Huiyang Shengji decoction promotes wound healing in diabetic mice by activating the EGFR/PI3K/ATK pathway.

BACKGROUND: Common chronic wounds include diabetic ulcers, venous ulcers, and pressure ulcers. The traditional Chinese medicine Huiyang Shengji decoction (HYSJD) has been shown to promote the healing of diabetic chronic wounds, however, its pharmacological mechanism is still unclear. PURPOSE: This study aimed to determine the mechanism of HYSJD in promoting the healing of diabetic chronic skin ulcers. METHODS: Ultra-performance liquid chromatography was combined with tandem mass spectrometry (UPLC-MS/MS) to analyze the main components of HYSJD and the absorbed components in mouse serum at 30 min after oral administration of HYSJD. db/db mouse models for chronic skin ulcers were constructed by full-thickness skin resection. Wound tissues at day 7 post wound formation were used to perform microarray analysis of growth factors and chemokine expression. GO and KEGG enrichment analysis was performed on differentially expressed proteins. ELISA assays were used to measure differential expressed cytokines in the serum and Western blot analysis was used to determine the expression levels of related pathway proteins in the skin wounds. RESULTS: UPLC-MS/MS analysis showed that the main chemical components of HYSJD were flavonoids, terpenes, alkaloids, phenylpropanoids, and carbohydrates. At 30 min after oral administration of HYSJD, five absorbed components were detected in the serum, these included formononetin, calycosin, hypaconitine, calycosin-7-glucoside, and sinapic acid. HYSJD was found to increase the wound healing rate in chronic skin ulcers in db/db mice at days 3, 7, and 14 post wound formation, and promote the proliferation of epidermal cells. Two proteins that were differentially expressed between the different groups, i.e., IGF-1 and EGFR, were further validated. Serum ELISA assays showed that serum EGFR in the HYSJD treatment group was significantly increased. KEGG pathway analysis suggested that the PI3K/AKT pathway involved in HYSJD promoting the proliferation of epidermal cells in chronic wounds in db/db mice. Experimental verification showed that HYSJD activated the PI3K/AKT signaling pathway in mouse wound skin. CONCLUSION: HYSJD promotes the proliferation of epidermal cells in chronic diabetic wounds by increasing EGFR expression in the wounds and activating the PI3K/AKT signaling pathway. Our study provides an experimental basis for the pharmacological mechanism of HYSJD.

Swimming improves cognitive reserve in ovariectomized rats and enhances neuroprotection after global cerebral ischemia.

Cognitive reserve has been proposed to account for different responses to brain damage or pathology. Factors implicated to influence cognitive reserve include cognitive engagement, physical activity, leisure activities, stress levels, and diet. Furthermore, long-term ovariectomy (OVX), such as occurs in women that have underwent surgical menopause, has been reported to increase the risk of cognitive impairment. In the current study, we examined whether swimming improves cognitive function in long-term OVX-rats. We also examined the neuroprotective effect of swimming after global cerebral ischemia (GCI) and explored the effect of swimming preconditioning on activation of the MAPK cascade signaling pathway, synaptic proteins and brain-derived growth factor (BDNF) - all factors implicated in regulating synaptic plasticity and neuroprotection in the brain. Adult Sprague-Dawley OVX-rats were randomly assigned into four groups: Sham (Sh), Sham + Swimming (Sh + Sw), Ischemia/Reperfusion (IR) and IR + Sw. Our results revealed that (1) Morris water maze and shuttle box test analysis revealed that swimming improved cognitive function in OVX-rats, (2) The levels of PSD95 and synaptophysin, as well as the protein expression of p-ERK, p-CREB and BDNF were all increased in the hippocampus after swimming with or without GCI, and (3) Swimming also increased the number of surviving neurons and IL4 protein expression, while decreasing the Iba1 (a microglia marker) level in the hippocampus. In conclusion, our study demonstrates that swimming improves memory in OVX-rats, and that swimming preconditioning enhances the neuroprotective ERK1/2/CREB/BDNF pathway signaling and ameliorates brain damage after GCI in OVX-rats, which may be closely related to induction of an IL4-mediated anti-inflammatory mechanism.

Paeonol ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice by inhibiting the maturation and activation of dendritic cells.

Paeonol, an active component derived from the traditional Chinese medicine Cortex Moutan, possesses anti-inflammatory, analgesic, antioxidant and anti-allergic properties. Psoriasis is a chronic, recurrent, inflammatory dermatosis accompanied by excessive activation of Toll­like receptors (TLRs) in dendritic cells (DCs), which are primarily responsible for initiating an immune response. We investigated the effect of paeonol on inflammation in an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated by R848. Mice were intragastrically administered 100 mg/kg (high), 50 mg/kg (medium) and 25 mg/kg (low) paeonol, respectively. We evaluated inflammation of psori-asis­like lesions based on histological changes, protein levels of myeloid differentiation factor 88 (MyD88) and TLR8 in skin lesions by western blotting, and levels of CD11c+ DCs in skin by immunoassay and in spleens by flow cytometry. Inflammatory cytokines [interleukin (IL)-23, IL-12 and IL-1ß] in skin lesions and BMDCs were also assessed by RT-PCR and ELISA. Application of paeonol decreased IMQ-induced keratinocyte proliferation, and infiltration of CD3+ cells, while the treatment ameliorated CD11c+ cells in the spleen and skin, and reduced MyD88 and TLR8 proteins in skin lesions. Paeonol inhibited IMQ-induced mRNA expression of IL-23, but not IL-12 and IL-1ß in BMDCs, along with significantly lower levels of DCs expressing MHCⅡ, CD80 and CD86 in vitro. These results indicate that paeonol suppresses the maturation and activation of DCs by decreasing MyD88 and TLR8 proteins in the TLR7/8 signaling pathway which finally alleviates psoriasis­like skin lesions. The TLR7/8 signaling pathway in DCs provides an important insight into the mechanism of psoriasis, and paeonol may be a potent therapeutic drug for psoriasis.