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Diabetic nephropathy (DN) is a common and serious micro-vascular complication of diabetes and a leading cause of end-stage renal disease globally. This disease primarily affects middle-aged and elderly individuals, especially those with a diabetes history of over 10 years and poor long-term blood glucose control. Small ubiquitin-related modifiers (SUMOs) are a group of reversible post-translational modifications of proteins that are widely expressed in eukaryotes. SUMO proteins intervene in the progression of DN by modulating various signaling cascades, such as Nrf2-mediated oxidative stress, NF-κB, TGF-β, and MAPK pathways. Recent advancements indicate that natural products regulating SUMOylation hold promise as targets for intervening in DN. In a previous article published in 2022, we reviewed the mechanisms by which SUMOylation intervenes in renal fibrosis and presented a summary of some natural products with therapeutic potential. Therefore, this paper will focus on DN. The aim of this review is to elucidate the mechanism of action of SUMOylation in DN and related natural products with therapeutic potential, thereby summarising the targets and candidate natural products for the treatment of DN through the modulation of SUMOylation, such as ginkgolic acid, ginkgolide B, resveratrol, astragaloside IV, etc., and highlighting that natural product-mediated modulation of SUMOylation is a potential therapeutic strategy for the treatment of DN as a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the regulatory effects of Ginkgolide B on the biological characteristics of brain T cells and their interactions with glial cells during the recovery phase of ischemic stroke in mice.Methods36 adult C57BL/6 mice were randomly assigned to three groups: sham-operated group (Sham group), control group (PBS group), and Ginkgolide B treatment group (GB group). The Sham group underwent only sham surgeries, whereas the PBS and GB groups were subjected to a middle cerebral artery occlusion (MCAO) model using the filament method, followed by intranasal administration of an equivalent volume of either PBS or Ginkgolide B solution for 14 days post-injury. Neurological function changes were evaluated in all three groups using the rotarod test and a neurological scoring system. On day 15, single-cell sequencing was performed on fresh tissues from the brain injury areas, surrounding cortex, corpus callosum, and striatum of mice in the PBS and GB group to assess the biological characteristics of T cells and their subpopulations, and further explore the interactions and mechanisms among T cells, microglia, and oligodendrocytes.ResultsCompared with the Sham group, both PBS and GB group exhibited significant improvements in neurological scores and reduced pre-fall motor durations (P < 0.001). Compared with the PBS group, the GB group showed a downward trend in neurological scores and an upward trend in pre-fall motor durations on days 5, 10, and 15 post-ischemic brain injury, with a significant increase in pre-fall motor duration on day 15 (P < 0.05). Compared with the PBS group, the GB group exhibited a significant increase in T cell proliferative activity in the brain 15 days post brain injury (P < 0.05). The number of proliferative T cells and the levels of lipid metabolism were significantly elevated (P < 0.05), and there was a significant increase in extracellular matrix remodeling in all T cells (P < 0.05). Additionally, the interactions between T cells and both microglia and oligodendrocytes, as well as among the microglia themselves and between microglia and oligodendrocytes, were significantly enhanced in the GB group. This was primarily evident in the strengthened interactions between CD74 and macrophage migration inhibitory factor (MIF), as well as colony stimulating factor 1 receptor (CSF1R) and colony stimulating factor 1 (CSF1) (P < 0.05). However, the inflammatory levels of T cells showed no significant differences compared with the PBS group.ConclusionA mouse model of ischemic stroke can be successfully established by MCAO operation. Ginkgolide B may promote neurological recovery post-brain injury in mice by modulating the biological characteristics of T cells within the brain and their interactions with glial cells.

This study aims to explore the effect of ginkgolide B (GB) on obese mice. An obese C57BL/6J mice model was induced by high-fat diet firstly, and then the obese mice were divided into 4 groups according to body weight randomly: Positive model group (PG), GB low dose group (GBL), GB medium dose group (GBM) and GB high dose group (GBH). After 8-week intervention, the obesity-related indexes (weight change, visceral fat coefficient and serum indexes) of mice in each group were measured. Results showed that the weight gain of mice in GBM and GBH were significantly decreased than in PG (P

Nanomedicine for treating post‐viral infectious disease syndrome is at an emerging stage. Despite promising results from preclinical studies on conventional antioxidants, their clinical translation as a therapy for treating post‐COVID conditions remains challenging. The limitations are due to their low bioavailability, instability, limited transport to the target tissues, and short half‐life, requiring frequent and high doses. Activating the immune system during coronavirus (SARS‐CoV‐2) infection can lead to increased production of reactive oxygen species (ROS), depleted antioxidant reserve, and finally, oxidative stress and neuroinflammation. To tackle this problem, we developed an antioxidant nanotherapy based on lipid (vesicular and cubosomal types) nanoparticles (LNPs) co‐encapsulating ginkgolide B and quercetin. The antioxidant‐loaded nanocarriers were prepared by a self‐assembly method via hydration of a lyophilized mixed thin lipid film. We evaluated the LNPs in a new in vitro model for studying neuronal dysfunction caused by oxidative stress in coronavirus infection. We examined the key downstream signaling pathways that are triggered in response to potassium persulfate (KPS) causing oxidative stress‐mediated neurotoxicity. Treatment of neuronally‐derived cells (SH‐SY5Y) with KPS (50 mM) for 30 min markedly increased mitochondrial dysfunction while depleting the levels of both glutathione peroxidase (GSH‐Px) and tyrosine hydroxylase (TH). This led to the sequential activation of apoptotic and necrotic cell death processes, which corroborates with the crucial implication of the two proteins (GSH‐Px and TH) in the long‐COVID syndrome. Nanomedicine‐mediated treatment with ginkgolide B‐loaded cubosomes and vesicular LNPs showed minimal cytotoxicity and completely attenuated the KPS‐induced cell death process, decreasing apoptosis from 32.6% (KPS) to 19.0% (MO‐GB), 12.8% (MO‐GB‐Quer), 14.8% (DMPC‐PEG‐GB), and 23.6% (DMPC‐PEG‐GB‐Quer) via free radical scavenging and replenished GSH‐Px levels. These findings indicated that GB‐LNPs‐based nanomedicines may protect against KPS‐induced apoptosis by regulating intracellular redox homeostasis. [ABSTRACT FROM AUTHOR]

To investigate the effects of ginkgolide B on the proliferation and apoptosis of esophageal cancer cells and the related mechanisms. Human esophageal cancer OE19 cells were cultured in vitro. They were divided into control group (no intervention), low/medium/high dose test group (adding 6.25, 12.50 and 25.00 μmol/L ginkgolide B, respectively), ginkgolide B group (12.50 μmol/L ginkgolide B), positive drug group (4 mg/L cisplatin) and inhibitor group [12.50 μmol/L ginkgolide B+10.00 μmol/L janus kinase 2/transcriptional activator 3 (JAK2/STAT3) pathway inhibitor AG490] and activator group (12.50 μmol/L ginkgolide B+0.50 μmol/L JAK2/STAT3 pathway activator Colivelin), 24 h after intervention, cell count kit 8 (CCK-8), 5-acetyl-2' deoxyuridine (EdU) method, Hoechst 33258 staining, real-time fluorescence quantitative PCR (RT-qPCR) and protein immunoblot (WB) were used to detect cell viability, proliferation rate, apoptosis rate and expression levels of related factors. The results show that: compared with the control group, the cell viability of the medium/high dose test group and positive drug group was decreased (P<0.05), therefore, in this study, 12.50 μmol/L ginkgolide B group with significant difference and lower concentration was selected as ginkgolide B group for follow-up tests. Compared with the control group, the cell proliferation rate, Cyclin D1 mRNA and protein expression levels, p-JAK2 and p-STAT3 protein expression levels of ginkgolide B group and positive drug group were decreased, while the apoptosis rate and Caspase-3 mRNA and protein expression levels were increased (P<0.05). Compared with the ginkgolide B group, the changes of all indexes in inhibitor group were further enhanced (P<0.05). while those in activator group were significantly reversed (P<0.05). Ginkgolide B can inhibit the proliferation of OE19 cells and promote apoptosis of esophageal cancer cells by down-regulating JAK2/STAT3 signaling pathway. This study revealed a new anticancer mechanism of ginkgolide B and provided a theoretical basis for the study of esophageal cancer. [ABSTRACT FROM AUTHOR]

Objective To investigate the regulatory effects of Ginkgolide B on the biological characteristics of brain T cells and their interactions with glial cells during the recovery phase of ischemic stroke in mice. Methods　36 adult C57BL/6 mice were randomly assigned to three groups: sham-operated group (Sham group), control group (PBS group), and Ginkgolide B treatment group (GB group). The Sham group underwent only sham surgeries, whereas the PBS and GB groups were subjected to a middle cerebral artery occlusion (MCAO) model using the filament method, followed by intranasal administration of an equivalent volume of either PBS or Ginkgolide B solution for 14 days post-injury. Neurological function changes were evaluated in all three groups using the rotarod test and a neurological scoring system. On day 15, single-cell sequencing was performed on fresh tissues from the brain injury areas, surrounding cortex, corpus callosum, and striatum of mice in the PBS and GB group to assess the biological characteristics of T cells and their subpopulations, and further explore the interactions and mechanisms among T cells, microglia, and oligodendrocytes. Results　Compared with the Sham group, both PBS and GB group exhibited significant improvements in neurological scores and reduced pre-fall motor durations (P < 0.001). Compared with the PBS group, the GB group showed a downward trend in neurological scores and an upward trend in pre-fall motor durations on days 5, 10, and 15 post-ischemic brain injury, with a significant increase in pre-fall motor duration on day 15 (P < 0.05). Compared with the PBS group, the GB group exhibited a significant increase in T cell proliferative activity in the brain 15 days post brain injury (P < 0.05). The number of proliferative T cells and the levels of lipid metabolism were significantly elevated (P < 0.05), and there was a significant increase in extracellular matrix remodeling in all T cells (P < 0.05). Additionally, the interactions between T cells and both microglia and oligodendrocytes, as well as among the microglia themselves and between microglia and oligodendrocytes, were significantly enhanced in the GB group. This was primarily evident in the strengthened interactions between CD74 and macrophage migration inhibitory factor (MIF), as well as colony stimulating factor 1 receptor (CSF1R) and colony stimulating factor 1 (CSF1) (P < 0.05). However, the inflammatory levels of T cells showed no significant differences compared with the PBS group. Conclusion　A mouse model of ischemic stroke can be successfully established by MCAO operation. Ginkgolide B may promote neurological recovery post-brain injury in mice by modulating the biological characteristics of T cells within the brain and their interactions with glial cells. [ABSTRACT FROM AUTHOR]

This study aims to explore the effect of ginkgolide B (GB) on obese mice. An obese C57BL/6J mice model was induced by high-fat diet firstly, and then the obese mice were divided into 4 groups according to body weight randomly: Positive model group (PG), GB low dose group (GBL), GB medium dose group (GBM) and GB high dose group (GBH). After 8-week intervention, the obesity-related indexes (weight change, visceral fat coefficient and serum indexes) of mice in each group were measured. Results showed that the weight gain of mice in GBM and GBH were significantly decreased than in PG (P<0.05), and the visceral fat coefficient of mice in GBH group was also reduced significantly (P<0.05) after GB treatment. Meanwhile, the serum indexes (TG, TC, LDL-C and HDL-C) of mice in GBM and GBH were obviously improved, especially in GBH. Besides, histopathologic findings showed that liver fat deposition was apparently reduced in GBM and GBH. Furthermore, qRT-PCR results showed that the mRNA expression level of PPARγ in liver of mice in GBM and GBH was significantly decreased (P<0.05) in comparison with PG, while the mRNA expression level of UCP-2 was significantly increased (P<0.05). In summary, this study demonstrated that GB of medium and high doses improved obesity in mice, and this ameliorating effect might be related to PPARγ-UCP-2 signaling pathway. [ABSTRACT FROM AUTHOR]

The risk of brain exposure to ionizing radiation increases gradually due to the extensive application of nuclear technology in medical, industrial, and aerospace fields. Radiation-induced brain injury (RBI) is highly likely to cause a wide range of neurological complications, including schizophrenia, Alzheimer's disease (AD), depression. Ginkgolide B (GB) is one of the effective active components extracted from ginkgo biloba leaves, exerts protective effects on CNS, which is involved in the regulation of the Hippo signaling pathway. MST1, as one of the core kinases of the Hippo pathway, participated in regulating cell proliferation, differentiation, and apoptosis. However, it remains unclear whether GB attenuates radiation brain injury (RBI) and whether the radioprotective effect of GB refers to MST1 signaling. Hence, our study aimed to explore the radiation protection effect and the potential mechanism of GB. C57BL/6 mice were stimulated with an X-ray (20 Gy) to establish an RBI model. Then, morris water maze test (MWM) and step-down passive avoidance test (SDPAT) were used to assess the learning and memory function of mice. The open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were used to assess changes in locomotor activity and hopelessness. Besides, X-ray-stimulated SH-SY5Y cells were used to verify the radioprotective effect of GB. Immunofluorescence double staining, Dihydroethidium (DHE), western blot, and flow cytometry were used to explore the role of DCC/MST1 signaling in RBI. In this study, X-ray-treated mice exhibited cognitive impairment and depression-like behavior, which was ameliorated by GB treatment. GB also reduced the ROS production and the number of TUNEL-positive cells in the hippocampus. Moreover, GB increased the protein levels of p-AKT and Bcl2, while decreased the protein levels of MST1, p-p38, p-JNK, cleaved-caspase-3 and Bax both in vivo and in vitro. Additionally, exogenous Netrin-1 alleviated X-ray-induced ROS production and apoptosis, whereas knockout of Netrin-1 receptor DCC abolished the protective effect of GB. Oxidative stress and MST1-mediated neuronal apoptosis participated in radiation-induced cognitive impairment and depression-like behaviors, and modulation of DCC by GB was an effective intervention against RBI. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a pathological state induced by the aberrant generation of pain signals within the nervous system. Ginkgolide B(GB), an active component found of Ginkgo. biloba leaves, has neuroprotective properties. This study aimed to explore the effects of GB on neuropathic pain and its underlying mechanisms. In the in vivo study, we adopted the rat chronic constriction injury model, and the results showed that GB(4 mg/kg) treatment effectively reduced pain sensation in rats and decreased the expressions of Iba-1 (a microglia marker), NLRP3 inflammasome, and inflammatory factors, such as interleukin (IL)-1β, in the spinal cord 7 days post-surgery. In the in vitro study, we induced microglial inflammation using lipopolysaccharide (500 ng/mL) / adenosine triphosphate (5 mM) and treated it with GB (10, 20, and 40 μM). GB upregulated the expression of mitophagy proteins, such as PINK1, Parkin, LC3 II/I, Tom20, and Beclin1, and decreased the cellular production of reactive oxygen species. Moreover, it lowered the expression of inflammation-related proteins, such as Caspase-1, IL-1β, and NLRP3 in microglia. However, this effect was reversed by Parkin shRNA/siRNA or the autophagy inhibitor 3-methyladenine (5 mM). These findings reveal that GB alleviates neuropathic pain by mitigating neuroinflammation through the activation of PINK1-Parkin-mediated mitophagy.

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba, a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba, can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba , a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba , can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis. Ginkgolide B possesses the antiatherosclerotic advantage of "multitarget and multipathway", which is closely linked to its regulating endothelial dysfunction, thrombosis, leukocyte action, and risk factors. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective To investigate the potential of ginkgolide B (GB) in mitigating vascular endothelial injury by antagonizing endoplasmic reticulum stress (ERS) and elucidate its underlying molecular mechanism. Methods An injury model of human bone marrow⁃derived endothelial progenitor cells (EPCs) induced by tunicamycin (TM) was established. Cell proliferation was assessed using MTS assay, while cell viability was determined through Calcein⁃AM/EthD⁃I double staining. Transwell assay was employed to evaluate cell migration ability. DCFHDA staining was utilized to measure intracellular ROS levels, and NADPH activity was quantified via ELISA. JC⁃1 and DiOC6 staining were performed for qualitative and quantitative assessment of mitochondrial membrane potential respectively. Qrt⁃pcr analysis was conducted to determine mRNA expression levels, whereas western blot analysis enabled detection of protein expression levels in the cells. Results GB dose⁃dependently attenuated tunicamycininduced ERS⁃mediated endothelial injury in hEPCs, as evidenced by decreased cell viability, impaired cell migration, and angiogenesis inhibition (P < 0.01) . Furthermore, GB treatment significantly reduced ROS production and NADPH levels within the cells (P < 0.01), while also inhibiting ERS⁃mediated decline in mitochondrial membrane potential concentration⁃dependently (P < 0.01) . Additionally, GB inhibited the expression of ERS⁃related proteins such as GRP78, ATF4, CHOP etc., regulated apoptosis⁃related protein Bcl⁃xl, Bax cleaved caspase⁃4 cytochrome c； thereby effectively counteracting endoplasmic reticulum stress⁃induced cellular damage. Conclusions GB exerts a protective effect on vascular endothelium by antagonizing endoplasmic reticulum stress； this mechanism may be attributed to its ability to reduce intracellular reactive oxygen species levels. It also suppresses the expression of ERS⁃related proteins (CHOP78 and ATF4), and modulates apoptosis⁃associated proteins (Bcl⁃xl, Bax, cleaved caspase⁃4, and cytochrome c) . [ABSTRACT FROM AUTHOR]

Objectives: Perinatal hypoxic–ischemic encephalopathy (HIE) is a condition that can lead to long‐term cognitive, motor, and behavioral impairments in newborns. Although brain hypothermia therapy is currently the standard treatment for HIE, it does not provide complete neuroprotection. As a result, there is a need to explore additional therapies to enhance treatment outcomes. This study aims to investigate the potential role of Ginkgolide B (GB) in promoting neuroplasticity and facilitating spontaneous recovery after HIE. Methods: In this study, we employed a neonatal rat model of HIE to investigate the effects of GB on spontaneous recovery. GB treatment was initiated 24 h after hypoxia and administered continuously for a duration of 14 days. We evaluated several outcome measures after the treatment period, including spontaneous behavioral recovery and brain repair. Additionally, we quantified the levels of netrin‐1 in both plasma and the peri‐ischemic zone after the occurrence of HIE. Results: We found that GB treatment significantly facilitated spontaneous behavioral recovery in the HIE pups. Furthermore, cognitive function was restored, and brain tissue repair had a noticeable acceleration. We observed increased cell proliferation in the subventricular, stratum, and subgranular zones. Of particular interest, we observed elevated levels of netrin‐1 in both plasma and the ischemic penumbra following GB treatment. Conclusion: Our findings suggest that GB promotes neuroplasticity and enhances spontaneous recovery in newborns affected by HIE. The observed upregulation of netrin‐1 may be crucial in mediating these effects. These results highlight the promising potential of GB as a post‐HIE therapy, particularly in enhancing spontaneous recovery and improving long‐term outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background The progressive deterioration of tissue–tissue crosstalk with aging causes a striking impairment of tissue homeostasis and functionality, particularly in the musculoskeletal system. Rejuvenation of the systemic and local milieu via interventions such as heterochronic parabiosis and exercise has been reported to improve musculoskeletal homeostasis in aged organisms. We have shown that Ginkgolide B (GB), a small molecule from Ginkgo biloba, improves bone homeostasis in aged mice by restoring local and systemic communication, implying a potential for maintaining skeletal muscle homeostasis and enhancing regeneration. In this study, we investigated the therapeutic efficacy of GB on skeletal muscle regeneration in aged mice. Methods Muscle injury models were established by barium chloride induction into the hind limb of 20‐month‐old mice (aged mice) and into C2C12‐derived myotubes. Therapeutic efficacy of daily administrated GB (12 mg/kg body weight) and osteocalcin (50 μg/kg body weight) on muscle regeneration was assessed by histochemical staining, gene expression, flow cytometry, ex vivo muscle function test and rotarod test. RNA sequencing was used to explore the mechanism of GB on muscle regeneration, with subsequent in vitro and in vivo experiments validating these findings. Results GB administration in aged mice improved muscle regeneration (muscle mass, P = 0.0374; myofiber number/field, P = 0.0001; centre nucleus, embryonic myosin heavy chain‐positive myofiber area, P = 0.0144), facilitated the recovery of muscle contractile properties (tetanic force, P = 0.0002; twitch force, P = 0.0005) and exercise performance (rotarod performance, P = 0.002), and reduced muscular fibrosis (collagen deposition, P

Stroke is a highly lethal and disabling disease of the central nervous system exacerbated by oxidative stress, inflammation, and ferroptosis. However, the blood–brain barrier makes it extremely difficult for most medications to enter the brain, necessitating extremely high drug concentrations. Thus, we developed platelet-derived nanoparticles to deliver ginkgolide B (GB), a compound that has anti-inflammatory, antioxidative stress, and ferroptosis inhibition properties and assists acute stroke recovery. GB was encapsulated in a platelet membrane (PM) with a particle size of approximately 68.32 ± 3.7 nm, and the encapsulation efficiency reached 79.43 ± 6.3%. Experiments showed that PM-derived nanoparticles with GB (PM-GB) increased the activity of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) and decreased malondialdehyde-(MDA) and reactive oxygen species-(ROS) levels in the brain. Additionally, the PM-GB group had higher ferroptosis suppressor protein (GPX4, FSP1) expression, approximately 4-folds, with lower levels of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, and ferroptosis marker protein (PTGS2) compared with the OGD group. In conclusion, PM-GB reduces ferroptosis and inflammation by inhibiting oxidative stress, which protects neural cells and promotes motor recovery in middle cerebral artery occlusion model rats (MCAO/R). [ABSTRACT FROM AUTHOR]

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Ginkgo biloba extract (GBE) helps lower cardiovascular disease risk. Diabetes mellitus (DM)-induced endothelial dysfunction is a critical and initiating factor in the beginning of diabetic vascular complications. It was reported that GBE causes an endothelial-dependent relaxation. This study was designed to figure out the molecular basis on which GBE protects from endothelial dysfunction in diabetes because the underlying mechanisms are unclear. Studies were performed in a normal control group and streptozotocin/nicotinamide-induced DM group. In aortas, notably diabetic aortas, GBE, and ginkgolide B (GB), a constituent of GBE, produced a dose-dependent relaxation. The relaxation by GB was abolished by prior incubation with L-NNA (an endothelial nitric oxide synthase (NOS) inhibitor), LY294002 (a phosphoinositide 3-kinase (PI3K) inhibitor), and Akt inhibitor, confirming the essential role of PI3K/Akt/eNOS signaling pathway. We also demonstrated that GB induced the phosphorylation of Akt and eNOS in aortas. The superoxide dismutase1 (SOD1) expression level decreased in DM aortas, but GB stimulation increased SOD activity and SOD1 expression in DM aortas. Our novel findings suggest that in DM aortas, endothelial-dependent relaxation induced by GB was mediated by activation of SOD1, resulting in activation of the Akt/eNOS signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: Ginkgolide B (GB) possesses anti-inflammatory, antioxidant, and anti-apoptotic properties against neurotoxicity induced by amyloid beta (Aβ), but the potential neuroprotective effects of GB in Alzheimer's therapies remain elusive. We aimed to conduct proteomic analysis of Aβ1-42 induced cell injury with GB pretreatment to uncover the underlying pharmacological mechanisms of GB. Methods: Tandem mass tag (TMT) labeled liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to analyze protein expression in Aβ1-42 induced mouse neuroblastoma N2a cells with or without GB pretreatment. Proteins with fold change >1.5 andp < 0.1 from two independent experiments were regarded as differentially expressed proteins (DEPs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to analyze the functional annotation information of DEPs. Two key proteins osteopontin (SPP1) and ferritin heavy chain 1 (FTH1) were validated in another three samples using western blot and quantitative real-time PCR. Results: We identified a total of 61 DEPs in GB treated N2a cells, including 42 upregulated and 19 downregulated proteins. Bioinformatic analysis showed that DEPs mainly participated in the regulation of cell death and ferroptosis by down-regulating SPP1 protein and up-regulating FTH1 protein. Conclusions: Our findings demonstrate that GB treatment provides neuroprotective effects on Aβ1-42 induced cell injury, which may be related to the regulation of cell death and ferroptosis. The research puts forward new insights into the potential protein targets of GB in the treatment of Alzheimer's disease (AD). [ABSTRACT FROM AUTHOR]

Cerebral ischemia-reperfusion injury (CI/RI) remains the main cause of disability and death in stroke patients due to lack of effective therapeutic strategies. One of the main issues related to CI/RI treatment is the presence of the blood-brain barrier (BBB), which affects the intracerebral delivery of drugs. Ginkgolide B (GB), a major bioactive component in commercially available products of Ginkgo biloba, has been shown significance in CI/RI treatment by regulating inflammatory pathways, oxidative damage, and metabolic disturbance, and seems to be a candidate for stroke recovery. However, limited by its poor hydrophilicity and lipophilicity, the development of GB preparations with good solubility, stability, and the ability to cross the BBB remains a challenge. Herein, we propose a combinatorial strategy by conjugating GB with highly lipophilic docosahexaenoic acid (DHA) to obtain a covalent complex GB-DHA, which can not only enhance the pharmacological effect of GB, but can also be encapsulated in liposomes stably. The amount of finally constructed Lipo@GB-DHA targeting to ischemic hemisphere was validated 2.2 times that of free solution in middle cerebral artery occlusion (MCAO) rats. Compared to the marketed ginkgolide injection, Lipo@GB-DHA significantly reduced infarct volume with better neurobehavioral recovery in MCAO rats after being intravenously administered both at 2 h and 6 h post-reperfusion. Low levels of reactive oxygen species (ROS) and high neuron survival in vitro was maintained via Lipo@GB-DHA treatment, while microglia in the ischemic brain were polarized from the pro-inflammatory M1 phenotype to the tissue-repairing M2 phenotype, which modulate neuroinflammatory and angiogenesis. In addition, Lipo@GB-DHA inhibited neuronal apoptosis via regulating the apoptotic pathway and maintained homeostasis by activating the autophagy pathway. Thus, transforming GB into a lipophilic complex and loading it into liposomes provides a promising nanomedicine strategy with excellent CI/RI therapeutic efficacy and industrialization prospects. [ABSTRACT FROM AUTHOR]

Abstract Background Postoperative cognitive dysfunction (POCD) are a common complication of the central nervous system following surgery and anesthesia. The specific pathogenesis and effective therapeutics of POCD need to be further studied. Ginkgolide B (GB), a platelet-activating factor receptor-specific antagonist, has been suggested to have strong anti-inflammatory effects. Here we tested the effects and mechanism of GB on POCD of aged rats. Methods Neurobehavioral tests were used to investigate the effect of GB pretreatment on POCD. The hippocampus were harvested to test the expression of proinflammatory cytokines by ELISA. The expression of the microglial marker ionized calcium-binding adaptor molecule-1 (Iba-1) in the hippocampus was evaluated by western blot assay and immunohistochemistry. A Nissl staining experiment was used to detect the neuronal numbers in the hippocampus. Results Surgery might result in the overexpression of platelet activating factor (PAF) in the plasma and hippocampus and might cause hippocampus-dependent memory impairment. GB pretreatment, inhibited the activation of microglia, reduced the levels of IL-1β and TNF-α, decreased the loss of neurons after surgery, and prevented POCD in aged rats. Conclusion Our findings suggested that PAF was involved in the development of POCD. Improvement of POCD by PAF antagonist GB was associated with the inhibition of microgliosis-mediated neuroinflammation and neuronal apoptosis in aged rats.

Ginkgo biloba is a medicinal plant used in complementary and alternative medicines. Ginkgo biloba extracts contain many compounds with medical functions, of which the most critical is ginkgolide B (GB). The major role that GB plays is to function as an antagonist to the platelet-activating factor, which is one of the causes of thrombosis and cardiovascular diseases. Currently, GB is obtained mainly through extraction and purification from the leaves of Ginkgo biloba; however, the yield of GB is low. Alternatively, the immobilized cultivation of ginkgo calluses with biomaterial scaffolds and the addition of organic elicitors to activate the cell defense mechanisms were found to stimulate increases in GB production. The aim of this study was to use Ginkgo biloba calluses for immobilized cultures with different elicitors to find a more suitable method of ginkgolide B production via a recycling process. [ABSTRACT FROM AUTHOR]

Ginkgolide B (GKB) is a natural terpenoid lactone found in leaves of Ginkgo biloba and has antioxidative, anti-inflammatory, and anti-tumor activities. Here, we assessed the inhibitory effect of GKB on the 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced metastatic potential in MCF-7 cells (a human hormone receptor-positive breast cancer cell line). Gelatin zymography showed that GKB inhibited TPA-induced matrix metalloprotease-9 (MMP-9) activity, and wound healing and Matrigel invasion assays showed GKB inhibited TPA-induced cell migration and invasiveness. Furthermore, GKB suppressed the TPA-induced mRNA expressions of epithelial to mesenchymal transition (EMT) markers Slug, Snail, and Fibronectin genes. Based on these results, we assessed the effects of GKB on the phosphorylation of mitogen-activated protein kinases (MAPKs) and the expressions of c-Jun and c-Fos (two subunits of activating protein-1 [AP-1] and key regulators of the expressions of metastatic factors). GKB inhibited the phosphorylations of p38 (p38 mitogen-activated protein kinases) and JNK (c-Jun N-terminal kinase) and the expressions and nuclear translocations of c-Jun and c-Fos. These results demonstrate that the anti-metastatic effect of GKB is mediated by MAPK/AP-1 pathways suppression and consequent inhibitions of the MMP-9 activities and mRNA levels of EMT markers in TPA-treated MCF-7 cells. Our results suggest that GKB might be able to suppress metastasis in hormone receptor-positive breast cancer. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is the leading cause of end‑stage renal disease. Although Ginkgo biloba extract has a protective effect on DN, the protective effect and mechanism of its active ingredient Ginkgolide B (GB) on DN remain unclear. The aim of the present study was to investigate whether GB improves DN via alleviating oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination in PA-G-induced mouse podocytes and DN mice. The study in vitro showed that GB effectively reduced serum total cholesterol, triglyceride concentrations and lipid accumulation in PA-G-induced MPC5 cells. In addition, GB promoted the expression of ferroptosis markers GPX4 and FTH1, while inhibited the expression of TfR1, fibrosis markers α-SMA and Collagen α1, as well as intracellular iron content and ROS levels. Interference of GPX4 expression with siRNA counteracted the effect of GB. And GB inhibited GPX4 ubiquitination in a dose-dependent manner. In vivo the experimental results showed that GB effectively reduced hyperglycemia, serum total cholesterol and triglyceride concentrations, reduced urinary albumin excretion and the number of renal lipid droplets, and improved changes in renal structure in DN mice. GB inhibited the expression of ferroptosis marker TfR1 and fibrosis markers α-SMA and Collagen α1, while promoted the expression of ferroptosis markers GPX4 and FTH1. In conclusion, the results suggested that GB may improve DN via protecting the kidney from ferroptosis and oxidative stress damage by inhibiting the ubiquitination of GPX4. These findings suggested that GB, a natural medicine, may be an effective therapeutic option for DN.

In this article, novel molecularly imprinted polymers based on 3D reduced graphene oxide aerogel (3D RGO‐GBMIPs) were successfully fabricated and applied as adsorbents for dispersed solid‐phase extraction (DSPE) of ginkgolide B (GB). After being prepared by surface molecular imprinted technology, 3D RGO‐GBMIPs were successively characterized by fourier transform infrared spectroscopy, thermogravimetric analysis, Raman spectroscopy, and scanning electron microscope. The results of adsorption experiments revealed that 3D RGO‐GBMIPs presented highly selective recognition properties and well reusability. The main variables influencing DSPE efficiency, including extraction solvent, 3D RGO‐GBMIPs dosage, category, and volume of eluent, as well as elution time were investigated. The DSPE results showed that 3D RGO‐GBMIPs had an obvious effect on the improvement of GB purity in ginkgo biloba extract, with a satisfactory recovery rate and yield. Therefore, 3D RGO‐GBMIPs are expected to be applied for the enrichment of GB from complex matrices. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a common and serious micro-vascular complication of diabetes and a leading cause of end-stage renal disease globally. This disease primarily affects middle-aged and elderly individuals, especially those with a diabetes history of over 10 years and poor long-term blood glucose control. Small ubiquitin-related modifiers (SUMOs) are a group of reversible post-translational modifications of proteins that are widely expressed in eukaryotes. SUMO proteins intervene in the progression of DN by modulating various signaling cascades, such as Nrf2-mediated oxidative stress, NF-κB, TGF-β, and MAPK pathways. Recent advancements indicate that natural products regulating SUMOylation hold promise as targets for intervening in DN. In a previous article published in 2022, we reviewed the mechanisms by which SUMOylation intervenes in renal fibrosis and presented a summary of some natural products with therapeutic potential. Therefore, this paper will focus on DN. The aim of this review is to elucidate the mechanism of action of SUMOylation in DN and related natural products with therapeutic potential, thereby summarising the targets and candidate natural products for the treatment of DN through the modulation of SUMOylation, such as ginkgolic acid, ginkgolide B, resveratrol, astragaloside IV, etc., and highlighting that natural product-mediated modulation of SUMOylation is a potential therapeutic strategy for the treatment of DN as a potential therapeutic strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zhang, Wu, Wang, Liu and Li.)

Background: Postoperative cognitive dysfunction (POCD) are a common complication of the central nervous system following surgery and anesthesia. The specific pathogenesis and effective therapeutics of POCD need to be further studied. Ginkgolide B (GB), a platelet-activating factor receptor-specific antagonist, has been suggested to have strong anti-inflammatory effects. Here we tested the effects and mechanism of GB on POCD of aged rats. Methods: Neurobehavioral tests were used to investigate the effect of GB pretreatment on POCD. The hippocampus were harvested to test the expression of proinflammatory cytokines by ELISA. The expression of the microglial marker ionized calcium-binding adaptor molecule-1 (Iba-1) in the hippocampus was evaluated by western blot assay and immunohistochemistry. A Nissl staining experiment was used to detect the neuronal numbers in the hippocampus. Results: Surgery might result in the overexpression of platelet activating factor (PAF) in the plasma and hippocampus and might cause hippocampus-dependent memory impairment. GB pretreatment, inhibited the activation of microglia, reduced the levels of IL-1β and TNF-α, decreased the loss of neurons after surgery, and prevented POCD in aged rats. Conclusion: Our findings suggested that PAF was involved in the development of POCD. Improvement of POCD by PAF antagonist GB was associated with the inhibition of microgliosis-mediated neuroinflammation and neuronal apoptosis in aged rats. [ABSTRACT FROM AUTHOR]

Ginkgolide B is a dietary diterpene with multiple pharmacological activities. However, current research on ginkgolide B is not comprehensive. The current study analyzed the metabolic profile of ginkgolide B in vivo and in vitro using ultra‐high‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry. To detect and identify the different metabolites in ginkgolide B, a novel data processing method was used as an assistant tool. A total of 53 different metabolites of ginkgolide B (38 phase I metabolites and 15 phase II metabolites) were detected relative to blank samples. The biotransformation route of ginkgolide B was identified as oxidation, dehydroxylation, hydrogenation, decarbonylation, demethylation, sulfate conjugation, glucose conjugation, methylation, and acetylation. The current study demonstrated a method for rapidly detecting and identifying metabolites and provided useful information to further characterize the pharmacology and mechanism of ginkgolide B. A method for the analysis of other diterpene metabolic components in vivo and in vitro was also established. [ABSTRACT FROM AUTHOR]

Introduction: Ginkgolide B (GB), which is an active constituent derived from Ginkgo biloba leaves, has been reported to ameliorate Alzheimer's disease (AD), ischemic stroke, as well as other neurodegenerative diseases due to its viable immunosuppressive and anti-inflammatory functions. However, it has yet to be proven whether GB inhibits neuronal apoptosis in ischemic stroke. Methods: In the present research, the inhibition function of GB on neuronal apoptosis and its underpinning process(s) after cerebral ischemia were studied through transient middle cerebral artery occlusion (t-MCAO) in an in vivo rat model as well as in cultured SH-SY5Y cells subjected to oxygen and glucose deprivation (OGD)/reoxygenation in vitro. The neurological score was calculated and Nissl and TUNEL staining were performed to evaluate the stroke outcome, neuronal loss, and neuronal apoptosis. Subsequently, the western blot was utilized to detect Bcl2 and p-AMPK/AMPK expression. Results: Compared to t-MCAO rats, rats receiving GB treatment showed a significant reduction of neuronal loss and apoptosis and improved neurological behavior at 72 h after MCAO. GB treatment also upregulated the expression of Bcl2 and p-AMPK. In vitro , GB suppressed the apoptosis in OGD/reoxygenation-challenged neuronal SH-SY5Y cells through AMPK activation. Conclusions: Our observations suggest that GB enhanced AMPK activation in neural cells, reducing neuronal apoptosis, thus eventually preventing ischemic stroke. [ABSTRACT FROM AUTHOR]

Synopsis: NF-κB signaling has been reported to play a key regulatory role in the pathogenesis of Alzheimer's disease (AD). The purpose of this study is to investigate the effects of ginkgolide on cell viability in an AD cellular model involving an APP/PS1 double gene-transfected HEK293 cell line (APP/PS1-HEK293) and further explore the mechanisms of action related to NF-κB signaling. The optimal time point and concentration of ginkgolide for cell proliferation were screened using a cell counting kit-8 assay. Based on the results, an in vitro study was performed by co-culture of APP/PS1-HEK293 with different dosages of ginkgolide, followed by an enzyme-linked immunosorbent assay to measure the levels of supernatant tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, as well as western blotting and real-time polymerase chain reaction to detect intracellular protein and mRNA expression of NF-κB p65, IκBa, Bcl-2, and Bax. APP/PS1-HEK293 cells exhibited the highest cell viability at a concentration of 100 µg/ml after 48 h of treatment with ginkgolide. The supernatant levels of TNF-α, IL-1β, and IL-6 in the high-dosage ginkgolide-treated groups were lower than those in the control group. Compared with the control group, there were decreased intracellular protein and mRNA expression of NF-κB p65 and Bax, but increased protein and mRNA expression of IκBa in both high-dosage and low-dosage groups. Ginkgolide may enhance cell viability, indicative of its neuroprotective effects on AD, at least partially via suppression of the NF-κB signaling pathway involving anti-apoptosis and anti-inflammation mechanisms. Therefore, ginkgolide might be a promising therapeutic agent against AD. [ABSTRACT FROM AUTHOR]

Background The therapeutics used to promote perforator flap survival function induces vascular regeneration and inhibit apoptosis. The present study aimed to explore the potential mechanism of the angiogenesis effects of Ginkgolide B (GB) in perforator flaps. Methods: A total of 72 rats were divided into three groups and treated with saline, GB, or GB + tunicamycin (TM; ER stress activator) for seven consecutive days, respectively. Apoptosis was assayed by determining the Bax/Bcl-2 ratio and caspase-3 level. Endoplasmic reticulum (ER) stress markers (CHOP, GRP78, and caspase-12) were detected by Western blot analysis. Oxidative stress was assessed by measuring the superoxide dismutase activity (SOD) and malondialdehyde (MDA), heme oxygenase-1(HO-1), and nuclear factor erythroid-2-related factor 2 (Nrf2) mRNA levels in the flaps. The percentage flap survival area and blood flow were assessed on postoperative day (POD) 7. Angiogenesis was visualized by hematoxylin and eosin and CD34 staining on POD 7. Results: GB increased the survival of perforator flaps, the flap survival area of GB, GB + TM, and control groups was 90.83 ± 1.93%, 70.93 ± 4.13%, and 62.97 ± 6.50%. GB decreased the Bax/Bcl-2 ratio and caspase-3 level. ER stress-related proteins were downregulated by GB. GB also decreased the MDA level and increased SOD activity, HO-1 and Nrf2 mRNA levels in the flaps. Further, GB induced regeneration of vascular vessels in comparison with saline or GB + TM. Conclusions: GB increased angiogenesis and alleviated oxidative stress by inhibiting ER stress, which increased the survival of perforator flaps. In contrast, GB + TM alleviated angiogenesis and induced oxidative stress by activating ER stress and decreasing the survival of perforator flaps.

Promoting angiogenesis in the ischemic penumbra is a well-established method of ischemic stroke treatment. Ginkgolide B (GB) has long been recognized for its neuroprotective properties following stroke. As previously reported, it appears that stroke-induced neurogenesis and angiogenesis interact or are dependent on one another. Although the pharmacodynamic effect of GB on cerebral blood flow (CBF) following ischemic stroke has been reported, the molecular mechanism underlying this effect remains unknown. As such, this study sought to elucidate the pharmacodynamic effects and underlying mechanisms of GB on post-stroke angiogenesis. To begin, GB significantly increased the proliferation, migration, and tube formation capacity of mouse cerebral hemangioendothelioma cells (b.End3) and human umbilical vein endothelial cells (HUVEC). Additionally, GB significantly improved angiogenesis after oxygen-glucose deprivation/reperfusion (OGD/R) in endothelial cells. The dynamics of CBF, brain microvascular neovascularization and reconstruction, and brain endothelial tissue integrity were examined in middle cerebral artery occlusion (MCAO) mice following GB administration. Through label-free target detection techniques, we discovered for the first time that GB can specifically target Creatine Kinase B (CKB) and inhibit its enzymatic activity. Additionally, we demonstrated through network pharmacology and a series of molecular biology experiments that GB inhibited CKB and then promoted angiogenesis via the CCT/TRiC-SK1 axis. These findings shed new light on novel therapeutic strategies for neurological recovery and endothelial repair following ischemic stroke using GB therapy.

Neuropathic pain is a pathological state induced by the aberrant generation of pain signals within the nervous system. Ginkgolide B(GB), an active component found of Ginkgo. biloba leaves, has neuroprotective properties. This study aimed to explore the effects of GB on neuropathic pain and its underlying mechanisms. In the in vivo study, we adopted the rat chronic constriction injury model, and the results showed that GB(4 mg/kg) treatment effectively reduced pain sensation in rats and decreased the expressions of Iba-1 (a microglia marker), NLRP3 inflammasome, and inflammatory factors, such as interleukin (IL)-1β, in the spinal cord 7 days post-surgery. In the in vitro study, we induced microglial inflammation using lipopolysaccharide (500 ng/mL) / adenosine triphosphate (5 mM) and treated it with GB (10, 20, and 40 μM). GB upregulated the expression of mitophagy proteins, such as PINK1, Parkin, LC3 II/I, Tom20, and Beclin1, and decreased the cellular production of reactive oxygen species. Moreover, it lowered the expression of inflammation-related proteins, such as Caspase-1, IL-1β, and NLRP3 in microglia. However, this effect was reversed by Parkin shRNA/siRNA or the autophagy inhibitor 3-methyladenine (5 mM). These findings reveal that GB alleviates neuropathic pain by mitigating neuroinflammation through the activation of PINK1-Parkin-mediated mitophagy. • Microglial cells are pivotal in the pathogenesis of neuropathic pain. • Improving mitochondrial autophagy could alleviate pain signal transmission. • GB is effective in alleviating chronic neuropathic pain by mitigating the production of inflammatory mediators. • Ginkgo biloba as a promising neuroprotective agent for alleviating neuralgia. [ABSTRACT FROM AUTHOR]

The glymphatic system plays a crucial role in maintaining optimal central nervous system (CNS) function by facilitating the removal of metabolic wastes. Aquaporin-4 (AQP4) protein, predominantly located on astrocyte end-feet, is a key pathway for metabolic waste excretion. β-Dystroglycan (β-DG) can anchor AQP4 protein to the end-feet membrane of astrocytes and can be cleaved by matrix metalloproteinase (MMP)-9 protein. Studies have demonstrated that hyperglycemia upregulates MMP-9 expression in the nervous system, leading to neuropathic pain. Ginkgolide B (GB) exerts an inhibitory effect on the MMP-9 protein. In this study, we investigated whether inhibition of MMP-9-mediated β-DG cleavage by GB is involved in the regulation of AQP4 polarity within the glymphatic system in painful diabetic neuropathy (PDN) and exerts neuroprotective effects. The PDN model was established by injecting streptozotocin (STZ). Functional changes in the glymphatic system were observed using magnetic resonance imaging (MRI). The paw withdrawal threshold (PWT) was measured to assess mechanical allodynia. The protein expressions of MMP-9, β-DG, and AQP4 were detected by Western blotting and immunofluorescence. Our findings revealed significant decreases in the efficiency of contrast agent clearance within the spinal glymphatic system of the rats, accompanied by decreased PWT, increased MMP-9 protein expression, decreased β-DG protein expression, and loss of AQP4 polarity. Notably, GB treatment demonstrated the capacity to ameliorate spinal cord glymphatic function by modulating AQP4 polarity through MMP-9 inhibition, offering a promising therapeutic avenue for PDN. • Ginkgolide B alleviates spinal glymphatic system dysfunction by inhibiting MMP-9 in PDN rats. • Ginkgolide B alleviates mechanically abnormal pain in PDN rats. • Ginkgolide B has neuroprotective effects on PDN. • MMP-9 specific inhibitor (MMP-9-IN-1) can alleviate mechanically abnormal pain in PDN rats. [ABSTRACT FROM AUTHOR]

The NLR family, pyrin domain containing 3 (NLRP3) inflammasome drives the progression of Alzheimer's disease (AD). Ginkgolide B (GB) is a potential anti-inflammatory compound that controls neuro-inflammation. The aim of this study was to evaluate the effect of GB on the NLRP3 inflammasome in AD. The effect of GB on the conversion between the M1 and M2 microglial phenotype was examined using quantitative real-time PCR and immunostaining. Western blotting assays and ELISA were used to detect changes in neuro-inflammation following GB treatment, including the NLRP3 inflammasome pathway and autophagy. In order to evaluate the cognitive function of male senescence-accelerated mouse prone 8 (SAMP8) mice, behavioral tests, including the Morris water maze and novel object recognition tests, were performed. GB significantly decreased the intracellular pro-inflammatory cytokine levels in lipopolysaccharide-treated BV2 cells and improved cognitive behavior in SAMP8 mice. Moreover, GB deactivated the NLRP3 inflammasome, and this effect was dependent on autophagy. Ubiquitination was associated with GB-induced autophagic NLRP3 degradation. These results were further validated in the hippocampus of SAMP8 mice. Thus, GB exerted a neuroprotective effect on the cognitive function of SAMP8 mice by suppressing the activation of NLRP3 inflammasome via autophagic degradation. [ABSTRACT FROM AUTHOR]

Ginkgolide B (GB) and Puerarin (Pue) are active pharmaceutical ingredients for the treatment of Parkinson’s disease (PD); however, both are poorly water-soluble, which limits their bioavailability. The present study used the niosome vesicle encapsulation technique to prepare a novel GB composite drug. The conditions for GB–Pue niosomal complex preparation were as follows: a hydration temperature of 60°C, a hydrophilic–lipophilic balance of 10.5, a drug–carrier mass ratio of 8:100, and a surfactant–cholesterol mass ratio of 1.5:1. The niosomal complex suspension was uniformly distributed and milky white in color, with no stratification over a duration of 1 month. It had an average particle size of 187.3 nm, a particle-size distribution of 0.237, a GB encapsulation efficiency (EE) of 68.2%, a GB drug-loading rate of 90.1%, a Pue EE of 40.5%, and a Pue drug-loading rate of 83.3%. The optimal storage temperature for the niosomal complex suspension was 4°C. Following an intravenous injection of the niosomal complex suspension into the rat tail, the area under the curve (AUC) from 0 to 4 h was 54.1 h µg mL−1, with a mean residence time (MRT) of 0.96 h, a distribution half-life (T1/2α) of 0.195 h, and a total clearance of 0.003 L h−1 kg−1. The AUC and MRT of the composite prescription were 1.1- and 1.4-times those of the commercial injection, respectively, showing significantly increased sustained release and bioavailability. Moreover, the distribution of GB in the brain tissue was 1.8-times that of the commercial injection. In conclusion, the novel GB niosomal composite drug, with excellent stability, improved pharmacokinetics, and brain tissue distribution, demonstrates great potential for the delivery of GB and Pue for PD therapeutics.

Objective(s): Diabetic cardiomyopathy is a leading factor of high morbidity and mortality in diabetic patients. Our previous results revealed that ginkgolide B alleviates endothelial dysfunction in diabetic rats. This study aimed to investigate the effect of ginkgolide B on cardiac dysfunction and its mechanism in diabetic rats.Materials and Methods: Diabetes was induced in rats through the intraperitoneal injection of streptozotocin (STZ). Hemodynamics was monitored to assess cardiac function. Oxidative stress was examined by detecting levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in serum, and expression of sirtuin (SIRT)1, heme oxygenase (HO)-1, and phosphorylated AMPK in the heart. Masson’s trichrome staining and expression of transforming growth factor (TGF)-β1, smooth muscle actin (α-SMA), and phosphorylated (p-) Smad2 and Smad3 were used to evaluate cardiac fibrosis. Inflammatory cytokine in serum and levels of p-PI3K, p-Akt, p-p38, and p-JNK in the heart were determined.Results: Ginkgolide B significantly improved hemodynamics in diabetic rats. Compared with diabetic rats, treatment with ginkgolide B significantly decreased levels of inflammatory cytokines, improved oxidative stress via reducing MDA concentration, and elevating SOD activity in serum and increasing expression of SIRT1, HO-1, and p-AMPK. Further, ginkgolide B alleviated cardiac fibrosis by decreasing expression of TGF-β1, α-SMA, and p-Smad2 and p-Smad3. Meanwhile, ginkgolide B reduced Levels of p-P38, and p-JNK, and increased levels of p-PI3K and p-Akt.Conclusion: The results suggested that ginkgolide B alleviated cardiac dysfunction by reducing oxidative stress and cardiac fibrosis.

Abstract Background Ginkgolide B (GKB) is a major active component of the extracts of Ginkgo biloba leaves, and it has been used as an anti-cancer agent. However, it is unknown whether GKB has the therapeutic effects on lung cancer. Here, we studied the effects of GKB on lung cancer cells. Methods The effects of GKB on lung cancer cell proliferation and invasion were analyzed by cell counting kit (CCK-8) and cell invasion assays, respectively. Apoptosis was detected by flow cytometry. Western blot analysis was used to confirm the expression of autophagy-associated proteins in GKB-treated cells. Immunofluorescence analysis was used to analyze the level of light chain 3B (LC3B). Results Treatment with GKB time-dependently inhibited the proliferation and decreased the invasive capacity of A549 and H1975 cells. GKB induced apoptosis of these cells, but there was no significant effect on apoptosis compared to the control treatment. GKB-induced inhibition of cell proliferation and GKB-induced cell death were due to autophagy rather than apoptosis. GKB-induced autophagy of lung cancer cells was dependent on beclin-1, and autophagy-induced inhibition of the NLRP3 inflammasome contributed to the anti-tumor effect of GKB. Conclusions GKB-mediated autophagy of lung cancer cells is beclin-1-dependent and results in inhibition of the NLRP3 inflammasome. Therefore, GKB might be a potential therapeutic candidate for the treatment of lung cancer.

Objective: Ginkgolide B (GB) possesses anti-inflammatory, antioxidant, and anti-apoptotic properties against neurotoxicity induced by amyloid beta (Aβ), but the potential neuroprotective effects of GB in Alzheimer’s therapies remain elusive. We aimed to conduct proteomic analysis of Aβ1-42 induced cell injury with GB pretreatment to uncover the underlying pharmacological mechanisms of GB. Methods: Tandem mass tag (TMT) labeled liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to analyze protein expression in Aβ1-42 induced mouse neuroblastoma N2a cells with or without GB pretreatment. Proteins with fold change >1.5 and p < 0.1 from two independent experiments were regarded as differentially expressed proteins (DEPs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to analyze the functional annotation information of DEPs. Two key proteins osteopontin (SPP1) and ferritin heavy chain 1 (FTH1) were validated in another three samples using western blot and quantitative real-time PCR. Results: We identified a total of 61 DEPs in GB treated N2a cells, including 42 upregulated and 19 downregulated proteins. Bioinformatic analysis showed that DEPs mainly participated in the regulation of cell death and ferroptosis by down-regulating SPP1 protein and up-regulating FTH1 protein. Conclusions: Our findings demonstrate that GB treatment provides neuroprotective effects on Aβ1-42 induced cell injury, which may be related to the regulation of cell death and ferroptosis. The research puts forward new insights into the potential protein targets of GB in the treatment of Alzheimer’s disease (AD).

Ginkgo biloba is a medicinal plant used in complementary and alternative medicines. Ginkgo biloba extracts contain many compounds with medical functions, of which the most critical is ginkgolide B (GB). The major role that GB plays is to function as an antagonist to the platelet-activating factor, which is one of the causes of thrombosis and cardiovascular diseases. Currently, GB is obtained mainly through extraction and purification from the leaves of Ginkgo biloba; however, the yield of GB is low. Alternatively, the immobilized cultivation of ginkgo calluses with biomaterial scaffolds and the addition of organic elicitors to activate the cell defense mechanisms were found to stimulate increases in GB production. The aim of this study was to use Ginkgo biloba calluses for immobilized cultures with different elicitors to find a more suitable method of ginkgolide B production via a recycling process.

Alzheimer's disease (AD) is a destructive neurodegenerative disease that currently has no effective treatment option available. Ginkgolide B (GB) is a terpene lactone derivative of Ginkgo biloba that possesses neuroprotective effects in various diseases. The aim of the present study was to investigate whether GB protects against cognitive impairment in AD by mitigating oxidative stress, inflammation and ferroptosis using senescence-accelerated P8 (SAMP8) mice. The results showed that GB improved the cognitive dysfunction of SAMP8 mice in the Morris water maze and novel object recognition test, which was associated with the attenuation of oxidative stress, inflammation and nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (GPX4) pathway-mediated ferroptosis. Furthermore, Ras-selective lethal small molecule 3, a GPX4 inhibitor and ferroptosis inducer, compromised GB-induced cognitive performance in SAMP8 mice. These findings suggested that GB alleviated AD-induced cognitive defects by mitigating oxidative stress, neuroinflammation and ferroptosis, and that the inhibition of ferroptosis is required for GB to have beneficial effects in AD. • Ginkgolide B attenuates cognitive dysfunction in SAMP8 mice. • Ginkgolide B mitigates oxidative stress, inflammation and GXP4-mediated ferroptosis in SAMP8 mice. • GPX4 inhibition abolishes Ginkgolide B-induced cognitive enhancement. [ABSTRACT FROM AUTHOR]

Activation of NOD-like receptor protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of neuropathic pain. Ginkgolide B contributes to the suppression of NLRP3 inflammasome activation to prevent hypoxic-ischemic brain injury. However, the role of ginkgolide B on neuropathic pain has not been reported yet. We have shown that administration of ginkgolide B lowered pain threshold measured by paw-withdrawal threshold and paw-withdrawal latency in rats subjected to chronic constriction injury. Nerve fibers in rats postchronic constriction injury were swollen, and the fibrous structure was disordered. Treatment with ginkgolide B attenuated the nerve fiber swelling and reduced the disordered fibrous structure. Ginkgolide B dosage dependently attenuated chronic constriction injury-induced increase of proinflammatory cytokines. Protein expression of NLRP3 and its downstream targets (caspase 1 and IL-1β) were increased by chronic constriction injury and reduced by ginkgolide B. Lastly, ginkgolide B counteracted with the promotive effects of chronic constriction injury on protein expression of TLR4 and p-NF-κB. In conclusion, ginkgolide B demonstrated anti-inflammatory and antinociceptive effects in rats’ model with neuropathic pain by suppression of TLR4-NF-κB-mediated NLRP3 inflammasome activation. [ABSTRACT FROM AUTHOR]

The therapeutics used to promote perforator flap survival function induces vascular regeneration and inhibit apoptosis. The present study aimed to explore the potential mechanism of the angiogenesis effects of Ginkgolide B (GB) in perforator flaps. Methods: A total of 72 rats were divided into three groups and treated with saline, GB, or GB + tunicamycin (TM; ER stress activator) for seven consecutive days, respectively. Apoptosis was assayed by determining the Bax/Bcl-2 ratio and caspase-3 level. Endoplasmic reticulum (ER) stress markers (CHOP, GRP78, and caspase-12) were detected by Western blot analysis. Oxidative stress was assessed by measuring the superoxide dismutase activity (SOD) and malondialdehyde (MDA), heme oxygenase-1(HO-1), and nuclear factor erythroid-2-related factor 2 (Nrf2) mRNA levels in the flaps. The percentage flap survival area and blood flow were assessed on postoperative day (POD) 7. Angiogenesis was visualized by hematoxylin and eosin and CD34 staining on POD 7. Results: GB increased the survival of perforator flaps, the flap survival area of GB, GB + TM, and control groups was 90.83 ± 1.93%, 70.93 ± 4.13%, and 62.97 ± 6.50%. GB decreased the Bax/Bcl-2 ratio and caspase-3 level. ER stress-related proteins were downregulated by GB. GB also decreased the MDA level and increased SOD activity, HO-1 and Nrf2 mRNA levels in the flaps. Further, GB induced regeneration of vascular vessels in comparison with saline or GB + TM. Conclusions: GB increased angiogenesis and alleviated oxidative stress by inhibiting ER stress, which increased the survival of perforator flaps. In contrast, GB + TM alleviated angiogenesis and induced oxidative stress by activating ER stress and decreasing the survival of perforator flaps. [ABSTRACT FROM AUTHOR]

This research delves into the effectiveness of Ginkgolide B (GB), a compound from Ginkgo biloba, in combating cell death caused by glaucoma, with a focus on mitochondrial impairment and the mitochondrial permeability transition pore (mPTP). Utilizing models of high intraocular pressure and in vitro glaucoma simulations, the study investigates GB's impact on retinal progenitor cells (RPCs) under oxygen-glucose deprivation/reperfusion (OGD/R) and in a rat glaucoma model. The study methodologies included apoptosis assessment, apoptotic marker analysis via Western blot, and mitochondrial structure and function evaluation. The findings reveal that GB notably decreases apoptosis in RPCs exposed to OGD/R in vitro, and reduces ischemia-reperfusion damage in vivo. GB's protective role is attributed to its ability to preserve mitochondrial integrity, maintain membrane potential, regulate calcium levels, and inhibit mPTP opening. These results underscore GB's potential as a therapeutic agent for acute primary angle-closure glaucoma, highlighting its capability to alleviate mitochondrial damage and apoptosis in RPCs and retinal nerve fiber layer cells. • Ginkgolide B can reduce OGD/R indued Retinal Progenitor Cells' apoptosis. • Ginkgolide B impacts on Retinal Progenitor Cells via inhibiting the opening of Mitochondrial Permeability Transition Pore. • GB is expected to be a protective agent against retinal ischemia-reperfusion injury by attenuating apoptotic damage in RNFL. [ABSTRACT FROM AUTHOR]

Thromboxane A 2 (TXA 2) is traditionally known for its role in inducing platelet aggregation, but our previous study has discovered its crucial involvement in hepatic glucolipid metabolism and adipose tissue inflammation. Ginkgolide B (GB), a naturally occurring terpene lactone, possesses various pharmacological functions through its antagonism of the platelet activating factor (PAF) receptor. However, the metabolic regulation mechanism link between the anti-obesity efficiency of GB and TXA 2 has remained elusive. Therefore, this research aimed to explore the potential of GB in protecting against obesity by inhibiting TXA 2 synthesis. The results showed that GB inhibited TXA 2 biosynthesis which shares a similar action with eicosapentaenoic acid (EPA) and aspirin. GB treatment ameliorated hyperglycemia by decreasing gluconeogenesis. Additionally, GB supplementation relieved hepatic lipid deposition and dyslipidemia. Furthermore, GB intervention promoted macrophage M2 polarization, thus mitigating adipose tissue inflammation. In summary, our study provided evidence that GB alleviated glucolipid metabolism disorders and adipose tissue inflammation through the inhibition of the TXA 2 pathway. These findings shed light on the mechanism underlying the anti-obesity efficacy of GB and lay foundations for the future use of GB as a functional dietary supplement to alleviate high-fat diet-induced obesity. [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, we introduce a method to formulate Ginkgolide B lipid microemulsion (GB-LM). We have assessed its general characteristics and pharmacokinetics in animals. Soybean oil (10.0%) and oleic acid (2.4%) were chosen as the oil phase, refined egg yolk lecithin (PC98T) (1.8%) as the surfactant, and glycerol (2.25%) as the co-surfactant. The optimized formulation process resulted in particles with average diameter of 185.9 ± 52.5 nm and the zeta potential of −19.8 ± 1.3 mV. The GB-LM remained steady for three months at room temperature. Giving each dose of 4 mg/kg to rats through the vein, a clearance rate of CL (L/h): 2.594 and C max (ng/mL) was achieved: 353.8 through pharmacokinetic analysis and statistical analysis. The AUC of GB-LM was about 1.57-fold higher than that of the products available in the market. In addition, brain tissue distribution studies show that after 0.5 h administration of GB, the concentration of GB in brain tissue can reach its maximum, and then significantly decrease after 2 hours. Therefore, the improved formulation of GB-LM shows encouraging results compared with present products in several features.

Objective(s): The aim of this study is to explore the potential neuroprotective effects of Ginkgolide B (GB), a main terpene lactone and active component in Ginkgo biloba, in hypoxia-induced neuronal damage, and to further investigate its possible mechanisms.Materials and Methods: 54 Sprague-Dawley rats were randomly divided into three groups: the untreated control group (n=18); the hypoxia group (n=18; exposed to 6000 m simulated plateau altitude for six days); and the GB group (n=18; intragastric administration of 12 mg/kg GB three days prior to rapid adaption to 6000 m and on the first two days of hypoxia). After hypoxia exposure for six days, we dissected out the brain hippocampi and performed hematoxylin and eosin staining, Nissl staining, and TUNEL staining. Homogenates of the hippocampi were used to test the oxidative stress indices including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and catalase. Bax and caspase-3 expression in the hippocampal tissue was measured using qRT-PCR.Results: Treatment with GB before exposure to hypoxia could protect neural cells and increase the number of Nissl bodies. TUNEL and qRT-PCR results demonstrated that GB treatment could decrease apoptotic cells in different areas of the hippocampus. Antioxidant defense systems such as SOD, GSH, and catalase were decreased (P

Stem cell transplantation has brought new hope for the treatment of neurological diseases. The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells. Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors, the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located. Accordingly, the optimal microenvironment for inducing stem cell differentiation is a hot topic. EGb761 is extracted from the leaves of the Ginkgo biloba tree. It is used worldwide and is becoming one of the focuses of stem cell research. Studies have shown that EGb761 can antagonize oxygen free radicals, stabilize cell membranes, promote neurogenesis and synaptogenesis, increase the level of brain-derived neurotrophic factors, and replicate the environment required during the differentiation of stem cells into nerve cells. This offers the possibility of using EGb761 to induce the differentiation of stem cells, facilitating stem cell transplantation. To provide a comprehensive reference for the future application of EGb761 in stem cell therapy, we reviewed studies investigating the influence of EGb761 on stem cells. These started with the composition and neuropharmacology of EGb761, and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.

Osteoporosis is characterized by reductions in bone mass, which could be attributed to the dysregulation of bone homeostasis, such as the loss of balance between bone-resorbing osteoclasts and bone-forming osteoblasts. Elevated levels of oxidative stress increase bone resorption by promoting osteoclastogenesis and inhibiting the osteogenesis. Ginkgolide B (GB), a small natural molecule from Ginkgo biloba , has been reported to possess pharmacological activities by regulating reactive oxygen species (ROS) in aging-related degenerative diseases. Herein, we assessed the therapeutic effects of GB on the bone phenotypes of mice with osteoporosis induced by (I) aging, (II) ovariectomy, and (III) glucocorticoids. In all three animal models, oral gavage of GB significantly improved bone mass consistent with the increase in the OPG-to-RANKL ratio. In the in vitro experiments, GB promoted osteogenesis in aged mesenchymal stem cells (MSCs) and repressed osteoclastogenesis in aged macrophages by reducing ROS. The serum protein profile in GB-treated aged mice revealed moderate rejuvenating effects; signaling pathways associated with ROS were also regulated. The anabolic and anti-catabolic effects of GB were illustrated by the reduction in ROS. Our results indicate that GB is effective in treating osteoporosis. The use of GB in patients with osteoporosis is worthy of further clinical investigation. [Display omitted] • Oral gavage of GB protects bone in aging, postmenopausal, iatrogenic osteoporotic conditions and steady-state conditions. • GB regulates bone homeostasis by upregulating ROS scavengers in aged mesenchymal stem cells. • GB prevents oxidative stress-induced osteoclastogenesis in aged macrophages. [ABSTRACT FROM AUTHOR]

The present study was undertaken to identify whether prostaglandin E2 receptor is the potential receptor/binding site for Ginkgolide A, Ginkgolide B, Ginkgolide K, and Bilobalide, the four main ingredients of the Ginkgo biloba L., leaves. Using functional assays, we identified EP4, coupled with Gs protein, as a target of Ginkgolide B. In human neuroblastoma SH‐SY5Y cells suffered from oxygen–glucose deprivation/reperfusion, Ginkgolide B‐activated PKA, Akt, and ERK1/2 as well as Src‐mediated transactivation of epidermal growth factor receptor. These resulted in downstream signaling pathways, which enhanced cell survival and inhibited apoptosis. Knockdown of EP4 prevented Ginkgolide B‐mediated Src, epidermal growth factor receptor (EGFR), Akt, and ERK1/2 phosphorylation and neuroprotective effects. Moreover, Src inhibitor prevented Ginkgolide B‐mediated EGFR transactivation and the downstream Akt and ERK1/2 activation, while the phosphorylation of PKA induced by Ginkgolide B was not affected, indicating Ginkgolide B might transactivate EGFR in a ligand‐independent manner. EP4 knockdown in a rat middle cerebral artery occlusion (MCAO) model prevented Ginkgolide B‐mediated infarct size reduction and neurological assessment improvement. At the same time, the increased expressions of p‐Akt, p‐ERK1/2, p‐PKA, p‐Src, and p‐EGFR and the deceased expression of cleaved capases‐3 induced by Ginkgolide B in cerebral cortex were blocked due to EP4 knockdown. In conclusion, Ginkgolide B exerts neuroprotective effects in rat MCAO model through the activation of EP4 and the downstream transactivation of EGFR. [ABSTRACT FROM AUTHOR]