[Exosome and prevention of Alzheimer's disease: based on theory of kidney storing essence].

The theory of kidney storing essence storage, an important part of the basic theory of traditional Chinese medicine(TCM), comes from the Chapter 9 Discussion on Six-Plus-Six System and the Manifestations of the Viscera in the Plain Questions, which says that "the kidney manages closure and is the root of storage and the house of Jing(Essence)". According to this theory, essence is the fundamental substance of human life activities and it is closely related to the growth and development of the human body. Alzheimer's disease(AD) is one of the common neurodegenerative diseases, with the main pathological features of Aß deposition and Tau phosphorylation, which activate neurotoxic reactions and eventually lead to neuronal dysfunction and cell death, severely impairing the patient's cognitive and memory functions. Although research results have been achieved in the TCM treatment of AD, the complex pathogenesis of AD makes it difficult to develop the drugs capable of curing AD. The stem cell therapy is an important method to promote self-repair and regeneration, and bone marrow mesenchymal stem cells(BMSCs) as adult stem cells have the ability of multi-directional differentiation. By reviewing the relevant literature, this paper discusses the association between BMSCs and the TCM theory of kidney storing essence, and expounds the material basis of this theory from the perspective of molecular biology. Studies have shown that TCM with the effect of tonifying the kidney in the treatment of AD are associated with BMSCs. Exosomes produced by such cells are one of the main substances affecting AD. Exosomes containing nucleic acids, proteins, and lipids can participate in intercellular communication, regulate cell function, and affect AD by reducing Aß deposition, inhibiting Tau protein phosphorylation and neuroinflammation, and promoting neuronal regeneration. Therefore, discussing the prevention and treatment of exosomes and AD based on the theory of kidney storing essence will provide a new research idea for the TCM treatment of AD.

Ginsenoside Rg1 treats ischemic stroke by regulating CKLF1/CCR5 axis-induced neuronal cell pyroptosis.

BACKGROUND: Ischemic stroke, a severe and life-threatening neurodegenerative condition, currently relies on thrombolytic therapy with limited therapeutic window and potential risks of hemorrhagic transformation. Thus, there is a crucial need to explore novel therapeutic agents for ischemic stroke. Ginsenoside Rg1 (Rg1), a potential neuroprotective agent, exhibits anti-ischemic effects attributed to its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. Nevertheless, the precise underlying mechanism of action remains to be fully elucidated. PURPOSE: This study aimed to explore whether Rg1 exerts anti-ischemic stroke effects by inhibiting pyroptotic neuronal cell death through modulation of the chemokine like factor 1 (CKLF1)/ C-C chemokine receptor type 5 (CCR5) axis. METHODS: In this study, the MCAO model was used as an ischemic stroke model, and experimental tests were performed after 6 hours of ischemia. The anti-ischemic effect of Rg1 was examined by TTC staining, nissl-staining and neurobehavioral tests. In the in vitro experiments, PC12 cells were subjected to stimulation with CKLF1's mimetic peptide C27 to assess the potential of CKLF1 to induce focal neuronal cell death. Additionally, the impact of CKLF1 mimetic peptide C27, antagonistic peptide C19, and CCR5 inhibitor MVC on PC12 cells subjected to oxygen-glucose deprivation (OGD) and subsequently treated with Rg1 was investigated. In vivo, Rg1 treatment was examined by quantitative real-time PCR (qPCR), ELISA, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), and co-immunoprecipitate (Co-IP) assays to perspective whether Rg1 treatment reduces CKLF1/CCR5 axis-induced pyroptotic neuronal cell death. In addition, to further explore the biological significance of CKLF1 in ischemic stroke, CKLF1-/- rats were used as the observation subjects in this study. RESULTS: The in vitro results suggested that CKLF1 was able to induce neuronal cells to undergo pyroptosis. In vivo pharmacodynamic results showed that Rg1 treatment was able to significantly improve symptoms in ischemic stroke rats. In addition, Rg1 treatment was able to inhibit the interaction between CKLF1 and CCR5 after ischemic stroke and inhibited CKLF1/CCR5 axis-induced pyroptosis. The results of related experiments in CKLF1-/- rats showed that Rg1 lost its therapeutic effect after CKLF1 knockdown. CONCLUSION: Our findings indicate that the activation of the NLRP3 inflammasome is initiated by the CKLF1/CCR5 axis, facilitated through the activation of the NF-κB pathway, ultimately resulting in the pyroptosis of neuronal cells. Conversely, Rg1 demonstrates the capability to mitigate neuronal cell damage following CKLF1-induced effects by suppressing the expression of CKLF1. Thus, CKLF1 represents a crucial target for Rg1 in the context of cerebral ischemia treatment, and it also holds promise as a potential target for drug screening in the management of ischemic stroke.

Paeoniae Radix Rubra extract attenuates cerebral ischemia injury by inhibiting ferroptosis and activating autophagy through the PI3K/Akt signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniae Radix Rubra (PRR), the root of Paeonia lactiflora Pall. or Paeonia veitchii Lynch, has been widely used to promote blood circulation and eliminate blood stasis in Chinese clinical practice, but its effect on cerebral ischemia is still rarely reported. AIM OF THE STUDY: The present study aimed to assess the potential therapeutic possibilities of the extract of PRR (PRRE) on cerebral ischemia, further exploring the underlying mechanism, and preliminary screening of the corresponding active components. MATERIALS AND METHODS: The neuroprotective effects of PRRE in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO) injury and mouse hippocampal neuronal cells (HT22 cell line) following oxidative stress were confirmed. The mechanism was investigated using immunohistochemical staining, western blotting, transmission electron microscopy (TEM), and immunofluorescence. The active components of PRRE were analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and molecular docking. RESULTS: The in vivo study showed that PRRE reduced infarct volume and improved neurological deficits in rats, and the expression of GPX4, FTH1, Beclin1, LC3 II, and p-Akt was upregulated in the rat hippocampi. In addition, the vitro research indicated that PRRE can also alleviate H2O2-induced HT22 cell damage by regulating cytokines such as malondialdehyde (MDA), reduced glutathione (GSH) and reactive oxygen species (ROS), and the expressions of GPX4 and Beclin1 were observed to be elevated. The PI3K/Akt signalling pathway was inhibited by LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K). Furthermore, the effective components of PRRE in regulating ferroptosis and autophagy are mainly defined as albiflorin, paeoniflorin, benzoyl paeoniflorin, oleanolic acid, and hederagenin. CONCLUSION: PRRE exerts neuroprotective effects against cerebral ischaemic injury by inhibiting ferroptosis and activating autophagy through the PI3K/Akt signalling pathway. This study provides an experimental basis for the potential application of PRRE as a novel therapeutic drug, and PI3K/Akt-associated ferroptosis and autophagy as therapeutic targets for cerebral ischemia.

Neurotrophic basis to the pathogenesis of depression and phytotherapy.

Depression is a major neuropsychiatric disease that considerably impacts individuals' psychosocial function and life quality. Neurotrophic factors are now connected to the pathogenesis of depression, while the definitive neurotrophic basis remains elusive. Besides, phytotherapy is alternative to conventional antidepressants that may minimize undesirable adverse reactions. Thus, further research into the interaction between neurotrophic factors and depression and phytochemicals that repair neurotrophic factors deficit is highly required. This review highlighted the implication of neurotrophic factors in depression, with a focus on the brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), and detailed the antidepressant activities of various phytochemicals targeting neurotrophic factors. Additionally, we presented future opportunities for novel diagnostic and therapeutic strategies for depression and provided solutions to challenges in this area to accelerate the clinical translation of neurotrophic factors for the treatment of depression.

Mongolian medicine Wenguanmu ointment treats eczema by inhibiting the CKLF-1/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The main clinical manifestations of eczema include itching, erythema, swelling and pain. Currently, allergies and TH1/TH2 cytokine imbalances are significant causes of eczema. TCM believes that eczema is mainly caused by incongruity between dry and wet. Wenguanmu ointment is a classic Mongolian medicine, which mainly composed of Xanthoceras sorbifolia Bunge, Coptis chinensis Franch and Bezoar. These ingredients can clear heat and dampness, dispel wind and dehumidification, anti-inflammatoryad analgesic. In this study, it was found that Wenguanmu ointment can treat eczema with anti-inflammatory, analgesic and antipruritic. AIM OF THE STUDY: In this study, the content of main components in Wenguanmu ointment was tested. Moreover, the therapeutic effect and mechanism of Wenguanmu ointment on eczema model mice were studied. MATERIALS AND METHODS: Kunming mice (25 ± 2 g) were randomly divided into 6 groups: Control group; Model group; Vehicle group; Wenguanmu ointment group; Compound dexamethasone acetate cream group; Chushizhiyang ointment group. The eczema mouse model was established by DNCB. HPLC and TLC tests were used to determine the content of the main components in Wenguanmu ointment. HE staining was used to assess skin damage in mice. In order to detect the anti-inflammatory effect of Wenguanmu ointment on eczema, The levels of IgE, TNF-α, IFN-γ, COX-2 and IL-4 in serum was measured by ELISA. Genecards and Online Mendelian Inheritance in Man databases were used to analyze potential target gene predictions, and it was speculated that Wenguanmu ointment was associated with NF-κB signaling pathway and chemokine signaling pathway. To detect this inference, RT-qPCR and western blotting were used to detect protein and mRNA levels of CKLF-1, IκB-α, and NF-κB. RESULTS: Wenguanmu ointment can repress the symptoms of eczema caused by 2, 4-dinitrochlorobenzene, and inhibit the level of serum immunoglobulin E. Simultaneously it restrain the elevation of miscellaneous pro-inflammatory cytokines and chemokines, as well as reducing the expression of CKLF-1 and NF-κB protein in the nucleus, and increasing the protein expression of IκB to improve eczema. CONCLUSIONS: The ameliorating effect of Wenguanmu ointment on eczema lesions can play a importment role by inhibiting the CKLF-1/NF-κB pathway.

Mahonia Alkaloids (MA) Ameliorate Depression Induced Gap Junction Dysfunction by miR-205/Cx43 Axis.

Depression has become an important disease threatening human health. In recent years, the efficacy of Traditional Chinese Medicine (TCM) in treating the disease has become increasingly prominent, so it is meaningful to find new antidepressant TCM. Mahonia fortune (Lindl.) Fedde is a primary drug in traditional formulas for the treatment of depression, and alkaloids are the main components of it. However, the detailed mechanism of Mahonia alkaloids (MA) on depression remains unclear. This study aimed to investigate the effect of MA on gap junction function in depression via the miR-205/Cx43 axis. The antidepressant effects of MA were observed by a rat model of reserpine-induced depression and a model of corticosterone (CORT)-induced astrocytes. The concentrations of neurotransmitters were measured by ELISA, the expression of Connexin 43 (Cx43) protein was measured by Immunohistochemistry and western-blot, brain derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB) proteins were measured by western-blot, the pathological changes of prefrontal cortex were observed by hematoxylin-eosin (H&E) staining. Luciferase reporter assay was performed to verify the binding of miR-205 and Cx43. The regulation effect of Cx43 on CREB was verified by interference experiment. Gap junction dysfunction was detected by fluorescent yellow staining. The results confirmed that MA remarkably decreased miR-205 expression and increased Cx43, BDNF, CREB expression in depression rat and CORT-induced astrocytes. In addition, after overexpression of miR-205 in vitro, the decreased expression of Cx43, BDNF and CREB could be reversed by MA. Moreover, after interfering with Cx43, the decreased expression of CREB and BDNF could be reversed by MA. Thus, MA may ameliorate depressive behavior through CREB/BDNF pathway regulated by miR-205/Cx43 axis.

New Therapeutic Approaches to and Mechanisms of Ginsenoside Rg1 against Neurological Diseases.

Neurological diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), stroke, cerebral infarction, ischemia-reperfusion injury, depression and, stress, have high incidence and morbidity and often lead to disability. However, there is no particularly effective medication against them. Therefore, finding drugs with a suitable efficacy, low toxicity and manageable effects to improve the quality of life of patients is an urgent problem. Ginsenoside Rg1 (Rg1) is the main active component of ginseng and has a variety of pharmacological effects. In this review, we focused on the therapeutic potential of Rg1 for improving neurological diseases. We introduce the mechanisms of Ginsenoside Rg1 in neurological diseases, including apoptosis, neuroinflammation, the microRNA (miRNA) family, the mitogen-activated protein kinase (MAPK) family, oxidative stress, nuclear factor-κB (NF-κB), and learning and memory of Rg1 in neurological diseases. In addition, Rg1 can also improve neurological diseases through the interaction of different signal pathways. The purpose of this review is to explore more in-depth ideas for the clinical treatment of neurological diseases (including PD, AD, HD, stroke, cerebral infarction, ischemia-reperfusion injury, depression, and stress). Therefore, Rg1 is expected to become a new therapeutic method for the clinical treatment of neurological diseases.

[Research progress on activities and mechanisms of anti-hepatitis B virus drugs].

Hepatitis B virus(HBV) is the pathogen causing hepatitis B, which is characterized by strong infectivity, high incidence, and widespread prevalence and has seriously threatened human health and affected their quality of life. Anti-HBV drugs in western medicine mainly include nucleosides(nucleic acids) and interferons, among which nucleosides(nucleic acids) are used more often. Due to the easy development of drug resistance, their therapeutic effects are not remarkable. Interferons can easily cause serious adverse reactions such as liver injury. Anti-HBV drugs in traditional Chinese medicine mainly include single Chinese herbs(Artemisiae Scopariae Herba, Artemisiae Annuae Herba, Salviae Miltiorrhizae Radix et Rhizoma, etc.) and Chinese herbal compounds(Yinchenhao Decoction, Xiaochaihu Decoction, Tiaogan Huaxian Pills, etc.), whose chemical compositions and action targets have not been fully identified. The combined medication is better than single medication, in that the former can improve drug resistance, make up each other's deficiencies, reduce adverse reactions, and prolong the action time. This study reviewed the anti-HBV activities and mechanisms of western drugs, Chinese herbs, and combined medications, in order to provide reference for the development and research of new anti-HBV drugs.

Mangiferin, a natural glucoxilxanthone, inhibits mitochondrial dynamin-related protein 1 and relieves aberrant mitophagic proteins in mice model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease featured to mitochondrial dysfunction in neuronal cells. Dynamin-related protein 1 (Drp1) is an important regulator of mitochondrial fission and subsequent mitophagy. Mangiferin (MGF) is a glucosyl xanthone mainly derived from Mangifera indica L., possessing multifaceted properties, e.g., antioxidant, anti-inflammatory, and enhancement of cognitive ability. Besides, it can cross the blood-brain barrier, thereby exerting a neuroprotective effect. However, so far, MGF's effect in balancing mitochondrial homeostasis via regulation of Drp1 level and mitophagic pathway in PD remains rarely reported. PURPOSE: We aimed to investigate the neuroprotective effect of MGF against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and examine the possible mechanisms. METHODS: We utilized C57BL/6 mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Behavioral parameters, containing the open field test, balance beam, pole test, and rotarod test, assessed the locomotor activity; immunohistochemistry assessed the number of TH-positive neurons; transmission electron microscopy detected ultrastructural mitochondrial morphology in the dopaminergic neuron; complex I enzymatic activity microplate assay kit measured the mitochondrial complex I activity; ATP determination kit measured ATP levels in mitochondria isolated from cells or striatal tissues; western blot measured the levels of Drp1 and mitophagic proteins. RESULTS: We observed that MGF could mitigate motor deficiency and improve the expression of tyrosine hydroxylase in the substantia nigra of MPTP-induced PD mice. Furthermore, MGF not only ameliorated mitochondrial ultrastructure, but also improved mitochondrial ATP content. Within mitochondria, MGF could reduce Drp1 expression and reverse the expressions of mitophagic proteins, including PINK1, Parkin, NIX, BNIP3, FUNDC1, and p62. CONCLUSION: Present study indicates that MGF benefits mitochondrial networks by recovering mitochondrial ultrastructure and ATP contents, reducing mitochondrial Drp1, and modulating mitophagic proteins in the MPTP-induced PD mice model, which revealed a novel acting mechanism of MGF in PD's treatment.

Novel Antidepressant Mechanism of Ginsenoside Rg1 in Regulating the Dysfunction of the Glutamatergic System in Astrocytes.

Ginsenoside Rg1, a traditional Chinese medicine monomer, has been shown to have antidepressant effects. We previously found that Rg1 exerts antidepressant effects by improving the gap junction channels (GJCs) dysfunction; however, the downstream mechanisms through which Rg1 ameliorates GJC dysfunction remain unclear. Since hemichannels directly release glutamate, GJC dysfunction decreases the expression levels of glutamate transporters in astrocytes, and glutamatergic system dysfunction plays an essential role in the pathogenesis of depression. The glutamatergic system may be a potential downstream target of Rg1 that exerts antidepressant effects. Therefore, in this study, we aimed to determine the downstream mechanisms by which Rg1 ameliorated GJC dysfunction and exerted its antidepressant effects. Corticosterone (CORT) is used to mimic high glucocorticoid levels in patients with depression in vitro. Primary cortical astrocytes were isolated and phosphorylation of connexin43 (Cx43) as well as the functions of hemichannels, GJCs, and the glutamatergic system were evaluated after drug treatment. Rg1 pretreatment reversed the anomalous activation of Cx43 phosphorylation as well as the dysfunction of hemichannels, GJCs, and the glutamatergic system induced by CORT. These results suggest that Rg1 can ameliorate CORT-induced dysfunction of the glutamatergic system in astrocytes by potentially reducing Cx43 phosphorylation and inhibiting opening of hemichannels, thereby improving GJC dysfunction.

Rg1 exerts protective effect in CPZ-induced demyelination mouse model via inhibiting CXCL10-mediated glial response.

Myelin damage and abnormal remyelination processes lead to central nervous system dysfunction. Glial activation-induced microenvironment changes are characteristic features of the diseases with myelin abnormalities. We previously showed that ginsenoside Rg1, a main component of ginseng, ameliorated MPTP-mediated myelin damage in mice, but the underlying mechanisms are unclear. In this study we investigated the effects of Rg1 and mechanisms in cuprizone (CPZ)-induced demyelination mouse model. Mice were treated with CPZ solution (300 mg· kg-1· d-1, ig) for 5 weeks; from week 2, the mice received Rg1 (5, 10, and 20 mg· kg-1· d-1, ig) for 4 weeks. We showed that Rg1 administration dose-dependently alleviated bradykinesia and improved CPZ-disrupted motor coordination ability in CPZ-treated mice. Furthermore, Rg1 administration significantly decreased demyelination and axonal injury in pathological assays. We further revealed that the neuroprotective effects of Rg1 were associated with inhibiting CXCL10-mediated modulation of glial response, which was mediated by NF-κB nuclear translocation and CXCL10 promoter activation. In microglial cell line BV-2, we demonstrated that the effects of Rg1 on pro-inflammatory and migratory phenotypes of microglia were related to CXCL10, while Rg1-induced phagocytosis of microglia was not directly related to CXCL10. In CPZ-induced demyelination mouse model, injection of AAV-CXCL10 shRNA into mouse lateral ventricles 3 weeks prior CPZ treatment occluded the beneficial effects of Rg1 administration in behavioral and pathological assays. In conclusion, CXCL10 mediates the protective role of Rg1 in CPZ-induced demyelination mouse model. This study provides new insight into potential disease-modifying therapies for myelin abnormalities.

Tetrahydroxy stilbene glycoside regulates TGF-ß/fractalkine/CX3CR1 based on network pharmacology in APP/PS1 mouse model.

Alzheimer's disease (AD) is a serious, progressive neurodegenerative disease that involves irreversible neuronal death. Tetrahydroxy stilbene glycoside (TSG) is an active compound extracted from P. multiflorum, a traditional Chinese herbal medicine, but its role in neuroprotection is unclear. Herein, we aimed to validate the effects of TSG on APP/PS1 model mice and the underlying mechanism. RNA-seq was performed to identify differentially expressed genes in APP/PS1 mouse, with PCR and immunohistochemistry used for validation. Experiments were performed after bioinformatic analysis for verification. Neuronal damage was observed by H&E staining. Key proteins involved in the pathway such as CX3CR1, Iba1 and TGF-ß were examined by immunohistochemical analysis. The KEGG analysis suggested that these genes might act by multiple pathways to build the pharmacological network of TSG in AD progression. These data provide the credible evidence that TSG improved neuronal damage and regulated neuroprotective mechanisms. Together, our work has detailed the whole and major genes in APP/PS1 model mouse regulated by TSG, and highlighted the anti-inflammatory function of TSG in mediating CX3CR1 and TGF-ß as the TGF-ß/fractalkine/CX3XR1 signaling pathway, especially in microglia. Moreover, TSG has potential value in synaptic transmission and neurotrophic action on neurodegenerative diseases. In summary, TSG is a promising candidate for preventing and treating the progression of AD.

Paeoniflorin: A neuroprotective monoterpenoid glycoside with promising anti-depressive properties.

BACKGROUND: Depression, as a prevalent and debilitating psychiatric disease, severely decreases the life quality of individuals and brings heavy burdens to the whole society. Currently, some antidepressants are applied in the treatment of severe depressive symptoms, while there are still some undesirable drawbacks. Paeoniflorin is a monoterpenoid glycoside that was firstly extracted from Paeonia lactiflora Pall, a traditional Chinese herb that is widely used in the Chinese herbal formulas for treating depression. PURPOSE: This review summarized the previous pre-clinical studies of paeoniflorin in treating depression and further discussed the potential anti-depressive mechanisms for that paeoniflorin to be further explored and utilized in the treatment of depression clinically. METHODS: Some electronic databases, e.g., PubMed and China National Knowledge Infrastructure, were searched from inception until April 2021. RESULTS: This review summarized the effective anti-depressive properties of paeoniflorin, which is related to its functions in the upregulation of the levels of monoaminergic neurotransmitters, inhibition of the hypothalamic-pituitary-adrenal axis hyperfunction, promotion of neuroprotection, promotion of hippocampus neurogenesis, and upregulation of brain-derived neurotrophic factor level, inhibition of inflammatory reaction, downregulation of nitric oxide level, etc. CONCLUSION: This review focused on the pre-clinical studies of paeoniflorin in depression and summarized the recent development of the anti-depressive mechanisms of paeoniflorin, which approves the role of paeoniflorin plays in anti-depression. However, more high-quality pre-clinical and clinical studies are expected to be conducted in the future.

[Advances of Akkermansia muciniphila in regulating host functions].

Akkermansia muciniphila, abbreviated as AKK and found in 2004, is an oval-shaped gram-negative bacterium isolated from a human feal. A. muciniphila is widely present in the intestinal tract of human. Its specialization in mucin degradation makes it a key organism at the mucosal interface between the lumen and host cells. More and more studies have shown that it can play the role of probiotics. Notably, declined levels of A. muciniphila have been observed in patients with diabetes, liver disease, cardiovascular disease, inflammatory bowel disease, neurodegenerative diseases, etc. In addition, A. muciniphila combined with traditional Chinese medicine, exhibited higher effect on regulating host functions, but the underlying mechanism was still unclear, requiring further in-depth research. Therefore, the aims of this review are to summarize the main effects of A. muciniphila on host health and its relationship with traditional Chinese medicine, summarize the main problems, and provide a reference for the further research of A. muciniphila and traditional Chinese medicine.

New amide alkaloids and carbazole alkaloid from the stems of Clausena lansium.

Five unreported alkaloids including four amide alkaloids (1a, 2a, 3a, and 3b) and one carbazole alkaloid (4) with two known compounds (1b, 2b) were obtained from the stems of Clausena lansium. Their structures were demonstrated by spectroscopic experiments. And the absolute configurations of compounds 1a, 1b, 2b, and 3b were determined by single X-ray diffraction analysis. The neuroprotection assay showed that compound 4 had moderate inhibition effect on PC12 cells induced by serum withdrawal at the concentration of 10 µM. And compounds 1a and 4 had weak protective effects on primary neurons against oxygen glucose deprivation injury at the concentration of 10 µM.

Korean red ginseng alleviate depressive disorder by improving astrocyte gap junction function.

ETHNOPHARMACOLOGICAL RELEVANCE: Korean red ginseng (KRG), a processed product of Panax ginseng C. A. Mey, show significant anti-depressive effect in clinic. However, its mechanism is still unclear. AIM OF THE STUDY: Gap junction intercellular communication (GJIC) dysfunction is a potential pathogenesis of depression. Therefore, this study's objective is to investigate whether the antidepressant effect of KRG is related to GJIC. MATERIALS AND METHODS: Rat were restraint 8 h every day for 28 consecutive days to prepare depression models, and meanwhile, rats were intragastrically administrated with normal saline, KRG solutions (25, 50 or 100 mg/kg) or fluoxetine (10 mg/kg) 1 h before stress. The behavioral performance was determined by forced swimming test, sucrose preference test and open field test. GJIC was determined by the Lucifer yellow (LY) diffusion distance in prelimb cortex (PLC). In addition, the level of Cx43, one of executors of GJIC, was tested by Western blot. To find out the protective effect of KRG against GJIC dysfunction directly, rats were intracranially injected with carbenoxolone (CBX, blocker of GJIC), and meanwhile normal saline, KRG (100 mg/kg) or fluoxetine (10 mg/kg) was administered daily. The behavioral performance of these rats was detected, and the LY localization injection PLC area was used to detect the gap junction function. RESULTS: Chronic resistant stress (CRS) induced depressive symptoms, as manifested by prolonged immobility time in forced swimming test and decreased sucrose consumption ratio. Administration of KRG alleviated these depressive symptoms significantly. GJIC determination showed that KRG improved the LY diffusion and increased Cx43 level in prefrontal cortex (PFC) significantly, indicated that GJIC dysfunction was alleviated by the treatment of KRG. However, the astrocytes number was also increased by the treatment of KRG, which maybe alleviate depression-like symptoms by increasing the number of astrocytes rather than improving GJIC. Injection of CBX produced depressive symptoms and GJIC dysfunction, as manifested by decreased sucrose consumption ratio and prolonged immobility time in forced swimming test, but no astrocytes number changes, KRG also reversed depressive symptoms and GJIC dysfunction, suggested that the improvement of depressive-like symptoms was improved by GJIC. CONCLUSIONS: KRG alleviate depressive disorder by improving astrocytic gap junction function.

Novel antidepressant mechanism of ginsenoside Rg1: Regulating biosynthesis and degradation of connexin43.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C. A. Meyer is a valuable medicinal herb and "alternative" remedy for the prevention and treatment of depression. Dysfunction of connexin43 (Cx43)-gap junction in astrocytes is predisposed to the precipitation of depression. Ginsenoside Rg1 (Rg1), the main bioactive constituent extracted from ginseng, is efficacious in the management of depression by upregulating the content of Cx43. Our previous results indicated that pretreatment with Rg1 significantly improved Cx43-gap junction in corticosterone (CORT)-treated astrocytes. However, the antidepressant mechanism underlying how Rg1 upregulates Cx43-gap junction in astrocytes hasn't been proposed. AIM OF THE STUDY: To dissect the mechanisms of Rg1 controlling Cx43 levels in primary astrocytes. METHODS: We examined the changes of the level of Cx43 mRNA, the degradation of Cx43, as well as the ubiquitin-proteasomal and autophagy-lysosomal degradation pathways of Cx43 followed by Rg1 prior to CORT in rat primary astrocytes isolated from prefrontal cortex and hippocampus. Furthermore, the recognized method of scrape loading/dye transfer was performed to detect Cx43-gap junctional function, an essencial indicator of the antidepressant effect. RESULTS: Pretreatment with Rg1 could reverse CORT-induced downregulation of Cx43 biosynthesis, acceleration of Cx43 degradation, and upregulation of two Cx43 degradation pathways in primary astrocytes. CONCLUSION: The findings in the present study provide the first evidence highlighting that Rg1 increases Cx43 protein levels through the upregulation of Cx43 mRNA and downregulation of Cx43 degradation, which may be attributed to the effect of Rg1 on the ubiquitin-proteasomal and autophagy-lysosomal degradation pathways of Cx43.

The Anti-Neuroinflammatory Effect of Fuzi and Ganjiang Extraction on LPS-Induced BV2 Microglia and Its Intervention Function on Depression-Like Behavior of Cancer-Related Fatigue Model Mice.

The Chinese herb couple Fuzi and Ganjiang (FG) has been a classic combination of traditional Chinese medicine that is commonly used clinically in China for nearly 2000 years. Traditional Chinese medicine suggests that FG can treat various ailments, including heart failure, fatigue, gastrointestinal upset, and depression. Neuroinflammation is one of the main pathogenesis of many neurodegenerative diseases in which microglia cells play a critical role in the occurrence and development of neuroinflammation. FG has been clinically proven to have an efficient therapeutic effect on depression and other neurological disorders, but its mechanism remains unknown. Cancer-related fatigue (CRF) is a serious threat to the quality of life of cancer patients and is characterized by both physical and psychological fatigue. Recent studies have found that neuroinflammation is a key inducement leading to the occurrence and development of CRF. Traditional Chinese medicine theory believes that extreme fatigue and depressive symptoms of CRF are related to Yang deficiency, and the application of Yang tonic drugs such as Fuzi and Ganjiang can relieve CRF symptoms, but the underlying mechanisms remain unknown. In order to define whether FG can inhibit CRF depression-like behavior by suppressing neuroinflammation, we conducted a series of experimental studies in vitro and in vivo. According to the UPLC-Q-TOF/MSE results, we speculated that there were 49 compounds in the FG extraction, among which 30 compounds were derived from Fuzi and 19 compounds were derived from Ganjiang. Our research data showed that FG can effectively reduce the production of pro-inflammatory mediators IL-6, TNF-α, ROS, NO, and PGE2 and suppress the expression of iNOS and COX2, which were related to the inhibition of NF-κB/activation of Nrf2/HO-1 signaling pathways. In addition, our research results revealed that FG can improve the depression-like behavior performance of CRF model mice in the tail suspension test, open field test, elevated plus maze test, and forced swimming test, which were associated with the inhibition of the expression of inflammatory mediators iNOS and COX2 in the prefrontal cortex and hippocampus of CRF model mice. Those research results suggested that FG has a satisfactory effect on depression-like behavior of CRF, which was related to the inhibition of neuroinflammation.

Efficacy of Traditional Chinese Medicine Combined with Selective Serotonin Reuptake Inhibitors on the Treatment for Parkinson's Disease with Depression: A Systematic Review and Meta-Analysis.

Depression is a common neuropsychiatric symptom of Parkinson's disease (PD), resulting in a lower quality of life and cognitive impairment in PD patients. Traditional Chinese medicine (TCM) formulas have been widely used in neurodegenerative disease and neuropsychic disorders to improve life quality of patients in ethnomedicine. TCM formulas combined with selective serotonin reuptake inhibitors (SSRIs) also have a positive effect on depressed PD compared with SSRIs as reported by several clinical studies. However, the results are discordant and failed to be conclusive. We aim to evaluate the efficacy of TCM formulas combined with SSRIs for depressed PD in this systematic review. We searched literatures from PubMed, Web of Science, Medline, Embase, Google Scholar, Chinese National Knowledge Infrastructure, Wanfang Database, and VIP Information Database before July 2020. We included randomized controlled trials investigating the efficacy of TCM formulas combined with SSRIs on depressed PD patients. This analysis was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Eleven randomized clinical trials involving 861 subjects were enrolled in this analysis. The overall results showed that TCM formulas combined with SSRIs significantly improved the depression score [weighted mean difference (WMD): -4.920, 95% confidence interval (CI): (-5.999, -3.840); [Formula: see text]¡ 0.001] and had a statistical significance on Unified Parkinson's Disease Rating Scale II score [WMD: -1.209, 95% CI: (-1.561, -0.857); [Formula: see text] < 0.001]. Furthermore, we observed that Chai-Hu-Shu-Gan Powder combined with SSRIs had a significant improvement on the depressive symptom in PD compared to the SSRIs alone [WMD: -5.390, 95% CI: (-7.66, -3.11); [Formula: see text] < 0.001]. No severe side events were reported in these included trials. This systematic review provided the evidences that TCM formulas combined with SSRIs might be helpful and safe in the treatment of depression of PD, including Chai-Hu-Shu-Gan Powder. Also, more randomized double-blinded trials with reliable design are required in the future.

Insight into Medicinal Chemistry Behind Traditional Chinese Medicines: p-Hydroxybenzyl Alcohol-Derived Dimers and Trimers from Gastrodia elata.

From an aqueous extract of "tian ma" (the steamed and dried rhizomes of Gastrodia elata), ten new compounds gastrodibenzins A-D (1-4) and gastrotribenzins A-F (5-10), along with known analogues (11-20), having structure features coupling between two and three p-hydroxybenzyl-derived units via carbon- and/or ether-bonds, were isolated and characterized by spectroscopic data analysis. Meanwhile, the new compounds 5a, 6a, 8a, 22, and 23, as well as the known derivatives 13a, 14a, 15, 17-21, 24, 25, and p-hydroxybenzyl aldehyde were isolated and identified from a refluxed aqueous solution of p-hydroxybenzyl alcohol. Methylation of 5a and 6a in methanol and ethylation of 6a, 8a, 13a, and 14a in ethanol produced 5 and 6 and 7, 8, 13, and 14, respectively. using ultra-performance liquid chromatography high-resolution electrospray ionization mass spectrometry (UPLC-HRESIMS) analysis of the refluxed solutions of p-hydroxybenzyl alcohol and the refluxed extracts of the fresh G. elata rhizome and "tian ma" extracts indicated consistent production and variation of the dimeric and trimeric derivatives of p-hydroxybenzyl alcohol upon extracting solvents and refluxing time. In various assays, the dimeric and trimeric derivatives showed more potent activities than p-hydroxybenzyl alcohol itself and gastrodin, which are the main known active constituents of "tian ma". These results revealed for the first time that the more effective dimers and trimers can be produced through condensation of the co-occurring p-hydroxybenzyl alcohol during processing and decocting of the G. elata rhizomes, demonstrating insights into medicinal chemistry behind application protocols of traditional Chinese medicines.