Mesenchymal stem cell (MSC)-based therapy has emerged as a promising treatment for spinal cord injury (SCI), but improving the neurogenic potential of MSCs remains a challenge. Mixed lineage leukemia 1 (MLL1), an H3K4me3 methyltransferases, plays a critical role in regulating lineage-specific gene expression and influences neurogenesis. In this study, we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla (SCAPs). We examined the expression of neural markers, and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells, immunofluorescence staining, and a SCI model. We employed a coimmunoprecipitation (Co-IP) assay, real-time RT-PCR, microarray analysis, and chromatin immunoprecipitation (ChIP) assay to investigate the molecular mechanism. The results showed that MLL1 knock-down increased the expression of neural markers, including neurogenic differentiation factor (NeuroD), neural cell adhesion molecule (NCAM), tyrosine hydroxylase (TH), βIII-tubulin and Nestin, and promoted neuron-like cell formation in SCAPs. In vivo, a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model. MLL1 can combine with WD repeat domain 5 (WDR5) and WDR5 inhibit the expression of neural markers in SCAPs. MLL1 regulates Hairy and enhancer of split 1 (HES1) expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5. Additionally, HES1 enhances the expression of neural markers in SCAPs. Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.
Animals ; Humans ; Rats ; Cell Differentiation ; Intracellular Signaling Peptides and Proteins/therapeutic use* ; Leukemia/metabolism* ; Mesenchymal Stem Cells ; Neurogenesis ; Stem Cells ; Transcription Factor HES-1/metabolism*

OBJECTIVE: To explore the specific pharmacological molecular mechanisms of Kai Xin San (KXS) on treating Alzheimer's disease (AD) based on network pharmacology and experimental validation. METHODS: The chemical compounds of KXS and their corresponding targets were screened using the Encyclopedia of Traditional Chinese Medicine (ETCM) database. AD-related target proteins were obtained from MalaCards database and DisGeNET databases. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis. Functional enrichment analysis predicted the potential key signaling pathways involved in the treatment of AD with KXS. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, the predicted key signaling pathway was validated experimentally. Positioning navigation and space search experiments were conducted to evaluate the cognitive improvement effect of KXS on AD rats. Western blot was used to further examine and investigate the expression of the key target proteins related to the predicted pathway. RESULTS: In total, 38 active compounds and 469 corresponding targets of KXS were screened, and 264 target proteins associated with AD were identified. The compound-target-disease and PPI networks identified key active ingredients and protein targets. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested a potential effect of KXS in the treatment of AD via the amyloid beta (A β)-glycogen synthase kinase-3 beta (GSK3 β)-Tau pathway. Molecular docking revealed a high binding affinity between the key ingredients and targets. In vivo, KXS treatment significantly improved cognitive deficits in AD rats induced by Aβ_1-42, decreased the levels of Aβ, p-GSK3β, p-Tau and cyclin-dependent kinase 5, and increased the expressions of protein phosphatase 1 alpha (PP1A) and PP2A (P<0.05 or P<0.01). CONCLUSION KXS exerted neuroprotective effects by regulating the Aβ -GSK3β-Tau signaling pathway, which provides novel insights into the therapeutic mechanism of KXS and a feasible pharmacological strategy for the treatment of AD.
Rats ; Animals ; Alzheimer Disease/drug therapy* ; Amyloid beta-Peptides ; Glycogen Synthase Kinase 3 beta ; Network Pharmacology ; Molecular Docking Simulation ; Glycogen Synthase Kinase 3/therapeutic use* ; Drugs, Chinese Herbal/therapeutic use*

The purpose of this study was to investigate the effect of aqueous extract of Corni Fructus on β-amyloid protein 25-35(Aβ_(25-35))-induced brain injury and neuroinflammation in Alzheimer's disease(AD) mice to provide an experimental basis for the treatment of AD by aqueous extract of Corni Fructus. Sixty C57BL/6J male mice were randomly divided into a sham group, a model group, a positive control group(huperizine A, 0.2 mg·kg~(-1)), a low-dose aqueous extract of Corni Fructus group(1.3 g·kg~(-1)), a medium-dose aqueous extract of Corni Fructus group(2.6 g·kg~(-1)), and a high-dose aqueous extract of Corni Fructus group(5.2 g·kg~(-1)). The AD model was induced by lateral ventricular injection of Aβ_(25-35) in mice except for those in the sham group, and AD model mice were treated with corresponding drugs by gavage for 24 days. The behavioral test was performed one week before animal dissection. Hematoxylin-eosin(HE) staining was performed to observe the morphology of neurons in the hippocampal region. Flow cytometry was used to detect the apoptosis level of primary hippocampal cells in mice. ELISA kits were used to detect the levels of β-amyloid protein 1-42(Aβ_(1-42)) and phosphorylated microtubule-associated protein Tau(p-Tau) in mouse brain tissues. Immunofluorescence and Western blot were used to detect the expression of related proteins in mouse brain tissues. MTT assay was used to detect the effect of compounds in aqueous extract of Corni Fructus on Aβ_(25-35)-induced N9 cell injury. Molecular docking was employed to analyze the interactions of caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol with β-amyloid precursor protein(APP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). Aqueous extract of Corni Fructus could improve the learning and memory abilities of Aβ_(25-35)-induced mice by increasing the duration of the autonomous activity, the rate of autonomous alternation, the preference coefficient, and the discrimination coefficient, and reduce Aβ_(25-35)-induced brain injury and neuroinflammation in mice by increasing the expression levels of interleukin-10(IL-10) and B-cell lymphoma-2(Bcl-2) in brain tissues, decreasing the expression levels of Aβ_(1-42), p-Tau, IL-6, TNF-α, cysteine aspartate-specific protease 3(caspase-3), cysteine aspartate-specific protease 9(caspase-9), and Bcl-2-associated X protein(Bax), and decreasing the number of activated glial cells in brain tissues. The results of cell experiments showed that esculetin and(+)-lyoniresinol could improve Aβ_(25-35)-induced N9 cell injury. Molecular docking results showed that caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol had good binding affinity with APP and weak binding affinity with IL-6 and TNF-α. Aqueous extract of Corni Fructus could ameliorate cognitive dysfunction and brain damage in Aβ_(25-35)-induced mice by reducing the number of apoptotic cells and activated glial cells in the brain and decreasing the expression level of inflammatory factors. Caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol may be the material basis for the anti-AD effect of aqueous extract of Corni Fructus.
Mice ; Male ; Animals ; Alzheimer Disease/drug therapy* ; Amyloid beta-Peptides/metabolism* ; Cornus/metabolism* ; Neuroinflammatory Diseases ; Tumor Necrosis Factor-alpha/metabolism* ; Interleukin-6 ; Aspartic Acid ; Cysteine/therapeutic use* ; Molecular Docking Simulation ; Mice, Inbred C57BL ; Brain Injuries ; Peptide Hydrolases ; Disease Models, Animal ; Mice, Transgenic

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.
Mice ; Animals ; Glucagon-Like Peptide 1/metabolism* ; Receptors, Glucagon/therapeutic use* ; Xenopus laevis/metabolism* ; Diabetes Mellitus, Type 2/drug therapy* ; Glycopeptides/therapeutic use* ; Obesity/drug therapy* ; Hypoglycemic Agents/pharmacology* ; Peptides/pharmacology*

Deficits in the clearance of amyloid β protein (Aβ) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer's disease (AD). Impaired uptake of Aβ by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβ clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aβ uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aβ deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβ clearance by blood monocytes and alleviating AD-like pathology.
Alzheimer Disease/pathology* ; Amyloid beta-Peptides/metabolism* ; Amyloid beta-Protein Precursor/metabolism* ; Animals ; Cognition ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Monocytes/pathology* ; Polysaccharides/therapeutic use* ; Proteoglycans

Obesity is an important risk factor of type 2 diabetes (T2D), which has become an important factor threatening human health. However, no perfect drug choice for obesity exists. Semaglutide is a kind of human glucagon-like peptide-1 (GLP-1) analog that promotes insulin secretion while inhibiting glucagon secretion through a glucose concentration-dependent mechanism. GLP-1 can also delay stomach emptying and suppress appetite to help lose weight. This review summarizes clinical evidence of the semaglutide effect on T2D and obesity and establishes expectations on future clinical trials for obesity treatment.
Diabetes Mellitus, Type 2/drug therapy* ; Glucagon-Like Peptide-1 Receptor/therapeutic use* ; Glucagon-Like Peptides ; Humans ; Hypoglycemic Agents/therapeutic use* ; Motivation ; Obesity/drug therapy*

Due to its complex pathogenesis and lack of effective therapeutic methods, Alzheimer's disease (AD) has become a severe public health problem worldwide. Recent studies have discovered the function of central nervous system lymphatic drainage, which provides a new strategy for the treatment of AD. Chinese herbal medicine (CHM) has been considered as a cure for AD for hundreds of years in China, and its effect on scavenging β-amyloid protein in the brain of AD patients has been confirmed. In this review, the mechanism of central nervous system lymphatic drainage and the regulatory functions of CHM on correlation factors were briefly summarized. The advances in our understanding regarding the treatment of AD via regulating the central lymphatic system with CHM will promote the clinical application of CHM in AD patients and the discovery of new therapeutic drugs.
Alzheimer Disease/drug therapy* ; Amyloid beta-Peptides ; Brain ; China ; Drugs, Chinese Herbal/therapeutic use* ; Humans

Growth factors play an important role in wound healing, and they mainly accelerate wound healing by activating the related signal pathways. Chinese scientists have been conducting basic and clinical researches on growth factors for 30 years, with a series of growth factor drugs being developed and widely used in the treatment of burns and trauma and chronic refractory ulcers. This paper expounds the frontier progress of growth factors on wound healing from the perspectives of immunity, nerve, fat, and so on, and puts forward the further thoughts of the research team on the regulation of wound healing by growth factors.
Burns/therapy* ; Humans ; Intercellular Signaling Peptides and Proteins/therapeutic use* ; Signal Transduction ; Wound Healing

Wound repair is a highly coordinated and mutually regulated complex process involving various kinds of cells, extracellular matrices and cytokines. A variety of growth factors play an important regulatory role in wound healing, and it is critical to achieve effective delivery and sustained function of growth factors. In recent years, the application of biomaterials in tissue engineering has shown great potential, and the effective delivery of growth factors by biomaterials has attracted increasing attention. Based on this, this paper introduces the mechanism of related growth factors in the process of wound healing, focusing on the recent progress of biomaterial delivery of growth factors to accelerate wound healing, in order to provide new enlightenment for clinical wound treatment.
Biocompatible Materials/metabolism* ; Extracellular Matrix/metabolism* ; Intercellular Signaling Peptides and Proteins/therapeutic use* ; Tissue Engineering ; Wound Healing

Neurodegenerative diseases are global public health problems that seriously affect the quality of human life. The incidence of neurodegenerative diseases is increasing year by year and there has been no effective treatment. Acanthopanax senticosus is a Chinese medicine for tonifying kidney and has a long medicinal and edible history. It contains many active ingredients such as saponins, coumarins, flavonoids, organic acids and polysaccharides, with pharmacological effects of anti-oxidation, anti-age, anti-inflammation, anti-fatigue and immune regulation. Modern medical studies have found that A. senticosus can act on the central nervous system, and its extracts and active ingredients can improve learning and memory ability, playing vital roles of anti-oxidation, anti-inflammation, anti-apoptosis, antagonizing against amyloid β protein(Aβ) toxicity, modulating neurotransmitter release, signaling pathways and brain energy metabolism, maintaining the structure and function of mitochondria, and epigenetic regulation. It treats neurodegenerative diseases via multiple components, multiple targets, and multiple pathways, with the characteristics of low toxic side effects. This study reviewed the pharmacological reports of A. senticosus on neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and ischemic stroke in China and abroad in recent ten years, and summarized the active ingredients and the mechanism underlying the neuroprotective effects of A. senticosus. Additionally, the significant advantages of A. senticosus in the treatment of neurodegenerative diseases and the limitations of the reports were discussed from the aspects of traditional Chinese medicine(TCM) theory and modern medical research. This study provided theoretical support for the drug development and clinical application of A. senticosus in treating neurodegenerative diseases and also facilitated the prevention and treatment of neurodegenerative diseases by kidney-tonifying method in TCM.
Amyloid beta-Peptides ; Anti-Inflammatory Agents ; Eleutherococcus/chemistry* ; Epigenesis, Genetic ; Humans ; Neurodegenerative Diseases/prevention & control* ; Plant Extracts/therapeutic use*