PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 µM) significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3ß/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

Association of Antipsychotic Drugs with Venous Thromboembolism: Data Mining of Food and Drug Administration Adverse Event Reporting System and Mendelian Randomization Analysis.

AIMS: Past observational studies have reported on the association between antipsychotic drugs and venous thromboembolism (VTE); however, the conclusions remain controversial, and its mechanisms are yet to be fully understood. Thus, in this study, we aim to determine the associations of antipsychotic drugs with VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), and their potential mechanisms. METHODS: We first mined the adverse event signals of VTE, DVT, and PE caused by antipsychotic drugs in Food and Drug Administration Adverse Event Reporting System (FAERS). Next, we used two-sample Mendelian randomization (MR) method to investigate the association of antipsychotic drug target gene expression with VTE, DVT, and PE, using single-nucleotide polymorphisms as genetic instruments. We not only used the expression of all antipsychotic drug target genes as exposure to perform MR analyses but also analyzed the effect of single target gene expression on the outcomes. RESULTS: In the FAERS, 1694 cases of VTE events were reported by 16 drugs. However, using the MR approach, no significant association was determined between the expression of all antipsychotic target genes and VTE, DVT, or PE, either in blood or brain tissue. Although the analysis of single gene expression data showed that the expression of nine genes was associated with VTE events, these targets lacked significant pharmacological action. CONCLUSIONS: Adverse event mining results have supported the claim that antipsychotic drugs can increase the risk of VTE. However, we failed to find any genetic evidence for this causal association and potential mechanisms. Thus, vigilance is still needed for antipsychotic drug-related VTE despite the limited supporting evidence.

A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.

Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems. Methods: Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD. Findings: IBRAIN accurately differentiated individuals with AD from NCs (AUC = 0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC = 0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR) = 6.52 [95% CI: 4.42∼9.62], p < 1 × 10-16), which offers similar powerful performance with Cerebrospinal Fluid (CSF) Aß (HR = 3.78 [95% CI: 2.63∼5.43], p = 2.13 × 10-14) and CSF Tau (HR = 3.77 [95% CI: 2.64∼5.39], p = 9.53 × 10-15) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta = -0.70, p < 1 × 10-16) in capturing longitudinal changes in individuals with conversion to AD than CSF Aß (beta = -0.26, p = 4.40 × 10-9) and CSF Tau (beta = 0.12, p = 1.02 × 10-5). Interpretation: Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials. Funding: Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.

Gut microbiota in Chinese and Japanese patients with cardiovascular diseases: a systematic review and meta-analysis.

BACKGROUND: Cardiovascular disease (CVD) is a major threat to public health. OBJECTIVE: Compare the gut microbial composition between Chinese and Japanese patients with cardiovascular diseases and healthy subjects. STUDY SELECTION: Observational studies with Chinese and Japanese populations. Reviews, duplicate, book chapters, and other irrelevant studies were excluded. DATA EXTRACTION: Independent searching by two investigators (LLJ, HJL). DATA SYNTHESIS: Data from eleven studies (with 960 subjects) were included for the meta-analysis. The meta-analysis showed that the abundance of Firmicutes in patients with cardiovascular disease was [ES=0.42, 95%CI, (0.34, 0.50), P<.01], while the abundance of Firmicutes in control subjects was [ES=0.36, 95%CI, (0.23, 0.49), P<.01] (ES: effect size). When compared to control subjects, the differential expression of Firmicutes abundance in patients with CVDs was [MD = 15.21, 95%CI (8.95, 21.48), P<.01] (MD: mean difference). The ratio of Firmicutes abundance in patients with CVDs to the control subjects was [RR=1.28, 95%CI (0.98, 1.67), P=.07]. The ratio of Firmicutes in coronary heart disease (CHD) patients and controls was [RR=1.42, 95%CI (1.05, 1.94), P=.02]. Firmicutes/Bacteroidetes ratio is [OR=1.64 95%CI (1.11, 2.42), P=.01]. CONCLUSION: Our data show that patients with cardiovascular disease had higher levels of gut Firmicutes when compared to healthy controls. In addition, gut microbial dysbiosis was present in patients with cardiovascular diseases. LIMITATIONS: Due to limited quality and quantity of selected studies, conclusions from the current study need to be validated by future studies. CONFLICT OF INTEREST: None.

Drug-induced kidney injury in Chinese critically ill pediatric patients.

Background: Drug-induced acute kidney injury (DIKI) is a common adverse drug reaction event but is less known in pediatric patients. The study explored the DIKI in Chinese pediatric patients using the Pediatric Intensive Care database (PIC). Method: We screened pediatric patients with acute kidney injury (AKI) using the KDIGO criteria from the PIC and then assessed the relationship between their drugs and DIKI using the Naranjo scale. For the fifteen frequently used DIKI-suspected drugs, we divided patients into drug-exposed and non-exposed groups, using the outcome of whether DIKI was presented or not. Propensity score matching (PSM) was used to control for the effects of four confounders, age, gender, length of hospital stay, and major diagnosis. Unconditional logistic regression was used to identify statistically significant differences between the two groups. Results: A total of 238 drugs were used 1,863 times by the 81 patients with DIKI during their hospital stay. After screening the Naranjo scale to identify the top 15 suspected DIKI drugs with a high frequency of use, we found that furosemide injection (p = 0.001), midazolam injection (p = 0.001), 20% albumin prepared from human plasma injection (p = 0.004), fentanyl citrate injection (p = 0.001), compound glycyrrhizin injection (p = 0.026), vancomycin hydrochloride for intravenous (p = 0.010), and milrinone lactate injection (p = 0.009) were associated with DIKI. Conclusion: In critically ill pediatric patients, DIKI is more likely to occur after using furosemide injection, midazolam injection, 20% albumin prepared from human plasma injection, fentanyl citrate injection, compound glycyrrhizin injection, vancomycin hydrochloride for intravenous, milrinone lactate injection.

Clinically Significant Cytochrome P450-Mediated Drug-Drug Interactions in Children Admitted to Intensive Care Units.

Objectives: Children admitted to intensive care units (ICUs) often require multiple medications due to the complexity and severity of their disease, which put them at an increased risk for drug interactions. This study examined cytochrome P450-mediated drug-drug interactions (DDIs) based on the Pediatric Intensive Care (PIC) database, with the aim of analyzing the incidence of clinically significant potential drug-drug interactions (pDDIs) and exploring the occurrence of actual adverse reactions. Methods: The Lexicomp database was used to screen cytochrome P450-mediated DDI pairings with good levels of reliability and clear clinical phenotypes. Patients exposed to the above drug pairs during the same period were screened in the PIC database. The incidence of clinically significant pDDIs was calculated, and the occurrence of adverse reactions was explored based on laboratory measurements. Results: In total, 84 (1.21%) of 6920 children who used two or more drugs were exposed to at least one clinically significant pDDI. All pDDIs were based on CYP3A4, with nifedipine + voriconazole (39.60%) being the most common drug pair, and the most frequent being the J02 class of drugs. Based on laboratory measurements, 15 adverse reactions were identified in 12 patients. Conclusions: Clinically significant cytochrome P450-mediated pDDIs existed in the children admitted to ICUs, and some of the pDDIs led to adverse clinical outcomes. The use of clinical decision support systems can guide clinical medication use, and clinical monitoring of patients' needs has to be enhanced.

Proximity hybridization induced DNA assembly for label-free surface-enhanced Raman spectroscopic detection of carcinoembryonic antigen.

In our research, label-free and surface-enhanced Raman dyes-free Raman spectroscopy which was used to detect carcinoembryonic antigen (CEA) according to poly adenine (Poly A)-regulated self-assembly methods was developed and studied. CEA induced partial hybridization of Ab-H2 and Ab-H1, and Ab-H1-CEA-Ab-H2 (a sandwich proximity CEA-DNA complex) was formed, which unfolded molecular beacon 1 (MB1) and modified the substrate. Subsequently, MB2-AuNPs were hybridized with MB1, and Ab-H1-CEA-Ab-H2 was released via toehold regulated displacements of DNA strands. Therefore, hybridization processes of MB2 and MB1 were induced and promoted by CEA-DNA complexes which worked as catalysts. The misplaced target then induced a next round of strand exchange, and the signals for determination of CEA were amplified by AuNPs absorbed on the substrate. It was indicated that the spectral characteristics of adenine at 736 cm-1 were consistent with the SERS spectrum of DNA. Adenine acted as an internal marker for label-free SERS detection of CEA. Moreover, satisfactory stability and reproducibility were found. Meanwhile, the antibody could specifically recognize the corresponding antigen. Since adenine was dominant in SERS spectra, which was also proximal to Au surface, the sensitivity of the novel method was high without modifications. The analytical performance of this method in determining serum CEA was satisfactory.

A Survey of Pharmacogenomics Testing Among Physicians, Pharmacists, and Researchers From China.

To elucidate current domestic factors influencing pharmacogenomics (PGx) implementation and its future in China, we conducted a questionnaire survey on PGx applications and testing. A questionnaire-based survey was created on the popular online professional survey platform "Wenjuanxing" (www.wjx.cn) and performed via the social media platform WeChat. Among 422 participants, there were physicians (27.7%), pharmacists (31.3%), and researchers (41.0%). We found that less than 50% of physicians were aware of the importance of PGx in drug therapy, while over 50% of pharmacists and researchers recognized the importance. Only 38.5% of physicians, 40.9% of pharmacists, and 55.5% of researchers concurred that PGx analysis could lower the economic burdens for patients. However, most of the responders affirmed that PGx should be effectively implemented in clinical practices. A lack of sector standards, a lack of clinical research, and a lack of guidelines were found to be the major factors for hindering PGx clinical application. Among drugs associated with PGx assays, the most common were warfarin and clopidogrel. Although PGx research has advanced rapidly in recent years in mainland China, the clinical implementation of PGx has a long way to go.

Neuroprotective effects of Hemocoagulase Agkistrodon on experimental traumatic brain injury.

Traumatic brain injury (TBI) is the major cause of disability and mortality among young people and is associated with neurodegenerative diseases. However, the available clinical options have limited effectiveness. Here, we investigated the neuroprotective effect of Hemocoagulase Agkistrodon (HCA), a thrombin-like enzyme (TLE) isolated and purified from snake venom. Rats subjected to experimental TBI were administered a single dose of HCA or vehicle 10 min after injury. Neurological function was assessed with modified neurological severity score (mNSS). Brain edema were evaluated by measuring brain water content. Levels of hemoglobin and inflammatory cytokines were detected by Enzyme-linked immunosorbent assay (ELISA). In addition, assays including Evans blue extravasation, Western blot analysis and immunofluorescence staining were utilized to determined blood-brain barrier (BBB) integrity. Our results showed that HCA treatment ameliorated neurological deficits (p < 0.01), alleviated brain edema (p < 0.01) and hemorrhage (p < 0.01), decreased the production of the proinflammatory cytokines IL-1ß (p < 0.01), TNF-α (p < 0.01) and IL-6 (p < 0.05), and increased the anti-inflammatory cytokine IL-10 at the contusion site (p < 0.01). Moreover, HCA administration reduced BBB disruption by regulating expression of tight junction proteins, including ZO-1, occludin and claudin-5 (ps < 0.01). Together, our results demonstrate that HCA might have therapeutic efficacy in acute TBI, suggesting a potential clinical application for mitigating the neuropathological damage associated with TBI.

Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method.

Purpose: Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China. Methods: Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). At the same time, we also collated drug combinations that may affect CYP (Cytochrome P) enzyme metabolism, which may cause DILI. Results: A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while the hepatic injury types of children were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the RUCAM assessment, the drugs that were most considered to cause or be associated with hepatic injury in newborns were medium and long chain fat emulsions (17%), sodium glycerophosphate (12%), and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%), and meropenem (8%) were the primary culprits of DILI in children. Drug combinations frequently seen in neonates that may affect CYP enzyme metabolism are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%), and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%), and diazepam + omeprazole (15.3%). Conclusions: In this study, medium and long chain fat emulsions and sodium glycerophosphate have been strongly associated with DILI in newborns, while omeprazole and methylprednisolone sodium succinate play an important role in the DILI of children. Also, attention should be paid to the effect on CYP enzymes when using multiple drugs at the same time. In future DILI cases, it is advisable to use the latest RUCAM for prospective study design so that complete case data and high RUCAM scores can be collected.

L-3-n-Butylphthalide improves synaptic and dendritic spine plasticity and ameliorates neurite pathology in Alzheimer's disease mouse model and cultured hippocampal neurons.

Alzheimer's disease (AD) is the most common cause of dementia among elderly people. Despite enormous efforts, the pathogenesis of AD still remains unclear and no drug has yet been proved to be disease-modifying. As the basis of learning and memory, the plasticity of synapse and dendritic spine has been impaired during AD progression. Previous studies have showed a protective effect of L-3-n-butylphthalide (L-NBP) on cognitive deficits in AD, we wonder whether this protective effect is associated with positive alterations on synapse and dendritic spines. In this study, we first of all confirmed the anti-dementia effect of L-NBP in 13-month-old APP/PS1 mice, and then investigated the alterations in synaptic and dendritic spine plasticity due to L-NBP treatment both in vivo and in vitro. We also conducted preliminary studies and found the possible mechanisms related to the inhibition of over-activated complement cascade and the remodeling of actin cytoskeleton. Besides, we also found extra benefits of L-NBP on presynaptic dystrophic neurites and attempted to give explanations from the view of autophagy regulation. Taken together, our study added some new evidence to the application of L-NBP in AD treatment and provided deeper insight into the relevant mechanisms for future study.

Molecular mechanisms of mitophagy and its roles in neurodegenerative diseases.

Neurodegenerative diseases are the most common diseases of the nervous system in elderly people, which are currently incurable and cause great burden to families and societies. Mitochondria are the energy factory of the cell and have extremely important effects on neuronal function. The elimination of dysfunctional mitochondria is essential for the mitochondrial metabolic homeostasis, energy supply, and neuronal survival. Recent studies suggest that the impaired mitophagy may lead to the accumulation of damaged mitochondria and therefore contribute to the progression of neurodegenerative diseases. This review mainly focuses on mitophagy, mitochondrial dynamics, and their abnormal changes in neurodegenerative diseases, as well as the therapeutic strategies targeting mitophagy that have shown promise in recent preclinical and clinical studies.

The MMP-2/TIMP-2 System in Alzheimer Disease.

Alzheimer Disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include Amyloid ß-protein (Aß) plaques and Neurofibrillary Tangles (NFTs), as well as extensive neuronal and synaptic loss. Matrix Metalloproteinase-2 (MMP-2) is a neutral, zinc-dependent protease that primarily targets extracellular matrix proteins. MMP-2 activity is strictly controlled, and its dysregulation has been implicated in a variety of pathologies, including AD. In this brief review, we discussed the contributions of dysregulated MMP-2 activity and an imbalanced interaction between MMP-2 and its endogenous inhibitor, Tissue Inhibitors of Metalloproteinase-2 (TIMP-2), to AD. We also described the underlying mechanisms of the effects of MMP-2/TIMP-2, both beneficial and detrimental, on AD, including: (1) MMP-2 directly degrades Aß resulting in the clearance of Aß deposits. Conversely, Aß-induced MMP-2 may contribute to brain parenchymal destruction. (2) MMP-2 induces breakdown of BBB, and this deleterious effect could be reversed by TIMP-2. (3) MMP-2 disrupts oxidative homeostasis in AD. (4) MMP-2 has both proinflammatory/pro-angiogenetic and antiinflammatory/ anti-angiogenetic effects on AD. Besides, we discuss the clinical utility of MMP- 2/TIMP-2 as therapeutic targets for AD.

TIMP1 preserves the blood-brain barrier through interacting with CD63/integrin ß 1 complex and regulating downstream FAK/RhoA signaling.

Blood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability are hallmark features of several neurological disorders, including traumatic brain injury (TBI). However, there is no viable therapeutic strategy to rescue BBB function. Tissue inhibitor of metalloproteinase-1 (TIMP1) has been considered to be beneficial for vascular integrity, but the molecular mechanisms underlying the functions of TIMP1 remain elusive. Here, we report that TIMP1 executes a protective role on neuroprotective function via ameliorating BBB disruption in mice with experimental TBI. In human brain microvessel endothelial cells (HBMECs) exposed to hypoxia and inflammation injury, the recombinant TIMP1 (rTIMP1) treatment maintained integrity of junctional proteins and trans-endothelial tightness. Mechanistically, TIMP1 interacts with CD63/integrin ß1 complex and activates downstream FAK signaling, leading to attenuation of RhoA activation and F-actin depolymerization for endothelial cells structure stabilization. Notably, these effects depend on CD63/integrin ß1 complex, instead of the MMP-inhibitory function. Together, our results identified a novel MMP-independent function of TIMP1 in regulating endothelial barrier integrity. Therapeutic interventions targeting TIMP1 and its downstream signaling may be beneficial to protect BBB function following brain injury and neurological disorders.

Protective effect of potassium 2-(l-hydroxypentyl)-benzoate on hippocampal neurons, synapses and dystrophic axons in APP/PS1 mice.

RATIONALE: As the hub of memory and space, hippocampus is very sensitive to a wide variety of injuries and is one of the earliest brain structures to develop neurodegenerative changes in AD. Previous research has showed a protective effect of potassium 2-(l-hydroxypentyl)-benzoate (PHPB) on cognitive deficits in animal models of AD. However, it is unclear whether this protective effect is associated with hippocampal alterations. OBJECTIVES: The present study was conducted to evaluate the protective effect of PHPB on hippocampal neurodegenerative changes in middle-aged APP/PS1 mice. METHODS: Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups. PHPB-treated APP/PS1 group received 30 mg/kg PHPB by oral gavage once daily for 12 weeks. Wild-type group and APP/PS1 group received the same volume of water alone. Twelve weeks later, mice (13-month-old) were tested for in vivo 1H-MRS examination and then sacrificed for subsequent biochemical and pathological examinations using transmission electron microscopy, Golgi staining, immunohistochemistry, and western blotting. RESULTS: We found that PHPB treatment significantly improved the micromorphology of hippocampal neurons and subcellular organelles, ameliorated synapse loss and presynaptic axonal dystrophy, increased hippocampal dendritic spine density and dendritic complexity, enhanced the expression of hippocampal synapse-associated proteins, and improved hippocampal metabolism in middle-aged APP/PS1 mice. CONCLUSIONS: Our study showed for the first time the protective effect of PHPB on hippocampal neurons, synapses, and dystrophic axons in APP/PS1 mice, which to some extent revealed the possible mechanism for its ability to improve cognition in animal models of AD.

Hsp90ß inhibitors prevent GLT-1 degradation but have no beneficial efficacy on absence epilepsy.

The loss of glutamate transporter-1 (GLT-1) is associated with temporal lobe epilepsy (TLE). A recent study reported that Hsp90ß interacted with GLT-1 and recruited it to 20S proteasome for degradation. Therefore, inhibiting Hsp90ß may be a new strategy for treating epilepsy. So far, no studies have shown whether the inhibition of Hsp90ß had therapeutic effects on absence epilepsy. Using a model of absence epilepsy, we demonstrated that 17-allylamino-17-demethoxygeldanamycin (17AAG) and Ganetespib (STA9090) had no therapeutic effect. Although this is a negative result, it also has a meaningful exploration value for whether Hsp90 inhibitors have therapeutic effects on other epilepsy types.

Protective Effects of L-3-n-Butylphthalide Against H2O2-Induced Injury in Neural Stem Cells by Activation of PI3K/Akt and Mash1 Pathway.

It has been reported that oxidative stress could result in damage to the developing brain. L-3-n-butylphthalide (L-NBP) could inhibit neuronal cell apoptosis and has neurogenesis effect in different animal and cellular models. However, whether L-NBP could protect the process of neurogenesis in neural stem cells (NSCs) against oxidative stress injury is still unclear. Here, in the present study, we evaluated the neuroprotective effect of L-NBP in NSCs against H2O2-induced injury and the possible mechanisms. The results showed that L-NBP elevated the proliferation of NSCs by upregulating cyclin D1, and PI3K/Akt might be a possible target in this process. Subsequently, L-NBP was found to promote the migration of NSCs and N-cadherin might be involved in. NSC differentiation was measured using immunofluorescence staining and the results demonstrated that L-NBP could promote the NSCs to differentiate more into neurons. The elevation of achaete-scute homolog1 (Mash1) expression might be a key factor as attenuation of endogenous Mash1 expression by short-interfering RNA could block L-NBP-promoted neuronal differentiation. In summary, L-NBP exerts protective effects in NSCs against H2O2-induced injury by promoting the proliferation, migration and neural differentiation of NSCs, indicating that L-NBP might be a potential therapeutic agent for the neurogenesis-based treatment for some brain diseases, such as Alzheimer's disease (AD).

From stroke to neurodegenerative diseases: The multi-target neuroprotective effects of 3-n-butylphthalide and its derivatives.

Discovering effective agents to slow or stop neurodegeneration is a challenging task. Over decades, only a few drugs were approved by Food and Drug Administration (FDA) and most ended in failure. The lessons learned have switched the strategy of drug discovery from designing highly selective ligands to a network pharmacology approach. This enables many natural products like butylphthalide (NBP) once again to be regarded as a valuable source of leads for drug discovery. In this review, we first start with the neuroprotective effects of NBPs on acute ischemic stroke, and later spread to their applications in major neurodegenerative diseases. The underlying mechanisms are also discussed in order to provide a direction for further study. Hopefully, this review could bring some new insights for drug development in this struggling field.

Dl-3-n-Butylphthalide (NBP): A Promising Therapeutic Agent for Ischemic Stroke.

BACKGROUND AND OBJECTIVE: Stroke is a leading cause of morbidity and mortality in both developed and developing countries all over the world. The only drug for ischemic stroke approved by FDA is recombinant tissue plasminogen activator (rtPA). However, only 2-5% stroke patients receive rtPAs treatment due to its strict therapeutic time window. As ischemic stroke is a complex disease involving multiple mechanisms, medications with multi-targets may be more powerful compared with single-target drugs. Dl-3-n-Butylphthalide (NBP) is a synthetic compound based on l-3-n- Butylphthalide that is isolated from seeds of Apium graveolens. The racemic 3-n-butylphthalide (dl- NBP) was approved by Food and Drug Administration of China for the treatment of ischemic stroke in 2002. A number of clinical studies indicated that NBP not only improved the symptoms of ischemic stroke, but also contributed to the long-term recovery. The potential mechanisms of NBP for ischemic stroke treatment may target different pathophysiological processes, including anti-oxidant, antiinflammation, anti-apoptosis, anti-thrombosis, and protection of mitochondria et al. Conclusion: In this review, we have summarized the research progress of NBP for the treatment of ischemic stroke during the past two decades.

L-3-n-Butylphthalide Regulates Proliferation, Migration, and Differentiation of Neural Stem Cell In Vitro and Promotes Neurogenesis in APP/PS1 Mouse Model by Regulating BDNF/TrkB/CREB/Akt Pathway.

Alzheimer's disease (AD) is characterized by extracellular accumulation of ß-amyloid peptides (Aß) and intracellular neurofibrillary tangles, along with cognitive decline and neurodegeneration. The cognitive deficit is considered to be due to the dysfunction of hippocampal neurogenesis. Although L-3-n-butylphthalide (L-NBP) has been shown beneficial effects in multiple AD animal models, the underlying molecular mechanisms are still elusive. In this study, we investigated the effects of L-NBP on neurogenesis both in vitro and in vivo. L-NBP promoted proliferation and migration of neural stem cells and induced neuronal differentiation in vitro. In APP/PS1 mice, L-NBP induced neurogenesis in the dentate gyrus and improved cognitive functions. In addition, L-NBP significantly increased the expressions of BDNF and NGF, tyrosine phosphorylation of its cognate receptor, and phosphorylation of Akt as well as CREB at Ser133 in the hippocampus of APP/PS1 mice. These results indicated that L-NBP might stimulate the proliferation, migration, and differentiation of hippocampal neural stem cells and reversed cognitive deficits in APP/PS1 mice. BDNF/TrkB/CREB/Akt signaling pathway might be involved.