To explore the effect and the probable mechanisms of JLD in the treatment of type 2 diabetes mellitus (T2DM) - associated cognitive impairment (TDACI).

The effect of JLD in combating TDACI was assessed in T2DM model mice by conducting Morris water maze (MWM) behaviour testing. Active components and their putative targets, as well as TDACI-related targets, were collected from public databases. Protein-protein interactions (PPIs), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and molecular docking were then utilized to explore potential molecular network mechanisms. Finally, the main targets were verified in animal model experiments.

MWM test showed that JLD improved aspects of behaviour in T2DM model mice. JLD improved glucose intolerance, tissue insulin sensitivity, lipid metabolism and enhanced synapse-associated protein expression in hippocampus tissue. Network pharmacology revealed 185 active components, 337 targets of JLD, and 7998 TDACI related targets were obtained . PPI network analyses revealed 39 core targets. GO and KEGG analyses suggested that JLD might improve TDACI by regulating gene expression, apoptotic processes and inflammatory responses mainly via PI3K-AKT and AGE-RAGE signaling pathways. Molecular docking revealed strong binding of the main components to core targets. JLD reduced hippocampus tissue expression of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL6), core targets of treatment of TDACI.

The findings suggested that JLD has the potential to improve TDACI through multiple components, multiple targets and multiple pathways. JLD may be a promising treatment for diabetic cognitive impairment.

Diabetic encephalopathy (DE) involves cognitive dysfunction and structural brain changes due to diabetes, with a complex pathogenesis and no specific treatments available. D-chiral inositol (DCI), a bioactive molecule from dietary sources, has hypoglycemic and anti-inflammatory effects, but its role in DE and the mechanisms involved are still unclear. This study focused on male db/db mice, treated continuously with D-chiral inositol (DCI) at doses of 35 and 70 mg/kg/day for 8 weeks. Cognitive function was evaluated using the Morris water maze test, while pathological changes in the hippocampus and cortex were assessed through hematoxylin-eosin (HE) staining and Nissl staining. Protein expression related to synapses, inflammation, apoptosis, and neurofibrillary tangles, as well as mRNA levels, were analyzed using qRT-PCR, immunohistochemistry, and Western blotting to evaluate DCI's effects on DE. The results showed that DCI improved learning and memory in db/db mice, reduced nuclear pyknosis and neuronal loss, normalized PSD95 and SYN protein levels, and modulated inflammatory and apoptosis-related factors in the hippocampus and cortex. Additionally, DCI increased the expression of BDNF, IκB-α, and p-GSK-3β (Ser9), while decreasing levels of NF-κB p65, p-GSK3 (α + β) (Y216 + Y279), P-Tau (Thr231), and P-Tau (Ser396). These findings suggest that DCI may alleviate DE by modulating the BDNF/NF-κB/GSK-3β signaling pathway.

Stroke is the second highest cause of death and leading cause of disability with high economic burden worldwide. The incidence of stroke is increasing faster and more prevalent for the global population over age 65. Ischemic stroke (IS) has a higher incidence than hemorrhagic stroke, accounting over 80 % of the total incidence of stroke. The rate of ischemic stroke is increasing in all age groups and both sexes. In present era, hypertension, high blood pressure and modern lifestyle are considered as the causes of the disease. The treatment options for stroke is still limited, mainly thrombolytic and thrombectomy therapy are available options. In the past decade, a number of therapeutic agents have been studied for the acute ischemic stroke to protect the brain from ischemic injury. Several study methods focus to improve neurons functions around the ischemic core and protect from the shock. Many signalling pathways including NF-kB, NrF, Nrf2-Keap1, PI3K/AKT, JAK/STAT signalling pathways are strongly associated for the indication. Controlling the signalling pathways by small molecules potentially improve the neuronal functions. In this article, we review the recent advancement of the drug discovery, controlling the signalling pathways by small molecules, and kinase inhibitors in ischemic stroke.

Antioxidants play a pivotal role in activating endogenous defense mechanisms, neutralizing free radicals, and mitigating oxidative stress. In this study, an antioxidant peptide library was constructed based on amino acid structure-activity relationships, focusing on ROS scavenging and enzymatic modulation. Through comprehensive chemical and biological evaluations, we identified the peptide CIRAKLC (designated as CL7), which exhibited exceptional ROS-scavenging capacity and enzyme-modulating activity, demonstrating superior in vitro antioxidant efficacy. CL7 exhibited excellent biocompatibility and effectively protected HepG2 cells from H2O2-induced ROS-mediated oxidative damage through both preventive and reparative mechanisms. Furthermore, CL7 modulated key enzymes (CAT, MDA, SOD, ALT, and AST), displaying hepatoprotective, anti-inflammatory, and antiaging effects, along with significant photoprotective efficacy. Molecular docking revealed key hydrogen bonding and electrostatic interactions when the peptide binds to redox-related receptors (Nrf2/Keap1 and IKK-β). These findings underscore CL7's robust antioxidant capacity and multifunctionality, highlighting its broad therapeutic potential in oxidative stress management.

Candida tropicalis is an important member of the non-Candida albicans species. It is closely associated with candidemia, especially common in neutropenic and critically ill patients. Drug-resistant C. tropicalis isolates have been found not only in clinical patients but also in animals, fruits, and the environment. In recent years, the detection rate of azole-resistant C. tropicalis isolates has increased. Drug-resistant C. tropicalis is related to persistent, recurrent, and breakthrough infections. Therefore, understanding its drug resistance is crucial for clinical treatment. The review explores the main mechanisms of C. tropicalis resistance to antifungal drugs and discusses the genetic basis involved in the antifungal resistance of C. tropicalis. In addition, current research on natural extracts, nanomaterials, etc. used for antifungal purposes has also been reviewed. The aim of this review is that in-depth research on the drug resistance mechanisms of C. tropicalis resistant strains can help guide clinical medication. Meanwhile, it can also provide new ideas for opening up new pathways, searching for new targets, and screening out safe and effective "antifungal candidates," with the expectation of improving the current clinical cure rates.

Drug-induced cardiotoxicity (DICT), defined as myocardial injury caused by direct or indirect toxicity of therapeutic agents, disrupts cardiovascular homeostasis, underscoring the urgent need for preventive strategies in clinical practice. Doxorubicin (DOX), a clinically established anthracycline chemotherapeutic, induces dose-dependent cardiotoxicity driven by reactive oxygen species overproduction. Notably, Dl-3-n-butylphthalide (NBP), a bioactive phytochemical derived from celery, has shown potential in mitigating DOX-induced cardiomyopathy via its antioxidant activity. Therefore, this study aimed to investigate the protective effects of NBP on DOX-induced cardiomyopathy, with a focus on elucidating the underlying mechanisms.

We developed both in vivo and in vitro models of DOX-induced cardiotoxicity. For the animal model, male C57BL/6 mice were administered with DOX (4 mg/kg, i.p.) once a week for 3 weeks. For the cell model, H9C2 myoblasts were exposed to 1 μM DOX for at least 6 h to establish acute cardiotoxicity.

Our results demonstrate that NBP significantly improves cardiac function, as evidenced by approximately 10% increase in cardiac functional parameters (ejection fraction and left ventricular shortening fraction). Besides, NBP exerts favorable effects on cardiac inflammation, apoptosis, fibrosis, and mitochondrial damage both in vivo and in vitro. Further mechanistic investigations revealed that NBP blocks the interaction between Kelch-like ECH-associated protein-1 (Keap1) and Nrf2, thereby preventing the formation of the Nrf2/Keap1 complex.

This study indicate that NBP alleviates DOX-induced cardiotoxicity by inhibiting Nrf2/Keap1 complex formation, highlighting its potential as a therapeutic agent for DICT and suggest that Nrf2/Keap1 may be a potential therapeutic target for the management of this condition.

Diabetic foot ulcers (DFU) are estimated to affect about 18.6 million people worldwide annually. The pathogenesis of DFU is complex, and the available drugs are not effective. Dl-3-n-butylphthalide (NBP) is a synthetic mixture of racemates used in China for the treatment of ischemic stroke. It was initially isolated from the seeds of Apium graveolens Linn, with studies showing its potential role in treating diabetes and its complications.

To predict and validate the mechanism by which NBP treats DFU.

Network pharmacological analysis was performed to identify pharmacological targets and signaling pathways mediating the treatment effect of NBP on DFU. In vivo and in vitro experiments were conducted to validate the therapeutic effects and mechanisms of NBP on DFU.

Network pharmacology analysis identified 26 pharmacological targets of NBP and predicted that NBP could treat DFU partially by modulating apoptosis and vascular signaling pathways. Results from animal experiments showed that NBP significantly improved DFU by increasing neovascularization and fibroblast proliferation. In vitro tests demonstrated that NBP treatment promoted the migration and proliferation of human umbilical vein endothelial cells and human dermal fibroblasts, while inhibiting the apoptosis of human umbilical vein endothelial cells, human dermal fibroblasts, and human keratinocytes cells.

This study found that NBP could treat DFU by decreasing the rate of apoptosis and increasing angiogenesis via the advanced glycation end products-receptor of advanced glycation end products signaling pathway and binding to the heme oxygenase 1, caspase 3, B cell leukemia/lymphoma 2, brain derived neurotrophic factor, and nuclear factor erythroid 2 L2 genes.

Diabetes-related cognitive dysfunction (DACD) is a comorbidity of type 2 diabetes that has a negative effect on patients' quality of life. Research has indicated that disruption of the gut microbiota (GM) may be linked to dementia with altered cognitive performance. Conversely, omega-3 polyunsaturated fatty acids (n-3 PUFAs) may reverse DACD. The present study aimed to assess the effects of an n-3 PUFA intervention and fecal microbiota transplantation (FMT) on high-fat and streptozotocin-induced DACD model rats. In DACD rats, n-3 PUFA treatment restored fasting blood glucose (FBG) levels and cognitive function, increased the expression of anti-inflammatory cytokines and downregulated the expression of proinflammatory cytokines in the cortex and colon. Additionally, the expression of the postsynaptic density protein-95 mRNA and protein varied with n-3 PUFA treatment. Treatment with n-3 PUFAs also increased the expression of tight junction proteins. Beneficial and short-chain fatty acid-producing bacteria were more abundant when rats were exposed to n-3 PUFAs. After FMT from the rats with DACD symptoms that were improved by the n-3 PUFA dietary intervention into another batch of DACD rats, we observed recovery in recipient DACD rats. These results indicated that the alleviation of DACD symptoms by n-3 PUFAs was attributed to gut microbiota remodeling.

The increasing prevalence of diabetes and its related cognitive impairments is a significant public health concern. With limited clinical treatment options and an incomplete understanding of the underlying mechanisms, traditional Chinese medicine (TCM) Naofucong is proposed as a potential neuroprotective agent against diabetic cognitive impairment (DCI). This study aims to investigate the therapeutic mechanisms of Naofucong in DCI. We hypothesize that Naofucong may improve cognitive function in diabetic rats by modulating the extracellular regulated protein kinases (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases (MAPK) signaling pathway, enhancing insulin-degrading enzyme (IDE) expression, reducing amyloid-beta (Aβ) deposition, decreasing phosphorylated Tau (p-Tau) levels, and alleviating oxidative stress. Diabetes was induced in specific-pathogen-free male Sprague-Dawley rats using streptozotocin, and the rats were treated with oral Naofucong for 12 weeks. We assessed cognitive function and measured neuronal damage, oxidative stress injury, and the expression levels of IDE, Aβ, amyloid precursor protein (APP), p-Tau, and components of the ERK/JNK/p38 MAPK pathway. Diabetic rats showed significant declines in cognitive function, neuronal damage, oxidative stress, low IDE expression, Aβ accumulation, high APP expression, abnormal Tau phosphorylation, and overactivation of the ERK/JNK/p38 MAPK pathway. Naofucong treatment significantly reversed these symptoms. Our findings suggest that Naofucong improves cognitive impairment in diabetic rats by inhibiting the ERK/JNK/p38 MAPK pathway, upregulating IDE, reducing Aβ deposition, suppressing APP and p-Tau expression, and alleviating neuronal damage and oxidative stress. This research provides a reference for the clinical prevention and treatment of DCI using TCM Naofucong.

Diabetes mellitus (DM) is one of the fastest growing diseases in terms of global incidence and seriously affects cognitive function. The incidence rate of cognitive dysfunction is up to 13% in diabetes patients aged 65-74 years and reaches 24% in those aged >75 years. The mechanisms and treatments of cognitive dysfunction associated with diabetes mellitus are complicated and varied. Previous studies suggest that hyperglycemia mainly contributes to cognitive dysfunction through mechanisms involving inflammation, autophagy, the microbial-gut-brain axis, brain-derived neurotrophic factors, and insulin resistance. Antidiabetic drugs such as metformin, liraglutide, and empagliflozin and other drugs such as fingolimod and melatonin can alleviate diabetes-induced cognitive dysfunction. Self-management, intermittent fasting, and repetitive transverse magnetic stimulation can also ameliorate cognitive impairment. In this review, we discuss the mechanisms linking diabetes mellitus with cognitive dysfunction and propose a potential treatment for cognitive decline associated with diabetes mellitus.

Cognitive decline is a significant concern for stroke survivors, affecting their quality of life and increasing their burden on the healthcare system. DL-3-n-butylphthalide (butylphthalide) has shown efficacy in the short-term treatment of various cognitive impairments. This study evaluated the efficacy of butylphthalide in preventing cognitive decline over a 12-month period in patients with ischaemic stroke.

This prospective following-up study involved patients newly diagnosed with ischaemic stroke between 1 month and 6 months after stroke onset and not in the acute phase. Patients were assigned to either the butylphthalide or control group. Cognitive function was assessed using the mini-mental state examination (MMSE) at baseline and at the 12-month follow-up. Statistical analyses included t-tests, χ2 tests and multivariate regression analyses.

Butylphthalide was negatively associated with the MMSE D-value (β=-0.122; 95% CI -1.932 to -0.298; p=0.003) and the MMSE D-value percentage (β=-0.117; 95% CI -0.057 to -0.011; p=0.004). A multivariate analysis indicated that butylphthalide treatment was negatively associated with both changes in orientation and language score. Additionally, the incidence of cognitive decline was significantly lower in the butylphthalide group (OR, 0.612; p=0.020) than the control group. An age of ≥60 years and lower educational level were identified as risk factors for lower cognitive score and cognitive decline.

This study demonstrated that butylphthalide is effective in preventing cognitive decline in patients with ischaemic stroke. These findings have significant implications for clinical practice, suggesting that butylphthalide could be incorporated into standard post-stroke care regimens to improve patient outcomes and reduce the healthcare burden. Additional multicentre double-blind trials are recommended to confirm these results in diverse populations.

Chuanxiong Rhizoma (Chuanxiong), a traditional Chinese medicine, has been widely used to treat various nervous and cardiovascular system-related conditions. Its active components, senkyunolide A (SA) and 3-n-butylphthalide (NBP), have been proven effective in treating nervous system diseases. A new method was established based on microdialysis coupled with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to estimate the concentrations of these components in brain extracellular fluid. Chromatographic separation was achieved using an Acquity UPLC BEH C8 column (2.1 × 100 mm, 1.7 μm) with acetonitrile and 0.1% formic acid as mobile phase. The calibration curves of SA and NBP were linear in the concentration ranges of 0.25-100.00 and 0.12-48.00 ng/mL, respectively, with a correlation coefficient above 0.9992. All validation parameters, including intra- and inter-day precision, accuracy, matrix effect and stability, were within the acceptance limits of bioanalytical guidelines. The validated method was successfully applied to study the pharmacokinetics of SA and NBP in rat brain microdialysis after oral administration of Chuanxiong extracts. The results showed that both components penetrated the brain and reached maximum concentrations in the microdialysates of 72.31 and 9.93 ng/mL at 1.50 and 1.58 h, respectively.

Studies have found that PM2.5 can damage the brain, accelerate cognitive impairment, and increase the risk of developing a variety of neurodegenerative diseases. However, the potential molecular mechanisms by which PM2.5 causes learning and memory problems are yet to be explored. In this study, we evaluated the neurotoxic effects in mice after 12 weeks of PM2.5 exposure, and found that this exposure resulted in learning and memory disorders, pathological brain damage, and M1 phenotype polarization on microglia, especially in the hippocampus. The severity of this damage increased with increasing PM2.5 concentration. Proteomic analysis, as well as validation results, suggested that PM2.5 exposure led to abnormal glucose metabolism in the mouse brain, which is mainly characterized by significant expression of hexokinase, phosphofructokinase, and lactate dehydrogenase. We therefore administered the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) to the mice exposed to PM2.5, and showed that inhibition of glycolysis by 2-DG significantly alleviated PM2.5-induced hippocampal microglia M1 phenotype polarization, and reduced the release of inflammatory factors, improved synaptic structure and related protein expression, which alleviated the cognitive impairment induced by PM2.5 exposure. In summary, our study found that abnormal glucose metabolism-mediated inflammatory polarization of microglia played a role in learning and memory disorders in mice exposed to PM2.5. This study provides new insights into the neurotoxicity caused by PM2.5 exposure, and provides some theoretical references for the prevention and control of cognitive impairment induced by PM2.5 exposure.

Diabetic cognitive dysfunction (DCD) has attracted increased attention, but its precise mechanism remains to be explored. Oligodendrocytes form myelin sheaths that wrap around axons. Granzyme B (GZMB) can cause axonal degeneration of the central nervous system. However, the role of GZMB in diabetic cognitive dysfunction (DCD) has not been reported. This study aimed to investigate whether GZMB promotes demyelination and participates in DCD by regulating the endoplasmic reticulum stress function of oligodendrocytes.

Streptozotocin was injected intraperitoneally to establish a diabetic model in C57BL/6 mice. The mice were randomly divided into four groups: control group, diabetic group, diabetic + SerpinA3N group, and diabetic + saline treatment group. We performed the Morris water maze test to assess the learning and memory abilities of the mice. An immunofluorescence assay was performed to detect the expression sites of GZMB and OLIG2 in the hippocampal CA1 region. Luxol Fast Blue staining and electron microscopy were performed to detect the myelin number and myelin plate densities. Immunohistochemistry was used to detect the expression levels of MBP and CNPase. Protein blotting was used to assess the expression levels of GZMB, PERK, p-PERK, eIF2α, p-eIF2α, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 as well as MBP and CNPase.

The GZMB inhibitor SerpinA3N reduces escape latency and increases the traversing platforms and residence time in the target area, improving DCD in mice. It also reduces endoplasmic reticulum stress in hippocampal oligodendrocytes and focal prolapse, further promoting MBP and CNPase expression and reducing demyelination.

Our findings suggest that inhibition of GZMB activity modulates oligodendrocyte endoplasmic reticulum stress and pyroptosis, reduces demyelination, and ameliorates diabetes-related cognitive impairment.

Diabetic encephalopathy (DE) is a complication of diabetes, especially type 2 diabetes (T2D), characterized by damage in the central nervous system and cognitive impairment, which has gained global attention. Despite the extensive research aimed at enhancing our understanding of DE, the underlying mechanism of occurrence and development of DE has not been established. Mounting evidence has demonstrated a close correlation between DE and various factors, such as Alzheimer's disease-like pathological changes, insulin resistance, inflammation, and oxidative stress. Of interest, nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor with antioxidant properties that is crucial in maintaining redox homeostasis and regulating inflammatory responses. The activation and regulatory mechanisms of NRF2 are a relatively complex process. NRF2 is involved in the regulation of multiple metabolic pathways and confers neuroprotective functions. Multiple studies have provided evidence demonstrating the significant involvement of NRF2 as a critical transcription factor in the progression of DE. Additionally, various molecules capable of activating NRF2 expression have shown potential in ameliorating DE. Therefore, it is intriguing to consider NRF2 as a potential target for the treatment of DE. In this review, we aim to shed light on the role and the possible underlying mechanism of NRF2 in DE. Furthermore, we provide an overview of the current research landscape and address the challenges associated with using NRF2 activators as potential treatment options for DE.

Ischemic stroke is a serious condition that results in high rates of illness and death. Anaerobic glycolysis becomes the primary means of providing energy to the brain during periods of low oxygen levels, such as in the aftermath of an ischemic stroke. This process is essential for maintaining vital brain functions and has significant implications for recovery following a stroke. Energy supply by anaerobic glycolysis and acidosis caused by lactic acid accumulation are important pathological processes after ischemic stroke. Numerous natural products regulate glucose and lactate, which in turn modulate anaerobic glycolysis. This article focuses on the relationship between anaerobic glycolysis and ischemic stroke, as well as the associated signaling pathways and natural products that play a therapeutic role. These natural products, which can regulate anaerobic glycolysis, will provide new avenues and perspectives for the treatment of ischemic stroke in the future.

HECTD3 (HECT domain E3 ubiquitin protein ligase 3) exerts biological activities in neuroinflammation of distinct diseases, such as autoimmune encephalomyelitis and donations after heart death. However, the effect of HECTD3 on diabetes-associated cognitive decline (DACD) remains unclear.

Wild-type or HECTD3-knockout rats were administered with streptozotocin to establish diabetic model. Pathological changes in the hippocampus were assessed by NISSL and haematoxylin and eosin staining. Morris water maze test was used to assess cognitive function. Neuronal survival and inflammation were investigated by immunofluorescence staining and ELISA assay. NLRP3 inflammasome and pyroptosis were assessed by western blot, immunofluorescence and flow cytometry assays.

HECTD3 was up-regulated in hippocampus of streptozotocin-induced diabetic rats and high glucose-induced PC12 cells. Knockout of HECTD3 increased the number of neurons and improved the learning and memory function. Moreover, knockout of HECTD3 promoted in vivo neuronal survival, and reduced levels of IL-1β, TNF-α, and IL-6 in the hippocampus. Silencing of HECTD3 increased cell viability, and reduced IL-1β, TNF-α, and IL-6 in high glucose-induced PC12 cells. Fluorescence intensities of NLRP3, GSDMD-N and caspase-1 were reduced in HECTD3-knockout diabetic rats, and knockdown of HECTD3 down-regulated protein expression of NLRP3, GSDMD-N, caspase-1, IL-1β, and IL-18 in high glucose-induced PC12 cells to suppress the pyroptosis. HECTD3 promoted the stability of mucosa-associated lymphoid tissue 1 (MALT1) through up-regulation of c-JUN and phospho (p)-JNK in high glucose-induced PC12 cells. Over-expression of MALT1 attenuated neuroprotective effects of HECTD3 silencing on high glucose-induced PC12 cells.

HECTD3 silencing exerted neuroprotective effect against DACD through MALT1-mediated JNK signalling.HighlightsHECTD3 was up-regulated in hippocampus of streptozotocin-induced diabetic rats and high glucose-induced PC12.Knockout of HECTD3 promoted in vivo neuronal survival, reduced inflammation and pyroptosis, and improved the learning and memory function in diabetic rats.Knockout of HECTD3 suppressed the activation of NLRP3 inflammasome in diabetic rats.Silencing of HECTD3 exerted neuroprotective effects through MALT1-mediated JNK signalling.

Recent studies have highlighted the involvement of pyroptosis-mediated cell death and neuroinflammation in ischemic stroke (IS) pathogenesis. DL-3-n-butylphthalide (NBP), a synthesized compound based on an extract from seeds of Apium graveolens, possesses a broad range of biological effects. However, the efficacy and the underlying mechanisms of NBP in IS remain contentious. Herein, we investigated the therapeutic effects of NBP and elucidated its potential mechanisms in neuronal cell pyroptosis and microglia inflammatory responses. Adult male mice underwent permanent distal middle cerebral artery occlusion (dMCAO), followed by daily oral gavage of NBP (80 mg/kg) for 1, 7, or 21 consecutive days. Gene Expression Omnibus (GEO) dataset of IS patients peripheral blood RNA sequencing was analyzed to identify differentially expressed pyroptosis-related genes (PRGs) during the ischemic process. Our results suggested that NBP treatment effectively alleviated brain ischemic damage, resulting in decreased neurological deficit scores, reduced infarct volume, and improved neurological and behavioral functions. RNA sequence data from human unveiled upregulated PRGs in IS. Subsequently, we observed that NBP downregulated pyroptosis-associated markers at days 7 and 21 post-modeling, at both the protein and mRNA levels. Additionally, NBP suppressed the co-localization of pyroptosis markers with neuronal cells to variable degrees and simultaneously mitigated the accumulation of activated microglia. Overall, our data provide novel evidence that NBP treatment significantly attenuates ischemic brain damage and promotes recovery of neurological function in the early and recovery phases after IS, probably by negatively regulating the pyroptosis cell death of neuronal cells and inhibiting toxic neuroinflammation in the central nervous system.

We explored the effect of inhibition of thioredoxin interacting protein (Txnip) on neuroprotection in Müller cells under high glucose. Wild-type (WT) and Txnip knockout (Txnip-/-) mice were used to establish a streptozotocin (STZ)-induced diabetes model and a Müller cells high glucose model. We detected BDNF expression and PI3K/AKT/CREB pathway activation levels in the retina and Müller cells of each group in vivo and in vitro experiments. The Txnip-/- STZ group showed higher expression of BDNF and phosphorylation of PI3K/AKT/CREB in retina, and less retinal photoreceptor apoptosis was observed in Txnip-/- diabetic group than in WT. After using an inhibitor of PI3K signaling pathway, BDNF expression was reduced; In vitro co-cultured with Müller cells in different groups, 661 W cells showed different situations, Txnip-/- Müller cells maximum downregulated Cleaved-caspase 3 expression in 661 W, accompanied by an increase in Bcl-2/Bax ratio. These findings indicate that inhibiting endogenous Txnip in mouse Müller cells can promote their expression and secretion of BDNF, thereby reducing HG induced photoreceptor apoptosis and having important neuroprotective effects on DR. The regulation of BDNF expression by Txnip may be achieved by activating the PI3K/AKT/CREB pathway. This study suggests that regulating Txnip may be a potential target for DR treatment.

To define the antifungal activity of n-butylphthalide alone or in combination with fluconazole in Candida glabrata and Candida tropicalis.

The antifungal activity of n-butylphthalide alone and in combination with fluconazole was investigated by the classical broth microdilution method and the time-killing curve method. The QRT-PCR method was used to determine gene expressions changes of mitochondrial respiratory chain enzymes, drug efflux pumps and drug target enzymes in Candida glabrata and Candida tropicalis after n-butylphthalide treatment.

The MIC values of n-butylphthalide against Candida glabrata and Candida tropicalis ranged from 16 to 64 μg·mL-1. The FICI value of the combination of n-butylphthalide and fluconazole against drug-resistant Candida glabrata and Candida tropicalis ranged from 0.5001 to 0.5315 with partial synergism. Time-killing curves showed that 256 μg·mL-1 n-butylphthalide significantly inhibited the growth of drug-resistant colonies of Candida glabrata and Candida tropicalis, and 128 μg·mL-1 n-butylphthalide combined with 1 μg·mL-1 fluconazole had an additive effect. N-butylphthalide could alter the expression of mitochondrial respiratory chain enzymes COX1, COX2, COX3, and CYTB genes in Candida glabrata and Candida tropicalis (P< 0.05) and downregulate the expression of the drug efflux pump genes CDR1 and CDR2 in drug-resistant Candida glabrata to 3.36% and 3.65%, respectively (P<0.001), but did not affect the drug target enzyme ERG11 in drug-resistant Candida tropicalis.

N-butylphthalide had antifungal activity against Candida glabrata and Candida tropicalis. N-butylphthalide improved the activity of fluconazole against drug-resistant Candida glabrata by affecting the expression of mitochondrial respiratory chain enzyme genes and reversing the high expression of drug efflux pump genes CDR1 and CDR2.

There is increasing evidence that type 2 diabetes mellitus (T2DM) is an independent risk factor for the occur of tendinopathy. Therefore, this study is the first to explore the dynamic changes of the "gene profile" of supraspinatus tendon in rats at different time points after T2DM induction through transcriptomics, providing potential molecular markers for exploring the pathogenesis of diabetic tendinopathy.

A total of 40 Sprague-Dawley rats were randomly divided into normal (NG, n = 10) and T2DM groups (T2DM, n = 30) and subdivided into three groups according to the duration of diabetes: T2DM-4w, T2DM-8w, and T2DM-12w groups; the duration was calculated from the time point of T2DM rat model establishment. The three comparison groups were set up in this study, T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG. Differentially expressed genes (DEGs) in 3 comparison groups were screened. The intersection of the three comparison groups' DEGs was defined as key genes that changed consistently in the supraspinatus tendon after diabetes induction. Cluster analysis, gene ontology (GO) functional annotation analysis and Kyoto encyclopedia of genes and genomes (KEGG) functional annotation and enrichment analysis were performed for DEGs.

T2DM-4w group vs. NG, T2DM-8w group vs. NG, and T2DM-12w group vs. NG detected 519 (251 up-regulated and 268 down-regulated), 459 (342 up-regulated and 117 down-regulated) and 328 (255 up-regulated and 73 down-regulated) DEGs, respectively. 103 key genes of sustained changes in the supraspinatus tendon following induction of diabetes, which are the first identified biomarkers of the supraspinatus tendon as it progresses through the course of diabetes.The GO analysis results showed that the most significant enrichment in biological processes was calcium ion transmembrane import into cytosol (3 DEGs). The most significant enrichment in cellular component was extracellular matrix (9 DEGs). The most significant enrichment in molecular function was glutamate-gated calcium ion channel activity (3 DEGs). The results of KEGG pathway enrichment analysis showed that there were 17 major pathways (p < 0.05) that diabetes affected supratinusculus tendinopathy, including cAMP signaling pathway and Calcium signaling pathway.

Transcriptomics reveals dynamic changes in the"gene profiles"of rat supraspinatus tendon at three different time points after diabetes induction. The 103 DEGs identified in this study may provide potential molecular markers for exploring the pathogenesis of diabetic tendinopathy, and the 17 major pathways enriched in KEGG may provide new ideas for exploring the pathogenesis of diabetic tendinopathy.

Migraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated.

We established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1β, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C.

At the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2.

Our data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine.

Alzheimer's disease (AD) is an incurable neurodegenerative disease that has become one of the most important diseases threatening global public health security. Dihuang Yinzi (DHYZ) is a traditional Chinese medicine that has been widely used for the treatment of AD and has significant therapeutic effects, but its specific mechanism of action is still unclear.The aim of the study is to investigate the specific mechanism of DHYZ in treating AD based on brain metabolomics and network pharmacology.

In this study, the classic APPswe/PS1E9 (APP/PS1) mice were selected as the AD animal model, and the mechanism of DHYZ was studied. The learning and memory ability of mice was detected by Y-maze test, and the ultrastructure of neural cells in the brain of the mice was observed by transmission electron microscope (TEM). Then, the mechanism of DHYZ intervention in AD was analyzed by constructing network pharmacology, and combined with brain metabolomics based on ultra performance liquid chromatography-mass spectrometry (UPLC-MS) to detect differential metabolic markers and their metabolic pathways. In addition, a joint analysis of differential metabolites and potential targets for DHYZ treatment of AD is conducted to deeply explore the relationship between key targets, differential metabolites, and metabolic pathways.

After 30 days of DHYZ treatment, the spatial work and reference memory ability of APP/PS1 mice were significantly improved, the structure of mitochondria and synapses in the neurons of the brain were basically normal. 202 potential targets for DHYZ treatment of AD were screened through network pharmacology, and after enrichment analysis, these targets showed correlation with redox reactions, mitochondrial and synaptic functional pathways. And 7 differential metabolites were identified in brain metabolomics are Nicotinic acid, N-Formyl-L-glutamic acid, 5-(2-Hydroxyethyl)-4-methylthiazole, D-Gulono-1,4-lactone, Norepinephrine, 3-Methylotrophicacid, Palmitic acid. These differential metabolites mainly involve nicotinite and nicotinamide metabolism, pertussis, cAMP signaling pathway, cysteine and methionine metabolism. Notablely, through matching analysis of targets and metabolites, a total of 20 genes were found to match Nicotinic acid, 51 genes were found to match norepinephrine, and 14 genes intersected with the two metabolites, enrichment analysis of the intersected genes showed that neuroactive light receptor interaction, serotonergic synapse, and cAMP signaling were significantly affected, which is consistent with previous network pharmacology results.

This study identified the main chemical ingredients of DHYZ intervention in AD may originated from Polygala tenuifolia Wild, Dendrobium nobile Line and Ophiogon japonicus (L.f) Ker-Gawl. Combined with Y Maze, TEM and brain metabolomics, revealed that DHYZ can improve the learning and memory abilities and brain pathological morphology of APP/PS1 mice by regulating nicotinic acid, 3-Methylthiopropionic acid, pertussis and their metabolic pathways, including nicotinate and nicotinamide metabolism, cAMP signaling pathway and cysteine and methionine metabolism. In short, this study provides a new research foundation and direction for the treatment of AD with traditional Chinese medicine.

Doxorubicin (DOX) is a widely used chemotherapeutic drug known to cause dose-dependent myocardial toxicity, which limits its clinical potential. DL-3-n-butylphthalide (NBP), a substance extracted from celery seed species, has a number of pharmacological properties, such as antioxidant, anti-inflammatory, and anti-apoptotic actions. However, whether NBP can protect against DOX-induced acute myocardial toxicity is still unclear. Therefore, this study was designed to investigate the potential protective effects of NBP against DOX-induced acute myocardial injury and its underlying mechanism. By injecting 15 mg/kg of DOX intraperitoneally, eight-week-old male C57BL6 mice suffered an acute myocardial injury. The treatment group of mice received 80 mg/kg NBP by gavage once daily for 14 days. To mimic the cardiotoxicity of DOX, 1uM DOX was administered to H9C2 cells in vitro. In comparison to the DOX group, the results showed that NBP improved cardiac function and decreased serum levels of cTnI, LDH, and CK-MB. Additionally, HE staining demonstrated that NBP attenuated cardiac fibrillar lysis and breakage in DOX-treated mouse hearts. Western blotting assay and immunofluorescence staining suggested that NBP attenuated DOX-induced oxidative stress, apoptosis, and inflammation both in vivo and in vitro. Mechanistically, NBP significantly upregulated the Nrf2/HO-1 signaling pathway, while the Nrf2 inhibitor ML385 prevented NBP from protecting the myocardium from DOX-induced myocardial toxicity in vitro. In conclusion, Our results indicate that NBP alleviates DOX-induced myocardial toxicity by activating the Nrf2/HO-1 signaling pathway.

Neuronal ferroptosis plays a critical role in the pathogenesis of cognitive deficits. The present study explored whether artemisinin protected type 2 diabetes mellitus (T2DM) mice from cognitive impairments by attenuating neuronal ferroptosis in the hippocampal CA1 region.

STZ-induced T2DM mice were treated with artemisinin (40 mg/kg, i.p.), or cotreated with artemisinin and Nrf2 inhibitor MEL385 or ferroptosis inducer erastin for 4 weeks. Cognitive performance was determined by the Morris water maze and Y maze tests. Hippocampal ROS, MDA, GSH, and Fe2+ contents were detected by assay kits. Nrf2, p-Nrf2, HO-1, and GPX4 proteins in hippocampal CA1 were assessed by Western blotting. Hippocampal neuron injury and mitochondrial morphology were observed using H&E staining and a transmission electron microscope, respectively.

Artemisinin reversed diabetic cognitive impairments, decreased the concentrations of ROS, MDA and Fe2+, and increased the levels of p-Nr2, HO-1, GPX4 and GSH. Moreover, artemisinin alleviated neuronal loss and ferroptosis in the hippocampal CA1 region. However, these neuroprotective effects of artemisinin were abolished by Nrf2 inhibitor ML385 and ferroptosis inducer erastin.

Artemisinin effectively ameliorates neuropathological changes and learning and memory decline in T2DM mice; the underlying mechanism involves the activation of Nrf2 to inhibit neuronal ferroptosis in the hippocampus.

To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia.

Randomized controlled trials were searched in electronic databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), Wan Fang, and China Biology Medicine from inception to 29 November 2022. Two reviewers independently screened the papers and extracted data from the included studies. The data were processed using RevMan5.4 statistical software.

Nine randomized controlled trials (n = 1024) were included in this meta-analysis. Regarding the primary outcomes, compared with butylphthalide monotherapy, combined butylphthalide and donepezil treatment exhibited significantly greater total clinical efficacy (relative risk = 1.24, 95% confidence interval [1.17, 1.31]) and did not increase the adverse event rate (relative risk = 1.39, 95% confidence interval [0.91, 2.14]). Regarding the secondary outcomes, the meta-analysis results for the Mini-Mental State Examination, abilities of daily living, and Montreal Cognitive Assessment scores and the interleukin-6, tumor necrosis factor-α, and superoxide dismutase blood levels all supported combined butylphthalide and donepezil treatment.

Butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice.

Postoperative cognitive dysfunction (POCD) is characterized by impaired cognitive function following general anesthesia and surgery. Oxidative stress is a significant pathophysiological manifestation underlying POCD. Previous studies have reported that the decline of nicotinamide adenine dinucleotide (NAD+) -dependent sirtuin 1 (SIRT1) contributes to the activation of oxidative stress. In this study, we investigated whether pretreatment of nicotinamide mononucleotide (NMN), an NAD+ intermediate, improves oxidative stress and cognitive function in POCD. The animal model of POCD was established in C57BL/6 J mice through 6 h isoflurane anesthesia-induced cognitive impairment. Mice were intraperitoneally injected with NMN for 7 days prior to anesthesia, after which oxidative stress and cognitive function were assessed. The level of oxidative stress was determined using flow cytometry analysis and assey kits. The fear condition test and the Y-maze test were utilized to evaluate contextual and spatial memory. Our results showed that cognitive impairment and increased oxidative stress were observed in POCD mice, as well as downregulation of NAD+ levels and related protein expressions of SIRT1 and nicotinamide phosphoribosyltransferase (NAMPT) in the hippocampus. And NMN supplementation could effectively prevent the decline of NAD+ and related proteins, and reduce oxidative stress and cognitive disorders after POCD. Mechanistically, the findings suggested that protection on cognitive function mediated by NMN pretreatment in POCD mice may be regulated by NAD+-SIRT1 signaling pathway. This study indicated that NMN preconditioning reduced oxidative stress damage and alleviated cognitive impairment in POCD mice.

NLRP3 inflammasome activation plays a key role in the development of diabetes-induced cognitive impairment. However, strategies to inhibit NLRP3 inflammasome activation remain elusive. Herein, we evaluated the impact of a walnut-derived peptide, TWLPLPR (TW-7), on cognitive impairment in high-fat diet/streptozotocin-induced type 2 diabetes mellitus (T2DM) mice and explored its underlying mechanisms in high glucose-induced HT-22 cells. In the Morris water maze test, TW-7 alleviated cognitive deficits in mice; this was confirmed at the level of synaptic structure and dendritic spine density in the mouse hippocampus using transmission electron microscopy and Golgi staining. TW-7 increased the expression of synaptic plasticity-related proteins and suppressed the NEK7/NLRP3 inflammatory pathway, as determined by western blotting and immunofluorescence analysis. The mechanism of action of TW-7 was verified in an HT-22 cell model of high glucose-induced insulin resistance. Collectively, TW-7 could regulate T2DM neuroinflammation and synaptic function-induced cognitive impairment by inhibiting NLRP3 inflammasome activation and improving synaptic plasticity.

Methamphetamine (METH) exposure commonly causes cognitive impairment. An angiotensin II receptor/neprilysin inhibitor (ARNI), LCZ696 has been demonstrated to inhibit inflammation, oxidative stress and apoptosis. The present study was designed to examine the effect of LCZ696 on METH-induced cognitive impairment and the underlying mechanism.

Following daily treatment of either saline or METH (5 mg/kg) for 5 consecutive days, the cognitive function was tested using the Y-maze and the Novel Object Recognition (NOR) in Experiment 1. In Experiment 2, mice were initially treated with saline or LCZ696 (60 mg/kg) for 9 consecutive days, followed by LCZ696, METH or saline for 5 days. Cognitive testing was carried out as Experiment 1. In Experiment 3, SH-SY5Y cells were treated with either METH (2.5 Mm) or ddH2O for 12 h. The apoptosis and reactive oxygen species (ROS) level of SH-SY5Y were examined. In Experiment 4, SH-SY5Y cells were pretreated with either ddH2O or LCZ696 (70um) for 30 min, followed by ddH2O or METH treatment for 12 h. Nrf2 and HO-1 protein expression was examined in the ventral tegemental area (VTA) of all the animals and SH-SY5Y cells.

LCZ696 significantly improved METH-induced cognitive impairment, in conjunction with decreased apoptosis and ROS levels in VTA of METH-treated mice and SH-SY5Y cells. METH significantly decreased Nrf2 and HO-1 protein expression in VTA of mice and SH-SY5Y cells, which was reversed by LCZ696 treatment.

LCZ696 yields a neuroprotective effect against METH-induced cognitive dysfunction via the Nrf2/HO-1 signaling pathway.

With the rapidly increasing prevalence of metabolic diseases such as type 2 diabetes mellitus (T2DM), neuronal complications associated with these diseases have resulted in significant burdens on healthcare systems. Meanwhile, effective therapies have remained insufficient. A novel fatty acid called S-9-PAHSA has been reported to provide metabolic benefits in T2DM by regulating glucose metabolism. However, whether S-9-PAHSA has a neuroprotective effect in mouse models of T2DM remains unclear.

This in vivo study in mice fed a high-fat diet (HFD) for 5 months used fasting blood glucose, glucose tolerance, and insulin tolerance tests to examine the effect of S-9-PAHSA on glucose metabolism. The Morris water maze test was also used to assess the impact of S-9-PAHSA on cognition in the mice, while the neuroprotective effect of S-9-PAHSA was evaluated by measuring the expression of proteins related to apoptosis and oxidative stress. In addition, an in vitro study in PC12 cells assessed apoptosis, oxidative stress, and mitochondrial membrane potential with or without CAIII knockdown to determine the role of CAIII in the neuroprotective effect of S-9-PAHSA.

S-9-PAHSA reduced fasting blood glucose levels significantly, increased insulin sensitivity in the HFD mice and also suppressed apoptosis and oxidative stress in the cortex of the mice and PC12 cells in a diabetic setting. By suppressing oxidative stress and apoptosis, S-9-PAHSA protected both neuronal cells and microvascular endothelial cells in in vivo and in vitro diabetic environments. Interestingly, this protective effect of S-9-PAHSA was reduced significantly when CAIII was knocked down in the PC12 cells, suggesting that CAIII has a major role in the neuroprotective effect of S-9-PAHSA. However, overexpression of CAIII did not significantly enhance the protective effect of S-9-PAHSA.

S-9-PAHSA mediated by CAIII has the potential to exert a neuroprotective effect by suppressing apoptosis and oxidative stress in neuronal cells exposed to diabetic conditions. Furthermore, S-9-PAHSA has the capability to reduce fasting blood glucose and LDL levels and enhance insulin sensitivity in mice fed with HFD.

Overproduction of reactive oxygen species by damaged mitochondria after ischemia is a key factor in the subsequent cascade of damage. Delivery of therapeutic agents to the mitochondria of damaged neurons in the brain is a potentially promising targeted therapeutic strategy for the treatment of ischemic stroke. In this study, we developed a ceria nanoenzymes synergistic drug-carrying nanosystem targeting mitochondria to address multiple factors of ischemic stroke. Each component of this nanosystem works individually as well as synergistically, resulting in a comprehensive therapy. Alleviation of oxidative stress and modulation of the mitochondrial microenvironment into a favorable state for ischemic tolerance are combined to restore the ischemic microenvironment by bridging mitochondrial and multiple injuries. This work also revealed the detailed mechanisms by which the proposed nanodelivery system protects the brain, which represents a paradigm shift in ischemic stroke treatment.

The relationship between oncological pathologies and neurodegenerative disorders is extremely complex and is a topic of concern among a growing number of researchers around the world. In recent years, convincing scientific evidence has accumulated that indicates the contribution of a number of etiological factors and pathophysiological processes to the pathogenesis of these two fundamentally different diseases, thus demonstrating an intriguing relationship between oncology and neurodegeneration. In this review, we establish the general links between three intersecting aspects of oncological pathologies and neurodegenerative disorders, i.e., oxidative stress, epigenetic dysregulation, and metabolic dysfunction, examining each process in detail to establish an unusual epidemiological relationship. We also focus on reviewing the current trends in the research and the clinical application of the most promising chemical structures and therapeutic platforms that have a modulating effect on the above processes. Thus, our comprehensive analysis of the set of molecular determinants that have obvious cross-functional pathways in the pathogenesis of oncological and neurodegenerative diseases can help in the creation of advanced diagnostic tools and in the development of innovative pharmacological strategies.

dl-3-n-Butylphthalide is a potent synthetic Chinese celery extract that is highly efficient in inducing neuroprotection in concussive head injury (CHI), Parkinson's disease, Alzheimer's disease, stroke as well as depression, dementia, anxiety and other neurological diseases. Thus, there are reasons to believe that dl-3-n-butylphthalide could effectively prevent Alzheimer's disease brain pathology. Military personnel during combat operation or veterans are often the victims of brain injury that is a major risk factor for developing Alzheimer's disease in their later lives. In our laboratory we have shown that CHI exacerbates Alzheimer's disease brain pathology and reduces the amyloid beta peptide (AβP) inactivating enzyme neprilysin. We have used TiO2 nanowired-dl-3-n-butylphthalide in attenuating Parkinson's disease brain pathology exacerbated by CHI. Nanodelivery of dl-3-n-butylphthalide appears to be more potent as compared to the conventional delivery of the compound. Thus, it would be interesting to examine the effects of nanowired dl-3-n-butylphthalide together with nanowired delivery of neprilysin in Alzheimer's disease model on brain pathology. In this investigation we found that nanowired delivery of dl-3-n-butylphthalide together with nanowired neprilysin significantly attenuated brain pathology in Alzheimer's disease model with CHI, not reported earlier. The possible mechanism and clinical significance is discussed based on the current literature.

Renal ischemia-reperfusion (I/R) injury leads to irreversible brain damage with serious consequences. Activation of oxidative stress and release of inflammatory mediators are considered potential pathological mechanisms. Butylphthalide (NBP) has anti-inflammatory and antioxidant effects on I/R injuries. However, it is unclear whether NBP can effectively mitigate renal I/R secondary to brain injury as well as its mechanism, which are the aims of this study. Both renal I/R injury rats and oxygen and glucose deprivation cell models were established and pre-intervened NBP. The Morris water maze assay was used to detect behavior. Hippocampal histopathology and function were examined after renal I/R. Apoptosis and tube-forming capacity of brain microvascular endothelial cells (BMVECs) were tested. Immunohistochemistry and Western blot were used to measure protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) pathway and NOD-like receptor C2 (NOD2)/Mitogen-activated protein kinases (MAPK)/Nuclear factor kappa-B (NF-κB) pathway. NBP treatment attenuated renal I/R-induced brain tissue damage and learning and memory dysfunction. NBP treatment inhibited apoptosis and promoted blood-brain barrier restoration and microangiogenesis. Also, it decreased oxidative stress levels and pro-inflammatory factor expression in renal I/R rats. Furthermore, NBP enhanced BMVECs' viability and tube-forming capacity while inhibiting apoptosis and oxidative stress. Notably, the alleviating effects of NBP were attributed to Nrf2/HO-1 pathway activation and NOD2/MAPK/NF-κB inhibition. This study demonstrates that NBP maintains BBB function by activating the Nrf2/HO-1 pathway and inhibiting the NOD2/MAPK/NF-κB pathway to suppress inflammation and oxidative stress, thereby alleviating renal I/R-induced brain injury.

Dl-3-n-butylphthalide (DL-NBP) has good neuroprotective function and is safe for use in patients with acute ischaemic stroke. DL-NBP induced anaphylactic shock is rarely reported. Here we describe the case of a 75-year-old woman who received an injection of DL-NBP (25 mg/100 mL intravenously guttae, twice daily) for acute ischaemic stroke. Approximately 5 min after the DL-NBP injection was administered, the patient developed a decrease in blood pressure and an increase in heart rate along with skin pruritus, mottlement of the lower limbs, discomfort, and the desire to defecate, following which DL-NBP was discontinued immediately. The patient recovered with antiallergic therapy and could tolerate further treatment. We emphasise that the increased use of DL-NBP in recent year raises the importance of attention to potential allergies in clinical use, especially in patients with a history of allergies to multiple drugs.

Apium graveolens is an indigenous plant in the family Apiaceae, or Umbelliferae, that contains many active compounds. It has been used traditionally to treat arthritic conditions, gout, and urinary infections. The authors conducted a scoping review to assess the quality of available evidence on the overall effects of celery when treating neurological disorders. A systematic search was performed using predetermined keywords in selected electronic databases. The 26 articles included upon screening consisted of 19 in vivo studies, 1 published clinical trial, 4 in vitro studies and 2 studies comprising both in vivo and in vitro methods. A. graveolens and its bioactive phytoconstituent, 3-n-butylphthalide (NBP), have demonstrated their effect on neurological disorders such as Alzheimer's disease, Parkinson's disease, stroke-related neurological complications, depression, diabetes-related neurological complications, and epilepsy. The safety findings were minimal, showing that NBP is safe for up to 18 weeks at 15 mg/kg in animal studies, while there were adverse effects (7%) reported when consuming NBP for 24 weeks at 600 mg daily in human trials. In conclusion, the safety of A. graveolens extract and NBP can be further investigated clinically on different neurological disorders based on their potential role in different targeted pathways.

Cognitive dysfunction is increasingly recognized as a complication and comorbidity of diabetes, supported by evidence of abnormal brain structure and function. Although few mechanistic metabolic studies have shown clear pathophysiological links between diabetes and cognitive dysfunction, there are several plausible ways in which this connection may occur. Since, brain functions require a constant supply of glucose as an energy source, the brain may be more susceptible to abnormalities in glucose metabolism. Glucose metabolic abnormalities under diabetic conditions may play an important role in cognitive dysfunction by affecting glucose transport and reducing glucose metabolism. These changes, along with oxidative stress, inflammation, mitochondrial dysfunction, and other factors, can affect synaptic transmission, neural plasticity, and ultimately lead to impaired neuronal and cognitive function. Insulin signal triggers intracellular signal transduction that regulates glucose transport and metabolism. Insulin resistance, one hallmark of diabetes, has also been linked with impaired cerebral glucose metabolism in the brain. In this review, we conclude that glucose metabolic abnormalities play a critical role in the pathophysiological alterations underlying diabetic cognitive dysfunction (DCD), which is associated with multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, inflammation, and others. Brain insulin resistance is highly emphasized and characterized as an important pathogenic mechanism in the DCD.