P. gingivalis in oral-prostate axis exacerbates benign prostatic hyperplasia via IL-6/IL-6R pathway.

BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common disease in elderly men. There is increasing evidence that periodontitis increases the risk of BPH, but the specific mechanism remains unclear. This study aimed to explore the role and mechanism of the key periodontal pathogen Porphyromonas gingivalis (P. gingivalis) in the development of BPH. METHODS: The subgingival plaque (Sp) and prostatic fluid (Pf) of patients with BPH concurrent periodontitis were extracted and cultured for 16S rDNA sequencing. Ligature-induced periodontitis, testosterone-induced BPH and the composite models in rats were established. The P. gingivalis and its toxic factor P. gingivalis lipopolysaccharide (P.g-LPS) were injected into the ventral lobe of prostate in rats to simulate its colonization of prostate. P.g-LPS was used to construct the prostate cell infection model for mechanism exploration. RESULTS: P. gingivalis, Streptococcus oralis, Capnocytophaga ochracea and other oral pathogens were simultaneously detected in the Pf and Sp of patients with BPH concurrent periodontitis, and the average relative abundance of P. gingivalis was found to be the highest. P. gingivalis was detected in both Pf and Sp in 62.5% of patients. Simultaneous periodontitis and BPH synergistically aggravated prostate histological changes. P. gingivalis and P.g-LPS infection could induce obvious hyperplasia of the prostate epithelium and stroma (epithelial thickness was 2.97- and 3.08-fold that of control group, respectively), and increase of collagen fibrosis (3.81- and 5.02-fold that of control group, respectively). P. gingivalis infection promoted prostate cell proliferation, inhibited apoptosis, and upregulated the expression of inflammatory cytokines interleukin-6 (IL-6; 4.47-fold), interleukin-6 receptor-α (IL-6Rα; 5.74-fold) and glycoprotein 130 (gp130; 4.47-fold) in prostatic tissue. P.g-LPS could significantly inhibit cell apoptosis, promote mitosis and proliferation of cells. P.g-LPS activates the Akt pathway through IL-6/IL-6Rα/gp130 complex, which destroys the imbalance between proliferation and apoptosis of prostate cells, induces BPH. CONCLUSION: P. gingivalis was abundant in the Pf of patients with BPH concurrent periodontitis. P. gingivalis infection can promote BPH, which may affect the progression of BPH via inflammation and the Akt signaling pathway.

A multi-scale feature fusion neural network for multi-class disease classification on the maize leaf images.

Maize is a globally important cereal crop, however, maize leaf disease is one of the most common and devastating diseases that afflict it. Artificial intelligence methods face challenges in identifying and classifying maize leaf diseases due to variations in image quality, similarity among diseases, disease severity, limited dataset availability, and limited interpretability. To address these challenges, we propose a residual-based multi-scale network (MResNet) for classifying multi-type maize leaf diseases from maize images. MResNet consists of two residual subnets with different scales, enabling the model to detect diseases in maize leaf images at different scales. We further utilize a hybrid feature weight optimization method to optimize and fuse the feature mapping weights of two subnets. We validate MResNet on a maize leaf diseases dataset. MResNet achieves 97.45% accuracy. The performance of MResNet surpasses other state-of-the-art methods. Various experiments and two additional datasets confirm the generalization performance of our model. Furthermore, thermodynamic diagram analysis increases the interpretability of the model. This study provides technical support for the disease classification of agricultural plants.

Cross-talk of pyroptosis-based subtypes, the development of a risk classifier and immune responses in cervical cancer.

BACKGROUND: Cervical cancer (CC) is one of the most common gynecology malignancies and has a dismal survival outcome. The prognostic value of pyroptosis and its role in the regulation of immune metabolism in CC remain unclear. METHODS: Two independent CC cohorts collected from public databases were integrated for unsupervised cluster analysis. All CC cases were assigned to different subsets based on the pyroptosis-related genes (PRGs). The differentially expressed genes (DEGs) between different subclusters were included in stepwise Cox regression for the risk classifier establishment. Next, single-cell sequencing analysis was conducted to explore the cellular location of each model gene. The CIBERSORT algorithm was applied to estimate immunocytes infiltration. Finally, a series of functional experiments were performed to detect the role of CDH3 in CC. RESULTS: Based on the 52 PRGs, the combined CC cohort was clustered into two subsets (C1 (n = 259) and C2 (n = 242)). Survival and Cox regression methods were used to create a pyroptosis-based risk classifier including four PRGs (PEG3, FSCN1, CDH3 and SLC2A1). For the immune environment in CC, the high-risk group had a lower infiltration level of B cells, memory-activated CD4 T cells and CD8 T cells and a higher infiltration abundance of neutrophils. The expression pattern of model genes was confirmed in CC cell lines by PCR assay. Furthermore, we observed that knockdown of CDH3 could suppress CC cell proliferation. CONCLUSION: Our project could offer promising reference for prognosis assessment, immune metabolism prediction and clinical decision-making of patients with CC.

Molecular Design-Based Breeding: A Kinship Index-Based Selection Method for Complex Traits in Small Livestock Populations.

Genomic selection (GS) techniques have improved animal breeding by enhancing the prediction accuracy of breeding values, particularly for traits that are difficult to measure and have low heritability, as well as reducing generation intervals. However, the requirement to establish genetic reference populations can limit the application of GS in pig breeds with small populations, especially when small populations make up most of the pig breeds worldwide. We aimed to propose a kinship index based selection (KIS) method, which defines an ideal individual with information on the beneficial genotypes for the target trait. Herein, the metric for assessing selection decisions is a beneficial genotypic similarity between the candidate and the ideal individual; thus, the KIS method can overcome the need for establishing genetic reference groups and continuous phenotype determination. We also performed a robustness test to make the method more aligned with reality. Simulation results revealed that compared to conventional genomic selection methods, the KIS method is feasible, particularly, when the population size is relatively small.

Periodontitis relates to benign prostatic hyperplasia via the gut microbiota and fecal metabolome.

Objectives: Periodontitis is associated with benign prostatic hyperplasia (BPH), whether it related to gut floramicrobiota and metabonomics is unclear. Methods: We established ligature-induced periodontitis (EP), testosterone-induced BPH, and composite rat models. Fecal samples were collected to detect gut microbiota by 16S rDNA sequencing and metabonomics were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). Results: Sequencing results revealed differential gut floramicrobiota composition between EP+BPH group and other three groups. The abundances of Ruminococcus flavefaciens were significantly increased in EP+BPH group compared with other groups. Tenericutes, Mollicutes, RF39 and Ruminococcus gnavus were significantly decreased in EP+BPH group compared with BPH group, while Ruminococcus callidus and Escherichia were significantly decreased compared with EP group. For gut metabonomics, LC-MS/MS showed that fecal metabolites and seven metabolic pathways were changed in EP+BPH group, such as biosynthesis of unsaturated fatty acids, steroid hormone biosynthesis. Correlation analysis showed that the alterations of gut metabolism were significantly correlated with differential gut floramicrobiota, such as Ruminococcus callidus and Ruminococcus flavefaciens. Conclusion: Our study highlights the relationship of periodontitis and BPH, the alterations of gut floramicrobiota and metabolites may be involved in two diseases, which provides new idea for prevention and treatment of patients with periodontitis concurrent BPH.

The causal association between smoking, alcohol consumption and risk of bladder cancer: A univariable and multivariable Mendelian randomization study.

Smoking and alcohol consumption are associated with bladder cancer risk in observational studies. We conducted a two-sample univariable and multivariable Mendelian randomization (MR) analysis to determine whether those associations are causal. We used 21, 126, 360, 39 single nucleotide polymorphisms (SNPs) as instrumental variables for number of cigarettes per day, lifetime smoking index, smoking initiation, and drinks per week, respectively. A total of 1115 cases with bladder cancer and 174 006 noncases from FinnGen consortium and 2883 cases with bladder cancer and 417 955 noncases from UK Biobank study were obtained. Genetic predisposition to cigarettes per day, lifetime smoking index and smoking initiation were positively associated with an increased risk of bladder cancer in both the FinnGen and UK Biobank consortium. The summary odds ratio (OR) of bladder cancer was 1.79 (95% confidence interval [CI], 1.31-2.45; P = .0002), 2.38 (95% CI, 1.45-3.88; P = .0005) and 1.91 (95% CI, 1.46-2.50; P = 1.59 × 10-06 ) for one SD increase in the number of cigarettes per day, lifetime smoking index and smoking initiation, respectively. The genetically instrumented number of drinks per week was not associated with bladder cancer (OR = 0.69; 95% CI, 0.44-1.10; P = .1237). Estimates were consistent in multivariable MR analyses by the adjustments of body mass index and education. Our study suggests a causal potential of the association of smoking but not alcohol consumption with bladder cancer according to current evidence.

Alterations of gut microbiota diversity, composition and metabonomics in testosterone-induced benign prostatic hyperplasia rats.

BACKGROUND: Studies had shown many diseases affect the stability of human microbiota, but how this relates to benign prostatic hyperplasia (BPH) has not been well understood. Hence, this study aimed to investigate the regulation of BPH on gut microbiota composition and metabonomics. METHODS: We analyzed gut samples from rats with BPH and healthy control rats, the gut microbiota composition and metabonomics were detected by 16S rDNA sequencing and liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: High-throughput sequencing results showed that gut microbiota beta-diversity increased (P < 0.01) in the BPH group vs. control group. Muribaculaceae (P < 0.01), Turicibacteraceae (P < 0.05), Turicibacter (P < 0.01) and Coprococcus (P < 0.01) were significantly decreased in the BPH group, whereas that of Mollicutes (P < 0.05) and Prevotella (P < 0.05) were significantly increased compared with the control group. Despite profound interindividual variability, the levels of several predominant genera were different. In addition, there were no statistically significant differences in several bacteria. BPH group vs. control group: Firmicutes (52.30% vs. 57.29%, P > 0.05), Bacteroidetes (46.54% vs. 41.64%, P > 0.05), Clostridia (50.89% vs. 54.66%, P > 0.05), Ruminococcaceae (25.67% vs. 20.56%, P > 0.05). LC-MS/MS of intestinal contents revealed that differential metabolites were mainly involved in cellular processes, environmental information processing, metabolism and organismal systems. The most important pathways were global and overview maps, lipid metabolism, amino acid metabolism, digestive system and endocrine system. Through enrichment analysis, we found that the differential metabolites were significantly enriched in metabolic pathways, steroid hormone biosynthesis, ovarian steroidogenesis, biosynthesis of unsaturated fatty acids and bile secretion. Pearson correlation analysis (R = 0.94) showed that there was a strong correlation between Prevotellaceae, Corynebacteriaceae, Turicibacteraceae, Bifidobacteriaceae and differential metabolites. CONCLUSION: Our findings suggested an association between the gut microbiota and BPH, but the causal relationship between the two groups is unclear. Thus, further studies are warranted to elucidate the potential mechanisms and causal relationships between BPH and gut microbiota.

Epidemiological trends of urinary tract infections, urolithiasis and benign prostatic hyperplasia in 203 countries and territories from 1990 to 2019.

BACKGROUND: Urinary tract infections (UTI), urolithiasis, and benign prostatic hyperplasia (BPH) are three of the most common nonmalignant conditions in urology. However, there is still a lack of comprehensive and updated epidemiological data. This study aimed to investigate the disease burden of UTI, urolithiasis, and BPH in 203 countries and territories from 1990 to 2019. METHODS: Data were extracted from the Global Burden of Disease 2019, including incident cases, deaths, disability-adjusted life-years (DALYs) and corresponding age-standardized rate (ASR) from 1990 to 2019. Estimated annual percentage changes (EAPC) were calculated to evaluate the trends of ASR. The associations between disease burden and social development degrees were analyzed using a sociodemographic index (SDI). RESULTS: Compared with 1990, the incident cases of UTI, urolithiasis, and BPH increased by 60.40%, 48.57%, and 105.70% in 2019, respectively. The age-standardized incidence rate (ASIR) of UTI increased (EAPC = 0.08), while urolithiasis (EAPC = - 0.83) and BPH (EAPC = - 0.03) decreased from 1990 to 2019. In 2019, the age-standardized mortality rate (ASMR) of UTI and urolithiasis were 3.13/100,000 and 0.17/100,000, respectively. BPH had the largest increase (110.56%) in DALYs in the past three decades, followed by UTI (68.89%) and urolithiasis (16.95%). The burden of UTI was mainly concentrated in South Asia and Tropical Latin America, while the burden of urolithiasis and BPH was recorded in Asia and Eastern Europe. Moreover, the ASIR and SDI of urolithiasis in high-SDI regions from 1990 to 2019 were negatively correlated, while the opposite trend was seen in low-SDI regions. In 2019, the ASIR of UTI in females was 3.59 times that of males, while the ASIR of urolithiasis in males was 1.96 times higher than that in females. The incidence was highest in the 30-34, 55-59, and 65-69 age groups among the UTI, urolithiasis, and BPH groups, respectively. CONCLUSION: Over the past three decades, the disease burden has increased for UTI but decreased for urolithiasis and BPH. The allocation of medical resources should be based more on the epidemiological characteristics and geographical distribution of diseases.

Global, regional, and national burden of kidney, bladder, and prostate cancers and their attributable risk factors, 1990-2019.

BACKGROUND: The burden of kidney, bladder, and prostate cancers has changed in recent decades. This study aims to investigate the global and regional burden of, and attributable risk factors for genitourinary cancers during the past 30 years. METHODS: We extracted data of kidney, bladder, and prostate cancers from the Global Burden of Disease 2019 database, including incidence, mortality, disability-adjusted life-years (DALYs), and attributable risk factors from 1990 to 2019. Estimated annual percentage changes (EAPC) were calculated to assess the changes in age-standardized incidence rate, age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR). The associations between cancers burden and socio-demographic index (SDI) were also analyzed. RESULTS: Compared with 1990, the global incident cases in 2019 were higher by 154.78%, 123.34%, and 169.11% for kidney, bladder, and prostate cancers, respectively. During the 30-year study period, there was a downward trend in ASMR and ASDR for bladder cancer (EAPC = - 0.68 and - 0.83, respectively) and prostate cancer (EAPC = - 0.75 and - 0.71, respectively), but an upward trend for kidney cancer (EAPC = 0.35 and 0.12, respectively). Regions and countries with higher SDI had higher incidence, mortality, and DALYs for all three types of cancers. The burden of bladder and prostate cancers was mainly distributed among older men, whereas the burden of kidney cancer increased among middle-aged men. Smoking related mortality and DALYs decreased, but high body mass index (BMI) and high fasting plasma glucose (FPG) related mortality and DALYs increased among kidney, bladder, and prostate cancers during the study period. CONCLUSIONS: Kidney, bladder, and prostate cancers remain major global public health challenges, but with distinct trend for different disease entity across different regions and socioeconomic status. More proactive intervention strategies, at both the administrative and academic levels, based on the dynamic changes, are needed.

Periodontitis Exacerbates Benign Prostatic Hyperplasia through Regulation of Oxidative Stress and Inflammation.

Epidemiological studies demonstrate that men with periodontitis are also susceptible to benign prostatic hyperplasia (BPH) and that periodontal treatment can improve the prostatic symptom. However, molecular links of this relationship are largely unknown. The goal of the current study was to elucidate the effects of experimental periodontitis on the hyperplasia of prostate and whether oxidative stress and inflammation participated in this process. For this purpose, ligature-induced periodontitis, testosterone-induced BPH, and the composite models in rats were established. Four weeks later, all the rats were sacrificed and the following items were measured: alveolar bone loss and histological examination of periodontal tissues were taken to assess the establishment of periodontitis model, prostate index and histological examination of prostate tissues were taken to test the establishment of the BPH model, inflammatory cytokines in plasma were assessed, and Bax/Bcl-2 proteins related to cell apoptosis were analyzed via western blot analysis. To further investigate whether oxidative stress participates in the aggravation of BPH, in vitro models were also conducted to measure the production of intracellular reactive oxygen species (ROS) and hydrogen peroxide (H2O2) concentration. We found that simultaneous periodontitis and BPH synergistically aggravated prostate histological changes, significantly increased Ki67 proliferation, and reduced apoptosis in rat prostate tissues. Also, our results showed that periodontal ligation induced increased Bcl-2 protein expression, whereas Bax expression was decreased in BPH rats than in normal rats. Compared with the control group, periodontitis and BPH both significantly enhanced inflammatory cytokine levels of TNF-α, IL-6, IL-1ß, and CRP. Furthermore, Porphyromonas gingivalis lipopolysaccharide induced enhanced generation of intracellular expression of ROS and H2O2 in BPH-1 cells. Our experimental evidence demonstrated that periodontitis might promote BPH development through regulation of oxidative stress and inflammatory process, thus providing new strategies for prevention and treatment of BPH.

Oxidative Stress Links Aging-Associated Cardiovascular Diseases and Prostatic Diseases.

The incidence of chronic aging-associated diseases, especially cardiovascular and prostatic diseases, is increasing with the aging of society. Evidence indicates that cardiovascular diseases usually coexist with prostatic diseases or increase its risk, while the pathological mechanisms of these diseases are unknown. Oxidative stress plays an important role in the development of both cardiovascular and prostatic diseases. The levels of oxidative stress biomarkers are higher in patients with cardiovascular diseases, and these also contribute to the development of prostatic diseases, suggesting cardiovascular diseases may increase the risk of prostatic diseases via oxidative stress. This review summarizes the role of oxidative stress in cardiovascular and prostatic diseases and also focuses on the main shared pathways underlying these diseases, in order to provide potential prevention and treatment targets.

UV-fluorescence probe for detection Ni2+ with colorimetric/spectral dual-mode analysis method and its practical application.

Fluorescence probe combines with fluorescence imaging technology has become the most powerful analytical method with their great advantages of high sensitivity and selectivity and real-time monitoring. Ni2+ is widely distributed in food, environment and living animals, thereof, it is of great significance for detection Ni2+ with high selectivity. Herein, a simple strategy is proposed to design and synthesiz a small molecule fluorescent probe Y1 by using "one-pot" method. The spectroscopic behaviors including UV-Vis absorption and fluorescence emission spectrum have been used to verify the feasibility of probe towards Ni2+ in water/EtOH (v/v = 2:8) mixtures under neutral condition. As expected, Y1 offers high selectivity and sensitivity for detection Ni2+ in aqueous solution with a good linear relationship and low detection limit within Ni2+ concentration variation from 0 to 13 µM (DOL = 0.0038 µM, R2 = 0.9983). It is remarkable that Y1 can be applied for real-time visualization Ni2+ change in sprouted potato and zebrafish with great photo-stability, highlighting that the practicability and feasibility of Y1 to detect and monitor Ni2+ in the field of food industry and biomedical field.

Development of Biomarker Signatures Associated with Anoikis to Predict Prognosis in Endometrial Carcinoma Patients.

PURPOSE: To generate a signature based on anoikis-related genes (ARGs) for endometrial carcinoma (EC) patients and elucidate the molecular mechanisms in EC. METHODS: On the basis of TCGA-UCEC dataset, we identified specific anoikis-related genes (ARGs) in EC. Cox-relative regression methods were used to generate an anoikis-related signature (ARS). The possible biological pathways of ARS-related genes were analyzed by GSEA. The clinical potency and immune status of ARS were analyzed by CIBERSORT method, ssGSEA algorithm, Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Moreover, the expression patterns of ARS genes were verified by HPA database. RESULTS: Seven anoikis genes (CDKN2A, E2F1, ENDOG, EZH2, HMGA1, PLK1, and SLC2A1) were determined to develop a prognostic ARS. Both genes of ARS were closely bound up with the prognosis of EC patients. The ARS could accurately classify EC cases with different clinical outcome and mirror the specific immune status of EC. We observed that ARS-high patients could not benefit from immunotherapy. Finally, all the hub genes of ARS were proved to be upregulated in EC tissues by immunohistology. CONCLUSION: ARS can be used to stratify the risk and forecast the survival outcome of EC patients and provide prominent reference for individualized treatment in EC.

Effects of cellulose/salicylaldehyde thiosemicarbazone complexes on PVA based hydrogels: Portable, reusable, and high-precision luminescence sensing of Cu2.

Novel portable, high-precision, and reusable fluorescent polyvinyl alcohol (PVA)-borax hydrogel sensors were prepared to detect Cu2+ in aqueous environment. A TEMPO-oxidized cellulose nanofibers/salicylaldehyde thiosemicarbazone (TOCN/ST) complex was further incorporated into the PVA-borax matrix. The in situ polymerization of TOCN/ST complex enhanced the mechanical properties of the hydrogels and improved the accuracy of detection. The resultant hydrogels were thermo reversible, and it converted to the liquid state during heating, which could greatly reduce the deviations caused in the detection of solid sensors. After cooling, the hydrogel could transform into the solid condition, which was easily portable. The sensor induced a significant luminescence quenching to the Cu2+ at 485 nm, with a detection limit of 0.086 µM. In the presence of ethylenediaminetetraacetic acid disodium, Cu2+ were tightly seized, causing the liberation of TOCN/ST complex and thus, a reversible "ON-OFF-ON" fluorescence behavior was displayed. The fluorescence intensity was maintained at 82 % after 10 uses, and the mechanical strength was maintained at 85 % after 3 uses. The anti-bacterial activity test also confirmed the TOCN/ST complex was extremely potent in suppressing the growth and reproduction of Escherichia coli. The proposed hydrogel provides a new insight into the detection of Cu2+ in aqueous environments.

Targeting the Chondroitin Sulfate Proteoglycans: Evaluating Fluorinated Glucosamines and Xylosides in Screens Pertinent to Multiple Sclerosis.

Chondroitin sulfate proteoglycans (CSPGs) are upregulated in insults to the central nervous system, including multiple sclerosis (MS), an inflammatory demyelinating condition of the central nervous system. CSPGs appear to be detrimental in MS, as they enhance immune responses and act as barriers to oligodendrocyte differentiation and thus remyelination. Despite their deleterious roles, strategies to selectively reduce CSPG production are lacking. The purpose of this study was to develop, screen, and describe a series of glucosamine derivatives and xylosides for their capacity to overcome detrimental CSPGs and inflammatory processes. Specifically, we assess the ability of analogues to interfere with CSPG biosynthesis, promote the outgrowth of oligodendrocyte precursor cells in an inhibitory environment, and lower inflammation by attenuating the proliferation of T lymphocytes. We highlight the beneficial activities of a novel compound, per-O-acetylated 4,4-difluoro-N-acetylglucosamine (Ac-4,4-diF-GlcNAc) in vitro, and report that it reduced inflammation and clinical severity in a mouse model of MS. Thus, this study represents an important advance, as we uncover that targeting CSPG biosynthesis with a potent inhibitor is an effective avenue to ameliorate inflammatory cascades and promote repair processes in MS and other neurological conditions.

Efficient regioselective O3-monodesilylation by hydrochloric acid in cyclodextrins.

An efficient O3-monodesilylation method has been developed for the derivatization of per-3-O-silylated cyclodextrin (CD) derivatives. Using hydrochloric acid as a reagent, the O3-monodesilylation was found to be regioselective, mild, practical and general as it can be applied to all α-, ß- and γ-CDs. The advantage of the methodology is that the acid-catalyzed O3-desilylation can be carried out in a stepwise manner so that different types of functional groups can be introduced to a CD molecule at different stage of the O3-desilylations. This makes the current methodology flexible and versatile. This current methodology constitutes one of the few methodologies available for the regioselective modification of CDs at the secondary face.

Fluorescent rhodanine-3-acetic acids visualize neurofibrillary tangles in Alzheimer's disease brains.

There is a high demand for the development of an imaging agent for neurofibrillary tangles (NFTs) detection in Alzheimer's diagnosis. In the present study, a series of rhodanine-3-acetic acids was synthesized and evaluated for fluorescence imaging of NFTs in brain tissues of AD patients. Five out of seven probes have shown excellent binding affinity to NFTs over amyloid plaques in the Thiazine red R displacement assay. However, the selectivity in this in vitro assay is not confirmed by the histopathological evaluation, which indicates significant differences in the binding sites in the assays. Probe 6 showed binding affinity (IC50=19nM) to tau aggregates which is the highest among this series. Probes 2, 3, 4 and 5 display IC50 values of lower than 100nM to tau aggregates to displace Thiazine red R. Evaluation of the cytotoxicity of these five probes with human liver carcinoma cells revealed that these compounds excert negligible cytotoxicity. The in vivo studies with zebrafish embryos confirmed negligible cytotoxicity at 24 and 72h post fertilization.

A rapid and convenient method for preparative separation of three indissolvable polyphenols from Euphorbia pekinensis by the flexible application of solvent extraction combined with counter-current chromatography.

A rapid and convenient method was established to preparatively isolate the three ellagic acid types of compounds, which were the main polyphenols in Euphorbia pekinensis, by flexibly applying solvent extraction combined with counter-current chromatography (CCC). The total extract (extracted using 95% ethanol) of E. pekinensis was pretreated by two simple steps before CCC isolation, following the procedure: the total extract was extracted by classical solvent extraction using petroleum ether and ethyl acetate, respectively, and then the ethyl acetate extract was suspended using 95% ethanol, after being allowed to stand overnight, the sediment was obtained. Partial sediment (100 mg) was then directly separated by CCC with a two-phase solvent system composed of chloroform-95% ethanol-water-85% formic acid (50:50:50:5, v/v/v/v). About 22 mg of 3,3'-dimethoxy ellagic acid (1), 12 mg of 3,3'-di-O-methyl-4-O-(ß-D-xylopyranosyl)ellagic acid (2), and 35 mg of ellagic acid (3) with purities of 96.0, 95.2, and 95.4% were obtained respectively in one step within 4 h. After being purified by washing with methanol, the purities of the three compounds obtained were all above 98%. The purities were determined by HPLC and their chemical structures were further identified by (1)H and (13)C NMR spectroscopy. The recoveries were calculated as 84.6, 85.7, and 89.5%, respectively. The result demonstrated that the present isolation method was rapid, economical and efficient for the preparative separation of polyphenols from E. pekinensis.

Design, synthesis and biological evaluation of trimethine cyanine dyes as fluorescent probes for the detection of tau fibrils in Alzheimer's disease brain and olfactory epithelium.

Shedding light on grey matter: Fluorescent trimethine cyanines were evaluated as imaging probes for neurofibrillary tangles in post-mortem brain sections of Alzheimer's disease patients. These probes bind to neurofibrillary tangles with high contrast and selectivity over amyloid ß plaques.

Structure-based optimization of oxadiazole-based GSK-3 inhibitors.

Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases ß-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3α and ß, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3α and 17 nM for GSK-3ß. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3α over GSK-3ß, with an IC50 of 35 nM for GSK-3α. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety.