Factors influencing the decline in stroke mortality: A statement for healthcare professionals from the American Heart Association/American Stroke Association

A comprehensive application: Molecular docking and network pharmacology for the prediction of bioactive constituents and elucidation of mechanisms of action in component-based Chinese medicine

The sesquiterpene lactone artemisinin from Artemisia annua L. is well established for malaria therapy, but its bioactivity spectrum is much broader. In this review, we give a comprehensive and timely overview of the literature regarding the immunosuppressive activity of artemisinin-type compounds toward inflammatory and autoimmune diseases. Numerous receptor-coupled signaling pathways are inhibited by artemisinins, including the receptors for interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), β3-integrin, or RANKL, toll-like receptors and growth factor receptors. Among the receptor-coupled signal transducers are extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), AKT serine/threonine kinase (AKT), mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) kinase (MEK), phospholipase C γ1 (PLCγ), and others. All these receptors and signal transduction molecules are known to contribute to the inhibition of the transcription factor nuclear factor κ B (NF-κB). Artemisinins may inhibit NF-κB by silencing these upstream pathways and/or by direct binding to NF-κB. Numerous NF-κB-regulated downstream genes are downregulated by artemisinin and its derivatives, for example, cytokines, chemokines, and immune receptors, which regulate immune cell differentiation, apoptosis genes, proliferation-regulating genes, signal transducers, and genes involved in antioxidant stress response. In addition to the prominent role of NF-κB, other transcription factors are also inhibited by artemisinins (mammalian target of rapamycin [mTOR], activating protein 1 [AP1]/FBJ murine osteosarcoma viral oncogene homologue [FOS]/JUN oncogenic transcription factor [JUN]), hypoxia-induced factor 1α (HIF-1α), nuclear factor of activated T cells c1 (NF-ATC1), Signal transducers and activators of transcription (STAT), NF E2-related factor-2 (NRF-2), retinoic-acid-receptor-related orphan nuclear receptor γ (ROR-γt), and forkhead box P-3 (FOXP-3). Many in vivo experiments in disease-relevant animal models demonstrate therapeutic efficacy of artemisinin-type drugs against rheumatic diseases (rheumatoid arthritis, osteoarthritis, lupus erythematosus, arthrosis, and gout), lung diseases (asthma, acute lung injury, and pulmonary fibrosis), neurological diseases (autoimmune encephalitis, Alzheimer's disease, and myasthenia gravis), skin diseases (dermatitis, rosacea, and psoriasis), inflammatory bowel disease, and other inflammatory and autoimmune diseases. Randomized clinical trials should be conducted in the future to translate the plethora of preclinical results into clinical practice.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/med.21842

The immunosuppressive activity of artemisinin-type drugs towards inflammatory and autoimmune diseases

The Dialogue Between Neuroinflammation and Adult Neurogenesis: Mechanisms Involved and Alterations in Neurological Diseases

Depression is a multigenetic or multifactorial syndrome. The central neuron system (CNS)-orientated, single target, and conventional antidepressants are insufficient and far from ideal. Traditional Chinese Medicine (TCM) has historically been used to treat depression up till today, particularly in Asia. Its holistic, multidrug, multitarget nature fits well with the therapeutic idea of systems medicine in depression treatment. Over the past two decades, although efforts have been made to understand TCM herbal antidepressants at the molecular level, many fundamental questions regarding their mechanisms of action remain to be addressed at the systems level in order to better understand the complicated herbal formulations in depression treatment. In this Mini Review, we review and discuss the mechanisms of action of herbal antidepressants and their acting targets in the pathological systems in the brain, such as monoamine neurotransmissions, hypothalamic-pituitary-adrenal (HPA) axis, neurotropic factor brain-derived neurotrophic factor (BDNF) cascade, and glutamate transmission. Some herbal molecules, constituents, and formulas are highlighted as examples to discuss their mechanisms of action and future directions for comprehensive researches at the systems level. Furthermore, we discuss pharmacological approaches to integrate the mechanism of action from the molecular level into the systems level for understanding of systems pharmacology of TCM formulations. Integration of the studies at the molecular level into the systems level not only represents a trend in TCM study but also promotes our understanding of the system-wide mechanism of action of herbal antidepressant formulations.

/pdf/traditional-chinese-medicine-in-depression-treatment-from-3gfcdb882v.pdf

Traditional Chinese Medicine in Depression Treatment: From Molecules to Systems

Alzheimer's disease (AD), the most common cause of dementia, is highly prevalent worldwide with no modifying therapy. Behavioral and psychological symptoms of dementia (BPSD) occur in most patients with AD, and depression is one of the most common AD-related BPSD. Kaixinsan (KXS) is an ancient Chinese herbal prescription widely used to treat dementia and forgetfulness. In this systematic review, we conducted a meta-analysis to assess preclinical evidence for the effects of KXS on cognitive impairment and depression. Thirty-eight articles involving 1,050 animals were included after searching from six databases from the inception up to June 2019. The primary outcome measures were behavioral outcome. Indicators of cognitive function in AD included escape latency, time spent on the target quadrant, and the number of target platform crossings in the Morris water maze (MWM) test. Indicators of depression included number of rearing events and total distance in the open-field test, duration of immobility in the forced swim test, and sucrose consumption or sucrose preference index in the sucrose preference test. The secondary outcomes were mechanisms of KXS for treatment of AD and depression. The results showed that KXS significantly reduced escape latency (P < 0.01), increased time spent in the target quadrant (P < 0.01), and increased the number of target platform crossings (P < 0.01) in the MWM test in AD models compared with control. The possible mechanisms for KXS-mediated improvements in cognitive function were antioxidant activity, anti-inflammatory activity, antiapoptotic activity, neuroprotection, and synapse protection. In addition, the results demonstrated that KXS significantly increased the number of rearing instances (P < 0.01) in the open-field test, decreased the duration of immobility (P < 0.01) in forced swim test, and increased sucrose consumption or sucrose preference index (P < 0.01) in the sucrose preference test in depression models compared with control. The mechanisms of KXS-mediated anti-depressive effects were HPA axis regulation, antioxidant activity, anti-inflammatory activity, synapse protection, and neuroprotection. The results of this study suggested that KXS can be used to effectively treat AD and depression through multiple mechanisms, extrapolating the therapeutic potential of KXS for treating AD-related BPSD.

/pdf/kaixinsan-a-well-known-chinese-herbal-prescription-for-4ncxcmh5kn.pdf

Kaixinsan, a Well-Known Chinese Herbal Prescription, for Alzheimer's Disease and Depression: A Preclinical Systematic Review.

Efficacy and safety of Chinese herbal medicine for depression: A systematic review and meta-analysis of randomized controlled trials.

Background: Ischemic stroke is the most common type of stroke while pharmacological therapy is limited. Ginsenosides are the major bioactive compounds in Ginseng and have been found to have various pharmacological effects in the nervous system. In the present study, we sought to evaluate the effects of Ginsenoside-Rb1 (G-Rb1), an important ingredient of ginsenosides, and the probable neuroprotective mechanisms in experimental ischemic strokes. Methods: Studies of G-Rb1 on ischemic stroke animal models were identified from 7 databases. No clinical trials should be included in the analysis. The primary outcome measures were neurological function score, infarct volume, evans blue content and/or brain water content (BWC). The second outcome measures were the possible neuroprotective mechanisms. All the data were analyzed by Rev Man 5.3. Result: Pooled preclinical data showed that compared with the controls, G-Rb1 could improve neurological function (Zea Longa (n = 367, P < 0.01); mNSS (n = 70, P < 0.01); Water maze test (n = 48, P < 0.01); Bederson (n = 16, P < 0.01)), infarct area (TTC (n = 211, P < 0.01); HE (n = 26, P < 0.01)), as well as blood-brain barrier function (BWC (n = 64, P < 0.01); Evans blue content (n=26, P<0.05)). It also can increase BDNF (n = 26, P < 0.01), Gap-43 (n = 16, P < 0.01), SOD (n = 30, P < 0.01), GSH (n = 16, P < 0.01), Nissl-positive cells (n = 12, P < 0.01), Nestin-positive cells (n = 10, P < 0.05), and reduce Caspase-3 (n = 36, P < 0.01), IL-1 (n = 32, P < 0.01), TNF-α (n = 72, P < 0.01), MDA (n = 18, P < 0.01), NO (n = 44, P < 0.01), NOX (n = 32, P < 0.05), ROS (n = 6, P < 0.05), NF-κB (P < 0.05) and TUNEL-positive cells (n = 52, P < 0.01). Conclusion: Available findings demonstrated the preclinical evidence of G-Rb1 that has a potential neuroprotective effect, largely through attenuating brain water content, promoting the bioactivities of neurogenesis, anti-apoptosis, anti-oxidative, anti-inflammatory, energy supplement and cerebral circulation.

Ginsenoside-Rb1 for Ischemic Stroke: A Systematic Review and Meta-analysis of Preclinical Evidence and Possible Mechanisms.

Objective: Ischemic stroke is a complex multifactorial disease caused by interactions among polygenetic, environmental, and lifestyle factors with limited effective treatments. Multi-herbal formulae have long been used for stroke via herbal compatibility under traditional Chinese medicine wisdom; however, there is still lack of evidences due to their unimaginable complexity. Herbal pairs represent the simplest and basic features of multi-herbal formulae, which are of great significance for clarifying herbal compatibility. Here, we aim to investigate the neuroprotective effects of herbal compatibility of Ginseng and Rhubarb on cerebral Ischemia/Reperfusion (I/R) injury model of rats. Methods: Male adult SD rats were randomly divided into sham group, normal saline (NS) group, Ginseng group, Rhubarb group and Ginseng + Rhubarb (GR) group, Carbenoxolone (CBX, gap junction specific inhibitor) group, and GR+ CBX group. Each group was further assigned into 4 subgroups according to ischemic time (6h, 1d, 3d, and 7d). The cerebral I/R injury model was established according to modified Zea Longa method. Neurological Deficiency Score (NDS) was assessed by the Zea-Longa scale; cerebral infarction area was detected by TTC (2,3,5-Triphenyltetrazolium chloride) staining; and the expression of Connexin-43 (Cx43) and Aquaporin-4 (AQP4) were detected based on immunofluorescence technique and Quantitative Real-time-PCR. Results: Compared with I/R group, both the independent and combined use of Ginseng and Rhubarb can significantly improve NDS (P < 0.05), decrease the percentage of cerebral infarction area around infarction penumbra (P < 0.05) and down-regulate the expression of Cx43 and AQP4 after I/R injury (P < 0.05). The GR had more significant effects than that of Ginseng and Rhubarb (P<0.05). Compared with GR group, GR+ CBX group significantly improved in NDS (P < 0.05), and decreased the percentage of cerebral infarction area (P < 0.05) and expression of Cx43 and AQP4 protein (P < 0.05) Conclusion: The herbal compatibility of ginseng and Rhubarb exerts synergistically neuroprotective function during acute cerebral I/R injury, mainly through reducing the expression of Cx43 and AQP4.

/pdf/herbal-compatibility-of-ginseng-and-rhubarb-exerts-5a443tpc2p.pdf

Herbal Compatibility of Ginseng and Rhubarb Exerts Synergistic Neuroprotection in Cerebral Ischemia/Reperfusion Injury of Rats.

Chinese herbal medicine for headache: A systematic review and meta-analysis of high-quality randomized controlled trials.

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