Significant Neuroprotective Effects Research Articles

Protective Effect of Ferulic Acid on Acetylcholinesterase and Amyloid Beta Peptide Plaque Formation in Alzheimer's Disease: An In Vitro Study.

Aim This study aims to comprehensively evaluate the effects of ferulic acid (FA) on acetylcholinesterase (AChE) enzyme activity and amyloid beta (Aβ) peptide plaque formation in an in vitro model of Alzheimer's disease (AD). Background ADis a progressive neurological condition marked by disrupted cholinergic signaling, accumulation of Aβ peptide, and tau protein hyperphosphorylation. Currently, no direct anti-Alzheimer drug that effectively prevents the cognitive decline from AD has been reported. To combat this, a multi-target drug addressing several molecular aspects would be ideal for AD. Natural compounds are preferred over synthetic drugs due to their accessibility, cost-efficiency, and lower toxicity The proven association between polyphenolconsumption and the prevention of AD has led to the investigation of the effect of FA, a polyphenolic compound, on acetylcholinesterase enzyme activity and Aβ peptide formation, the key targets of AD. Materials and method The free radical scavenging ability of FA was assessed by xanthine oxidase inhibitory activity. Furthermore, FA was also evaluated for its inhibitory activity against AChE enzyme and amyloid beta peptide formation to evaluate the neuroprotective potential of FA. Results The results showed that FA has the potential to be an AChE inhibitor, thus helping in blocking the activity of AChE and also reducing the incidence of amyloid beta plaque formation. Furthermore, the compound also exhibited a significant antioxidant property which was demonstrated by the xanthine oxidase enzyme inhibitory effect. Conclusion From the observed results, FA has significant antioxidant and neuroprotective effects which are compared with those of their respective standards. More research is required to determine the efficacy and safety of this compound as a treatment for neurodegenerative diseases like AD because the precise mechanism and degree of its AChE inhibitory effects in the brain are still elusive. A potent, selective, and effective drug is desperately needed to treat patients with AD and those at risk of developing the disease.

High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation

Human monoamine oxidase B (hMAO-B) has emerged as a pivotal therapeutic target for Parkinson's disease. Due to adverse effects and shortage of commercial drugs, there is a need for novel, highly selective, and reversible hMAO-B inhibitors with good blood-brain barrier permeability. In this study, a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma, which resulted in the discovery of 75 active compounds, including phenolic acids, volatile oils, and phthalides, two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent, selective, reversible and had good blood‒brain permeability. Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism. Sedanolide (IC50 = 103 nmol/L; SI = 645) and neocnidilide (IC50 = 131 nmol/L; SI = 207) demonstrated their excellent potential as hMAO-B inhibitors. They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline. In SH-SY5Y cell assays, sedanolide (EC50 = 0.962 μmol/L) and neocnidilide (EC50 = 1.161 μmol/L) exhibited significant neuroprotective effects, comparable to the positive drugs rasagiline (EC50 = 0.896 μmol/L) and safinamide (EC50 = 1.079 μmol/L). These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.

Abstract TP288: Selective Brain Hypothermia Induced by Thermoelectric Cooling

Background: Stroke or Traumatic Brain Injury (TBI) are leading causes of disability and death in the United States. Hypothermia is a known neuronal protectant. Current hypothermia interventions include intravascular, intranasal, and surface brain cooling technologies but these interventions have not been well utilized clinically. Cooling the brain a few degrees below normothermia (T<36°C) has been shown to yield significant neuroprotective effects. Noninvasive surface cooling methods are most desirable given their less patient complications, provided the desired therapeutic hypothermia effect (T 33-36°C) can be maintained. Method: These investigators propose a novel noninvasive solid state technology that employs addressable Peltier thermoelectric cooling elements to generate hypothermia. ThermoPelt’s closed-looped microcontroller design provides the ability to address individual Peltier elements to selectively reduce the temperature of localized regions of the brain, thus allowing precision therapeutic hypothermic conditions to be realized. Results: Assessment of ThermoPelt performance was accomplished with use of virtual prototype (engineering mathematical model representations of the brain) and early, in vitro experimental physical prototype testing. Preliminary results obtained from virtual and physical prototype tests verify ThermoPelt feasibility to achieve hypothermic conditions. Conclusion: In this new method of generating hypothermia, the preliminary findings demonstrate that our noninvasive ThermoPelt technology is capable of reducing brain temperature at controlled rates to selectively target specific head and neck regions.

Mangiferin alleviates 6-OHDA-induced Parkinson's disease by inhibiting AKR1C3 to activate Wnt signaling pathway

Parkinson's disease (PD) is a neurodegenerative disorder with a lack of effective treatment options. mangiferin, a bioactive compound derived from mango, has been shown to possess strong neuroprotective properties. In this study, we investigated the neuroprotective effects of mangiferin on PD and its underlying mechanisms using both in vitro and in vivo models of 6-OHDA-induced PD. Additionally, we conducted molecular docking experiments to evaluate the interaction between mangiferin and AKR1C3 and β-catenin. Our results demonstrated that treatment with mangiferin significantly attenuated 6-OHDA-induced cell damage in PC12 cells, reducing intracellular oxidative stress, improving mitochondrial membrane potential, and restoring the expression of tyrosine hydroxylase (TH), a characteristic protein of dopaminergic neurons. Furthermore, mangiferin reduced the accumulation of α-synuclein and inhibited the expression of AKR1C3, thereby activating the Wnt/β-catenin signaling pathway. In vivo studies revealed that mangiferin improved motor dysfunction in 6-OHDA-induced PD mice. Molecular docking analysis confirmed the interaction between mangiferin and AKR1C3 and β-catenin. These findings indicate that mangiferin exerts significant neuroprotective effects in 6-OHDA-induced PD by inhibiting AKR1C3 and activating the Wnt/β-catenin signaling pathway. Therefore, mangiferin may emerge as an innovative therapeutic strategy in the comprehensive treatment regimen of PD patients, providing them with better clinical outcomes and quality of life.

Dendrobium nobile Lindl. alkaloid decreases Tau hyperphosphorylation via regulating PI3K/Akt/GSK-3β pathway in vitro and in vivo

Ethnopharmacological relevantDendrobium is a traditional and precious Chinese medicinal herb. The Compendium of Materia Medica describes its effects as “benefiting intelligence and dispelling shock, lightning the body and extending life”. Dendrobium nobile Lindl. is a precious variety of Dendrobium. Our previous data showed Dendrobium nobile Lindl. alkaloid (DNLA) has significant neuroprotective effects and can improve cognitive dysfunction. However, the specific effects and mechanisms of action of its main active component, DNLA, on cognitive dysfunction caused by Tau hyperphosphorylation, are still unclear. Aim of the researchThis study aimed to determine the effects of DNLA on phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3β (GSK-3β) pathway, thus to explore the mechanisms of DNLA to inhibit Tau hyperphosphorylation. Materials and methodsWe used wortmannin (WM) and GF-109203X (GFX)-induced hyperphosphorylation of Tau in N2a cells and rats to detect the protective mechanism of DNLA in vivo and in vitro. In vitro, the effect of modeling method on Tau hyperphosphorylation was screened and verified by Western Blotting (WB), and the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3β pathway by different concentrations of DNLA was detected by WB. In vivo, MWM was used to detect the effect of DNLA on model rats, and then Nissl staining was used to detect the loss of neurons. Finally, WB was used to detect the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3β pathway by different concentrations of DNLA. ResultsDNLA could rescue the abnormal PI3K/Akt/GSK-3β pathway and reverse the hyperphosphorylation of Tau induced by WM and GFX in N2a cells. Furthermore, DNLA improved the learning and memory of WM and GFX-induced model rats. Moreover, DNLA regulated PI3K/Akt/GSK-3β pathway and reduced the p-Tau and neuronal damage in the hippocampus of model rats. ConclusionDNLA may be a promising candidate for reducing hyperphosphorylation of Tau.

Neuroprotection and Mechanism of Gas-miR36-5p from Gastrodia elata in an Alzheimer's Disease Model by Regulating Glycogen Synthase Kinase-3β.

Alzheimer's disease (AD) is currently the most common neurodegenerative disease. Glycogen synthase kinase 3β (GSK-3β) is a pivotal factor in AD pathogenesis. Recent research has demonstrated that plant miRNAs exert cross-kingdom regulation on the target genes in animals. Gastrodia elata (G. elata) is a valuable traditional Chinese medicine that has significant pharmacological activity against diseases of the central nervous system (CNS). Our previous studies have indicated that G. elata-specific miRNA plays a cross-kingdom regulatory role for the NF-κB signaling pathway in mice. In this study, further bioinformatics analysis suggested that Gas-miR36-5p targets GSK-3β. Through western blot, RT-qPCR, and assessments of T-AOC, SOD, and MDA levels, Gas-miR36-5p demonstrated its neuroprotective effects in an AD cell model. Furthermore, Gas-miR36-5p was detected in the murine brain tissues. The results of the Morris water maze test and western blot analysis provided positive evidence for reversing the learning deficits and hyperphosphorylation of Tau in AD mice, elucidating significant neuroprotective effects in an AD model following G. elata RNA administration. Our research emphasizes Gas-miR36-5p as a novel G. elata-specific miRNA with neuroprotective properties in Alzheimer's disease by targeting GSK-3β. Consequently, our findings provide valuable insights into the cross-kingdom regulatory mechanisms underlying G. elata-specific miRNA, presenting a novel perspective for the treatment of Alzheimer's disease.

Palladium-catalyzed synthesis and anti-AD biological activity evaluation of N-aryl-debenzeyldonepezil analogues.

A series of novel N-aryl-debenzeyldonepezil derivatives (1-26) were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. In vitro cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue 13 possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Furthermore, Compound 13 did not show significant cytotoxicity on SH-SY5Y. These results suggest that 13 is a potential multifunctional active molecule for treating Alzheimer's disease.

Characterizing cannabis-prevalent terpenes for neuroprotection reveal a role for α and β-pinenes in mitigating amyloid β-evoked neurotoxicity and aggregation in vitro

BackgroundCannabis sativa L. (C. sativa) can efficiently synthesize of over 200 terpenes, including monoterpenes, sesquiterpenes and triterpenes that may contribute to the known biological activities of phytocannabinoids of relevance for the burgeoning access to medicinal cannabis formulations globally; however, to date have been uncharacterized. We assessed twelve predominant terpenes in C. sativa for neuroprotective and anti-aggregative properties in semi-differentiated PC12 neuronal cell line that is robust and validated as a cell model responsive to amyloid β (Aβ1–42) protein exposure and oxidative stress. MethodsCell viability was assessed biochemically using the MTT assay in the presence of myrcene, β-caryophyllene, terpinolene, limonene, linalool, humulene, α-pinene, nerolidol, β-pinene, terpineol, citronellol and friedelin (1–200 μM) for 24 hr. Sub-toxic threshold test concentrations of each terpene were then applied to cells, alone or with concomitant incubation with the lipid peroxidant tert-butyl hyrdroperoxide (t-BHP; 0–250 μM) or amyloid β (Aβ1–42; 0–1 μM) to assess neuroprotective effects. Direct effects of each terpene on Aβ fibril formation and aggregation were also evaluated using the Thioflavin T (ThT) fluorometric kinetic assay and transmission electron microscopy (TEM) to visualize fibril and aggregate morphology. ResultsTerpenes were intrinsically benign to PC12 cells up to 50 μM, with higher concentrations of β-caryophyllene, humulene and nerolidol inducing some loss of PC12 cell viability. No significant protective effects of terpenes were observed following t-BHP (0–200 µM) administration, with some enhanced toxicity instead demonstrated from both β-caryophyllene and humulene treatment (each at 50 µM). α-pinene and β-pinene demonstrated a significant neuroprotective effect against amyloid β exposure. α-pinene, β-pinene, terpineol, terpinolene and friedelin were associated with a variable inhibition of Aβ1–42 fibril and aggregate density. ConclusionsThe outcomes of this study underline a neuroprotective role of α-pinene and β-pinene against Aβ-mediated neurotoxicity associated with an inhibition of Aβ1–42 fibrilization and density. This demonstrates the bioactive potential of selected terpenes for consideration in the development of medicinal cannabis formulations targeting neurodegenerative diseases.

Bovine Serum Albumin Nanoparticles Enhanced the Intranasal Bioavailability of Silybin in Rats.

Silybin (SLB), an important flavonoid from silymarin, displays significant hepatoprotective, anticancer, antioxidant, and neuroprotective effects. However, its therapeutic efficacy is limited by its low solubility and bioavailability. To address these challenges, we engineered bovine serum albumin (BSA) nanoparticles (NP) loaded with SLB (BSA-NP/SLB) using the coacervation method. BSA-SLB NP exhibited a spherical shape, a mean size of 197 nm, a polydispersity index of 0.275, a zeta potential of -34 mV, and an entrapment efficiency of 67%. X-ray diffraction analysis indicated amorphization of SLB upon encapsulation. Formulation stability was upheld over 180 days. In vitro release assays demonstrated controlled diffusion-erosion release, with approximately 40% SLB released within 0.5 h and 100% over 12 h. Intranasal administration of BSA-NP/SLB in rats improved SLB bioavailability by fourfold compared to free SLB. These findings highlight the promising potential of intranasally administered BSA-NP/SLB as an alternative approach to enhance SLB bioavailability, paving the way for innovative therapeutic applications.

Design, synthesis, and evaluation of n-butylphthalide and ligustrazine hybrids as potent neuroprotective agents for the treatment of ischemic stroke in vitro and in vivo

A series of novel NBP-TMP hybrids with neuroprotective effects were designed and synthesized for the treatment of ischemic stroke. The anti-cerebral ischemic activity of these compounds was screened by evaluating their neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cell injury model in vitro. Nine compounds 7e, 7h-7i, 7k, 7m-7p and 7r showed better activities on cell viability and LDH levels compared to NBP at the concentration of 6.25 μM. Among them, compound 7m showed the best potency with a percentage of protection 90.2 % compared to NBP (69.2 %) and other compounds. Preliminary structure-activity analysis revealed that the introduction of iodine and N-methylpiperazine groups could significantly improve the neuroprotective effect. Further mechanism research showed that compound 7m could reduce the damage to neuronal mitochondria caused by OGD/R by reducing ROS and increasing mitochondrial membrane potential (MMP), and reduce the apoptosis and necrosis of neurons to play a neuroprotective role. In addition, 7m could regulate the levels of mitochondrial apoptosis pathway-related proteins Bcl-2, Bax, and caspase 3. Finally, in vivo experiments showed that the compound 7m significantly inhibited ischemia-reperfusion injury and cerebral blood flow in rats, and showed a more significant neuroprotective effect than the positive drug NBP at a dose concentration of 20 mg/kg. In conclusion, our results suggest that 7m may be used as a novel lead compound for the future development of anti-cerebral ischemic agents.

Rare 7,9′-dinorlignans with neuroprotective activity from the roots of Lindera aggregata (Sims) Kosterm

Linderagatins C–F (1−4), the first examples of naturally occurring diaryltetrahydrofuran-type 7,9′-dinorlignans, were characterized from the roots of Lindera aggregata (Sims) Kosterm. The structures of these dinorlignans were elucidated by extensive spectroscopic analysis. The absolute configurations were determined based on calculated and experimental ECD data. A biosynthetic pathway for these dinorlignans was hypothetically proposed. Compounds 2 and 3 showed significant neuroprotective effects on erastin-induced ferroptosis in HT-22 cells with EC50 values of 23.4 and 21.8 μM, respectively.

The study of therapeutic efficacy and mechanisms of Schisandra chinensis and Evodia rutaecarpa combined treatment in a rat model of Alzheimer's disease

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs used to treat neurodegenerative diseases. This study investigates the combined effects of SC and ER on learning and memory in an Alzheimer's disease rat model and their underlying mechanisms. MethodsHigh-performance liquid chromatography was employed to analyze the primary active constituents of Schisandra and Evodia. The effects of the combined treatment of Schisandra and Evodia on learning and memory in an Alzheimer's disease rat model were evaluated through Morris water maze and Hematoxylin-Eosin staining experiments. Immunohistochemical analysis was conducted to investigate the impact of S-E on Aβ1-42 and P-tau proteins. Western blotting and real-time quantitative polymerase chain reaction were utilized to quantify the expression of pivotal proteins and genes within the BDNF/TRKB/CREB and GSK-3β/Tau pathways. ResultsThe treatment group exhibited significant neuroprotective effects, ameliorating learning and memory impairments in the Alzheimer's disease rat model. The treatment regimen modulated the activity of the BDNF/TRKB/CREB and GSK-3β/Tau pathways by influencing the expression of relevant genes, thereby reducing the generation of Aβ1-42 and P-Tau proteins and inhibiting the deposition of senile plaques. Furthermore, among the three treatment groups, the combined treatment demonstrated notably superior therapeutic effects on Alzheimer's disease compared to the single-drug treatment groups.

Mitochondrial trafficking as a protective mechanism against chemotherapy drug-induced peripheral neuropathy: Identifying the key site of action

AimsChemotherapy induced peripheral neuropathy (CIPN) is a common side effect seen in patients who have undergone most chemotherapy treatments to which there are currently no treatment methods. CIPN has been shown to cause axonal degeneration leading to Peripheral Neuropathy (PN), which can lead to major dosage reduction and may prevent further chemotherapy treatment due to oftentimes debilitating pain. Previously, we have determined the site-specific action of Paclitaxel (PTX), a microtubule targeting agent, as well as the neuroprotective effect of Fluocinolone Acetonide (FA) against Paclitaxel Induced Peripheral Neuropathy (PIPN). Main methodsMitochondrial trafficking analysis was determined for all sample sets, wherein FA showed enhanced anterograde (axonal) mitochondrial trafficking leading to neuroprotective effects for all samples. Key findingsUsing this system, we demonstrate that PTX, Monomethyl auristatin E (MMAE), and Vincristine (VCR), are toxic at clinically prescribed levels when treated focally to axons. However, Cisplatin (CDDP) was determined to have a higher toxicity when treated to cell bodies. Although having different targeting mechanisms, the administration of FA was determined to have a significant neuroprotective effect for against all chemotherapy drugs tested. SignificanceThis study identifies key insights regarding site of action and neuroprotective strategies to further development as potential therapeutics against CIPN. FA was treated alongside each chemotherapy drug to identify the neuroprotective effect against CIPN, where FA was found to be neuroprotective for all drugs tested. This study found that treatment with FA led to an enhancement in the anterograde movement of mitochondria based on fluorescent imaging.

SIRT1-dependent mitochondrial biogenesis supports therapeutic effects of vidarabine against rotenone-induced neural cell injury

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, which is distinguished by the loss of dopaminergic (DA) neurons in the substantia nigra and the formation of intraneuronal. Numerous studies showed that the damage and dysfunction of mitochondria may play key roles in DA neuronal loss. Thus, it is necessary to seek therapeutic measures for PD targeting mitochondrial function and biogenesis. In this study, through screening the purchased compound library, we found that marine derived vidarabine had significant neuroprotective effects against rotenone (ROT) induced SH-SY5Y cell injury. Further studies indicated that vidarabine pretreatment significantly protected ROT-treated SH-SY5Y cells from toxicity by preserving mitochondrial morphology, improving mitochondrial function, and reducing cell apoptosis. Vidarabine also reduced the oxidative stress and increased the expression levels of PGC-1α, NRF1, and TFAM proteins, which was accompanied by the increased mitochondrial biogenesis. However, the neuroprotective effects of vidarabine were counteracted in the presence of SIRT1-specific inhibitor Ex-527. Besides, vidarabine treatment attenuated the weight loss, alleviated the motor deficits and inhibited the neuronal injury in the MPTP induced mouse model. Thus, vidarabine may exert neuroprotective effects via a mechanism involving specific connections between the SIRT1-dependent mitochondrial biogenesis and its antioxidant capacity, suggesting that vidarabine has potential to be developed into a novel therapeutic agent for PD.

Li, P HY-021068 alleviates cerebral ischemia-reperfusion injury by inhibiting NLRP1 inflammasome and restoring autophagy function in mice

Cerebral ischemia-reperfusion injury (CIRI) is a severe pathological condition that involves oxidative stress, inflammatory response, and neuronal damage. HY-021068 belongs to a new drug of chemical class 1, which is a potential thromboxane synthase inhibitor. Our preliminary experiment found that HY-021068 has significant anti-neuroinflammatory and neuroprotective effects. However, the protective effect and mechanism of HY-021068 in CIRI remain unclear. To investigate the protective effect and mechanism of HY-021068 in CIRI mice. In mice, CIRI was induced by bilateral common carotid artery occlusion and reperfusion. Mice were treated with HY-021068 or LV-NLRP1-shRNA (lentivirus-mediated shRNA transfection to knock down NLRP1 expression). The locomotor activity, neuronal damage, pathological changes, postsynaptic density protein-95 (PSD-95) expression, NLRP1 inflammasome activation, autophagy markers, and apoptotic proteins were assessed in CIRI mice. In this study, treatment with HY-021065 and LV-NLRP1-shRNA significantly improved motor dysfunction and neuronal damage after CIRI in mice. HY-021065 and NLRP1 knockdown significantly ameliorated the pathological damage and increased PSD-95 expression in the cortex and hippocampus CA1 and CA3 regions. The further studies showed that compared with the CIRI model group, HY-021065 and NLRP1 knockdown treatment inhibited the expressions of NLRP1, ASC, caspase-1, and IL-1β, restored the expressions of p-AMPK/AMPK, Beclin1, LC3II/LC3I, p-mTOR/m-TOR and P62, and regulated the expressions of BCL-2, Caspase3, and BAX in brain tissues of CIRI mice in CIRI mice. These results suggest that HY-021068 exerts a protective role in CIRI mice by inhibiting NLRP1 inflammasome activation and regulating autophagy function and neuronal apoptosis. HY-021068 is expected to become a new therapeutic drug for CIRI.

Neuroprotective Bioorthogonal Catalysis in Mitochondria Using Protein‐Integrated Hydrogen‐Bonded Organic Frameworks

AbstractMitochondria‐targeted bioorthogonal catalysis holds promise for controlling cell function precisely, yet achieving selective and efficient chemical reactions within organelles is challenging. In this study, we introduce a new strategy using protein‐integrated hydrogen‐bonded organic frameworks (HOFs) to enable synergistic bioorthogonal chemical catalysis and enzymatic catalysis within mitochondria. Utilizing catalytically active tris(4,4′‐dicarboxylicacid‐2,2′‐bipyridyl) ruthenium(II) to self‐assemble with [1,1′‐biphenyl]‐4,4′‐biscarboximidamide, we synthesized nanoscale RuB‐HOFs that exhibit high photocatalytic reduction activity. Notably, RuB‐HOFs efficiently enter cells and preferentially localize to mitochondria, where they facilitate bioorthogonal photoreduction reactions. Moreover, we show that RuB‐HOFs encapsulating catalase can produce hydrogen sulfide (H2S) in mitochondria through photocatalytic reduction of pro‐H2S and degrade hydrogen peroxide through enzymatic catalysis simultaneously, offering a significant neuroprotective effect against oxidative stress. Our findings not only introduce a versatile chemical toolset for mitochondria‐targeted bioorthogonal catalysis for prodrug activation but also pave the way for potential therapeutic applications in treating diseases related to cellular oxidative stress.

Neuroprotective Bioorthogonal Catalysis in Mitochondria Using Protein-Integrated Hydrogen-Bonded Organic Frameworks.

Mitochondria-targeted bioorthogonal catalysis holds promise for controlling cell function precisely, yet achieving selective and efficient chemical reactions within organelles is challenging. In this study, we introduce a new strategy using protein-integrated hydrogen-bonded organic frameworks (HOFs) to enable synergistic bioorthogonal chemical catalysis and enzymatic catalysis within mitochondria. Utilizing catalytically active tris(4,4'-dicarboxylicacid-2,2'-bipyridyl) ruthenium(II) to self-assemble with [1,1'-biphenyl]-4,4'-biscarboximidamide, we synthesized nanoscale RuB-HOFs that exhibit high photocatalytic reduction activity. Notably, RuB-HOFs efficiently enter cells and preferentially localize to mitochondria, where they facilitate bioorthogonal photoreduction reactions. Moreover, we show that RuB-HOFs encapsulating catalase can produce hydrogen sulfide (H2 S) in mitochondria through photocatalytic reduction of pro-H2 S and degrade hydrogen peroxide through enzymatic catalysis simultaneously, offering a significant neuroprotective effect against oxidative stress. Our findings not only introduce a versatile chemical toolset for mitochondria-targeted bioorthogonal catalysis for prodrug activation but also pave the way for potential therapeutic applications in treating diseases related to cellular oxidative stress.

Identification of Uncaria rhynchophylla in the Potential Treatment of Alzheimer's Disease by Integrating Virtual Screening and In Vitro Validation.

Uncaria rhynchophylla (Gouteng in Chinese, GT) is the main medicine in many traditional recipes in China. It is commonly used to alleviate central nervous system (CNS) disorders, although its mechanism in Alzheimer's disease is still unknown. This study was designed to predict and validate the underlying mechanism in AD treatment, thus illustrating the biological mechanisms of GT in treating AD. In this study, a PPI network was constructed, KEGG analysis and GO analysis were performed, and an "active ingredient-target-pathway" network for the treatment of Alzheimer's disease was constructed. The active ingredients of GT were screened out, and the key targets were performed by molecular docking. UHPLC-Q-Exactive Orbitrap MS was used to screen the main active ingredients and was compared with the network pharmacology results, which verified that GT did contain the above ingredients. A total of targets were found to be significantly bound up with tau, Aβ, or Aβ and tau through the network pharmacology study. Three SH-SY5Y cell models induced by okadaic acid (OA), Na2S2O4, and H2O2 were established for in vitro validation. We first found that GT can reverse the increase in the hyperphosphorylation of tau induced by OA to some extent, protecting against ROS damage. Moreover, the results also indicated that GT has significant neuroprotective effects. This study provides a basis for studying the potential mechanisms of GT in the treatment of AD.

Different ratios of Schisandra chinensis and Evodia rutaecarpa combination for treating Alzheimer's disease.

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs that have been used for many years to treat neurodegenerative diseases. In Chinese medicine, multiple herbs are often used in combination to enhance their efficacy, and different combination ratios can produce different therapeutic effects, thus flexibly responding to the needs of various patients. This study aimed to investigate the effects of different ratios of Schisandra and Evodia herbs on learning and memory impairment in rats with Alzheimer's disease (AD) and their specific mechanisms of action. Morris water maze and hematoxylin and eosin (HE) staining experiments were performed to evaluate the effects of different ratios of Schisandra-Evodia on learning memory in AD model rats. Immunohistochemical experiments were performed to investigate the effects of Schisandra-Evodia on the Aβ1-42 and P-Tau proteins, and protein immunoblotting (WB) was performed to determine the expression of key proteins in two pathways, BDNF/TrkB/CREB and GSK-3β/Tau. Our experimental results show that all Schisandra-Evodia groups showed significant neuroprotective effects, improved learning memory impairment, and reduced levels of Aβ1-42 and P-Tau proteins in AD model rats. Schisandra-Evodia upregulated BDNF, P-TrkB/TrkB, and P-CREB/CREB protein expression and downregulated GSK-3β and P-Tau/Tau protein expression. Among the different Schisandra-Evodia ratio groups, the 2:1 group showed the strongest therapeutic effect on AD. Our research results indicate that Schisandra-Evodia can reduce Aβ1-42 and P-Tau protein content by modulating the activity of two pathways, BDNF/TrkB/CREB and GSK-3β/Tau, thus improving neuronal cell damage and cognitive deficits caused by AD. In addition, we found that a Schisandra-Evodia ratio of 2:1 had the most profound therapeutic effect on AD.

Design and synthesis of 9-phenanthranilamide derivatives and the study of anti-inflammatory, antioxidant and neuroprotective activities

Oxidative stress and a series of excessive inflammatory responses are major obstacles to neurological functional recovery after ischemic stroke. In this study, we synthesized several novel 9-phenanthranilamide derivatives and evaluated their anti-inflammatory and antioxidant activities. Among the initially screened compounds, most could strongly inhibi lipopolysaccharide (LPS)-stimulated production of IL-1β, IL-6 and TNF-α in microglial cells. Additionally, compounds 8b, 8q, 8r and 8s significantly inhibited the production of NO, and they also had dose-dependent protective effects on PC12 neuronal cells induced by H2O2. The antineuroinflammatory effects of 8r and 8s were associated with the downregulation of LPS-induced inflammatory mediators of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and both compounds inhibited the NF-κB signaling pathway. Further examinations showed that 8s had a significant neuroprotective effect on rats with middle cerebral artery occlusion (MCAO). It decreased the infarct volume and the neurological deficit score. Overall, our results suggested that compound 8s might be a promising agent for stroke treatment.