AMPK/PGC-1α and p53 modulate VDAC1 expression mediated by reduced ATP level and metabolic oxidative stress in neuronal cells.

Voltage-dependent anion channel 1 (VDAC1) is a pore protein located in the outer mitochondrial membrane. Its channel gating mediates mitochondrial respiration and cell metabolism, and it has been identified as a critical modulator of mitochondria-mediated apoptosis. In many diseases characterized by mitochondrial dysfunction, such as cancer and neurodegenerative diseases, VDAC1 is considered a promising potential therapeutic target. However, there is limited research on the regulatory factors involved in VDAC1 protein expression in both normal and pathological states. In this study, we find that VDAC1 protein expression is up-regulated in various neuronal cell lines in response to intracellular metabolic and oxidative stress. We further demonstrate that VDAC1 expression is modulated by intracellular ATP level. Through the use of pharmacological agonists and inhibitors and small interfering RNA (siRNA), we reveal that the AMPK/PGC-1α signaling pathway is involved in regulating VDAC1 expression. Additionally, based on bioinformatics predictions and biochemical verification, we identify p53 as a potential transcription factor that regulates VDAC1 promoter activity during metabolic oxidative stress. Our findings suggest that VDAC1 expression is regulated by the AMPK/PGC-1α and p53 pathways, which contributes to the maintenance of stress adaptation and apoptotic homeostasis in neuronal cells.

Pharmacophore-based drug design of AChE and BChE dual inhibitors as potential anti-Alzheimer's disease agents.

For the Alzheimer's disease (AD) with complex pathogenesis, single target drugs represent one of the most effective therapeutic strategies in clinical. However, the traditional concept of "a disease, a target" is difficult to find very effective drugs, and multi-target drugs have already become new hot spot in drug development for this disease. In our present study, our efforts toward discovering new cholinesterase (ChE) inhibitors aided by computational methods will provide useful information as anti-AD agents in the future. The best 3D-QSAR acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors pharmacophore hypotheses Hypo1 A and Hypo1 B were generated and validated by HypoGen program in Discovery Studio 2016 based on the training set of flavonoids, and then they were used as 3D query for screening the ZINC database. Next, the hit molecules were then subjected to the ADMET and molecular docking study to prioritize the compounds. Finally, 6 compounds showed good estimated activities and promising ADMET properties. The result of best compound ZINC08751495 with AChE estimate activity (0.028), BChE estimate activity (1.55), AChE fit value (9.369), BChE fit value (8.415), AChE -CDOCKER ENERGY (30.22), BChE -CDOCKER ENERGY (33.13) has the potential for further development as a supplement to treat Alzheimer's disease.

An overview on natural farnesyltransferase inhibitors for efficient cancer therapy.

As one of the world's five terminally ills, tumours can cause important genetic dysfunction. However, some current medicines for tumours usually have strong toxic side effects and are prone to drug resistance. Studies have found that farnesyltransferase inhibitors (FTIs) extracted from natural materials have a good inhibiting ability on tumours with fewer side effects. This article describes several FTIs extracted from natural materials and clarifies the current research progress, which provides a new choice for the treatment of tumours.

ACOT7, a candidate and novel serum biomarker of Alzheimer's disease.

Alzheimer's disease (AD) is the most common fatal neurodegenerative disease among the elderly worldwide, characterized by memory and cognitive impairment. The identification of biomarkers for AD is crucial and urgent to facilitate the diagnosis and intervention. The aim of this study was to evaluate the diagnostic value of acyl-Coenzyme A thioesterase 7 (ACOT7) as a serum biomarker for the prediction of AD. In our study, we observed a significant increase in ACOT7 expression in patients (n = 366) with AD and animal (n = 8-12) models of AD, compared to the control group. A significant negative correlation was found between ACOT7 levels and Mini-Mental State Examination (MMSE) scores (r = -0.85; p < 0.001). The analysis of the receiver operating characteristic curve (ROC) showed that the area under the curve (AUC) for ACOT7 was 0.83 (95% confidence intervals: 0.80-0.86). The optimal cut-off point of 62.5 pg./mL was selected with the highest sum of sensitivity and specificity. The diagnostic accuracy of serum ACOT7 for AD was 77% (95% confidence intervals: 72-82%), with a sensitivity of 80% (95% confidence intervals: 75-84%) and a specificity of 74% (95% confidence intervals: 69-79%). Moreover, the ROC analysis showed that the AUC of Aß42/40 ratio is 0.70, and the diagnostic accuracy was 72%, with 69% sensitivity and 76% specificity. Compared with the AD traditional marker Aß42/40 ratio, ACOT7 shows better superiority as a new serum candidate biomarker of AD. By suppressing the ACOT7 gene, our study provides evidence of the involvement of ACOT7 in the metabolism of amyloid precursor protein (APP), resulting in alterations in the expression levels of Aß42, BACE1 and ßCTF. ACOT7 has the ability to modulate the amyloidogenic pathway of APP metabolism, while it does not have an impact on the non-amyloidogenic pathway. In conclusion, the findings of our study suggest that serum ACOT7 may serve as a promising and non-invasive biomarker for AD.

Anti-Alzheimer's disease potential of traditional chinese medicinal herbs as inhibitors of BACE1 and AChE enzymes.

Alzheimer's disease (AD) is a common neurodegenerative disease that often occurs in the elderly population. At present, most drugs for AD on the market are single-target drugs, which have achieved certain success in the treatment of AD. However, the efficacy and safety of single-target drugs have not achieved the expected results because AD is a multifactorial disease. Multi-targeted drugs act on multiple factors of the disease network to improve efficacy and reduce adverse reactions. Therefore, the search for effective dual-target or even multi-target drugs has become a new research trend. Many of results found that the dual-target inhibitors of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and acetylcholinesterase (AChE) found from traditional Chinese medicine have a good inhibitory effect on AD with fewer side effects. This article reviews sixty-six compounds extracted from Chinese medicinal herbs, which have inhibitory activity on BACE1 and AChE. This provides a theoretical basis for the further development of these compounds as dual-target inhibitors for the treatment of AD.

The attenuation effect of potassium 2-(1-hydroxypentyl)-benzoate in a mouse model of diabetes-associated cognitive decline: The protein expression in the brain.

AIMS: dl-PHPB (potassium 2-(1-hydroxypentyl)-benzoate) has been shown to have neuroprotective effects against acute cerebral ischemia, vascular dementia, and Alzheimer's disease. The aim of this study was to investigate the effects of dl-PHPB on memory deficits and preliminarily explore the underlying molecular mechanism. METHODS: Blood glucose and behavioral performance were evaluated in the KK-Ay diabetic mouse model before and after dl-PHPB administration. Two-dimensional difference gel electrophoresis (2D-DIGE)-based proteomics was used to identify differentially expressed proteins in brain tissue. Western blotting was used to study the molecular mechanism of the related signaling pathways. RESULTS: Three-month-old KK-Ay mice were given 150 mg/kg dl-PHPB by oral gavage for 2 months, which produced no effect on the level of serum glucose. In the Morris water maze test, KK-Ay mice treated with dl-PHPB showed significant improvements in spatial learning and memory deficits compared with vehicle-treated KK-Ay mice. Additionally, we performed 2D-DIGE to compare brain proteomes of 5-month KK-Ay mice treated with and without dl-PHPB. We found 14 altered proteins in the cortex and 11 in the hippocampus; two of the 25 altered proteins and another four proteins that were identified in a previous study on KK-Ay mice were then validated by western blot to further confirm whether dl-PHPB can reverse the expression levels of these proteins. The phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase-3ß (PI3K/Akt/GSK-3ß) signaling pathway was also changed in KK-Ay mice and dl-PHPB treatment could reverse it. CONCLUSIONS: These results indicate that dl-PHPB may play a potential role in diabetes-associated cognitive impairment through PI3K/Akt/GSK-3ß signaling pathway and the differentially expressed proteins may become putative therapeutic targets.

Alix: A Candidate Serum Biomarker of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common fatal neurodegenerative disease of the elderly worldwide. The identification of AD biomarkers will allow for earlier diagnosis and thus earlier intervention. The aim of this study was to find such biomarkers. It was observed that the expression of Alix was significantly decreased in brain tissues and serum samples from AD patients compared to the controls. A significant correlation between Alix levels and cognitive decline was observed (r = 0.80; p < 0.001) as well as a significant negative correlation between Alix and Aß40 in serum levels (r =-0.60, p < 0.001). The receiver operating characteristic curve (ROC) analysis showed the area under the curve (AUC) of Alix was 0.80, and the optimal cut-off point of 199.5 pg/ml was selected with the highest sum of sensitivity and specificity. The diagnostic accuracy for serum Alix was 74%, with 76% sensitivity and 71% specificity respectively, which could differentiate AD from controls. In addition, the expression of Alix was found to be significantly decreased in AD compared to vascular dementia (VaD). ROC analysis between AD and VaD showed that the AUC was 0.777, which could be indicative of the role of serum Alix as a biomarker in the differential diagnosis between AD and VaD. Most surprisingly, the decreased expression of Alix was attenuated after the treatment of Memantine in different AD animal models. In conclusion, our results indicate the possibility of serum Alix as a novel and non-invasive biomarker for AD for the first time.

Cofilin 2 in Serum as a Novel Biomarker for Alzheimer's Disease in Han Chinese.

The identification of biomarkers of Alzheimer's disease (AD) is an important and urgent area of study, not only to aid in the early diagnosis of AD, but also to evaluate potentially new anti-AD drugs. The aim of this study was to explore cofilin 2 in serum as a novel biomarker for AD. The upregulation was observed in AD patients and different AD animal models compared to the controls, as well as in AD cell models. Memantine and donepezil can attenuate the upregulation of cofilin 2 expression in APP/PS1 mice. The serum levels of cofilin 2 in AD or mild cognitive impairment (MCI) patients were significantly higher compared to controls (AD: 167.9 ± 35.3 pg/mL; MCI: 115.9 ± 15.4 pg/mL; Control: 90.5 ± 27.1 pg/mL; p < 0.01). A significant correlation between cofilin 2 levels and cognitive decline was observed (r = -0.792; p < 0.001). The receiver operating characteristic curve (ROC) analysis showed the area under the curve (AUC) of cofilin 2 was 0.957, and the diagnostic accuracy was 80%, with 93% sensitivity and 87% specificity. The optimal cut-off value was 130.4 pg/ml. Our results indicate the possibility of serum cofilin 2 as a novel and non-invasive biomarker for AD. In addition, the expression of cofilin 2 was found to be significantly increased in AD compared to vascular dementia (VaD), and only an increased trend but not significant was detected in VaD compared to the controls. ROC analysis between AD and VaD showed that the AUC was 0.824, which could indicate a role of cofilin 2 as a biomarker in the differential diagnosis between AD and VaD.

The pathological roles of NDRG2 in Alzheimer's disease, a study using animal models and APPwt-overexpressed cells.

AIMS: To investigate the roles of N-myc downstream-regulated gene 2 (NDRG2) in the pathology of aging and neurodegenerative disease such as Alzheimer's disease (AD). RESULTS: In this study, we confirmed the upregulation of NDRG2 in the brains of aging and AD animal models. To explore the role of NDRG2 in the pathology of AD at molecular level, we conducted a cell-based assay of highly expressed wild-type human APP695 SK-N-SH cells (SK-N-SH APPwt). By silencing and overexpressing gene of NDRG2, we demonstrated that NDRG2-mediated increase in Aß1-42 was through the pathways of BACE1 and GGA3. NGRG2 improved tau phosphorylation via enhanced activity of CDK5 and decreased Pin1, but it was not affected by GSK3ß pathway. NDRG2 might also induce cell apoptosis through the extrinsic (caspase 8) apoptotic pathway by interaction with STAT3. CONCLUSION: Our study confirmed the upregulation of NDRG2 in AD animal models and demonstrated its important roles in AD pathology. NDRG2 might be a potential target for studying and treatment of AD.

Translational study of Alzheimer's disease (AD) biomarkers from brain tissues in AßPP/PS1 mice and serum of AD patients.

The aim of this study was to investigate potential biomarkers of Alzheimer's disease (AD). Changes in protein expression in brain tissues from AßPP/PS1 transgenic mice were evaluated using two-dimensional gel electrophoresis combined with LC-MS/MS. A total of 23 differentially expressed proteins were successfully identified in brain tissues of which 11 were validated by western blot. Then, the levels of these differentially expressed proteins in serum from AD patients and healthy controls were examined. Of these 11 proteins, levels of 5 changed in the same direction in the serum of AD patients as they did in mouse brain: cathepsin B, VDAC1, and cofilin-2 increased, and Alix and ACAP1 decreased. Alix, cofilin-2, and ACAP1 have not been previously associated with AD. More importantly, the serum levels of Alix, cofilin-2, and ACAP1 were significantly different between AD patients and healthy controls. Furthermore, the expressions of cathepsin B, cofilin-2, VDAC1, and ACAP1 strongly correlated with the Mini-Mental State Examination scores of the AD patients. The results indicate that these proteins are putative biomarkers of AD which may be useful in its diagnosis and in the evaluation of new anti-AD drugs both in pre-clinical and clinical studies.

[Allelopathy of grape root aqueous extracts].

Taking the tissue-cultured seedlings of grape cultivar Red Globe as test objects, this paper examined the effects of their root aqueous extracts on seedling's growth, with the allelochemicals identified by LC-MS. The results showed that 0.02 g x ml(-1) (air-dried root mass in aqueous extracts volume; the same below), 0.1 g x ml(-1), and 0.2 g x ml(-1) of the aqueous extracts inhibited the growth of the seedlings significantly, and the inhibition effect increased with increasing concentration of the extracts. The identified allelochemicals of the extracts included p-hydroxybenzoic acid, salicylic acid, phenylpropionic acid, and coumaric acid. Pot experiment showed that different concentration (0.1, 1, and 10 mmol x L(-1)) salicylic acid and phenylpropionic acid inhibited the seedling' s growth remarkably. With the increasing concentration of the two acids, the plant height, stem diameter, shoot- and root fresh mass, leaf net photosynthetic rate and starch content, and root activity of the seedlings decreased, while the leaf soluble sugar and MDA contents increased. No obvious change pattern was observed in leaf protein content.

[Effects of grape-replanting on soil bacterial and fungal populations].

Rhizosphere and non-rhizosphere soil samples were collected from the vineyards having been planted for 3 and 30 years, and PCR-DGGE technique was adopted to study the effects of grape-replanting on the population structure and diversity of soil bacteria and fungi. The bacterial and fungal diversities were higher in 30-year-planted vineyard than in 3-year-planted vineyard, and higher in rhizosphere soil than in non-rhizosphere soil. After 30 years replanting, the population structure of bacteria and fungi approached the same in rhizosphere soil and non-rhizosphere soil but differed from that in fallow soil; while in the 3-year-planted vineyard, the population structure in rhizosphere soil was different from that in non-rhizosphere soil and fallow soil. Comparing with that in 3-year-planted vineyard, the rhizosphere soil microbial population in 30-year-planted vineyard had a greater change. In bacterial population, Flavobacterium sp. (DQ339585) and Bacillus sp. (AY039821) decreased while Pedobacter sp. (AJ871084) increased; in fungal population, Omphalina farinolens (EF413029) appeared, Pestalotiopsis sp. (DQ657877, DQ657875, DQ657871), Phacidium lacerum (DQ470976), and Lecythophora decumbens (AF353597) decreased, while Pilidium acerinum voucher (AY48709) increased. Bacillus sp., Flavobacterium sp. , and Pestalotiopsis sp. had antagonism to pathogen, and their decrease reduced the resistance of grape against pathogen. The increase of Pilidium acerinum voucher might relate to the severe disease after grape-replanting.