A selenium-based NIR-II photosensitizer for a highly effective and safe phototherapy plan.

High efficiency, stability, long emission wavelength (NIR-II), and good biocompatibility are crucial for photosensitizers in phototherapy. However, current Food and Drug Administration (FDA)-approved organic fluorophores exhibit poor chemical stability and photostability as well as short emission wavelength, limiting their clinical usage. To address this, we developed Se-IR1100, a novel organic photosensitizer with a photostable and thermostable benzobisthiadiazole (BBTD) backbone. By incorporating selenium as a heavy atom and constructing a D-A-D structure, Se-IR1100 exhibits a maximum fluorescence emission wavelength of 1100 nm. Compared with FDA-approved indocyanine green (ICG), DSPE-PEGylated Se-IR1100 nanoparticles exhibit prominent photostability and long-lasting photothermal effects. Upon 808 nm laser irradiation, Se-IR1100 NPs efficiently convert light energy into heat and reactive oxygen species (ROS), inducing cancer cell death in cellular studies and living organisms while maintaining biocompatibility. With salient photostability and a photothermal conversion rate of 55.37%, Se-IR1100 NPs hold promise as a superior photosensitizer for diagnostic and therapeutic agents in oncology. Overall, we have designed and optimized a multifunctional photosensitizer Se-IR1100 with good biocompatibility that performs NIR-II fluorescence imaging and phototherapy. This dual-strategy method may offer novel approaches for the development of multifunctional probes using dual-strategy or even multi-strategy methods in bioimaging, disease diagnosis, and therapy.

Nitrogen addition promotes terrestrial plants to allocate more biomass to aboveground organs: A global meta-analysis.

A significant increase in reactive nitrogen (N) added to terrestrial ecosystems through agricultural fertilization or atmospheric deposition is considered to be one of the most widespread drivers of global change. Modifying biomass allocation is one primary strategy for maximizing plant growth rate, survival, and adaptability to various biotic and abiotic stresses. However, there is much uncertainty as to whether and how plant biomass allocation strategies change in response to increased N inputs in terrestrial ecosystems. Here, we synthesized 3516 paired observations of plant biomass and their components related to N additions across terrestrial ecosystems worldwide. Our meta-analysis reveals that N addition (ranging from 1.08 to 113.81 g m-2 year-1 ) increased terrestrial plant biomass by 55.6% on average. N addition has increased plant stem mass fraction, shoot mass fraction, and leaf mass fraction by 13.8%, 12.9%, and 13.4%, respectively, but with an associated decrease in plant reproductive mass (including flower and fruit biomass) fraction by 3.4%. We further documented a reduction in plant root-shoot ratio and root mass fraction by 27% (21.8%-32.1%) and 14.7% (11.6%-17.8%), respectively, in response to N addition. Meta-regression results showed that N addition effects on plant biomass were positively correlated with mean annual temperature, soil available phosphorus, soil total potassium, specific leaf area, and leaf area per plant. Nevertheless, they were negatively correlated with soil total N, leaf carbon/N ratio, leaf carbon and N content per leaf area, as well as the amount and duration of N addition. In summary, our meta-analysis suggests that N addition may alter terrestrial plant biomass allocation strategies, leading to more biomass being allocated to aboveground organs than belowground organs and growth versus reproductive trade-offs. At the global scale, leaf functional traits may dictate how plant species change their biomass allocation pattern in response to N addition.

Methane emissions may be driven by hydrogenotrophic methanogens inhabiting the stem tissues of poplar.

Living trees in forests emit methane (CH4 ) from their stems. However, the magnitudes, patterns, drivers, origins, and biogeochemical pathways of these emissions remain poorly understood. We measured in situ CH4 fluxes in poplar stems and soils using static chambers and investigated the microbial communities of heartwood and sapwood by sequencing bacterial 16S, archaeal 16S, and fungal ITS rRNA genes. Methane emissions from poplar stems occurred throughout the sampling period. The mean CH4 emission rate was 2.7 mg m-2 stem d-1 . Stem CH4 emission rate increased significantly with air temperature, humidity, soil water content, and soil CH4 fluxes, but decreased with increasing sampling height. The CO2 reduction and methylotrophic methanogenesis were the major methanogenic pathways in wood tissues. The dominant methanogen groups detected in stem tissues were Methanobacterium, Methanobrevibacter, Rice Cluster I, Methanosarcina, Methanomassiliicoccus, Methanoculleus, and Methanomethylophilaceae. In addition, three methanotrophic genera were identified in the heartwood and sapwood - Methylocystis, Methylobacterium, and Paracoccus. Overall, stem CH4 emissions can originate directly from the internal tissues or co-occur from soils and stems. The co-existence of methanogens and methanotrophs within heartwood and sapwood highlights a need for future research in the microbial mechanisms underlying stem CH4 exchange with the atmosphere.

[Neuroprotective effect of curcumin to Aß of double transgenic mice with Alzheimer's disease].

OBJECTIVE: To observe the changes in Aß40, Aß42 and ADDLs in brains of 3 month-old APPswe/PS1dE9 double transgenic mice after six-month intervention with curcumin, in order to discuss the neuroprotective effect of curcumin. METHOD: APPswe/PS1dE9dtg mice were randomly divided into the model group, the Rosiglitazone group (10 mg x kg(-1) x d(-1)) and curcumin high (400 mg x kg9-1) x d(-1)), medium (200 mg x kg(-1) x d(-1)) and low (100 mg x kg(-1) x d(-1)) dosage groups, with C57/BL6J mice of the same age and the same background in the normal control group. After 6 months, the immunohistochemical staining (IHC) and the Western blot method were used to observe the changes in positive cell of Aß40, Aß42 and ADDLs in hippocampal CA1 area, their distribution and protein expressions. RESULT: Both of the immunohistochemical staining and the Western blot method showed more positive cell of Aß40, Aß42 and ADDLs in hippocampal CA1 area and higher protein expressions in the model group than the normal group (P < 0.01). IHC showed a lower result in the Rosiglitazone group than the model group (P < 0.05), while Western blot showed a much lower result (P < 0.01). The number of Aß40, Aß42 and ADDLs positive cells and the protein expressions decreased in the curcumin high group, the medium group showed a significant decrease (P < 0.01), and the low dose group also showed reductions in the protein expressions of Aß40 and Aß42. CONCLUSION: The six-month intervention with curcumin can significantly reduce the expressions of hippocampal Aß40, Aß42 and ADDLs in brains of APPswe/PS1dE9 double transgenic mice. Whether curcumin can impact Aß cascade reaction by down-regulating expressions of Aß40, Aß42 and ADDLs and show the neuroprotective effect needs further studies.

Soil methane emissions from plain poplar (Populus spp.) plantations with contrasting soil textures.

The forest soil methane (CH4) flux exhibits high spatiotemporal variability. Understanding these variations and their driving factors is crucial for accurately assessing the forest CH4 budget. In this study, we monitored the diurnal and seasonal variations in soil CH4 fluxes in two poplar (Populus spp.) plantations (Sihong and Dongtai) with different soil textures using the static chamber-based method. The results showed that the annual average soil CH4 flux in the Sihong and Dongtai poplar plantations was 4.27 ± 1.37 kg CH4-C ha-1 yr-1 and 1.92 ± 1.07 kg CH4-C ha-1 yr-1, respectively. Both plantations exhibited net CH4 emissions during the growing season, with only weak CH4 absorption (-0.01 to -0.007 mg m-2 h-1) during the non-growing season. Notably, there was a significant difference in soil CH4 flux between the clay loam of the Sihong poplar plantation and the sandy loam of the Dongtai poplar plantation. From August to December 2019 and from July to August and November 2020, the soil CH4 flux in the Sihong poplar plantation was significantly higher than in the Dongtai poplar plantation. Moreover, the soil CH4 flux significantly increased with rising soil temperature and soil water content. Diurnally, the soil CH4 flux followed a unimodal variation pattern at different growing stages of poplars, with peaks occurring at noon and in the afternoon. However, the soil CH4 flux did not exhibit a consistent seasonal pattern across different years, likely due to substantial variations in precipitation and soil water content. Overall, our study emphasizes the need for a comprehensive understanding of the spatiotemporal variations in forest soil CH4 flux with different soil textures. This understanding is vital for developing reasonable forest management strategies and reducing uncertainties in the global CH4 budget.

Fire effects on soil CH4 and N2O fluxes across terrestrial ecosystems.

Fire, as a natural disturbance, significantly shapes and influences the functions and services of terrestrial ecosystems via biotic and abiotic processes. Comprehending the influence of fire on soil greenhouse gas dynamics is crucial for understanding the feedback mechanisms between fire disturbances and climate change. Despite work on CO2 fluxes, there is a large uncertainty as to whether and how soil CH4 and N2O fluxes change in response to fire disturbance in terrestrial ecosystems. To narrow this knowledge gap, we performed a meta-analysis synthesizing 3615 paired observations from 116 global studies. Our findings revealed that fire increased global soil CH4 uptake in uplands by 23.2 %, soil CH4 emissions from peatlands by 74.7 %, and soil N2O emissions in terrestrial ecosystems (including upland and peatland) by 18.8 %. Fire increased soil CH4 uptake in boreal, temperate, and subtropical forests by 20.1 %, 38.8 %, and 30.2 %, respectively, and soil CH4 emissions in tropical forests by 193.3 %. Additionally, fire negatively affected soil total carbon (TC; -10.3 %), soil organic carbon (SOC; -15.6 %), microbial biomass carbon (MBC; -44.8 %), dissolved organic carbon (DOC; -27 %), microbial biomass nitrogen (MBN; -24.7 %), soil water content (SWC; -9.2 %), and water table depth (WTD; -68.2 %). Conversely, the fire increased soil bulk density (BD; +10.8 %), ammonium nitrogen (NH4+-N; +46 %), nitrate nitrogen (NO3--N; +54 %), pH (+4.4 %), and soil temperature (+15.4 %). Our meta-regression analysis showed that the positive effects of fire on soil CH4 and N2O emissions were significantly positively correlated with mean annual temperature (MAT) and mean annual precipitation (MAP), indicating that climate warming will amplify the positive effects of fire disturbance on soil CH4 and N2O emissions. Taken together, since higher future temperatures are likely to prolong the fire season and increase the potential of fires, this could lead to positive feedback between warming, fire events, CH4 and N2O emissions, and future climate change.

2'-Hydroxychalcone Induces Autophagy and Apoptosis in Breast Cancer Cells via the Inhibition of the NF-κB Signaling Pathway: In Vitro and In Vivo Studies.

2'-Hydroxychalcone is a hydroxyl derivative of chalcones, which are biosynthetic precursors of flavonoids and rich in the human diet. The anticancer activity of 2'-hydroxychalcone has been reported in several cancers but remains to be investigated in breast cancer. In the current study, 2'-hydroxychalcone showed significant cytotoxicity against breast cancer cell lines MCF-7 and CMT-1211. It could inhibit breast cancer cell proliferation, migration, and invasion in vitro and suppress tumor growth and metastasis in vivo. Mechanistic investigation revealed that the NF-κB pathway was significantly inhibited by 2'-hydroxychalcone treatment accompanied by an excessive intracellular accumulation of reactive oxygen species, induction of endoplasmic reticulum stress, and activation of JNK/MAPK. In addition, 2'-hydroxychalcone elevated the autophagic levels in breast cancer cells equipped with increasing numbers of autophagy vesicles and complete autophagic flux. Finally, autophagy-dependent apoptosis was observed in 2'-hydroxychalcone-induced cell death. In conclusion, 2'-hydroxychalcone enhances the autophagic levels and induces apoptosis in breast cancer cells, which could be contributed to the inhibition of the pro-survival NF-κB signaling, indicating a promising potential for 2'-hydroxychalcone in future anticancer drug development.

[Effect of curcumin on hippocampal IRS-1 and p-IRS-1 expressions in APP/PS1 double transgenic mice].

OBJECTIVE: To observe the effect of curcumin on the expressions of insulin receptor substrate-1 (IRS-1) and phosphated insulin receptor substrate-1 (p-IRS-1I) in APP/PS1 double transgenic mice of the AD model. METHOD: Three-month-old APP/ PSI double transgenic mice were randomly divided into the model group, the positive rosiglitazone control group and curcumin high (400 mg . kg-1 . d-1), medium (200 mg . kg-1 . d-1) and low (100 mg . kg-1 . d-1) dose groups. The normal group was composed of non-transgenic mice under the same background. After they were orally administered for three months, they were detected with immunohistochemistry, Western blot and RT-PCR. RESULT: According to IRS-1 and p-IRS-1 immumohistochemical staining, the expression of IRS-1 positive cells in hippocampus CA1 area in model mice was significantly higher than that of the normal control group (P<0. 01). Compared with the model group, the number of IRS-1 positive cells in hippocampus CA1 area decreased (P <0. 05 or P <0. 01) and the number of p-IRS-1 positive cells in hippocampus CA1 area increased in all of curcumin intervention groups. Western blot results were consistent with IRS-1 and p-IRS-1 protein expressions and immunohistochemistry results. RT-PCR test showed opposite IRS-1 mRNA expression results with immunohistochemistry and Western blot results. CONCLUSION: Curcumin can recover increased IRS-1 and decreased p-IRS-1 in hippocampus of APP/PS1 double transgenic mice, increase IRS-1 mRNA expression, and improve the insulin-signaling transduction in APP/PS1 double transgenic mice. This suggests that curcumin can regulate the insulin-signaling transduction mechanism and show an anti-AD effect.

MicroRNAs in equine Endometritis: A review of pathophysiology and molecular insights for diagnostic and therapeutic strategies.

Endometritis plays an important role in mare infertility. Certain infectious agents interfere with the innate immune system of endometrium, causing a systemic inflammatory response that lasts for a long time and circulates via the blood or cellular degeneration, leading to endometritis due to bacterial endotoxins. Different small, non-coding RNA molecules are involved in many biological functions. For instance, microRNAs (miRNAs) are involved in the post-transcriptional regulation of gene expression. These miRNAs are important regulators of gene expression, primarily via inhibiting transcription and translation processes. This manuscript reviews: (1) pathomorphological findings in equine endometritis, (2) the expression and effects of eca-miR-17, eca-miR-223, eca-miR-200a, eca-miR-155, and eca-miR-205 in endometritis and (3) the therapeutic role of miRNA in equine endometritis. The miRNAs have a vital regulatory role in a wide range of inflammatory diseases by regulating the molecular mechanism of cytokines that cause inflammation through signal pathways. This review emphasizes the demand for cutting-edge genetic technologies and the development of novel pharmaceutical preparations to improve our understanding of the genes encoding by these miRNAs. It also focuses on the efficacy of miRNAs for control, early diagnosis, and prevention of endometritis.

Sodium New Houttuyfonate Induces Apoptosis of Breast Cancer Cells via ROS/PDK1/AKT/GSK3ß Axis.

BACKGROUND: Sodium new houttuyfonate (SNH) has been reported to have anti-inflammatory, anti-fungal, and anti-cancer effects. However, few studies have investigated the effect of SNH on breast cancer. The aim of this study was to investigate whether SNH has therapeutic potential for targeting breast cancer. METHODS: Immunohistochemistry and Western blot analysis were used to examine the expression of proteins, flow cytometry was used to detect cell apoptosis and ROS levels, and transmission electron microscopy was used to observe mitochondria. RESULTS: Differentially expressed genes (DEGs) between breast cancer-related gene expression profiles (GSE139038 and GSE109169) from GEO DataSets were mainly involved in the immune signaling pathway and the apoptotic signaling pathway. According to in vitro experiments, SNH significantly inhibited the proliferation, migration, and invasiveness of MCF-7 (human cells) and CMT-1211 (canine cells) and promoted apoptosis. To explore the reason for the above cellular changes, it was found that SNH induced the excessive production of ROS, resulting in mitochondrial impairment, and then promoted apoptosis by inhibiting the activation of the PDK1-AKT-GSK3ß pathway. Tumor growth, as well as lung and liver metastases, were suppressed under SNH treatment in a mouse breast tumor model. CONCLUSIONS: SNH significantly inhibited the proliferation and invasiveness of breast cancer cells and may have significant therapeutic potential in breast cancer.

6-Gingerol via overexpression of miR-322-5p impede lipopolysaccharide-caused inflammatory response in RAW264.7 cells.

Acute lung injury (ALI) and sepsis are complicated syndromes that are often left untreated in critically ill patients. 6-Gingerol is a phenolic phytochemical compound that is found in fresh ginger, has pharmacological effects against inflammation. This study explored the roles of 6-gingerol in a mouse model of acute lung injury caused by lipopolysaccharide (LPS) and RAW-264.7 cells inflammation. The LPS-induced animal model underwent histopathological examinations, and RAW-264.7 cells viability was determined by Cell counting Kit-8 (CCk-8) assay. Additionally, qRT-PCR, Immunofluorescence, Western blot, and ELISA were used in vivo and in vitro to identify inflammatory factors and proteins associated with NF-κB and MAPK signaling pathways. In a histological examination 6-gingerol exhibited protective effects. Moreover, 6-gingerol elevated cell viability and downregulated inflammatory factors Interlukin-1ß (IL-1ß), Interlukin-6 (IL-6) and Tumor necrosis factor-α (TNF-α) in LPS-treated RAW-264.7 cells. Furthermore, 6-gingerol decreased phosphorylation of P65, P38 and the level of JNK in NF-κB and MAPK pathways. Importantly, 6-gingerol increased transcript abundance of miR-322-5p which suppressed by LPS and miR-322-5p downregulation negated the protective functions of 6-gingerol. The protective activity of 6-gingerol was mediated by miR-322-5p up-regulation.

Establishment of a new cell line of canine inflammatory mammary cancer: IMC-118.

Canine inflammatory mammary cancer (IMC) has long been regarded as an attractive animal model for research into human inflammatory breast cancer (IBC), Although some canine mammary tumour cell lines corresponding to human mammary cancer cell lines have been established, there is still a need to supplement the canine mammary tumour cell bank. The goal of this study was to create a new type of IMC cell line. The primary tumour, IMC-118, was identified as IMC by pathology examination. Immunohistochemistry analysis revealed negative immunoreactivity to oestrogen receptor (ER), but positive immunoreactivity to progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2). Immunofluorescence (IF) analysis revealed that the IMC-118 cell line from this primary tumour was negative for ER but positive for PR and HER-2, and was also positive for epithelial and mesenchymal cell markers. This cell line was cultured stably for more than 50 passages and grew well after cryopreservation. In vivo, tumour masses and metastases in the lungs were discovered after inoculating the IMC-118 cells into the nude mice model. As a result, a novel canine IMC cell line, IMC-118, was effectively established, and could be employed as a promising model for immunotherapy and epithelial-mesenchymal transition mechanism of IMC research in both dogs and humans.

Spatiotemporal patterns and drivers of stem methane flux from two poplar forests with different soil textures.

In forest ecosystems, the majority of methane (CH4) research focuses on soils, whereas tree stem CH4 flux and driving factors remain poorly understood. We measured the in situ stem CH4 flux using the static chamber-gas chromatography method at different heights in two poplar (Populus spp.) forests with separate soil textures. We evaluated the relationship between stem CH4 fluxes and environmental factors with linear mixed models and estimated the tree CH4 emission rate at the stand level. Our results showed that poplar stems were a net source of atmospheric CH4. The mean stem CH4 emission rates were 97.51 ± 6.21 µg·m-2·h-1 in Sihong and 67.04 ± 5.64 µg·m-2·h-1 in Dongtai. The stem CH4 emission rate in Sihong with clay loam soils was significantly higher (P < 0.001) than that in Dongtai with sandy loam soils. The stem CH4 emission rate also showed a seasonal variation, minimum in winter and maximum in summer. The stem CH4 emission rate generally decreased with increasing sampling height. Although the differences in CH4 emission rates between stem heights were significant in the annual averages, these differences were driven by differences observed in the summer. Stem CH4 emission rates were significantly and positively correlated with air temperature (P < 0.001), relative humidity (P < 0.001), soil water content (P < 0.001) and soil CH4 flux (P < 0.001). At these sites, the soil emitted CH4 to the atmosphere in summer (mainly from June to September) but absorbed CH4 from the atmosphere during the other season. At the stand level, tree CH4 emissions accounted for 2-35.4% of soil CH4 uptake. Overall, tree stem CH4 efflux could be an important component of the forest CH4 budget. Therefore, it is necessary to conduct more in situ monitoring of stem CH4 flux to accurately estimate the CH4 budget in the future.

Effects of different acupuncture treatment methods on post-stroke cognitive impairment: study protocol for a multicenter randomized controlled trial.

BACKGROUND: Cognitive impairment is a common dysfunction after stroke that seriously affects the overall recovery of patients. Cognitive rehabilitation training is currently the main treatment to improve cognitive function, but its curative effect is limited. Acupuncture is a core component of traditional Chinese medicine (TCM), and some previous clinical studies have shown that it might be effective in treating post-stroke cognitive impairment (PSCI), but further evidence from large-sample studies is needed. The overall objective of this trial is to obtain further data to develop an optimized acupuncture treatment for PSCI by comparing the effects of different acupuncture treatment methods on cognitive function in PSCI patients. METHODS/DESIGN: In this multicenter, prospective, randomized controlled trial, 206 eligible stroke inpatients who meet the trial criteria will be randomly assigned to 2 groups: an electroacupuncture (EA) plus needle retention (NR) group and an EA group. Both groups of patients will undergo the same routine cognitive rehabilitation treatments. All treatments will be given 5 times per week for 8 weeks. The primary outcomes will be assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment scale (MOCA). The secondary outcome will be measured by the Barthel Index (BI). All outcomes will be evaluated at baseline, week 4, week 8, and the third and sixth month after the end of treatment. DISCUSSION: Our aim is to evaluate the effects of two different acupuncture treatment methods for treating PSCI patients. This study is expected to provide data to be used in developing an optimized acupuncture treatment method for PSCI treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027849. Registered on 30 November 2019, http://www.chictr.org.cn/showproj.aspx?proj=46316.

Effect of Chinese herbal compound GAPT on the early brain glucose metabolism of APP/PS1 transgenic mice.

A number of studies have shown that early-stage Alzheimer's disease (AD) is associated with abnormal brain glucose metabolism before cognitive decline, which may be the key pathological change of asymptomatic AD. The pathogenesis of AD in traditional Chinese medicine is kidney deficiency and turbid phlegm. Based on this, GAPT (a mixture of herbal extracts) was made to invigorate kidney Yang and eliminate phlegm. Previous studies have shown that GAPT can improve and delay the memory decline, but the specific therapeutic target of AD in an early stage has not been studied. The aim of this study was to investigate the effect of GAPT on glucose metabolism in the early stage of AD. Eighty-eight 3-month-old male APP/PS1 transgenic mice were randomly divided into model group; donepezil group; and low, middle and high GAPT dosage groups. Twelve 3-month-old C57BL/6J mice were used as a control group. The Morris water maze test and the Step-Down Passive-Avoidance test were used to evaluate learning and memory ability. Cerebral extraction and the accumulation of glucose were scanned with a micro-positron-emission tomography (PET) imaging system. Immunohistochemistry, western blot analysis and polymerase chain reaction (PCR) were used to detect the expression of the PI3K/AKT-mTOR signalling pathway-related proteins and messenger RNAs (mRNAs) in hippocampus of APP/PS1 transgenic mice after 3 months of drug administration. GAPT can shorten the escape latency and error numbers compared to the model group. In micro-PET imaging analysis, GAPT can increase the glucose uptake average rate in the frontal lobe, temporal lobe, parietal lobe and hippocampus. The immunohistochemistry, western blot analysis and PCR results indicated that GAPT can increase the expression of PI3K, AKT, GLUT1 and GLUT3 in the hippocampus of APP/PS1 transgenic mice. In summary, GAPT can improve brain glucose metabolism damage in APP/PS1 transgenic mice, mainly by increasing brain glucose uptake, increasing glucose transport and improving the insulin signalling pathway.

Banxia Xiexin decoction ameliorated cognition via the regulation of insulin pathways and glucose transporters in the hippocampus of APPswe/PS1dE9 mice.

Reduced glucose utilization and deficient energy metabolism that occur in the early stages of Alzheimer's disease correlate with impaired cognition, and this information is evidence that Alzheimer's disease is a metabolic disease that is associated with brain insulin/insulin-like growth factor resistance. This research aimed to investigate the effects of Banxia Xiexin decoction (BXD) on cognitive deficits in APPswe/PS1dE9 double transgenic mice and verify the hypothesis that BXD treatment improves cognitive function via improving insulin signalling, glucose metabolism and synaptic plasticity in the hippocampus of APPswe/PS1dE9 double transgenic mice. We used 3-month-old APPswe/PS1dE9 double transgenic mice as the case groups and wild-type littermates of the double transgenic mice from the same colony as the control group. Forty-five APPswe/PS1dE9 double transgenic mice were randomly divided into the model group, donepezil group and BXD group. The mice in the control and model groups were administered 0.5% carboxymethyl cellulose orally. The Morris water maze and step-down test were conducted to evaluate the cognitive performance of APPswe/PS1dE9 double transgenic mice after BXD treatment. Ultrastructure of synapses was observed in the hippocampal CA1 area. Proteins involved in insulin signalling pathways and glucose transports in the hippocampus were assessed through immunohistochemical staining and western blot. After 3 months intervention, we found that BXD treatment improved cognitive performance and the synaptic quantity and ultrastructure, restored insulin signalling and increased the expression of glucose transporter 1 (GLUT1) and GLUT3 levels. These findings suggest that the beneficial effect of BXD on cognition may be due to the improvement of insulin signalling, glucose metabolism and synaptic plasticity.

Curcumin regulates insulin pathways and glucose metabolism in the brains of APPswe/PS1dE9 mice.

Recent studies have shown the therapeutic potential of curcumin in Alzheimer's disease (AD). In 2014, our lab found that curcumin reduced Aß40, Aß42 and Aß-derived diffusible ligands in the mouse hippocampus, and improved learning and memory. However, the mechanisms underlying this biological effect are only partially known. There is considerable evidence in brain metabolism studies indicating that AD might be a brain-specific type of diabetes with progressive impairment of glucose utilisation and insulin signalling. We hypothesised that curcumin might target both the glucose metabolism and insulin signalling pathways. In this study, we monitored brain glucose metabolism in living APPswe/PS1dE9 double transgenic mice using a micro-positron emission tomography (PET) technique. The study showed an improvement in cerebral glucose uptake in AD mice. For a more in-depth study, we used immunohistochemical (IHC) staining and western blot techniques to examine key factors in both glucose metabolism and brain insulin signalling pathways. The results showed that curcumin ameliorated the defective insulin signalling pathway by upregulating insulin-like growth factor (IGF)-1R, IRS-2, PI3K, p-PI3K, Akt and p-Akt protein expression while downregulating IR and IRS-1. Our study found that curcumin improved spatial learning and memory, at least in part, by increasing glucose metabolism and ameliorating the impaired insulin signalling pathways in the brain.

Effects of curcumin on synapses in APPswe/PS1dE9 mice.

Significant losses of synapses have been demonstrated in studies of Alzheimer's disease (AD), but structural and functional changes in synapses that depend on alterations of the postsynaptic density (PSD) area occur prior to synaptic loss and play a crucial role in the pathology of AD. Evidence suggests that curcumin can ameliorate the learning and memory deficits of AD. To investigate the effects of curcumin on synapses, APPswe/PS1dE9 double transgenic mice (an AD model) were used, and the ultra-structures of synapses and synapse-associated proteins were observed. Six months after administration, few abnormal synapses were observed upon electron microscopy in the hippocampal CA1 areas of the APPswe/PS1dE9 double transgenic mice. The treatment of the mice with curcumin resulted in improvements in the quantity and structure of the synapses. Immunohistochemistry and western blot analyses revealed that the expressions of PSD95 and Shank1 were reduced in the hippocampal CA1 areas of the APPswe/PS1dE9 double transgenic mice, but curcumin treatment increased the expressions of these proteins. Our findings suggest that curcumin improved the structure and function of the synapses by regulating the synapse-related proteins PSD95 and Shank1.

Curcumin ameliorates insulin signalling pathway in brain of Alzheimer's disease transgenic mice.

Deficits in glucose, impaired insulin signalling and brain insulin resistance are common in the pathogenesis of Alzheimer's disease (AD); therefore, some scholars even called AD type 3 diabetes mellitus. Curcumin can reduce the amyloid pathology in AD. Moreover, it is a well-known fact that curcumin has anti-oxidant and anti-inflammatory properties. However, whether or not curcumin could regulate the insulin signal transduction pathway in AD remains unclear. In this study, we used APPswe/PS1dE9 double transgenic mice as the AD model to investigate the mechanisms and the effects of curcumin on AD. Immunohistochemical (IHC) staining and a western blot analysis were used to test the major proteins in the insulin signal transduction pathway. After the administration of curcumin for 6 months, the results showed that the expression of an insulin receptor (InR) and insulin receptor substrate (IRS)-1 decreased in the hippocampal CA1 area of the APPswe/PS1dE9 double transgenic mice, while the expression of phosphatidylinositol-3 kinase (PI3K), phosphorylated PI3K (p-PI3K), serine-threonine kinase (AKT) and phosphorylated AKT (p-AKT) increased. Among the curcumin groups, the medium-dose group was the most effective one. Thus, we believe that curcumin may be a potential therapeutic agent that can regulate the critical molecules in brain insulin signalling pathways. Furthermore, curcumin could be adopted as one of the AD treatments to improve a patient's learning and memory ability.