， and alkaloids in Mori Folium， and compared the conventional and emerging methods. Furthermore， we summarized our research achievements in the extraction of active components from Mori Folium and the blood glucose-lowering effect and mechanisms. This review aims to provide theoretical support for the optimization of the extraction process， the research on the blood glucose-lowering components and mechanism， and the development of new drugs and clinical application of Mori Folium.
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Objective:To investigate the protective effect of interfering peptide TAT-GluA2CT on hippocampal neurons in the Lithium chlorine-Pilocarpine status epilepticus model and the optimal time of administration.Methods:Male SD rats (72 cases) were induced to status epilepticus by using Lithium chlorine-Pilocarpine, while a control group ( n=12) was established.The 72 rats were divided into epilepsy group ( n=12), TAT-sham peptide group ( n=12), TAT-GluA2CT peptide group ( n=48) according to the random number table method, and the TAT-GluA2CT peptide group were further divided into the pre-1 h group ( n=12), the post-2 h group ( n=12), the post-4 h group( n=12), and the post-6 h group ( n=12) according to the administration time of the TAT-GluA2CT peptide.Nissl staining and terminal dUTP nick end labeling (TUNEL) assay were performed on 6 rats each from control group, epilepsy group, TAT-shampeptide group, pre-1 h group, post-2 h group, post-4 h group, and post-6 h group to observe the morphological changes and apoptosis of neurons in the CA1 region of the rat hippocampus.Western blot and co-immunopercipitation test were used to detect the expression of GluA2[second subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) recepter] and the coupling of GluA2/transmembrane AMPA receptor regulatory protein (TARP γ-8) complex in control group, epilepsy group, pre-1 h group, post-2 h group, post-4 h group and post-6 h group.The t-test was used to compare the data differences between 2 groups, and one-way ANOVA was adopted to compare the differences between the groups. Results:Compared with the epilepsy group, the number of neurons in each TAT-GluA2CT peptide group increased significantly, and the difference was statistically significant( epilepsy group 20.07±3.51, pre-1 h group 39.40±2.39, post-2 h group 38.43±2.42, post-4 h group 30.30±2.55, and post-6 h group 27.93±3.20, F=235.28, P<0.05). Compared with the epilepsy group, the number of apoptotic cells in each TAT-GluA2CT peptide group was significantly reduced, and the difference was statistically significant(epilepsy group 31.47±3.19, pre-1 h group 7.30±3.45, post-2 h group 9.27±3.81, post-4 h group 12.86±3.08, and post-6 h group 14.43±3.13, F=248.60, P<0.05). Compared with the control group, the expression of hippocampal GluA2 decreased after epilepsy induction, and the difference was statistically significant(control group 21 626.53±2 700.58, epilepsy group 14 578.16±2 917.02, pre-1 h group 13 375.47±3 180.54, post-2 h group 15 244.10±1 390.41, post-4 h group 15 799.16±4 559.49, post-6 h group 15 722.95±1 756.01, F=3.83, P<0.05). No statistical difference was observed in the expression of GluA2 between the TAT-GluA2CT peptide group and the epilepsy group( F=0.45, P=0.77). Compared with the epilepsy group, GluA2/TARPγ-8 complex coupling was decreased in each TAT-GluA2CT peptide group, and the difference was statistically significant(epilepsy group 24 509.80±3 718.54, pre-1 h group 12 055.18±5 847.11, post-2 h group 9 630.51±5 805.17, post-4 h group 12 749.35±7 108.45, post-6 h group 11 092.98±7 330.08, F=10.68, P<0.05). Compared with the epilepsy group, the incubation period of seizures in the pre-1 h group was prolonged and the seizure rating was decreased, with statistically significant differences[epilepsy group (18.58±3.99) min, pre-1 h group (103.25±9.21) min, t=29.23, P<0.05]. Conclusions:TAT-GluA2CT peptide can attenuate the neuronal damage in hippocampus of epileptic rats.The neuroprotective effect of TAT-GluA2CT peptide was most obvious at 1 h before or 2 h after administration of Pilocarpine.
RÉSUMÉ
Epilepsy occurs as a result of episodic abnormal synchronous discharges in cerebral neuronal networks.It is characterized by an imbalance between excitatory and inhibitory neurotransmission.Although various non-conventional mechanisms are implicated in epileptic synchronization, glutamate excitatory neurons play an essential role.AMPA receptors mediate fast synaptic excitation within and between brain regions relevant to epilepsy, and play a role in epileptogenesis and in seizure-induced brain damage.However, direct modulation of AMPA receptors may have undesirable consequences, given its wide expression within the central nervous system and critical roles on brain circuitry development.Hippocampal CA1 region, as the main site of epilepsy, selectively regulates the high expression of AMPA receptor GluA2 subunit and transmembrane AMPA receptor regulatory protein family(TARPs)γ-8 subtype and its complex GluA2/TARPγ-8, whether it can produce anti-epileptic and avoid adverse reactions.