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Bilobalide induces the expression of Aβ degrading enzymes to facilitate Aβ clearance in primary astrocyte culture A Western blot and its quantification showing the protein levels of NEP, IDE, and MMP2 in astrocyte culture treated by bilobalide at indicated concentrations. B Aβ clearance assay showing Aβ42 levels in the culture medium of astrocytes treated by bilobalide at indicated concentrations. C Diagram showing the astrocyte-neuron co-culture in transwell system. D ELISA results showing Aβ40 and Aβ42 levels in the culture medium of APP/PS1 neuron co-cultured with control or bilobalide (5 μM) pretreated astrocytes. *P < 0.05, **P < 0.01, ***P < 0.001.
Source publication
The pathogenesis of Alzheimer’s disease (AD) involves multiple cell types including endothelial cells, glia, and neurons. It suggests that therapy against single target in single cell type may not be sufficient to treat AD and therapies with protective effects in multiple cell types may be more effective. Here, we comprehensively investigated the e...
Citations
... Numerous studies have shown that MMP-2 plays an important role in BBB damage induced by ischemic stroke, in which MMP-2 proteolytically degrades two core barrier structures of the BBB, namely the tight junctions (TJs) and the basement membrane of the brain capillaries (Abdullah et al., 2015;Chen et al., 2017;Jie et al., 2015). Emerging studies have shown that astrocytes (Xiang et al., 2021), brain microvascular endothelial cells (ECs) (Vittal Rao et al., 2021), microglia (Wu, Gao, et al., 2020), and neurons (DeVault et al., 2018) constitutively express MMP-2, especially with high levels of MMP-2 expression in astrocytic end-feet that are closely connected with ECs (Yang & Rosenberg, 2015). However, whether MMP-2 interferes with the interaction between the main cell types of the BBB is undetermined in an ischemic stroke. ...
We have previously demonstrated a rapid secretion of matrix metalloproteinase‐2 (MMP‐2) in the ischemic brain. Since Scube2 can interact with Sonic hedgehog (Shh) to maintain blood–brain barrier (BBB) integrity via regulating the interaction between brain capillary endothelial cells (ECs) and perivascular astrocytes, and it is also a substrate of MMP‐2, we hypothesized that the secreted MMP‐2 could degrade Scube2 and contribute to ischemic BBB disruption. Using an in vitro ischemic model of 90‐min oxygen–glucose deprivation/3‐h reoxygenation (OGD/R) and an in vivo mouse stroke model of 90‐min middle cerebral artery occlusion (MCAO) with 3‐h reperfusion, we established an important role of MMP‐2‐mediated Scube2 degradation in early ischemic BBB disruption. Exposure of C8‐D1A cells and bEnd.3 cells to OGD/R increased MMP secretion in both cells, and C8‐D1A cells appeared to secrete more MMPs than bEnd.3 cells. Co‐IP and double‐immunostaining revealed that Scube2 co‐localized well with MMP‐2 in C8‐D1A cells and could be pulled down by MMP‐2 antibodies. In MCAO mice, Scube2 protein showed a drastic reduction in ischemic brain tissue, which was accompanied by suppressed expression of Shh and its downstream molecules. Of note, specific knockdown of astrocytic Scube2 with AAV‐shScube2 augmented MCAO‐induced Shh suppression and exacerbated BBB leakage and inflammatory reactions in the ischemic brain. Last, incubation of bEnd.3 cells with conditioned medium derived from OGD‐treated C8‐D1A cells led to a significant inhibition of the Shh pathway in bEnd.3 cells and degradation of VE‐cadherin and ZO‐1. Inhibition of MMP‐2 with SB‐3CT or over‐expression of Scube2 with plasmids in C8‐D1A cells alleviated the above effect of C8‐D1A cells‐derived conditioned medium. Taken together, our data indicate that ischemia‐induced secretion of MMP‐2 may contribute to early BBB disruption in ischemic stroke via interrupting the shared Scube2‐Shh pathway between brain capillary ECs and perivascular astrocytes.
... For example, one study demonstrated that enhancing the astrocytic clearance of Aβ using a small-molecule drug improved synaptic plasticity and cognitive function in AD mouse models [62]. Another study showed that inhibiting astrocytic pro-inflammatory cytokine production reduced synapse loss and improved cognitive function in a mouse model of AD [63]. ...
The blood–brain barrier (BBB) is a highly intricate neurovascular structure that plays a crucial role in maintaining neural homeostasis by selectively allowing certain molecules to enter the central nervous system (CNS). However, in the context of Alzheimer’s Disease (AD), a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function, the BBB’s functionality becomes impaired. This impairment leads to the breakdown of the barrier and disrupts its ability to regulate molecular transport effectively. Consequently, cellular infiltration into the CNS occurs, along with aberrant signaling and clearance of molecules, ultimately contributing to neurological deficits. One of the key factors implicated in the failure of amyloid-beta (Aβ) transport, a hallmark of AD, is the decreased expression of low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 plays a crucial role in facilitating the transport of Aβ across the BBB. Additionally, the increased levels of the receptor for advanced glycation end products (RAGE) further contribute to the deregulation of the BBB in AD. These molecular imbalances significantly impact Aβ clearance and contribute to the development and progression of AD. In this review, we aimed to summarize the critical aspects of Aβ transporters in the BBB that become dysfunctional during the pathogenesis of AD.
... In addition, neuroprotective astrocytes release several anti-inflammatory molecules such as TGF-β, IL-4, and IL-13, thereby enhancing microglia autophagy; this ameliorates the cognitive impairment caused by AD (Liddelow and Barres, 2017;Qin et al., 2020). Although it is debatable whether astrocytes can directly alter the Aβ produced in AD, in vitro studies have shown that reactive astrocytes can scavenge Aβ and minimize inflammatory damage (Liu et al., 2016;Xiang et al., 2021). The crosstalk between astrocytes and microglia may provide new concepts for the treatment of AD. ...
Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer's disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes; these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer's disease. Our literature search found that phenotypic changes occur continuously in Alzheimer's disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer's disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer's disease.
... It contains two main groups of bioactive components: 24% favonol glycosides and 6% terpene trilactones [12]. Bilobalide (BB) is one of the main components of terpene trilactone [13], approximately accounting for 2.9-3.2% of EGb76 [14]. Currently, BB has been used as a phytopharmaceutical or food supplement in numerous countries [15]. ...
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Bilobalide (BB) is a sesquiterpene isolated from Ginkgo biloba, and its role in IPF is poorly understood. Mice were intratracheally instilled with 2.5 mg/kg bleomycin (BLM) to induce IPF and then treated with 2.5, 5, and 10 mg/kg BB daily for 21 days. Treatment with BB ameliorated pathological injury and fibrosis of lung tissues in BLM-induced mice. BB suppressed BLM-induced inflammatory response in mice as demonstrated by reduced inflammatory cells counts (leukocytes, neutrophils, macrophages, and lymphocytes) and pro-inflammatory factors (CCL2 and TNF-α), as well as increased CXCL10 levels in BALF. The expression of BLM-induced hydroxyproline, LDH, and pro-fibrotic mediators including fibronectin, collagen I, α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, and MMP-9 in lung tissue was inhibited by BB treatment, and the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression was increased. BB blocked the phosphorylation of JNK and NF-κB, and the nuclear translocation of NF-κB in the lung tissue of mice induced by BLM. Additionally, it abated the activation of NLRP3 inflammasome in lung tissue induced by BLM, which led to the downregulation of IL-18 and IL-1β in BALF. Our present study suggested that BB might ameliorate BLM-induced pulmonary fibrosis by inhibiting the early inflammatory response, which is probably via the inhibition of the JNK/NF-κB/NLRP3 signal pathway. Thus, BB might serve as a therapeutic potential agent for pulmonary inflammation and fibrosis.
... Correspondingly, about nine natural compounds and phytochemicals influence STAT3 signaling for hypertensive heart disease and IBD (Zhao et al., 2016). Among all mentioned above, these natural compounds belong to flavonoids (baicalin and quercetin), polyphenols (curcumin, gallic acid, and rosmarinic acid), terpenoids (celastrol and bilobalide), phenylpropanoids (imperatorin), and 3-deoxy-2β,16-dihydroxynagilactone E. Those natural compounds accomplished treatment for myocardial ischemia/reperfusion injury , diabetic cardiomyopathy (Abdelsamia et al., 2019), IBD (Zhao et al., 2016), alcoholic liver disease (ALD) (Zhu et al., 2017), neuropathic pain , psoriasis (Zhang et al., 2021a), hypertensive heart disease , AD (Xiang et al., 2021), cancer cachexia (Chen et al., 2020a), and cancer (Shan et al., 2019). The underlying mechanisms for these compounds treating diseases preferred restraining STAT3 signaling activation. ...
JAK/STAT signaling pathways are closely associated with multiple biological processes involved in cell proliferation, apoptosis, inflammation, differentiation, immune response, and epigenetics. Abnormal activation of the STAT pathway can contribute to disease progressions under various conditions. Moreover, tofacitinib and baricitinib as the JAK/STAT inhibitors have been recently approved by the FDA for rheumatology disease treatment. Therefore, influences on the STAT signaling pathway have potential and perspective approaches for diverse diseases. Chinese herbs in traditional Chinese medicine (TCM), which are widespread throughout China, are the gold resources of China and have been extensively used for treating multiple diseases for thousands of years. However, Chinese herbs and herb formulas are characterized by complicated components, resulting in various targets and pathways in treating diseases, which limits their approval and applications. With the development of chemistry and pharmacology, active ingredients of TCM and herbs and underlying mechanisms have been further identified and confirmed by pharmacists and chemists, which improved, to some extent, awkward limitations, approval, and applications regarding TCM and herbs. In this review, we summarized various herbs, herb formulas, natural compounds, and phytochemicals isolated from herbs that have the potential for regulating multiple biological processes via modulation of the JAK/STAT signaling pathway based on the published work. Our study will provide support for revealing TCM, their active compounds that treat diseases, and the underlying mechanism, further improving the rapid spread of TCM to the world.
... Bilobalide (BB), a lactone extracted from Ginkgo biloba leaves, has potent anti-inflammatory and antioxidant properties [12]. BB is used to treat neurological diseases such as Alzheimer's disease [13] and multiple sclerosis [14] by reducing neuronal inflammation and damage. Moreover, BB protects chondrogenic (ATDC5) cell lines from proinflammatory interleukin (IL)-17-induced inflammatory injury; however, the protective effects of BB on cartilage metabolism and the underlying mechanisms are unknown. ...
Background
Uncoupled extracellular matrix (ECM) causes cartilage degeneration and osteoarthritis (OA) by suppressing the synthesis and activating the degradation of ECM components. Gingko biloba is a natural Chinese herb with a variety of biological functions; however, the extent to which it can protect against OA and the mechanisms involved are unknown.
Methods
In our study, using bioinformatics tools, we were able to identify an important lactone, bilobalide (BB), from Gingko biloba . In vitro experiments were performed to evaluate the potential therapeutic effects of BB on ECM homeostasis. In vivo experiments were conducted to assess the protection of systemic administration of BB on cartilage degeneration. Molecular mechanisms underlying BB-regulated anti-arthritic role were further explored.
Results
In interleukin-1β-incubated human chondrocytes, in vitro treatment with BB increased the expression of cartilage anabolic proteins, while inhibiting the activities of ECM degrading enzymes. In a mice model, systemic administration of BB, in vivo, prevented post-traumatic cartilage erosion and attenuated the formation of abnormal osteophytes in the subchondral bone. Mechanistically, the activation of the adenosine 5′-monophosphate-activated protein kinase (AMPK)-sirtuin 1 (SIRT1) signaling pathway was involved in the anti-arthritic effects of BB. In vitro, blocking BB’s chondroprotection with the AMPK-specific inhibitor Compound C abrogated it.
Conclusions
These results demonstrated that BB extracted from Gingko biloba regulates ECM balance to prevent OA by activating the AMPK-SIRT1 signaling pathway. This study proposed the monomer BB, a traditional Chinese medicine, as a de novo therapeutic insight for OA.
Graphical Abstract
Schematic representation of the experimental design. Based on the bioinformatic analysis, bilobalide (BB), a natural herb Gingko biloba -derived ingredient, was identified as a candidate for treating osteoarthritis. In vitro, BB treatment not only facilitates cartilage extracellular matrix synthesis but also inhibits proteolytic enzyme activities. In vivo intraperitoneal injection of BB improves cartilage degeneration and subchondral bone sclerosis. BB, in particular, had anti-arthritic effects by activating the AMPK-SIRT1 signaling pathway.
... [12,43,[74][75][76][77][78] -Anti-inflammatory (decrease in TNF-α, IL-1β, and IL-6 levels); -Neuroprotective (reduction in neuroinflammation and protection against βA deposition in AD); -Hepatoprotective; -Antioxidant via multiple pathways; -Cardioprotective. [12,43,[57][58][59] Ginkgolic acid (organic acid) ...
... -Anti-inflammatory (decrease in TNF-α, IL-1β, and IL-6 levels); -Neuroprotective (reduction in neuroinflammation and protection against βA deposition in AD); -Hepatoprotective; -Antioxidant via multiple pathways; -Cardioprotective. [12,43,[57][58][59] Ginkgolic acid (organic acid) Leaves. ...
... [12,43,[74][75][76][77][78] -Anti-inflammatory (decrease in TNF-α, IL-1β, and IL-6 levels); -Neuroprotective (reduction in neuroinflammation and protection against βA deposition in AD); -Hepatoprotective; -Antioxidant via multiple pathways; -Cardioprotective. [12,43,[57][58][59] Ginkgolic acid (organic acid) ...
... -Anti-inflammatory (decrease in TNF-α, IL-1β, and IL-6 levels); -Neuroprotective (reduction in neuroinflammation and protection against βA deposition in AD); -Hepatoprotective; -Antioxidant via multiple pathways; -Cardioprotective. [12,43,[57][58][59] Ginkgolic acid (organic acid) Leaves. ...
Neurodegenerative diseases, cardiovascular disease (CVD), hypertension, insulin resistance, cancer, and other degenerative processes commonly appear with aging. Ginkgo biloba (GB) is associated with several health benefits, including memory and cognitive improvement, in Alzheimer’s disease (AD), Parkinson’s disease (PD), and cancer. Its antiapoptotic, antioxidant, and anti-inflammatory actions have effects on cognition and other conditions associated with aging-related processes, such as insulin resistance, hypertension, and cardiovascular conditions. The aim of this study was to perform a narrative review of the effects of GB in some age-related conditions, such as neurodegenerative diseases, CVD, and cancer. PubMed, Cochrane, and Embase databases were searched, and the PRISMA guidelines were applied. Fourteen clinical trials were selected; the studies showed that GB can improve memory, cognition, memory scores, psychopathology, and the quality of life of patients. Moreover, it can improve cerebral blood flow supply, executive function, attention/concentration, non-verbal memory, and mood, and decrease stress, fasting serum glucose, glycated hemoglobin, insulin levels, body mass index, waist circumference, biomarkers of oxidative stress, the stability and progression of atherosclerotic plaques, and inflammation. Therefore, it is possible to conclude that the use of GB can provide benefits in the prevention and treatment of aging-related conditions.
Background:
Neurovascular glial unit (NVGU) dysfunction has been reported to be an early and critical event in the pathophysiology of Alzheimer's disease (AD) and vascular dementia (VD). Although herbal medicines, with their favorable safety profiles and low adverse effects, have been suggested to be useful for the treatment of cognitive impairment, the potential role of the NVGU as the target of the effects of herbal medicines is still unclear.
Purpose:
This review aimed to retrieve evidence from experimental studies of phytopharmaceuticals targeting the NVGU for the treatment of cognitive impairment in AD and VD, and discussed the potential of phytopharmaceuticals to improve cognitive impairment from the perspective of the NVGU.
Study design and methods:
We systematically searched PubMed, Google Scholar, Web of Science, and CNKI. The keywords used for searching information on the NVGU in the treatment of cognitive impairments included "Alzheimer's disease," "Vascular dementia," "Herbal medicines," "Natural products," "Neurovascular," "Adverse reaction," and "Toxicity, etc." We selected studies on the basis of predefined eligibility criteria.
Results:
NVGU mainly consists of endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons, and damage to these cells can induce cognitive impairment by impairing the blood-brain barrier (BBB) and cerebral blood flow (CBF) as well as neuronal function. The active components of herbal medicines, including Ginkgo biloba L., Ginseng Radix et Rhizoma, Epimedium Folium, Chuanxiong Rhizoma, Carthami flos, and Acorus tatarinowii Schott, as well as traditional Chinese medicine prescriptions have shown the potential to improve BBB function and increase CBF to prevent cognitive impairment by inhibiting astrocyte and microglia activation, protecting oligodendrocyte myelin function, reducing neuronal apoptosis, and promoting angiogenesis.
Conclusions:
Herbal medicines demonstrate great potential to prevent cognitive impairment. Multiple components from herbal medicines may function through different signaling pathways to target the NVGU. Future studies using novel drug-carrier or delivery systems targeting the NVGU will certainly facilitate the development of phytopharmaceuticals for AD and VD.
