Alzheimer-like behavior and synaptic dysfunction in 3 × Tg-AD mice are reversed with calcineurin inhibition.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Current treatments are unable to achieve satisfactory therapeutic effects or reverse the progression of the disease. Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and neuronal calcineurin may be hyperactivated in AD. To investigate the effects and underlying mechanisms of FK506, a calcineurin inhibitor, on Alzheimer-like behavior and synaptic dysfunction in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease, we investigated the effect of FK506 on cognitive function and synaptic plasticity in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease. The results showed that FK506 treatment ameliorated cognitive deficits, as indicated by the decreased latency in the water maze, and attenuated tau hyperphosphorylation in 3 × Tg-AD mice. Treatment with FK506 also reduced the levels of certain markers of postsynaptic deficits, including PSD-95 and NR2B, and reversed the long-term potentiation deficiency and dendritic spine impairments in 3 × Tg-AD mice. These findings suggest that treatment with calcineurin inhibitors such as FK506 can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial Alzheimer's disease and related tauopathies.

Differential epitranscriptome and proteome modulation in the brain of neonatal mice exposed to isoflurane or sevoflurane.

BACKGROUND: Repeated neonatal exposure to anesthetics may disturb neurodevelopment and cause neuropsychological disorders. The m6A modification participates in the gene regulation of neurodevelopment in mouse fetuses exposed to anesthetics. This study aims to explore the underlying molecular mechanisms of neurotoxicity after early-life anesthesia exposure. METHODS: Mice were exposed to isoflurane (1.5%) or sevoflurane (2.3%) for 2 h daily during postnatal days (PND) 7-9. Sociability, spatial working memory, and anxiety-like behavior were assessed on PND 30-35. Synaptogenesis, epitranscriptome m6A, and the proteome of brain regions were evaluated on PND 21. RESULTS: Both isoflurane and sevoflurane produced abnormal social behaviors at the juvenile age, with different sociality patterns in each group. Synaptogenesis in the hippocampal area CA3 was increased in the sevoflurane-exposed mice. Both anesthetics led to numerous persistent m6A-induced alterations in the brain, associated with critical metabolic, developmental, and immune functions. The proteins altered by isoflurane exposure were mainly associated with epilepsy, ataxia, and brain development. As for sevoflurane, the altered proteins were involved in social behavior. CONCLUSIONS: Social interaction, the modulation patterns of the m6A modification, and protein expression were altered in an isoflurane or sevoflurane-specific way. Possible molecular pathways involved in brain impairment were revealed, as well as the mechanism underlying behavioral deficits following repeated exposure to anesthetics in newborns.

Circular RNA nuclear receptor interacting protein 1 promoted biliary tract cancer epithelial-mesenchymal transition and stemness by regulating the miR-515-5p/AKT2 axis and PI3K/AKT/mTOR signaling pathway.

Biliary tract cancer (BTC) is a devastating malignancy that is notoriously difficult to diagnose and is associated with high mortality. Circular RNA (circRNA) is a class of endogenous non-coding RNA which has been regarded as the key regulator of tumor initiation and progression, including BTC. Circular RNA nuclear receptor interacting protein 1 (circ_NRIP1), as a circular RNA, is abnormally expressed in many human tumors and exhibits diverse functions in cancer progression. However, its biological significance in BTC has not been thoroughly investigated. In this research, we elucidated that circ_NRIP1 was notably overexpressed in both BTC tissues and cells. We further established a correlation between circ_NRIP1 expression and clinicopathological features in BTC patients, highlighting its clinical relevance. Through functional assays, we observed that knockdown of circ_NRIP1 significantly inhibited tumor cell proliferation, invasion, stemness maintenance, and epithelial-mesenchymal transition, indicating its active involvement in promoting BTC progression. Additionally, it attenuated growth of xenograft and metastasis models. Mechanically, we revealed that circ_NRIP1 served as the competing endogenous RNA to sequester miR-515-5p through complementary base pairing mechanism, thereby upregulated AKT2 expression and indirectly activated PI3K/AKT/mTOR signaling pathway. Generally, targeting the circ_NRIP1/miR-515-5p/AKT2 axis and aberrant activation of the PI3K/AKT/mTOR pathway may hold promising therapeutic strategies for BTC. Our research contributes to a better understanding of the underlying biological basis of BTC and paves the way for the development of innovative treatment approaches.

A general approach to S-rhodamines from diaryl thioethers and their application in constructing pH probes.

A general strategy for the efficient preparation of S-rhodamines from the condensation of diaryl thioether and 2-carboxybenzaldehydes was reported. We further took a morpholine containing spirolactam structure as an example to illustrate that these S-rhodamine dyes could be utilized to construct fluorescent probes based on the ring-opening process. This work provided a general approach for the synthesis of novel S-rhodamine dyes, thus possibly facilitating the development of fluorescence imaging.

The signal axis GATA2-EDN1-AGT induced hypertension from obstructive sleep apnea-hypopnea syndrome with the clinical and animal study.

Hypertension occurred in 50% obstructive sleep apnea-hypopnea syndrome (OSAHS) patients meanwhile OSAHS occurred in 30% hypertension patients. The present study aimed to explore the molecular mechanism of GATA2-EDN1-AGT induced hypertension in the development of obstructive sleep apnea-hypopnea syndrome. OSAHS patients (56 cases: 36 cases of male, 20 cases of female, 42~60 years old) were divided into two groups (case group: patients with hypertension monitored by 24 h ambulatory blood pressure and polysomnography; control group: patients without hypertension). Wistar rats were used to establish the OSAHS model (narrow pharyngeal cavity). PaO2 and PaCO2 of patients and rats were measured by an automatic blood gas analyzer. The profile of total protein in the OSAHS group and normal group was evaluated. Protein-protein-interaction (PPI) was carried out to show all matter proteins related. The levels of EDN-1, AGTII and atrial natriuretic peptide (ANP) in blood samples of patients and rats were analyzed by enzyme-linked immunosorbent assay (ELISA). The expression of GATA2, EDN1, endothelin-converting enzyme 1 (ECE-1) and AGTⅡ was measured. The results showed that SaO2 and AHI were positively associated with systolic pressure (P<0.05) in OSAHS patients. There was no correlation among other indexes (P>0.05). It was also observed that GATA2 had a strong relationship with AGTⅡ and EDN1. The results of ELISA presented that the levels of EDN1, AGTⅡ and ANP in the OSAHS group of human and animal models were significantly increased (P<0.05). The results of immunochemistry showed that the expression of GATA2 and AGTⅡ in the vascular of OSAHS group was upregulated manifestly (P<0.05). It was concluded that OSAHS can induce AHI, which increases hypertension via the GATA2-EDN1-AGT Ⅱ axis.

PCAT1 induced by transcription factor YY1 promotes cholangiocarcinoma proliferation, migration and invasion by sponging miR-216a-3p to up-regulate oncogene BCL3.

This study was designed to illustrate the function and role of PCAT1 in CCA. The relative expression was confirmed by RT-qPCR and western blot. The biological function of PCAT1 was evaluated by CCK8, EdU, colony formation, wound healing, transwell, and subcutaneous tumor formation assays. Protein levels of EMT markers were measured by western blot. The binding relationship was predicted by JASPAR and starBase. The binding of YY1 to PCAT1 promoter was assessed by ChIP and luciferase reporter. The binding capacity between miR-216a-3p and PCAT1 as well as BCL3 was assessed by luciferase reporter and AGO2-RIP assays. In this study, we found that PCAT1 was up-regulated in CCA tissues and cells, and the PCAT1 overexpression was associated with poor prognosis. Moreover, PCAT1 was assessed as an independent risk factor of prognosis for CCA patients. Amplified PCAT1 was found to promote tumor proliferation, migration, invasion and EMT process, whereas PCAT1 knockdown inhibited these malignant phenotypes. Mechanistically, PCAT1 was predominantly localized in the cytoplasm and competitively bound miR-216a-3p to increase BCL3 expression. In addition, PCAT1 was activated by transcription factor YY1. This study revealed that PCAT1 acted as an oncogene in CCA, and the YY1/PCAT1/miR-216a-3p/BCL3 axis exhibited critical functions in CCA progression.

Enhanced photosynthetic nitrogen use efficiency and increased nitrogen allocation to photosynthetic machinery under cotton domestication.

Domestication involves dramatic phenotypic and physiological diversifications due to successive selection by breeders toward high yield and quality. Although photosynthetic nitrogen use efficiency (PNUE) is a major trait for understanding leaf nitrogen economy, it is unclear whether PNUE of cotton has been improved under domestication. Here, we investigated the effect of domestication on nitrogen allocation to photosynthetic machinery and PNUE in 25 wild and 37 domesticated cotton genotypes. The results showed that domesticated genotypes had higher nitrogen content per mass (Nm), net photosynthesis under saturated light (Asat), and PNUE but similar nitrogen content per area (Na) compared with wild genotypes. As expected, in both genotypes, PNUE was positively related to Asat but negatively correlated with Na. However, the relative contribution of Asat to PNUE was greater than the contribution from Na. Domesticated genotypes had higher nitrogen allocation to light-harvesting (NL, nitrogen in light-harvesting chlorophyll-protein complex), to bioenergetics (Nb, total nitrogen of cytochrome f, ferredoxin NADP reductase, and the coupling factor), and to Rubisco (Nr) than wild genotypes; however, the two genotype groups did not differ in PNUEp, the ratio of Asat to Np (itself the sum of NL, Nb, and Nr). Our results suggest that more nitrogen allocation to photosynthetic machinery has boosted Asat under cotton domestication. Improving the efficiency of nitrogen use in photosynthetic machinery might be future aim to enhance Asat of cotton.

LncRNA NORAD promotes proliferation, migration and angiogenesis of hepatocellular carcinoma cells through targeting miR-211-5p/FOXD1/VEGF-A axis.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death around the world. Despite improvement in the prevention and treatment of HCC, the clinical prognosis is still poor with increasing mortality. Non-coding RNAs play pivotal roles in HCC oncogenesis, but the detailed mechanism is poorly known. Therefore, the functions and interaction of lncRNA NORAD and miR-211-5p in HCC was investigated in this study. METHODS: Quantitative real-time PCR method was used to analyze the expression of NORAD and miR-211-5p in clinical HCC tissues and cultured cell lines. Knockdown of NORAD and overexpression of miR-211-5p were then carried in HCC cells. Moreover, bioinformatics analysis and luciferase report assays were further employed to analyze the interaction between miR-211-5p and NORAD or FOXD1. RESULTS: Increased lncRNA NORAD and decreased miR-211-5p expression were first detected in HCC compared with the peritumorial area. Further studies showed that knockdown of NORAD or overexpression of miR-211-5p impaired the proliferation, migration and angiogenesis of HCC cells. Mechanistically, we found that NORAD functions as a sponge for miR-211-5p. Moreover, it was revealed that decreased miR-211-5p induced the expression of FOXD1 as well as its downstream target VEGF-A, thereby contributes to enhanced angiogenesis of HCC. CONCLUSION: Elevated NORAD works as a sponge for miR-211-5p in HCC, thus release the inhibition effect of the latter on its downstream target FOXD1 and VEGF-A, which finally promotes angiogenesis. These results provide new insights into the interaction between NORAD and miR-211-5p in HCC and their potential usage as targets for the development of novel therapeutics against HCC.

Hepatoprotective potential of kirenol on ethanol-induced liver toxicity in albino rats and acetaminophen-induced oxidative stress-mediated apoptosis in hepatic HepG2 cells.

Liver diseases are a major health issue in both men and women and cause significant mortality worldwide. The hepatoprotective effects of kirenol were evaluated in acetaminophen (APAP)-induced toxicity in HepG2 cells and ethanol (EtOH)- induced hepatotoxicity in rats. The cytotoxicity of kirenol (IC50 , 25 µM/ml) and APAP (20 µg/ml) with sylimarin (IC50 , 15 µg/ml) was observed in HepG2 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, reactive oxygen species formation, mitochondrial membrane potential, and oxidative stress markers such as thiobarbituric acid-reactive substance, suproxide dismutase, and catalase were assayed. Rats were administered a different dose (10, 20, and 30 mg/kg/day) for a period of 4 weeks before a single dose of EtOH (40% vol/vol) 3 g/kg/day. EtOH administered rats appeared to have lower body weight gain, severe hepatic and kidney damage as proved by elevated aspartate transaminase, alanine transaminase, alkaline phosphatase, uric acid, increased malondialdehyde (MDA), and inflammatory markers, and reduced glutathione (GSH) levels. Results showed that the kirenol treatment enhanced the GSH and reduced MDA in the liver and renal tissues and restored TNF-α and IL-6. Histoanalysis proved the protective effects of kirenol. In conclusion, it was proved that the kirenol demonstrated a hepato-protective effect in APAP- and EtOH-induced liver toxicity in HepG2 cells and rats, respectively.

Menadione sodium bisulfite inhibits the toxic aggregation of amyloid-ß(1-42).

Protein misfolding and aggregation are associated with amyloidosis. The toxic aggregation of amyloid-ß 1-42 (Aß42) may disrupt cell membranes and lead to cell death and is thus regarded as a contributing factor in Alzheimer's disease (AD). 1,4-naphthoquinone (NQ) has been shown to exhibit strong anti-aggregation effects on amyloidogenic proteins such as insulin and α-synuclein; however, its high toxicity and poor solubility limit its clinical application. Menadione sodium bisulfite (MSB, also known as vitamin K3), is used clinically in China to treat hemorrhagic diseases caused by vitamin K deficiency and globally as a vitamin K supplement. We hypothesized that MSB could inhibit amyloid formation since its backbone structure is similar to NQ. To test our hypothesis, we first investigated the effects of MSB on Aß42 amyloid formation in vitro. We found that MSB inhibited Aß42 amyloid formation in a dose dependent manner, delayed the secondary structural conversion of Aß42 from random coil to ordered ß-sheet, and attenuated the ability of Aß42 aggregates to disrupt membranes; moreover, the quinone backbone rather than lipophilicity is esstial for the inhibitory effects of MSB. Next, in cells expressing a pathogenic APP mutation (Osaka mutation) that results in the formation of intraneuronal Aß oligomers, MSB inhibited the intracellular aggregation of Aß. Moreover, MSB treatment significantly extended the life span of Caenorhabditis elegans CL2120, a strain that expresses human Aß42. Together, these results suggest that MSB and its derivatives may be further explored as potential therapeutic agents for the prevention or treatment of AD.

Effects of gelling bath on the physical properties of alginate gel beads and the biological characteristics of entrapped HepG2 cells.

Optimizing alginate gel beads is necessary to support the survival, proliferation, and function of entrapped hepatocytes. In this study, gelling bath was modified by decreasing calcium ion concentration and increasing sodium ion concentration. Alginate gel beads (using 36% G sodium alginate) prepared in the modified gelling bath had more homogeneous structure and better mass transfer properties compared with the traditional gelling bath that contains only calcium ions. Moreover, alginate gel beads generated in the modified gelling bath could significantly promote the HepG2 cell proliferation and the growth of cell spheroids, and maintain the albumin secretion ability similar to alginate gel beads prepared in the traditional gelling bath with only calcium ions. The mass transfer properties and cell proliferation were similar in ALG beads with different M/G ratio (36% G and 55% G) generated in the modified gelling bath, whereas they were significantly increased compared with alginate gel beads (55% G) in traditional gelling bath. These results indicated that adjusting the gelling bath was a simple and convenient method to enhance the mass transfer properties of alginate gel beads for 3D hepatocyte culture, which might provide more hepatocytes for the bioartificial liver support system.

Engineering islet for improved performance by optimized reaggregation in alginate gel beads.

After islet isolation, diffusion has become the main mechanism to transport oxygen and nutrients into the core of islets. However, diffusion has limitations, by which nutrients cannot effectively reach the core of large islets and can eventually cause core cell death and islet loss. This problem can be resolved by dispersing islets into single islet cells, but single islet cells do not exhibit insulin release function in in vitro culture. In this study, we intended to establish a new islet engineering approach by forming islet cell clusters to improve islet survival and function. Therefore, alginate gels were used to encapsulate islet cells to form artificial islets after dispersion of islets into single cells. The shape of the islet cell clusters was similar to native islets, and the size of the islet cell clusters was limited to a maximum diameter of 100 µm. By limiting the diameter of this engineered islet cell cluster, cell viability was nearly 100%, a significant improvement over natural islets. Importantly, islet cell clusters express the genes of islets, including Isl-1, Gcg, and insulin-1, and insulin secretion ability was maintained in vitro.

Stirring rate regulates the proliferation and metabolism of microencapsulated recombinant CHO cells.

Stirred tank bioreactors are the most widely used method for the large-scale culture of mammalian cells. However, the scale of stirred tank bioreactors is limited by insufficient oxygen/nutrient mixing and the accumulation of waste products in high cell density cultures. The most effective method to solve these problems is to increase the stirring rate; this usually leads to increased cell proliferation, but can decrease the utilization of nutrients for recombinant protein synthesis. To investigate the effects of stirring rate on the proliferation, metabolism, and recombinant protein yield of microencapsulated recombinant Chinese hamster ovary (rCHO) cells, the cells were cultured under different stirring rates, and cell viability, metabolic activity, and protein yield were measured. Microencapsulation promoted Desmodus rotundus salivary plasminogen activator expression, and higher stirring rates promoted increases in microencapsulated cell density and metabolic activity. However, the maximum yield of recombinant protein was obtained at a moderate stirring rate, whereas protein yield was decreased at the highest tested stirring rate. The stirring rate had a significant impact on the growth and protein expression of microencapsulated rCHO cells, and a specific stirring rate was identified to maximize the yield of recombinant protein.

Growth and production of microencapsulated recombinant CHO in a stirred tank bioreactor.

Microencapsulation supplies cells with a three-dimensional microenvironment enhancing the metabolic activity, cell density and recombinant protein expression in a stirred tank bioreactor which is used widely to culture mammalian cells in many biochemical processes. In this paper, we address the growth and Desmodus rotundus salivary plasminogen activator (DSPA) production of recombinant CHO (rCHO) in a stirred tank bioreactor. Cells were cultured using two different methods--in an unmicroencapsulated versus microencapsulated culture--and compared differences between them in terms of cell reproduction and DSPA protein productivity. Compared to the unmicroencapsulated rCHO, microencapsulated cells got higher cell density and prolonged the plateau phase. Microencapsulated rCHO promoted DSPA production, with a maximum rate that was 4.8 times higher than in unmicroencapsulated cells, and the accumulated production of DSPA was 3.3 higher than in unmicroencapsulated cells. Negative relationship was found between specific growth rate and DSPA production capacity of unit cells. These findings will facilitate the methods for higher DSPA production in stirred tank bioreactors.

Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation.

Phosphotyrosyl phosphatase activator (PTPA) is decreased in the brains of Alzheimer's disease (AD) and the AD transgenic mouse models. Here, we investigated whether down-regulation of PTPA affects cell viability and the underlying mechanisms. We found that PTPA was located in the integral membrane of mitochondria, and knockdown of PTPA induced cell apoptosis in HEK293 and N2a cell lines. PTPA knockdown decreased mitochondrial membrane potential and induced Bax translocation into the mitochondria with a simultaneous release of Cyt C, activation of caspase-3, cleavage of poly (DNA ribose) polymerase (PARP), and decrease in Bcl-xl and Bcl-2 protein levels. Over-expression of Protein phosphatase 2A (PP2A) catalytic subunit (PP2AC ) did not rescue the apoptosis induced by PTPA knockdown, and PTPA knockdown did not affect the level of and their phosphorylation of mitogen-activated protein kinases (MAPKs), indicating that PP2A and MAPKs were not involved in the apoptosis induced by PTPA knockdown. In the cells with over-expression of tau, PTPA knockdown induced PP2A inhibition and tau hyperphosphorylation but did not cause significant cell death. These data suggest that PTPA deficit causes apoptotic cell death through mitochondrial pathway and simultaneous tau hyperphosphorylation attenuates the PTPA-induced cell death. Phosphotyrosyl phosphatase activator (PTPA) is decreased in the brains of Alzheimer's disease (AD) and AD transgenic mouse models. Here, we investigated whether down-regulation of PTPA affects cell viability. We found that PTPA located in the integral membrane of mitochondria, and knockdown of PTPA induced cell apoptosis in HEK293 and N2a cell lines by decreasing mitochondrial membrane potential, which leads to translocation of Bax and a simultaneous release of Cyt C. In the cells with tau over-expression, PTPA knockdown inactivated PP2A to phosphorylate tau to avoid cell apoptosis which induced by PTPA knockdown.

[Association between the level of high sensitivity C-reactive protein and risk of breast cancer among non-diabetic females: a prospective study in Kailuan group].

OBJECTIVE: To evaluate the association between high sensitivity C-reactive protein (hsCRP) and breast cancer incidence among the non-diabetic females in a large-scale cohort study in Kailuan group. METHODS: The Kailuan cohort was established on May 1, 2006. Baseline information on demography, lifestyle, medical history, and anthropometry, i.e., body height and weight, were collected during the baseline interview, and breast cancer incidence, mortality and other related outcome information were obtained by follow-up every two years and the related health condition database information were collected every year. Multivariable Cox proportional-hazards regression model was used to calculate the hazard ratios (HRs) and 95%CI (confidence interval) between the level of hsCRP at baseline interview and breast cancer incidence adjusted for age group, body mass index (BMI), marital status (married and single) and tobacco smoking (smokers and non-smokers) when appropriate. RESULTS: By Dec 31, 2011, a total of 17 402 females were enrolled in the cohort. There were 85 286 person-years of follow-up with a mean follow-up period of (58.81 ± 4.52) months. A total of 75 incident breast cancer cases were collected. Subjects with the highest level (>3 mg/L) of hsCRP at baseline interview were associated with a significantly increased risk of breast cancer (adjusted HR = 1.80, 95%CI = 1.03-3.15) compared with those with the lowest level (<1 mg/L). CONCLUSIONS: Elevated levels of hsCRP at baseline interview may be associated with an increased risk of breast cancer among non-diabetic females. Further follow-up and etiological exploration will help to evaluate the association between the hsCRP level and the risk of breast cancer more reliably.

LOXL1-AS1 inhibits JAK2 ubiquitination and promotes cholangiocarcinoma progression through JAK2/STAT3 signaling.

This study thoroughly investigated the role of the long non-coding RNA LOXL1-AS1 in the pathogenesis of cholangiocarcinoma (CCA). Through bioinformatics analysis and tissue samples validation, the study found that LOXL1-AS1 was significantly elevated in CCA, with its high expression closely tied to clinical pathological features and prognosis. In vitro and in vivo experiments revealed that LOXL1-AS1 was crucial in regulating CCA cell apoptosis, proliferation, migration, and invasion. Further investigations using FISH, subcellular localization experiments, RNA pull down, and RIP uncovered that LOXL1-AS1 primarily resided in the cytoplasm and influenced CCA progression by modulating the JAK2/STAT3 signaling pathway. Notably, LOXL1-AS1 might regulate the activity of JAK2 through modulating its ubiquitination and degradation. YY1 had also been found to act as an upstream transcription factor of LOXL1-AS1 to impact CCA cell malignancy. These findings shed light on the pivotal role of LOXL1-AS1 in CCA and offered potential directions for novel therapeutic strategies, providing a fresh perspective on tumor pathogenesis.

Gallic Acid Alleviates Cognitive Impairment by Promoting Neurogenesis via the GSK3ß-Nrf2 Signaling Pathway in an APP/PS1 Mouse Model.

Background: Neuronal loss occurs early and is recognized as a hallmark of Alzheimer's disease (AD). Promoting neurogenesis is an effective treatment strategy for neurodegenerative diseases. Traditional Chinese herbal medicines serve as a rich pharmaceutical source for modulating hippocampal neurogenesis. Objective: Gallic acid (GA), a phenolic acid extracted from herbs, possesses anti-inflammatory and antioxidant properties. Therefore, we aimed to explore whether GA can promote neurogenesis and alleviate AD symptoms. Methods: Memory in mice was assessed using the Morris water maze, and protein levels were examined via western blotting and immunohistochemistry. GA's binding site in the promoter region of transcription regulator nuclear factor erythroid 2-related factor 2 (Nrf2) was calculated using AutoDock Vina and confirmed by a dual luciferase reporter assay. Results: We found that GA improved spatial memory by promoting neurogenesis in the hippocampal dentate gyrus zone. It also improved synaptic plasticity, reduced tau phosphorylation and amyloid-ß concentration, and increased levels of synaptic proteins in APP/PS1 mice. Furthermore, GA inhibited the activity of glycogen synthase kinase-3ß (GSK-3ß). Bioinformatics tools revealed that GA interacts with several amino acid sites on GSK-3ß. Overexpression of GSK-3ß was observed to block the protective effects of GA against AD-like symptoms, while GA promoted neurogenesis via the GSK-3ß-Nrf2 signaling pathway in APP/PS1 mice. Conclusions: Based on our collective findings, we hypothesize that GA is a potential pharmaceutical agent for alleviating the pathological symptoms of AD.

Upregulation of miR-650 is correlated with down-regulation of ING4 and progression of hepatocellular carcinoma.

BACKGROUND: In the last decade, studies in hepatocellular carcinoma (HCC) demonstrate dysregulation of miRNAs expression. For instance, miR-650 has been implicated in gastric and colorectal cancer tumorigenicity; however, the role of miR-650 remains unknown in HCC. METHODS: In this study, we performed a comprehensive analysis to examine the miR-650 expression level in 248 HCC and 120 paracarcinomatous liver (PCL) tissues. The correlations between miR-650 expression level and the clinicopathological characteristics (HCC tumorigenicity) were evaluated. The role of miR-650 played in HCC was investigated by Q-PCR, western blot, and MTT. RESULTS: We found that miR-650 expression was significantly increased in HCC patients and significantly associated with the patients' age (P = 0.0019), differentiation capability (P = 0.0108), and also tumor stage (P = 0.0069). Moreover, we compared the expression level of both ING4 and miR-650 in 122 HCC patients by western blot and real-time PCR. Statistical result showed a significant negative correlation between them (r(s) = -0.2011, P = 0.0264). Transfection and MTT test suggested that miR-650 decreased the expression of ING4 and stimulate liver cells proliferation significantly. CONCLUSION: These data suggested that miR-650 is correlated with the pathogenesis of HCC and is involved in the HCC tumorigenesis process by inhibiting the expression of ING4.

Alopecia Universalis in an Elderly Chinese Man Induced by Sacubitril/Alisartan, a Novel Angiotensin Receptor-Neprilysin Inhibitor.

Drug-induced alopecia areata is a rare adverse event wherein medications such as antimicrobials, anticonvulsants, and biologics, trigger the premature transition of actively growing hairs into the telogen phase. Herein, a unique case of alopecia universalis observed during a clinical trial involving sacubitril/alisartan, a novel angiotensin receptor-neprilysin inhibitor (ARNI) has been reported. This case contributes to the range of cutaneous reactions that might be observed in association with ARNI therapy.