The interaction between alpha-synuclein and mitochondrial dysfunction in Parkinson's disease.

Parkinson's disease (PD) is an aging-associated neurodegenerative disorder with the hallmark of abnormal aggregates of alpha-synuclein (α-syn) in Lewy bodies (LBs) and Lewy neurites (LNs). Currently, pathogenic α-syn and mitochondrial dysfunction have been considered as prominent roles that give impetus to the PD onset. This review describes the α-syn pathology and mitochondrial alterations in PD, and focuses on how α-syn interacts with multiple aspects of mitochondrial homeostasis in the pathogenesis of PD.

New paraconic acids from the endophytic fungus Xylariaceae sp. J4.

Three new paraconic acids, xylariacinics A-C (1-3), were isolated from the endophyte Xylariaceae sp. J4 harbored in the medicinal plant Blumea balsamifera. Their structures were elucidated on the basis of extensive spectroscopic data including HRMS, and NMR. The antibacterial efficacies of compounds 1-3 were evaluated against a panel of bacteria such as Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. Their antifungal activities were also tested against Colletotrichum gloeosporioides. Unfortunately, all of them were inactive.

Trans-cranial Doppler predicts early neurologic deterioration in anterior circulation ischemic stroke after successful endovascular treatment.

BACKGROUND: Early neurologic deterioration (END) may occur in patients with anterior circulation ischemic stroke (ACIS) after receiving endovascular treatment (EVT). Hemodynamic insufficiency, re-occlusion, and post-re-canalization hyper-perfusion are likely to play a critical role in END. We hypothesized that hemodynamic changes can predict END in patients with ACIS post-successful EVT using trans-cranial Doppler (TCD). METHODS: We utilized a prospectively maintained database of ACIS patients treated with EVT between September 2016 and June 2018 in the Xuanwu Hospital, Capital Medical University. TCD parameters including peak systolic velocity (PSV), bilateral mean flow velocity (MFV), and pulse index (PI) were determined via the middle cerebral arteries within 72 h post-EVT. A logistic regression model was applied to detect independent predictors for END. RESULTS: Totally, 112 EVT patients were included in this study and 80/112 patients experienced successful re-canalization with <50% residual stenosis, while 17/80 (21.3%) patients suffered END, for which vasogenic cerebral edema (11/17) was considered as a leading role and followed by symptomatic intra-cranial hemorrhage (4/17) and ischemia progression (2/17). For the 80 patients, the PSV (median: 127 cm/s vs. 116 cm/s, P = 0.039), the ratio of ipsilateral-MFV/contra-lateral-MFV (iMFV/cMFV) (median: 1.29 vs. 1.02, P = 0.036) and iMFV/mean blood pressure (MBP) (median: 0.97 vs. 0.79, P = 0.008) in END patients were higher than those of non-END. Using the receiver-operating characteristic curve to obtain cut-off values for PSV, PI, iMFV/cMFV, and iMFV/MBP for END, we found that PI ≥0.85 (odds ratio: 11.03, 95% confidence interval: 1.92-63.46, P = 0.007) and iMFV/MBP ≥0.84 (odds ratio: 9.20, 95% confidence interval: 2.07-40.84, P = 0.004) were independent predictors of END in a multivariate logistic regression model, with a sensitivity of 82.4% and 76.5% and a specificity of 42.9% and 66.7%, respectively, and had the positive predictive values of 29.0% and 38.2%, and negative predictive values of 90.0% and 91.3%, with an area under the receiver-operating characteristic curve of 0.57 and 0.71, respectively. CONCLUSION: TCD examination of EVT patients may be used as a real-time tool to detect END predictors, such as the higher PI and iMFV/MBP, allowing for better post-thrombectomy management in ACIS patients.

[Genome survey and characteristic analysis of SSR in Callicarpa nudiflora].

Callicarpa nudiflora,which is a big brand of Li nationality medicine with Hainan characteristics,has the effects of dissolving stasis,hemostasis,anti-inflammatory and antibacterial. At present,there is a lack of information about the reference genome of C. nudiflora. The study of the genome size,heterozygosity rate and characteristics of SSR of C. nudiflora,can provide an effective basis for the formulation of the whole genome de novo sequencing strategy and development of SSR molecular markers of C. nudiflora. To realize this purpose,high throughput sequencing platform Illumina Hiseq was used to sequence the genome structure of C. nudiflora and K-mer analysis was applied to estimate genome size,repeat sequences and heterozygosity rate. Simple-sequence repeat( SSR) loci that are suitable as markers were identified by MISA software. The results showed the estimated genome size of C. nudiflora was 822. 43 Mb,with a 0. 85% heterozygosity rate and 71. 67% repeats,and the GC content of genome was about 49. 20%. Therefore,C. nudiflora belongs to a complex genome with high heterozygosity and repetition. SSR molecular genetic markers were analyzed in the genome sequence,and a total of 206 049 SSRs were identified,among which mono-nucleotide,di-nucleotide and tri-nucleotide repetitive motifs summed up to 198 993,accounting for 96. 57% of the total SSRs. Among the 2-6 nucleotide repeats,AT/AT,AAT/ATT,AGCC/CTGG,AAAAT/ATTTT and AGATAT/ATATCT have the largest number,respectively. This report represents the first genome-wide characterization of C. nudiflora,and provides a reference for the construction of the library for the fine sequencing of the genome,and a molecular basis for the development of SSR molecular markers as well as for the protection and utilization of gene resources.

[Secondary metabolites from Epicoccum nigrum 14one,an endophytic fungus isolated from plant Leptogium masiaticum].

Phytochemical investigation of the culture of Epicoccum nigrum,an endolichenic fungus inhabiting Leptogium masiaticum,led to the isolation of 11 compounds. Based on NMR spectroscopy and HRESIMS data,their structures were determined as one alkaloid fusaricide( 1),and seven benzofuran derivatives including epicoccone( 2),4,6-dihydroxy-5-methoxy-7-methyl-1,3-dihydro isobenzofuran( 3),5-methyl-epicoccone B( 4),3,6,7-trihydroxy-5-methoxy-4-methylisobenzo furan-1( 3 H)-one( 5),3-methoxyepicoccone B( 6),2,3,4-trihydroxy-6-( hydroxymethyl)-5-methylbenzyl-alcohol( 7),and isoochracinic acid( 8),together with three epicoccolide analogs epicocconigrones A( 9),epicoccolide B( 10),and epicocconigrones B( 11). Compounds 1,9 and 10 showed potent microorganism inhibitory effects. These results indicated the potential perspective of this endophytic fungus as an eco-friendly biocide.

Dauricine suppresses the growth of pancreatic cancer in vivo by modulating the Hedgehog signaling pathway.

Pancreatic cancer is a highly malignant cancer associated with high expression levels of sonic hedgehog signaling molecule (Shh), patched 1 (Ptch1), smoothened frizzled class receptor (Smo) and glioma-associated oncogene family zinc finger 1 (Gli1) in the hedgehog (Hh) signaling pathway. Inhibition of the Hh signaling pathway is a potential therapeutic target for pancreatic cancer. The aim of the present study was to investigate the effects of dauricine in a pancreatic cancer BxPC-3 ×enograft animal model and examine the underlying molecular mechanisms through Hh signaling pathway. High-and low-dose dauricine treatment significantly suppressed tumor growth with no concomitant effect on the spleen index. In addition, dauricine induced apoptosis and cell cycle arrest in pancreatic cancer BxPC-3 cells. The inhibitory effects of dauricine on pancreatic cancer may be mediated by the suppression of the Hh signaling pathway, as indicated by the decreases in the gene and protein expression levels of Shh, Ptch1, Smo and Gli1. The effects of dauricine were similar to those of 5-fluorouracil. Dauricine, a naturally occurring alkaloid, may be a potential anticancer agent for the treatment of pancreatic cancer.

Phylogenetic Reconstruction and Divergence Time Estimation of Blumea DC. (Asteraceae: Inuleae) in China Based on nrDNA ITS and cpDNA trnL-F Sequences.

The genus Blumea is one of the most economically important genera of Inuleae (Asteraceae) in China. It is particularly diverse in South China, where 30 species are found, more than half of which are used as herbal medicines or in the chemical industry. However, little is known regarding the phylogenetic relationships and molecular evolution of this genus in China. We used nuclear ribosomal DNA (nrDNA) internal transcribed spacer (ITS) and chloroplast DNA (cpDNA) trnL-F sequences to reconstruct the phylogenetic relationship and estimate the divergence time of Blumea in China. The results indicated that the genus Blumea is monophyletic and it could be divided into two clades that differ with respect to the habitat, morphology, chromosome type, and chemical composition of their members. The divergence time of Blumea was estimated based on the two root times of Asteraceae. The results indicated that the root age of Asteraceae of 76-66 Ma may maintain relatively accurate divergence time estimation for Blumea, and Blumea might had diverged around 49.00-18.43 Ma. This common ancestor had an explosive expansion during the Oligocene and Miocene and two major clades were differentiated during these epochs 29.60 Ma (17.76-45.23 Ma 95% HPD (Highest Posterior Density). Evidence from paleogeography and paleoclimate studies has confirmed that Blumea experienced differentiation and an explosive expansion during the Oligocene and Miocene.

Down-regulated lncRNA DLX6-AS1 inhibits tumorigenesis through STAT3 signaling pathway by suppressing CADM1 promoter methylation in liver cancer stem cells.

BACKGROUND: Liver cancer stem cells (LCSCs) are a small subset of cells characterized by unlimited self-renewal, cell differentiation, and uncontrollable cellular growth. LCSCs are also resistant to conventional therapies and are thus believed to be held responsible for causing treatment failure of hepatocellular carcinoma (HCC). It has been recently found that long non-coding RNAs (lncRNAs) are important regulators in HCC. This present study aims to explore the underlying mechanism of how lncRNA DLX6-AS1 influences the development of LCSCs and HCC. METHODS: A microarray-based analysis was performed to initially screen differentially expressed lncRNAs associated with HCC. We then analyzed the lncRNA DLX6-AS1 levels as well as CADM1 promoter methylation. The mRNA and protein expression of CADM1, STAT3, CD133, CD13, OCT-4, SOX2, and Nanog were then detected. We quantified our results by evaluating the spheroid formation, proliferation, and tumor formation abilities, as well as the proportion of tumor stem cells, and the recruitment of DNA methyltransferase (DNMT) in LCSCs when lncRNA DLX6-AS1 was either overexpressed or silenced. RESULTS: LncRNA DLX6-AS1 was upregulated in HCC. The silencing of lncRNA DLX6-AS1 was shown to reduce and inhibit spheroid formation, colony formation, proliferation, and tumor formation abilities, as well as attenuate CD133, CD13, OCT-4, SOX2, and Nanog expression in LCSCs. Furthermore, downregulation of lncRNA DLX6-AS1 contributed to a reduction in CADM1 promoter methylation via suppression of DNMT1, DNMT3a, and DNMT3b in LCSCs and inactivating the STAT3 signaling pathway. CONCLUSION: This study demonstrated that down-regulated lncRNA DLX6-AS1 may inhibit the stem cell properties of LCSCs through upregulation of CADM1 by suppressing the methylation of the CADM1 promoter and inactivation of the STAT3 signaling pathway.

New α-pyrones from an endophytic fungus, Hypoxylon investiens J2.

Four new α-pyrones, hypotiens A-D (1-4), were isolated from a fungal endophyte, Hypoxylon investiens J2, harbored in the medicinal plant Blumea balsamifera. Their structures were determined through detailed HRMS and NMR spectroscopic data. Compounds 1-4 are new α-pyrone derivatives containing an unusual dimethyl substitution in the highly unsaturated side chain. Their plausible biosynthetic pathway was discussed. Biological assay indicated that compounds 1-4 showed no antimicrobial, quorum sensing inhibitory, and cytotoxic activities. The specific side chain in α-pyrone derivatives 1-4 might be responsible for the weak pharmacological activities.

Early Neurological Deterioration after Recanalization Treatment in Patients with Acute Ischemic Stroke: A Retrospective Study.

BACKGROUND: Early neurological deterioration (END) is a prominent issue after recanalization treatment. However, few studies have reported the characteristics of END after endovascular treatment (EVT) as so far. This study investigated the incidence, composition, and outcomes of END after intravenous recombinant tissue plasminogen activator (IV rt-PA) and EVT of acute ischemic stroke, and identified risk factors for END. METHODS: Medical records of patients who received recanalization treatment between January 1, 2014, and December 31, 2015 were reviewed. Patients were classified into IV rt-PA or EVT group according to the methods of recanalization treatment. The END was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) ≥4 or an increase in Ia of NIHSS ≥1 within 72 h after recanalization treatment. Clinical data were compared between the END and non-END subgroups within each recanalization group. RESULTS: Of the 278 patients included in the study, the incidence of END was 34.2%. The incidence rates of END were 29.8% in the IV rt-PA group and 40.2% in the EVT group. Ischemia progression (68.4%) was the main contributor to END followed by vasogenic cerebral edema (21.1%) and symptomatic intracranial hemorrhage (10.5%). Multivariate logistic regression showed that admission systolic blood pressure (SBP) ≥160 mmHg (odds ratio [OR]: 2.312, 95% confidence interval [CI]: 1.105-4.837) and large artery occlusion after IV rt-PA (OR: 3.628, 95% CI: 1.482-8.881) independently predicted END after IV rt-PA; and admission SBP ≥140 mmHg (OR: 5.183, 95% CI: 1.967-13.661), partial recanalization (OR: 4.791, 95% CI: 1.749-13.121), and nonrecanalization (OR: 5.952, 95% CI: 1.841-19.243) independently predicted END after EVT. The mortality rate and grave outcome rate at discharge of all the END patients (26.3% and 55.8%) were higher than those of all the non-END patients (1.1% and 18.6%; P < 0.01). CONCLUSIONS: END was not an uncommon event and associated with death and grave outcome at discharge. High admission SBP and unsatisfactory recanalization of occluded arteries might predict END.

Neuroprotective effect of formononetin in ameliorating learning and memory impairment in mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia among elderly population. Deranged ß-amyloid (Aß) trafficking across the blood-brain barrier is known to be a critical element in the pathogenesis of AD. In the vascular endothelial cells of hippocampus, Aß transport is mainly mediated by low-density lipoprotein-associated protein 1 (LRP1) and the receptor for advanced glycation end (RAGE) products; therefore, LRP1 and RAGE endothelial cells are potential therapeutic targets for AD. In this study, we explored the effects of Formononetin (FMN) on learning and memory improvement in APP/PS1 mice and the related mechanisms. We found that FMN significantly improved learning and memory ability by suppressing Aß production from APP processing, RAGE-dependent inflammatory signaling and promoted LRP1-dependent cerebral Aß clearance pathway. Moreover, FMN treatment alleviated ultrastructural changes in hippocampal vascular endothelial cells. In conclusion, we believe that FMN may be an efficacious and promising treatment for AD.

NIR Rapid Assessments of Blumea balsamifera (Ai-na-xiang) in China.

Blumea balsamifera (Ai-na-xiang) is used as an important plant source of natural borneol, which is widely used in the pharmaceutical industry. The aim of this study was to establish the methods based on near infrared (NIR) spectroscopy for determining the geographical origin of B. balsamifera, as well as developing a method for the quantitative rapid analysis of the active pharmaceutical ingredients (APIs). A total of 109 samples were collected from China in 2013 and arbitrarily divided into calibration and prediction sets using the Kennard-Stone algorithm. The l-borneol and total flavone contents of the samples were measured by gas chromatography and ultraviolet-visible spectroscopy, respectively. The NIR spectra were acquired using an integrating sphere and a partial least squares (PLS) model was built using the optimum wavelength regions, which were selected using a synergy interval partial least-squares (SiPLS) algorithm. The root mean square errors of prediction of the l-borneol and total flavone models were 0.0779 and 2.2694 mg/g, with R² of 0.9069 and 0.8013, respectively. A discriminant model to determine the geographical origin of B. balsamifera (Guizhou and Hainan) was also established using a partial least squares discriminant analysis method with an optimum pretreatment method. The prediction accuracy rate of the model was 100%. NIR spectroscopy can be used as a reliable and environmentally friendly method to determine the API and the origin of different B. balsamifera samples.

Variations in Essential Oil Yield, Composition, and Antioxidant Activity of Different Plant Organs from Blumea balsamifera (L.) DC. at Different Growth Times.

Blumea balsamifera, also named Ainaxiang, is widely used as an ancient medicinal herb in tropical and subtropical Asia. It is rich in essential oils. In this work the essential oils of B. balsamifera from different plant organs and in different months were extracted, and then analyzed by gas chromatography-mass spectrometry. The results showed that essential oil yield of young leaves was the highest (0.65 mL/100 g), followed by mature leaves (0.57 mL/100 g), and the oil yield was higher in October (0.47 mL/100 g) than other months. A total of 44 compounds were identified, representing 92.64%-96.71% of the oil. Eighteen common chemical components were found among the six plant organs, representing >80% of the oil constituents. l-borneol was the main ingredient in leaves, and its content was the highest in senescent leaves and in December. In the essential oils of young shoots and young stems, the main component was dimethoxydurene. Antioxidant activity was also determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ß-carotene bleaching (BCB) assays. The results indicated that the ß-carotene bleaching activity was far stronger than the DPPH radical-scavenging capacity, and the young leaves and young shoots showed stronger antioxidant activity. Dimethoxydurene, ß-caryophyllene, and α-caryophyllene play a positive role in good antioxidant activity, while ß-eudesmol, phytol, and tetradecanal play a negative role. The antioxidant activity revealed in this study might help in developing this promising bioresource for use in the medicinal and cosmetic industries.

Hydroxysafflor yellow A attenuates carbon tetrachloride-induced hepatic fibrosis in rats by inhibiting ERK5 signaling.

Hepatic stellate cells (HSCs) undergo activation during the development of liver fibrosis. Transcription factor myocyte enhancer factor (MEF2) 2C plays a key role in this process. In the present study, we investigated the effect of hydroxysafflor yellow A (HSYA) on hepatic fibrosis and further investigated potential mechanisms in vivo. Sprague-Dawley rats were administered with CCl(4) together with or without HYSA for 12 weeks. The effect of HYSA on hepatic fibrosis was evaluated using hematoxylin-eosin and Van Gieson staining. Messenger RNA expression was quantified by real-time polymerase chain reaction, and protein was quantified by Western blot or immunohistochemistry. Our results revealed that CCl(4) treatment induced micronodular hepatic fibrosis with a pronounced deposition of collagen fibers. Treatment with HYSA resulted in a significant decrease in fibrosis, protein expression of α-SMA, and MEF-2C gene expression. This was accompanied by a decreased expression of Tß-RI, Tß-RII, MEKK3, MEK5, and phosphorylation of ERk5. HYSA alone had no effect on the measured parameters. Our findings demonstrate that HSYA protected, at least in part, the rat liver from CCl(4)-caused fibrogenesis through inhibition of hepatic stellate cell (HSC) activation, attenuation of transforming growth factor beta (TGF-ß) signaling. HSYA may become a novel and promising agent for the inhibition of hepatic fibrosis.

Emodin protects rat liver from CCl(4)-induced fibrogenesis via inhibition of hepatic stellate cells activation.

AIM: To investigate the role of emodin in protecting the liver against fibrogenesis caused by carbon tetrachloride (CCl(4)) in rats and to further explore the underlying mechanisms. METHODS: Rat models of experimental hepatic fibrosis were established by injection with CCl(4); the treated rats received emodin via oral administration at a dosage of 20 mg/kg twice a week at the same time. Rats injected with olive oil served as a normal group. Histopathological changes were observed by hematoxylin and eosin staining. The activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and hepatic hydroxyproline content were assayed by biochemical analyses. The mRNA and protein relevant to hepatic stellate cell (HSC) activation in the liver were assessed using real-time reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, western blotting and enzyme-linked immunosorbent assay. RESULTS: The degree of hepatic fibrosis increased markedly in the CCl(4) group compared to the normal group (P < 0.01), and decreased markedly in the emodin group compared to the CCl(4) group according to METAVIR scale (P < 0.01) compared with those in the normal control group (51.02 +/- 10.64 IU/L and 132.28 +/- 18.14 IU/L). The activities of serum ALT and AST were significantly higher in rats injected with CCl(4) (289.25 +/- 68.84 IU/L and 423.89 +/- 35.67 IU/L, both P < 0.05). The activities of serum ALT and AST were significantly reduced by administration of emodin (176.34 +/- 47.29 IU/L and 226.1 +/- 44.52 IU/L, both P < 0.05). Compared with the normal controls (54.53 +/- 13.46 mg/g), hepatic hydroxyproline content was significantly higher in rats injected with CCl(4) (120.27 +/- 28.47 mg/g, P < 0.05). Hepatic hydroxyproline content was significantly reduced in the rats treated with emodin at 20 mg/kg (71.25 +/- 17.02 mg/g, P < 0.05). Emodin significantly protected the liver from injury by reducing serum AST and ALT activities and reducing hepatic hydroxyproline content. The mRNA levels of transforming growth factor-beta1 (TGF-beta1), Smad4 and alpha-SMA in liver tissues were significantly down-regulated in SD rats that received emodin treatment. Furthermore, significant down-regulation of serum TGF-beta1 protein levels and protein expression of Smad4 and alpha-SMA in liver tissues was also observed in the rats. Emodin inhibited HSC activation by reducing the abundance of TGF-beta1 and Smad4. CONCLUSION: Emodin protects the rat liver from CCl(4)-induced fibrogenesis by inhibiting HSC activation. Emodin might be a therapeutic antifibrotic agent for the treatment of hepatic fibrosis.