Aripiprazole combined with nerve growth factor improves cognitive function in mice with schizophrenia model.

The pathogenesis and treatment of cognitive dysfunction in patients with schizophrenia (SCZ) remains a challenge. Exploring new effective treatment strategies is relevant for the improvement of cognitive function. Aripiprazole (ARI) is an atypical antipsychotic that improves some cognitive functions. Nerve growth factor (NGF) has been shown to improve cognitive function in certain neurological impairments and partial neurological deficits, but its mechanism of action in cognitive dysfunction in SCZ is unclear. In this study, we established schizophrenia mouse model with dizocilpine (MK-801); treated mice with ARI alone or in combination with NGF; assessed spontaneous activity and cognitive function using open field test and Morris water maze test; and measured brain-derived neurotrophic factor (BDNF) protein and mRNA expression levels using immunohistochemistry and molecular biology assays. The results showed that ARI alone or in combination with NGF can improve increased spontaneous activity and spatial learning memory deficits in model mice by elevating BDNF expression levels in prefrontal cortex (PFC) and hippocampus (HIP). The results suggest that ARI combined with NGF can improve cognitive function in SCZ, which provides new ideas and directions for the clinical treatment of cognitive dysfunction in SCZ.

Study on correlations of BDNF, PI3K, AKT and CREB levels with depressive emotion and impulsive behaviors in drug-naïve patients with first-episode schizophrenia.

BACKGROUND: The pathogenesis of schizophrenia is still unknown. Nearly a half of schizophrenic patients have depressive symptoms and even some impulsive behaviors. The definite diagnosis of schizophrenia is an immense challenge. Molecular biology plays an essential role in the research on the pathogenesis of schizophrenia. OBJECTIVE: This study aims to analyze the correlations of serum protein factor levels with depressive emotion and impulsive behaviors in drug-naïve patients with first-episode schizophrenia. METHODS: Seventy drug-naïve patients with first-episode schizophrenia and sixty-nine healthy volunteers from the health check center in the same period participated in this study. In both the patient group and control group, brain-derived neurotrophic factor (BDNF), phosphatidylin-ositol-3-kinase (PI3K), protein kinase B (AKT), and cAMP-response element binding protein (CREB) levels in the peripheral blood were tested by enzyme-linked immunosorbent assay (ELISA). The depressive emotion and impulsive behaviors were evaluated with Chinese versions of the Calgary Depression Scale for Schizophrenia (CDSS) and Short UPPS-P Impulsive Behavior Scale (S-UPPS-P), respectively. RESULTS: The serum levels of BDNF, PI3K, and CREB in the patient group were lower than those in the control group, while AKT level, total CDSS score and total S-UPPS-P score were all higher. In the patient group, total CDSS score, and total S-UPPS-P score were both correlated negatively with BDNF, PI3K, and CREB levels but positively with AKT level, and the lack-of-premeditation (PR) sub-scale score was not significantly correlated with BDNF, PI3K, AKT, and CREB levels. CONCLUSION: Our study results showed that the peripheral blood levels of BDNF, PI3K, AKT, and CREB in drug-naïve patients with first-episode schizophrenia were significantly different from those in the control group. The levels of these serum protein factors are promising biomarkers to predict schizophrenic depression and impulsive behaviors.

Genistein Modified with 8-Prenyl Group Suppresses Osteoclast Activity Directly via Its Prototype but Not Metabolite by Gut Microbiota.

Postmenopausal osteoporosis is a significant threat to human health globally. Genistein, a soy-derived isoflavone, is regarded as a promising anti-osteoporosis drug with the effects of promoting osteoblastogenesis and suppressing osteoclastogenesis. However, its oral bioavailability (6.8%) is limited by water solubility, intestinal permeability, and biotransformation. Fortunately, 8-prenelylated genistein (8PG), a derivative of genistein found in Erythrina Variegate, presented excellent predicted oral bioavailability (51.64%) with an improved osteoblastogenesis effect, although its effects on osteoclastogenesis and intestinal biotransformation were still unclear. In this study, an in vitro microbial transformation platform and UPLC-QTOF/MS analysis method were developed to explore the functional metabolites of 8PG. RANKL-induced RAW264.7 cells were utilized to evaluate the effects of 8PG on osteoclastogenesis. Our results showed that genistein was transformed into dihydrogenistein and 5-hydroxy equol, while 8PG metabolites were undetectable under the same conditions. The 8PG (10-6 M) was more potent in inhibiting osteoclastogenesis than genistein (10-5 M) and it down-regulated NFATC1, cSRC, MMP-9 and Cathepsin K. It was concluded that 8-prenyl plays an important role in influencing the osteoclast activity and intestinal biotransformation of 8PG, which provides evidence supporting the further development of 8PG as a good anti-osteoporosis agent.

A new strategy for discovering effective substances and mechanisms of traditional Chinese medicine based on standardized drug containing plasma and the absorbed ingredients composition, a case study of Xian-Ling-Gu-Bao capsules.

ETHNOPHARMACOLOGICAL RELEVANCE: The overall therapeutic effect of traditional Chinese medicine formulae (TCMF) was achieved by the interactions of multiple components with multiple targets. However, current pharmacology research strategies have struggled to identify effective substance groups and encountered challenges in elucidating the underlying mechanisms of TCMF. AIM: In this study, a comprehensive strategy was proposed and applied to elucidate the interactions of the multiple components that underlie the functions of the famous TCMF: Xian-Ling-Gu-Bao (XLGB) capsule on bone metabolism in vivo and to elucidate the molecular mechanisms underlying the effects of XLGB on bone cells, especially on osteoblasts. METHODS: The efficacy of XLGB in the protection against bones loss in ovariectomized (OVX) rats was confirmed by Micro-CT analysis. The anti-osteoporosis mechanism involved in the systemic regulatory actions of XLGB was elucidated by transcriptome sequencing analysis on bone marrow mesenchymal stem cells isolated from OVX rats. Moreover, the components absorbed in XLGB-treated plasma were characterized by mass spectrometry analysis, and subsequently, a standardized preparation process of drug-containing plasma was established. The synergistic osteogenic effect of the multiple components in plasma was investigated by a combination and then knockout of components using pre-osteoblast MC3T3-E1 cells. In order to decipher the underlying mechanism of XLGB, the targets of the absorbed components on bone were predicted by target prediction and network pharmacology analysis, then several interactions were validated by biochemical and cell-based assay. RESULTS: A total of 18 genes, including HDC, CXCL1/2, TNF, IL6 and Il1b, were newly found to be the major target genes regulated by XLGB. Interestingly, we found that a combination of the three absorbed components, i.e. MSP, rather than their single form at the same concentration, stimulated the formation of calcified nodules in MC3T3-E1 cells, suggesting a synergistic effect of these components. Besides, target prediction and experimental validation confirmed the binding affinity of corylin and icaritin for estrogen receptor α and ß, the inhibitory activity of isobavachin and isobavachalcone on glycogen synthase kinase-3ß, and the inhibitory activity of isobavachalcone on cathepsin K. The cell-based assay further confirmed the result of the biochemical assay. A network that integrated absorbed components of XLGB-targets-perturbation genes-pathways against osteoporosis was established. CONCLUSION: Our current study provides a new systemic strategy for discovering active ingredient groups of TCM formulae and understanding their underlying mechanisms.

A novel strategy for exploring food originated anti-adipogenesis substances and mechanism by structural similarity evaluation, ADME prediction, network pharmacology and experimental validation.

Screening potential functional substances based on active compounds is still a challenge faced by researchers since hundreds and thousands of possible compounds exist in natural products (food, herb, etc.). In this study, an integrated strategy by a combination of structural similarity evaluation, ADME (absorption, distribution, metabolism, excretion) prediction, network pharmacology and experimental validation (SANE strategy) was proposed and applied to explore anti-adipogenesis substances. This strategy was divided into four parts: first, potential compounds were screened based on representative active compounds by similarity evaluation and ADME prediction. Second, the activity of targeted compounds was evaluated in vitro based on the molecular biology method. Third, network pharmacology was used to explore potential targets and pathways. Last, the core pharmacological mechanism was confirmed by modern pharmacology methods. As a result, 8-prenylgenistein (8PG) was screened with chemical structure similarity with genistein and improved ADME propriety. Meanwhile, 8PG was found to present significant anti-adipogenesis effects in pre-adipocyte 3T3-L1 cells and primary human bone marrow stromal cells (hBMSC). Through using methods including: chemical staining, functional assays, and Real time PCR, 8PG was found to present more potency than genistein in suppressing the adipocyte differentiation. Further, the potential pharmacological mechanism was predicted, and significant effects of 8PG on activating the Wnt/ß-catenin pathway in 3T3-L1 cells and hBMSC were confirmed by  immunoblotting in the absence/presence of signaling pathway blocker and immunofluorescence staining. A new insight for exploring more potent compounds based on accurate effect compounds is provided in our work. Moreover, a potential compound (8PG), suppressing adipogenesis, was also supplied.