Zhiming He

Background: Depression-associated memory impairment is a clinically significant comorbidity that responds poorly to conventional antidepressants. Dihydromyricetin (DHM), a natural dihydroflavonoid, exhibits neuroprotective and antidepressant-like effects, but its impact on stress-induced memory deficits and the underlying mechanisms remain unclear. Methods: A chronic restraint stress (CRS) mouse model was employed. DHM was intraperitoneally administered daily (20 mg/kg bodyweight) for 8 consecutive days. Depression-like behavior and memory functions were assessed with the tail suspension test, the object recognition memory (ORM) task, and the Y-maze test. Network pharmacology, molecular docking, and molecular dynamics (MD) simulations were integrated to predict potential targets and associated signal pathways. Expression of hippocampal PKA, p-CREB, CREB, and BDNF was measured through Western blotting. Results: CRS significantly increased immobility time in the tail suspension test and impaired both recognition memory (ORM) and spatial working memory (Y-maze), without affecting locomotor activity. DHM treatment effectively reversed behavioral despair and memory deficits. Network pharmacology identified 47 intersecting targets between DHM and depression-related memory impairment, with CREB1, ESR1 and NOS1 as core hub nodes. KEGG enrichment particularly implicated the involvement of the cAMP signaling pathway and other signaling pathways, which are associated with depression and/or memory impairment. Molecular docking predicted strong binding affinities of DHM to CREB1 (−9.225 kcal/mol), NOS1 (−9.113 kcal/mol) and ESR1 (−7.903 kcal/mol). MD simulations confirmed the thermodynamic stability of DHM-ESR1 and DHM-NOS1 complexes. Western blot analysis demonstrated that DHM treatment significantly increased the levels of hippocampal PKA, p-CREB and BDNF, without altering total CREB expression in CRS mice. Conclusions: DHM alleviated CRS-induced depression-like behaviors and memory deficits, possibly through regulation of multiple signaling pathways, including the hippocampal PKA-CREB-BDNF signaling pathway. These findings highlight DHM as a promising natural therapeutic candidate for depression-associated cognitive impairment.

Background: Age-related macular degeneration (AMD) is a common retinal disorder, causing blindness in aged individuals. One of the traditional Chinese medicines, modified Zhujing pill (MZP), has been widely used to treat various ocular disorders, including AMD; however, its protective mechanisms remain elusive. In this study, we explored the functional role of MZP in high-fat-diet-fed mice, a commonly used model for AMD. Methods: Compounds of MZP water extract were identified by high-performance liquid chromatography (HPLC)/mass spectrometry (MS)/MS. The mice were divided into three groups: group 1 mice fed with control diet (CD), group 2 mice fed with high-fat diet (HFD), and group 3 mice fed with HFD for 12 weeks; groups 1 and 2 were then treated with physiological saline, while group 3 was treated with MZP for 4 weeks. The cholesterol level and expression of cholesterol homeostasis-associated genes, antioxidant genes, and proinflammatory cytokines in mouse tissues were measured using biochemical approaches. Mouse cecum microbiota compositions and metabolic functions were analyzed using 16rRNA sequencing and bioinformatics approach. Results: HFD-fed mice had high levels of cholesterol in the retinal pigment epithelial (RPE) cells, liver, and serum, a decreased expression of cholesterol homeostasis-associated genes and antioxidant genes in the RPE and liver, and an increased expression of proinflammatory cytokines. MZP treatment counteracted HFD-induced pathologic effects. Additionally, HFD altered cecum bacterial compositions and diversities associated with individual metabolic pathways. These metabolic pathways are involved in the biosynthesis of bacterial metabolites, mitochondrial function, oxidative stress, and inflammation. MZP reversed most of the changes back to control characteristics. Conclusion: We postulate that the beneficial effects of MZP against AMD are possibly related to lowering the cholesterol level, suppressing oxidative stress and inflammation, and modulating gut microbiota and associated functions.

Background: Age-related macular degeneration (AMD) is the commonest cause of retinal disorders in the aged population. Ziyin-Mingmu decoction (ZD) has been widely used to treat AMD patients over thousands of years, however the underlying functional mechanisms of ZD are largely elusive. In this study, we aim to elucidate the therapeutic mechanisms of ZD in AMD models. Methods: An in vivo AMD mouse model and an in vitro AMD model were established. Cholesterol level in mouse tissues was measured. Expression of antioxidant genes and proinflammatory cytokines in mouse tissues and in human retinal pigment epithelial (RPE) cells were detected using biochemical approaches. Gut microbiota community and functional pathways were analysed using bioinformatics approach. Compounds in ZD were identified using HPLC/MS. Results: High fat diet (HFD)-fed mice had significantly higher levels of cholesterol in the retina, RPE, liver and serum, and markedly decreased expression of cholesterol metabolism-associated genes in those tissues, compared to mice fed with normal diet. Similarly, expression of antioxidant and inflammation genes was dysregulated in HFD-fed mouse tissues. ZD treatment reversed these HFD-induced pathological effects. HFD also altered the composition of cecum bacterial communities and associated metabolic pathways, which returned to control levels by ZD. In vitro assays showed that H₂O₂ significantly increased oxidative stress and enhanced expression of proinflammatory cytokines. Co-treatment with ZD significantly counteracted these changes. HPLC/MS identified 105 compound in water extracted ZD and most are polyphenols. Conclusion: Our data suggests that protection of ZD against AMD is possibly through mitigating cholesterol level, oxidative stress and inflammation, and modulating gut microbiota by polyphenols.

Abiotic stimuli severely restrict the growth and development of plants, resulting in massive losses in the quality and yield of crops. Exploring genes that can improve crop tolerance to abiotic stress is important. In a previous study, we found that overexpression of the Arabidopsis nucleotide-binding domain leucine-rich repeat (NB-LRR) gene AtRPM1(D505V) increased disease resistance in rice. In this research, we found that AtRPM1(D505V) transgenic plants were more sensitive to abscisic acid (ABA) than wild type (WT) plants. Abiotic-stress resistance in AtRPM1(D505V) transgenic plants was investigated. We found that AtRPM1(D505V) transgenic plants exhibited improved resistance to drought and salt stress; the phonotype and survival rates of transgenic rice were better than WT plants. The expression of stress responsive genes including OsDREB2A, OsDREB2B, OsRD22, and OsRD29A were significantly upregulated in AtRPM1(D505V) overexpressed plants than in WT plants. Moreover, the activities of catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) were significantly increased in AtRPM1(D505V) overexpressed plants than in WT plants under drought and salt stress. Under cold stress, the expression of stress responsive genes and the activities of antioxidant enzymes in AtRPM1(D505V) transgenic plants were significantly lower than in WT plants. Our research demonstrated that AtRPM1(D505V) confers drought and salt resistance to transgenic rice. Therefore, AtRPM1(D505V) could act as a potential candidate gene to cultivate drought- and salt-tolerant plants.

Depression is a complex mental disorder, affecting approximately 280 million individuals globally. The pathobiology of depression is not fully understood, and the development of new treatments is urgently needed. Dihydromyricetin (DHM) is a natural flavanone, mainly distributed in Ampelopsis grossedentata. DHM has demonstrated a protective role against cardiovascular disease, diabetes, liver disease, cancer, kidney injury and neurodegenerative disorders. In the present study, we examined the protective effect of DHM against depression in a chronic depression mouse model induced by corticosterone (CORT). Animals exposed to CORT displayed depressive-like behaviors; DHM treatment reversed these behaviors. Network pharmacology analyses showed that DHM’s function against depression involved a wide range of targets and signaling pathways, among which the inflammation-linked targets and signaling pathways were critical. Western blotting showed that CORT-treated animals had significantly increased levels of the advanced glycation end product (AGE) and receptor of AGE (RAGE) in the hippocampus, implicating activation of the AGE-RAGE signaling pathway. Furthermore, enzyme-linked immunosorbent assay (ELISA) detected a marked increase in the production of proinflammatory cytokines, interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNFα) in the hippocampus of CORT-treated mice. DHM administration significantly counteracted these CORT-induced changes. These findings suggest that protection against depression by DHM is mediated by suppression of neuroinflammation, predominantly via the AGE-RAGE signaling pathway.

Depression, a mood disorder, affects one in fifteen adults, has multiple risk factors and is associated with complicated underlying pathological mechanisms. P-coumaric acid (p-CA), a phenolic acid, is widely distributed in vegetables, fruits and mushrooms. P-CA has demonstrated a protective role against oxidative stress and inflammation in various diseases, including cardiovascular disease, diabetes and cancer. In the current study, we investigated the protection of p-CA against depression and memory impairment in a corticosterone (CORT)-induced chronic depressive mouse model. CORT administration resulted in depression-like behaviors and memory impairment. P-CA treatment alleviated CORT-induced depression-related behaviors and memory impairment. Network pharmacology predicted that p-CA had multiple targets and mediated various signaling pathways, of which inflammation-associated targets and signaling pathways are predominant. Western blotting showed CORT-induced activation of the advanced glycation end product (AGE)-receptor of AGE (RAGE) (AGE-RAGE) signaling and increased expression of the proinflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNFα) in the hippocampus, while p-CA treatment inactivated AGE-RAGE signaling and decreased the levels of IL-1β and TNFα, suggesting that protection against depression and memory impairment by p-CA is mediated by the inhibition of inflammation, mainly via the AGE-RAGE signaling pathway. Our data suggest that p-CA treatment will benefit patients with depression.

The aim of this study was to explore the specific role of miR-29c-3p in Alzheimers disease (AD). Animal models of AD were established by injecting streptozotocin (STZ) into mice through the lateral ventricle, while cell models of AD were induced by 10μM β-amyloid (Aβ). We detected miR-29c-3p and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) contents and measured AD cell proliferation and apoptosis. A low miR-29c-3p level and a high BACE1 level were detected in the brain tissue of AD animal models and AD cell models. Aβ-processed cells had markedly lower proliferation activity, higher apoptosis, increased phosphorylation of tau protein was over phosphorylated, but the overexpression of miR-29c-3p or the silencing of BACE1 significantly enhanced the cell proliferation activity and reduced cell apoptosis by regulating the contents of related proteins. Inhibition of miR-29c-3p or overexpression of BACE1 aggravated Aβ-induced side effects. We used Targetscan7.2 to predict the downstream target genes of miR-29c-3p. Then, we detected that there were target binding sites between miR-29c-3p and BACE1. The rescue experiment identified BACE1 as a functional target for miR-29c-3p. AD leads to decreased miR-29c-3p level and increased BACE1 level. MiR-29c-3p has specific binding sites with the 3-untranslated region (3-UTR) of BACE1 and thus negatively regulates the BACE1 level, thereby affecting the progression of AD.

Alzheimer’s disease (AD) is a progressive neurological degenerative illness with a hidden onset. Its pathogenesis is complicated, although with molecular biology research on cancer and targeted research on pathogenic mechanisms, good progress has not yet been made. Therefore, this work built a multifactor-driven neuronal apoptosis dysfunction module for the purpose of probing its underlying pathogenic mechanisms. We performed differential expression analysis, coexpression analysis, enrichment analysis, and hypergeometric tests to calculate the underlying regulatory effects of multifactors on the modules by the way of the whole gene expression profile of AD and identify a series of ncRNA (miR-320a) and TF (NFKB1). Additionally, we screened 10 modules corresponding to the Hub gene, which tend to regulate the physiological progress of inflammation, regulation of autophagy, cerebral cortex neuron differentiation, glial cell apoptotic, and so on. Meanwhile, Alzheimer’s disease is triggered by signaling pathways such as the MPK signaling pathway. In this study, a dysfunction module is utilized to verify that miR-590-3 and SP1 motility factors can regulate neurons in Alzheimer’s disease through the MPK signaling pathway, not only providing new insights into the pathogenesis of Alzheimer’s disease but also laying a solid theoretical foundation for the biologists to further cure Alzheimer’s disease.