Intelligent responsive copper-diethyldithiocarbamate-based multifunctional nanomedicine for photothermal-augmented synergistic cancer therapy.

The design of multifunctional nanomedicine through the combination of multimodal treatments to achieve the optimal antitumor effect is essential for cancer therapy. Herein, we design and develop a multifunctional theranostic nanoplatform using an iron ion-doxorubicin (DOX) nanoscale coordination polymer (Fe/DOX NCP) as a shell coating on the surface of polyvinyl pyrrolidone (PVP) stabilized copper-diethyldithiocarbamate nanoparticles (Cu(DDC)2 NPs) for combined tumor chemo-/photothermal/chemodynamic therapy. The obtained Cu(DDC)2@Fe/DOX NPs display pH/laser dual-responsive degradation behavior and also exhibit favorable photothermal performance. Under 808 nm laser irradiation, Cu(DDC)2@Fe/DOX NPs can convert light into heat, which not only kills tumor cells via hyperthermia in photothermal therapy (PTT), but also accelerates the degradation of Fe/DOX NCPs to release Fe3+ and DOX. The liberated Fe3+ can be used to catalyze hydrogen peroxide via the Fenton reaction to produce highly toxic hydroxyl radicals (˙OH) in chemodynamic therapy (CDT). The released DOX and the exposed Cu(DDC)2 can cause significant cell death in combined chemotherapy via a superimposed effect. In vitro and in vivo results prove that Cu(DDC)2@Fe/DOX NPs with laser irradiation present remarkable anticancer performances in hyperthermia-enhanced chemo-/CDT. Therefore, this study provides a new strategy for highly efficient synergistic cancer therapy.

Si-Ni-San alleviates early life stress-induced depression-like behaviors in adolescence via modulating Rac1 activity and associated spine plasticity in the nucleus accumbens.

Background: Early life stress (ELS) is a major risk factor for depression in adolescents. The nucleus accumbens (NAc) is a key center of the reward system, and spine remodeling in the NAc contributes to the development of depression. The Si-Ni-San formula (SNS) is a fundamental prescription for treating depression in traditional Chinese medicine. However, little is known about the effects of SNS on behavioral abnormalities and spine plasticity in the NAc induced by ELS. Purpose: This study aimed to investigate the therapeutic effect and the modulatory mechanism of SNS on abnormal behaviors and spine plasticity in the NAc caused by ELS. Methods: We utilized a model of ELS that involved maternal separation with early weaning to explore the protective effects of SNS on adolescent depression. Depressive-like behaviors were evaluated by the sucrose preference test, the tail suspension test, and the forced swimming test; anxiety-like behaviors were monitored by the open field test and the elevated plus maze. A laser scanning confocal microscope was used to analyze dendritic spine remodeling in the NAc. The activity of Rac1 was detected by pull-down and Western blot tests. Viral-mediated gene transfer of Rac1 was used to investigate its role in ELS-induced depression-like behaviors in adolescence. Results: ELS induced depression-like behaviors but not anxiety-like behaviors in adolescent mice, accompanied by an increase in stubby spine density, a decrease in mushroom spine density, and decreased Rac1 activity in the NAc. Overexpression of constitutively active Rac1 in the NAc reversed depression-related behaviors, leading to a decrease in stubby spine density and an increase in mushroom spine density. Moreover, SNS attenuated depression-like behavior in adolescent mice and counteracted the spine abnormalities in the NAc induced by ELS. Additionally, SNS increased NAc Rac1 activity, and the inhibition of Rac1 activity weakened the antidepressant effect of SNS. Conclusion: These results suggest that SNS may exert its antidepressant effects by modulating Rac1 activity and associated spine plasticity in the NAc.

Inhibition of Streptococcus mutans Biofilm Formation by the Joint Action of Oxyresveratrol and Lactobacillus casei.

Microbial dysbiosis in dental plaque contributes to the occurrence of dental caries, to which Streptococcus mutans is a major contributor. Lactobacillus casei can be used as probiotic therapy to treat caries by replacing S. mutans within the dental plaque. However, the effects of probiotic treatment are not always stable. Oxyresveratrol (ORV), a plant-derived polyphenol, displays opposite effects in that it inhibits cariogenic and promotes commensal bacteria. Thus, the objectives of this study are to investigate the effects of ORV on bacterial proportions in S. mutans-L. casei biofilm and to elucidate how ORV weakens the competitiveness of S. mutans. Quantitative real-time PCR confirms a decreased S. mutans-L. casei ratio in dual-species biofilm by action of ORV. The culture supernatant of L. casei after being incubated with ORV (ORVLC) is prepared to explore the joint action of ORV and L. casei. ORVLC displays the strongest anti-biofilm effect against S. mutans when compared with the effects of L. casei supernatant or ORV alone. As a result of this treatment, both exopolysaccharides and bacteria contents in the biofilm are greatly reduced. The biofilm is transformed from water-insoluble glucan-dominant to water-soluble glucan-dominant by ORVLC through the modulation of the glycometabolism-related genes of S. mutans. As for the interactions between ORV and L. casei, ORV promotes L. casei to produce acetic acid, which provides L. casei with a competitive advantage against S. mutans. Taken together, ORV may be very suitable as an adjuvant medicine for probiotic therapy in the control of dental caries. IMPORTANCE The homeostatic imbalance in dental plaque associated with a sharp increase in the number of cariogenic bacteria such as Streptococcus mutans is critical for the occurrence and development of caries. Probiotic therapy can restore ecological balance by replacing cariogenic pathogens with probiotics. The current study innovatively finds that oxyresveratrol, a natural polyphenol, can provide probiotic Lactobacillus casei with competitive dominance in its dual-species biofilm with S. mutans. The joint action of oxyresveratrol and L. casei strongly inhibits the biofilm formation of S. mutans. Additionally, oxyresveratrol promotes L. casei to produce acetic acid, which facilitates L. casei to compete with S. mutans. Through the effects of these two mechanisms, oxyresveratrol leads to a significantly decreased S. mutans-L. casei ratio in their dual-species biofilm. Thus, oxyresveratrol is speculated to be an ideal medicine for the prevention and treatment of caries by regulating oral flora balance.

A Neural Circuit from the Paraventricular Thalamus to the Bed Nucleus of the Stria Terminalis for the Regulation of States of Consciousness during Sevoflurane Anesthesia in Mice.

BACKGROUND: The neural circuitry underlying sevoflurane-induced modulation of consciousness is poorly understood. This study hypothesized that the paraventricular thalamus bed nucleus of the stria terminalis pathway plays an important role in regulating states of consciousness during sevoflurane anesthesia. METHODS: Rabies virus-based transsynaptic tracing techniques were employed to reveal the neural pathway from the paraventricular thalamus to the bed nucleus of the stria terminalis. This study investigated the role of this pathway in sevoflurane anesthesia induction, maintenance, and emergence using chemogenetic and optogenetic methods combined with cortical electroencephalogram recordings. Both male and female mice were used in this study. RESULTS: Both γ-aminobutyric acid-mediated and glutamatergic neurons in the bed nucleus of the stria terminalis receive paraventricular thalamus glutamatergic projections. Chemogenetic inhibition of paraventricular thalamus glutamatergic neurons prolonged the sevoflurane anesthesia emergence time (mean ± SD, hM4D-clozapine N-oxide vs. mCherry-clozapine N-oxide, 281 ± 88 vs. 172 ± 48 s, P < 0.001, n = 24) and decreased the induction time (101 ± 32 vs. 136 ± 34 s, P = 0.002, n = 24), as well as the EC5 0 for the loss or recovery of the righting reflex under sevoflurane anesthesia (mean [95% CI] for the concentration at which 50% of the mice lost their righting reflex, 1.16 [1.12 to 1.20] vs. 1.49 [1.46 to 1.53] vol%, P < 0.001, n = 20; and for the concentration at which 50% of the mice recovered their righting reflex, 0.95 [0.86 to 1.03] vs. 1.34 [1.29 to 1.40] vol%, P < 0.001, n = 20). Similar results were observed during suppression of the paraventricular thalamus bed nucleus-stria terminalis pathway. Optogenetic activation of this pathway produced the opposite effects. Additionally, transient stimulation of this pathway efficiently induced behavioral arousal during continuous steady-state general anesthesia with sevoflurane and reduced the depth of anesthesia during sevoflurane-induced burst suppression. CONCLUSIONS: In mice, axonal projections from the paraventricular thalamic neurons to the bed nucleus of the stria terminalis contribute to regulating states of consciousness during sevoflurane anesthesia.

Carbon Dots with Intrinsic Bioactivities for Photothermal Optical Coherence Tomography, Tumor-Specific Therapy and Postoperative Wound Management.

Carbon dots (CDs) are considered as promising candidates with superior biocompatibilities for multimodel cancer theranostics. However, incorporation of exogenous components, such as targeting molecules and chemo/photo therapeutic drugs, is often required to improve the therapeutic efficacy. Herein, an "all-in-one" CDs that exhibit intrinsic bioactivities for bioimaging, potent tumor therapy, and postoperative management is proposed. The multifunctional CDs derived from gallic acid and tyrosine (GT-CDs) consist of a graphitized carbon core and N, O-rich functional groups, which endow them with a high near-infrared (NIR) photothermal conversion efficiency of 33.9% and tumor-specific cytotoxicity, respectively. A new imaging modality, photothermal optical coherence tomography, is introduced using GT-CDs as the contrast agent, offering the micrometer-scale resolution 3D tissue morphology of tumor. For cancer therapy, GT-CDs initiate the intracellular generation of reactive oxygen species in tumor cells but not normal cells, further induce the mitochondrial collapse and subsequent tumor cellular apoptosis. Combined with NIR photothermal treatment, synergistic antitumor therapy is achieved in vitro and in vivo. GT-CDs also promote the healing process of bacteria-contaminated skin wound, demonstrating their potential to prevent postoperative infection. The integrated theranostic strategy based on versatile GT-CDs supplies an alternative easy-to-handle pattern for disease management.

The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization.

The metal cation symporter ZIP8 (SLC39A8) is a transmembrane protein that imports the essential micronutrients iron, manganese, and zinc, as well as heavy toxic metal cadmium (Cd). It has been recently suggested that selenium (Se), another essential micronutrient that has long been known for its role in human health and cancer risk, may also be transported by the ZIP8 protein. Several mutations in the ZIP8 gene are associated with the aberrant ion homeostasis of cells and can lead to human diseases. However, the intricate relationships between ZIP8 mutations, cellular Se homeostasis, and human diseases (including cancers and illnesses associated with Cd exposure) have not been explored. To further verify if ZIP8 is involved in cellular Se transportation, we first knockout (KO) the endogenous expression of ZIP8 in the HeLa cells using the CRISPR/Cas9 system. The elimination of ZIP8 expression was examined by PCR, DNA sequencing, immunoblot, and immunofluorescence analyses. Inductively coupled plasma mass spectrometry indicated that reduced uptake of Se, along with other micronutrients and Cd, was observed in the ZIP8-KO cells. In contrast, when ZIP8 was overexpressed, increased Se uptake could be detected in the ZIP8-overexpressing cells. Additionally, we found that ZIP8 with disease-associated single-point mutations G38R, G204C, and S335T, but not C113S, showed reduced Se transport ability. We then evaluated the potential of Se on Cd cytotoxicity prevention and therapy of cancers. Results indicated that Se could suppress Cd-induced cytotoxicity via decreasing the intracellular Cd transported by ZIP8, and Se exhibited excellent anticancer activity against not all but only selected cancer cell lines, under restricted experimental conditions. Moreover, clinical-based bioinformatic analyses revealed that up-regulated ZIP8 gene expression was common across multiple cancer types, and selenoproteins that were significantly co-expressed with ZIP8 in these cancers had been identified. Taken together, this study concludes that ZIP8 is an important protein in modulating cellular Se levels and provides insights into the roles of ZIP8 and Se in disease prevention and therapy.

Exploration of the Modulatory Property Mechanism of ELeng Capsule in the Treatment of Endometriosis Using Transcriptomics Combined With Systems Network Pharmacology.

Endometriosis is a common gynecological disease and causes severe chronic pelvic pain and infertility. Growing evidence showed that traditional Chinese medicine (TCM) plays an active role in the treatment of endometriosis. ELeng Capsule (ELC) is a Chinese medicine formula used for the treatment of endometriosis for several years. However, the mechanisms of ELC have not been fully characterized. In this study, network pharmacology and mRNA transcriptome analysis were used to study various therapeutic targets in ELC. As a result, 40 compounds are identified, and 75 targets overlapped with endometriosis-related proteins. The mechanism of ELC for the treatment of endometriosis is based on the function modules of inducing apoptosis, inhibiting angiogenesis, and regulating immunity mainly through signaling molecules and interaction (neuroactive ligand-receptor interaction), immune system-associated pathways (toll-like receptor signaling pathway), vascular endothelial growth factor (VEGF) signaling, and MAPK signaling pathway based on network pharmacology. In addition, based on RNA-sequence analysis, we found that the mechanism of ELC was predominantly associated with the regulation of the function modules of actin and cytoskeleton, epithelial-mesenchymal transition (EMT), focal adhesion, and immunity-associated pathways. In conclusion, ELC exerted beneficial effects on endometriosis, and the potential mechanism could be realized through functional modules, such as inducing apoptosis and regulating angiogenesis, cytoskeleton, and EMT. This work not only provides insights into the therapeutic mechanism of TCM for treating endometriosis but also offers an efficient way for drug discovery and development from herbal medicine.

Short reaction times coupled with alkalization improves the release of phosphorus from Al-waste activated sludge.

In this study, the performance and mechanism of P release from Al-waste activated sludge (WAS) via wet-chemical treatment at different reaction times were investigated. The maximum P release (46% of TP) was achieved at 20 min when the pH was maintained at 2 during acidic treatment. During alkali treatment, the maximum P concentration (363.96 mg/L, 46.07%) was achieved at 10 min when pH was initially adjusted to 12. Acidic treatment took twice as long to achieve the same efficiency of released P as the alkali treatment. Furthermore, P release mainly originated from Al-P and Ca-P during acidic treatment and Al-P dissolution during alkali treatment. The cost of chemical consumption was 483.96 USD/ton TS sludge with acidic treatment, which was 8.49 times higher than that of alkali treatment without pH control. Thus, short reaction times (ca. 10 min) coupled with alkalization provide an effective approach for improving P release from Al-WAS.

Monochromatic Blue Light Activates Suprachiasmatic Nucleus Neuronal Activity and Promotes Arousal in Mice Under Sevoflurane Anesthesia.

Background: Monochromatic blue light (MBL), with a wavelength between 400-490 nm, can regulate non-image-forming (NIF) functions of light in the central nervous system. The suprachiasmatic nucleus (SCN) in the brain is involved in the arousal-promoting response to blue light in mice. Animal and human studies showed that the responsiveness of the brain to visual stimuli is partly preserved under general anesthesia. Therefore, this study aimed to investigate whether MBL promotes arousal from sevoflurane anesthesia via activation of the SCN in mice. Methods: The induction and emergence time of sevoflurane anesthesia under MBL (460 nm and 800 lux) exposure was measured. Cortical electroencephalograms (EEGs) were recorded and the burst-suppression ratio (BSR) was calculated under MBL during sevoflurane anesthesia. The EEGs and local field potential (LFP) recordings with or without locally electrolytic ablated bilateral SCN were used to further explore the role of SCN in the arousal-promoting effect of MBL under sevoflurane anesthesia. Immunofluorescent staining of c-Fos was conducted to reveal the possible downstream mechanism of SCN activation. Results: Unlike the lack of effect on the induction time, MBL shortened the emergence time and the EEG recordings showed cortical arousal during the recovery period. MBL resulted in a significant decrease in BSR and a marked increase in EEG power at all frequency bands except for the spindle band during 2.5% sevoflurane anesthesia. MBL exposure under sevoflurane anesthesia enhances the neuronal activity of the SCN. These responses to MBL were abolished in SCN lesioned (SCNx) mice. MBL evoked a high level of c-Fos expression in the prefrontal cortex (PFC) and lateral hypothalamus (LH) compared to polychromatic white light (PWL) under sevoflurane anesthesia, while it exerted no effect on c-Fos expression in the ventrolateral preoptic area (VLPO) and locus coeruleus (LC) c-Fos expression. Conclusions: MBL promotes behavioral and electroencephalographic arousal from sevoflurane anesthesia via the activation of the SCN and its associated downstream wake-related nuclei. The clinical implications of this study warrant further study.

Oxyresveratrol promotes biofilm formation, cell attachment and aggregation of Streptococcus gordonii in the presence of sucrose.

Streptococcus gordonii is a commensal colonizer of oral cavity that initiates the formation of dental plaque. Oxyresveratrol is a natural purification from plants with antibacterial effects on various oral bacteria including Streptococcus mutans. The aim of this study was to investigate the effects of oxyresveratrol on S. gordonii. The basic viability, biofilm formation and cell aggregation of S. gordonii treated with oxyresveratrol were investigated. Oxyresveratrol dose-dependently inhibited the growth of S. gordonii in the absence of sucrose. However, in the presence of sucrose, it promoted biofilm formation under MIC. Both the biofilm formation and extracellular polysaccharides synthesis reached the maximum level at ½ MIC (250 µg/mL) oxyresveratrol. The gene expressions of abpA, abpB, scaA, gtfG, hsa, cshA, cshB, ccpA, srtA and sspB were upregulated when treated with 62.5 and 125 µg/mL oxyresveratrol. A total eight of the ten genes were significantly upregulated at 250 µg/mL oxyresveratrol except abpB and sspB, which were downregulated at 250 µg/mL without significance. In conclusion, oxyresveratrol has dual-effects on S. gordonii. Considering its specific biofilm suppressive effect on S. mutans, it might be a candidate for bacterial interspecies modulator applied in caries prevention.

Modular Characteristics and Mechanism of Action of Herbs for Endometriosis Treatment in Chinese Medicine: A Data Mining and Network Pharmacology-Based Identification.

Endometriosis is a common benign disease in women of reproductive age. It has been defined as a disorder characterized by inflammation, compromised immunity, hormone dependence, and neuroangiogenesis. Unfortunately, the mechanisms of endometriosis have not yet been fully elucidated, and available treatment methods are currently limited. The discovery of new therapeutic drugs and improvements in existing treatment schemes remain the focus of research initiatives. Chinese medicine can improve the symptoms associated with endometriosis. Many Chinese herbal medicines could exert antiendometriosis effects via comprehensive interactions with multiple targets. However, these interactions have not been defined. This study used association rule mining and systems pharmacology to discover a method by which potential antiendometriosis herbs can be investigated. We analyzed various combinations and mechanisms of action of medicinal herbs to establish molecular networks showing interactions with multiple targets. The results showed that endometriosis treatment in Chinese medicine is mainly based on methods of supplementation with blood-activating herbs and strengthening qi. Furthermore, we used network pharmacology to analyze the main herbs that facilitate the decoding of multiscale mechanisms of the herbal compounds. We found that Chinese medicine could affect the development of endometriosis by regulating inflammation, immunity, angiogenesis, and other clusters of processes identified by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The antiendometriosis effect of Chinese medicine occurs mainly through nervous system-associated pathways, such as the serotonergic synapse, the neurotrophin signaling pathway, and dopaminergic synapse, among others, to reduce pain. Chinese medicine could also regulate VEGF signaling, toll-like reporter signaling, NF-κB signaling, MAPK signaling, PI3K-Akt signaling, and the HIF-1 signaling pathway, among others. Synergies often exist in herb pairs and herbal prescriptions. In conclusion, we identified some important targets, target pairs, and regulatory networks, using bioinformatics and data mining. The combination of data mining and network pharmacology may offer an efficient method for drug discovery and development from herbal medicines.

Effects of the natural compound, oxyresveratrol, on the growth of Streptococcus mutans, and on biofilm formation, acid production, and virulence gene expression.

Streptococcus mutans is one of the major pathogens of dental caries. Oxyresveratrol, a natural compound found in plants, exerts inhibitory effects on many bacterial species but its effect on S. mutans is unknown. The objective of this study was to clarify the antibacterial effect of oxyresveratrol on S. mutans, including effects on basic viability, acidogenicity, acidurity, and extracellular polysaccharide synthesis. The expression of nine genes that encode virulence and protective factors in S. mutans was measured by qRT-PCR. Oxyresveratrol showed a dose-dependent inhibitory effect on survival of S. mutans. At 250 µg ml-1 , oxyresveratrol reduced the S. mutans survival rate, inhibited synthesis of water-insoluble glucans, compromised biofilm formation, and significantly down-regulated the expression of glucosyltransferase-I (gtfB) and glucosyltransferase-SI (gtfC). However, the enzymatic activity of lactate dehydrogenase protein was increased and the expression of lactate dehydrogenase (ldh) and ATP synthase subunit beta (atpD) genes were also up-regulated. Besides, glucosyltransferase S (gtfD) up-regulation indicated that water-soluble glucan synthesis was promoted. The vicR, liaR, and comDE genes, which exert a self-protective function in response to external stress, were also up-regulated. In conclusion, oxyresveratrol inhibited the growth of S. mutans and also reduced biofilm formation, acid production, and synthesis of water-insoluble glucans by this organism. In addition, oxyresveratrol also activated a series of S. mutans self-protection mechanisms.

Effects of Phytosterol Ester on the Fatty Acid Profiles in Rats with Nonalcoholic Fatty Liver Disease.

Both serum and hepatic fatty acid (FA) compositions differ among nonalcoholic hepatic steatosis, nonalcoholic steatohepatitis, and healthy subjects. The severity of the above liver disease is closely associated with the concentration and composition of FAs. Our previous study found that phytosterol ester (PSE) could alleviate hepatic steatosis in nonalcoholic fatty liver disease rats. The aims of this work were to explore the effects of PSE (0.05/100 g·body weight) on FA profiles and the mRNA levels of FA metabolism-related genes. Compared with a high-fat diet alone group, PSE treatment significantly decreased hepatic saturated fatty acid levels (P < .05) and increased monounsaturated fatty acid (especially C16:1 n-7) levels in the liver, serum, and adipose tissue and polyunsaturated fatty acid levels in the serum and liver (P < .05) after 12 weeks of intervention. In particular, PSE treatment increased the level of C22:5 n-3, an FA that was negatively correlated with the degree of hepatic steatosis in the serum, liver, and adipose tissue. The increases in some unsaturated fatty acids are probably related to the upregulation of stearoyl-coenzyme A desaturase-1 and fatty acid desaturase-1.

Danggui Buxue Decoction, a Classical Formula of Traditional Chinese Medicine, Fails to Prevent Myelosuppression in Breast Cancer Patients Treated With Adjuvant Chemotherapy: A Prospective Study.

Danggui Buxue Decoction (DBD), a classical formula of traditional Chinese medicine (TCM), has an impact on promoting hematopoiesis. The aim of our study was to determine whether DBD can prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. We conducted a phase II randomized prospective controlled clinical study. From December 2013 to February 2015, 106 patients were enrolled and randomly assigned (1:1) to the TCM group and control group. The primary end point was incidence of grade 3-4 neutropenia. The secondary end points included incidence of grade 3-4 neutropenia in each cycle, incidence of anemia, and incidence of thrombopenia during 4 cycles. Seventeen patients withdrew from this study, and 89 patients were included in the final analysis. Incidences of grade 3-4 neutropenia during 4 cycles were 57.1% in the TCM group and 59.6% in the control group, and there was no significant difference ( P = .816). Similarly, no significant differences were observed between the 2 groups for incidence of grade 3-4 neutropenia in each cycle. While incidences of anemia were 54.8% and 66.6% for the TCM group and control group, respectively ( P = .280), incidences of thrombopenia were 11.9% for the TCM group and 4.3% for the control group ( P = .248). No significant differences were observed for the incidence of other nonhematological toxicities between the 2 groups. DBD failed to prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. Further studies are warranted to validate the efficacy of DBD in selected patients.

Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aß and Tau pathologies.

Considering the complicated pathogenesis of Alzheimer's disease (AD), multi-targets have become a focus in the discovery of drugs for treatment of this disease. In the current work, we established a multi-target strategy for discovering active reagents capable of suppressing both Aß level and Tau hyperphosphorylation from natural products, and found that the ethanol extract of Thamnolia vermicularis (THA) was able to improve learning ability in APP/PS1 transgenic mice by inhibiting both Aß levels and Tau hyperphosphorylation. SH-SY5Y and CHO-APP/BACE1 cells and primary astrocytes were used in cell-based assays. APP/PS1 transgenic mice [B6C3-Tg(APPswe, PS1dE9)] were administered THA (300 mg·kg-1·d-1, ig) for 100 d. After the administration was completed, the learning ability of the mice was detected using a Morris water maze (MWM) assay; immunofluorescence staining, Congo red staining and Thioflavine S staining were used to detect the senile plaques in the brains of the mice. ELISA was used to evaluate Aß and sAPPß contents, and Western blotting and RT-PCR were used to investigate the relevant signaling pathway regulation in response to THA treatment. In SH-SY5Y cells, THΑ (1, 10, 20 µg/mL) significantly stimulated PI3K/AKT/mTOR and AMPK/raptor/mTOR signaling-mediated autophagy in the promotion of Aß clearance as both a PI3K inhibitor and an AMPK indirect activator, and restrained Aß production as a suppressor against PERK/eIF2α-mediated BACE1 expression. Additionally, THA functioned as a GSK3ß inhibitor with an IC50 of 1.32±0.85 µg/mL, repressing Tau hyperphosphorylation. Similar effects on Aß accumulation and Tau hyperphosphorylation were observed in APP/PS1 transgenic mice treated with THA. Furthermore, administration of THA effectively improved the learning ability of APP/PS1 transgenic mice, and markedly reduced the number of senile plaques in their hippocampus and cortex. The results highlight the potential of the natural product THA for the treatment of AD.