It has been confirmed that mitochondrial impairment may underlie both sporadic and familial Parkinson's disease (PD). Mitochondrial fission/fusion and biogenesis are key processes in regulating mitochondrial homeostasis. Therefore, we explored whether the protective effect of resveratrol in rotenone-induced neurotoxicity was associated with mitochondrial fission/fusion and biogenesis. The results showed that resveratrol could not only promote mitochondrial mass and DNA copy number but also improve mitochondrial homeostasis and neuron function in rats and PC12 cells damaged by rotenone. We also observed effects with alterations in proteins known to regulate mitochondrial fission/fusion and biogenesis in rotenone-induced neurotoxicity. Therefore, our findings suggest that resveratrol may prevent rotenone-induced neurotoxicity through regulating mitochondrial fission/fusion and biogenesis.

In pancreaticobiliary maljunction (PBM), the sphincter of Oddi can not control bile and pancreatic juice flow, which may lead to two-way reflux of bile and pancreatic juice, thus causing chronic inflammation, thickening, fibrosis and metaplasia of the common bile duct wall. These pathophysiological changes have been linked to disruption of the epithelium barrier in the common bile duct. We hypothesized that the expression of tight junction-associated proteins may be dysregulated in the common bile duct in PBM. In the current study, we sought to analyze the expression of tight junction-associated proteins in the common bile duct epithelium of pediatric patients with PBM.

Hearing loss has been associated with cognitive decline in the elderly and is considered to be an independent risk factor for dementia. One of the most common causes for acquired sensorineural hearing loss is exposure to excessive noise, which has been found to impair learning ability and cognitive performance in human subjects and animal models. Noise exposure has also been found to depress neurogenesis in the hippocampus. However, the effect is mainly attributed to the oxidant stress of noise on the cognitive brain. In the present study, young adult CBA/CAJ mice (between 1.5 and 2 months of age) were briefly exposed a high sound level to produce moderate-to-severe hearing loss. In both the blood and hippocampus, only transient oxidative stress was observed after noise exposure. However, a deficit in spatial learning/memory was revealed 3 months after noise exposure. Moreover, the deficit was correlated with the degree of hearing loss and was associated with a decrease in neurogenesis in the hippocampus. We believe that the observed effects were likely due to hearing loss rather than the initial oxidant stress, which only lasted for a short period of time.

Ultrafine aluminum oxide, which are abundant in ambient and involved occupational environments, are associated with neurobehavioral alterations. However, few studies have focused on the effect of sex differences following exposure to environmental Al₂O₃ ultrafine particles. In the present study, male and female mice were exposed to Al₂O₃ nanoparticles (NPs) through a respiratory route. Only the female mice showed depression-like behavior. Although no obvious pathological changes were observed in mice brain tissues, the neurotransmitter and voltage-gated ion channel related gene expression, as well as the small molecule metabolites in the cerebral cortex, were differentially modulated between male and female mice. Both mental disorder-involved gene expression levels and metabolomics analysis results strongly suggested that glutamate pathways were implicated in sex differentiation induced by Al₂O₃ NPs. Results demonstrated the potential mechanism of environmental ultrafine particle-induced depression-like behavior and the importance of sex dimorphism in the toxic research of environmental chemicals.

Staphylococcus aureus causes a wide range of infectious diseases. Treatment of these infections has become increasingly difficult due to the widespread emergence of antibiotic-resistant strains; therefore, it is essential to explore effective alternatives to antibiotics. A secreted protein of S. aureus, known as eLtaS, is an extracellular protein released from the bacterial membrane protein, LtaS. However, the role of eLtaS in S. aureus pathogenesis remains largely unknown. Here we show eLtaS dramatically aggravates S. aureus infection by binding to C3b and then inhibiting the phagocytosis of C3b-deposited S. aureus. Furthermore, we developed a monoclonal antibody against eLtaS, MAE4, which neutralizes the activity of eLtaS and blocks staphylococcal evasion of phagocytosis. Consequently, MAE4 is capable of protecting mice from lethal S. aureus infection. Our findings reveal that targeting of eLtaS by MAE4 is a potential therapeutic strategy for the treatment of infectious diseases caused by S. aureus.

Fibroblasts are rich in the surrounding microenvironment of hepatocellular carcinoma (HCC) because most HCCs occur in fibrotic or cirrhotic livers. However, the role of cancer-associated fibroblasts (CAFs) in HCC metastasis remains obscure. Here, we reported that CAFs promote the migration and invasion of HCC cells in vitro and facilitate the HCC metastasis to the bone, brain and lung in NOD/SCID mice. The RayBio human chemokine antibody array revealed that CAFs secret higher levels of CCL2, CCL5, CCL7 and CXCL16 than peri-tumor fibroblasts. CCL2 and CCL5 increase the migration but not the invasion of HCC cells, while CCL7 and CXCL16 promote both migration and invasion of HCC cells. Moreover, CCL2 and CCL5 stimulate the activation of the hedgehog (Hh) pathway, while CCL7 and CXCL16 enhance the activity of the transforming growth factor-β (TGF-β) pathway in HCC cells. The neutralizing antibodies of chemokines notably attenuate the effect of CAFs on HCC metastasis and compromised the activation of Hh and TGF-β pathways in HCC cells. In summary, CAF-secreted CCL2, CCL5, CCL7 and CXCL16 promote HCC metastasis through the coordinate activation of Hh and TGF-β pathways in HCC cells.

Sirtuin protein family member 3 (Sirt3) has been suggested as a positive regulator in alleviating oxidative stress by acting on the mitochondrial antioxidant machinery in solid tumors; however, its role and regulation in hematological malignancies has been poorly understood. Here, we show that contrary to what has been reported in solid tumors, in K562 leukemia cells elevated Sirt3 was associated with mitochondrial stress, and depletion of Sirt3 decreased reactive oxygen species (ROS) generation and lipid oxidation, but increased the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), suggesting an opposite role of Sirt3 in regulating oxidative stress in the leukemia cells. Notably, loss of autophagy by deletion of autophagy essential gene or by pharmacological inhibition on autophagic degradation caused a significant accumulation of Sirt3. However, induced activation of autophagy did not cause autophagic degradation of Sirt3. Furthermore, inhibiting proteasome activity accumulated Sirt3 in autophagy-intact but not autophagy-defective cells, and disrupting functional autophagy either genetically or pharmacologically caused significantly less ubiquitination of Sirt3. Therefore, our data suggest that basal but not enhanced autophagy activity maintains ubiquitination-proteasomal degradation of Sirt3 to limit lipid oxidative stress, representing an adaptive mechanism by which autophagy, in collaboration with the ubiquitination-proteasomal system, controls oxidative stress by controlling the levels of certain proteins in K562 leukemia cells.

Chemoresistance is common in patients with biliary tract cancer (BTC) including gallbladder cancer (GBC) and cholangiocarcinoma (CC). Therefore, it is necessary to identify effective chemotherapeutic agents for BTC. In the present study, we for the first time tested the effect of farnesoid X receptor (FXR) agonists GW4064 and CDCA (chenodeoxycholic acid) in combination with cisplatin (CDDP) on increasing the chemosensitivity in BTC. Our results show that co-treatment of CDDP with FXR agonists remarkably enhance chemosensitivity of BTC cells. Mechanistically, we found that activation of FXR induced expression of small heterodimer partner (SHP), which in turn inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and resulted in down-regulation of Bcl-xL expression in BTC cells, leading to increased susceptibility to CDDP. Moreover, the experiments on tumor-bearing mice showed that GW4064/CDDP co-treatment inhibited the tumor growth in vivo by up-regulating SHP expression and down-regulating STAT3 phosphorylation. These results suggest CDDP in combination with FXR agonists could be a potential new therapeutic strategy for BTC.

Epidemiological studies have indicated that noise exposure is associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the nature of the connection between noise exposure and T2DM remains to be explored.

In this study, we examined the effect of progesterone on histopathologic and functional outcomes of intracerebral hemorrhage (ICH) in 10- to 12-month-old mice. Progesterone or vehicle was administered by intraperitoneal injection 1 hour after collagenase-induced ICH and then by subcutaneous injections at 6, 24, and 48 hours. Oxidative and nitrosative stress were assayed at 12 hours post-ICH. Injury markers were examined on day 1, and lesion was examined on day 3. Neurologic deficits were examined for 28 days. Progesterone posttreatment reduced lesion volume, brain swelling, edema, and cell degeneration and improved long-term neurologic function. These protective effects were associated with reductions in protein carbonyl formation, protein nitrosylation, and matrix metalloproteinase-9 activity and attenuated cellular and molecular inflammatory responses. Progesterone also reduced vascular endothelial growth factor expression, increased neuronal-specific Na(+)/K(+) ATPase ɑ3 subunit expression, and reduced protein kinase C-dependent Na(+)/K(+) ATPase phosphorylation. Furthermore, progesterone reduced glial scar thickness, myelin loss, brain atrophy, and residual injury volume on day 28 after ICH. With multiple brain targets, progesterone warrants further investigation for its potential use in ICH therapy.

MiR-206 is low expression in lung cancers and associated with cancer metastasis. However, the roles of miR-206 in epithelial-mesenchymal transition (EMT) and angiogenesis in lung cancer remain unknown. In this study, we find that hepatocyte growth factor (HGF) induces EMT, invasion and migration in A549 and 95D lung cancer cells, and these processes could be markedly inhibited by miR-206 overexpression. Moreover, we demonstrate that miR-206 directly targets c-Met and inhibits its downstream PI3k/Akt/mTOR signaling pathway. In contrast, miR-206 inhibitors promote the expression of c-Met and activate the PI3k/Akt/mTOR signaling, and this effect could be attenuated by the PI3K inhibitor. Moreover, c-Met overexpression assay further confirms the significant inhibitory effect of miR-206 on HGF-induced EMT, cell migration and invasion. Notably, we also find that miR-206 effectively inhibits HGF-induced tube formation and migration of human umbilical vein endothelial cells (HUVECs), and the mechanism is also related to inhibition of PI3k/Akt/mTOR signaling. Finally, we reveal the inhibitory effect of miR-206 on EMT and angiogenesis in xenograft tumor mice model. Taken together, miR-206 inhibits HGF-induced EMT and angiogenesis in lung cancer by suppressing c-Met/PI3k/Akt/mTOR signaling. Therefore, miR-206 might be a potential target for the therapeutic strategy against EMT and angiogenesis of lung cancer.

Epigallocatechin gallate (EGCG) is the most abundant component of green tea catechins and has strong physiological activities. In this study, two novel EGCG glycosides (EGCG-G1 and EGCG-G2) were chemoselectively synthesized by a chemical modification strategy. Each of these EGCG glycosides underwent structure identification, and the structures were assigned as follows: epigallocatechin gallate-4''-O-β-d-glucopyranoside (EGCG-G1, 2) and epigallocatechin gallate-4',4''-O-β-d-gluco-pyranoside (EGCG-G2, 3). The EGCG glycosides were evaluated for their anticancer activity in vitro against two human breast cell lines (MCF-7 and MDA-MB-231) using MTT assays. The inhibition rate of EGCG glycosides (EGCG-G1 and EGCG-G2) is not obvious. The EGCG glycosides are more stable than EGCG in aqueous solutions, but exhibited decreasing antioxidant activity in the DPPH radical-scavenging assay (EGCG > EGCG-G2 > EGCG-G1). Additionally, the EGCG glycosides exhibited increased water solubility: EGCG-G2 and EGCG-G1 were 15 and 31 times as soluble EGCG, respectively. The EGCG glycosides appear to be useful, and further studies regarding their biological activity are in progress.

The H3N8 virus and the H3N2 virus are the main subtypes of canine influenza virus (CIV). H3N8 CIV mainly circulates in America, and H3N2 CIV mainly circulates in Asia. However, there was an outbreak of the Asian H3N2 virus in the United States (US) in 2015. Thus, it is important to evaluate the presence of subtype H3N8 virus in dogs in China. From May 2015 to November 2015, 600 sera from pet dogs were collected from Guangzhou, Shanghai, Beijing and Shenzhen for hemagglutination inhibition (HI) assays and microneutralization (MN) assays. Fifty-two (8.66%) of the 600 sera were positive for the subtype H3N2 virus, which matched the previous reports. Five (0.83%) of 600 sera were positive for the subtype H3N8 virus (H3N8 EIV or H3N8 AIV or H3N8 CIV), which is the first report of subtype H3N8 virus infection among dogs in China and remind us to play more attention to this subtype virus. Therefore, further serological and virological surveillance of influenza virus infection among dogs in China is imperative.

In biomedical research, events revealing complex relations between entities play an important role. Biomedical event trigger identification has become a research hotspot since its important role in biomedical event extraction. Traditional machine learning methods, such as support vector machines (SVM) and maxent classifiers, which aim to manually design powerful features fed to the classifiers, depend on the understanding of the specific task and cannot generalize to the new domain or new examples.

Single-walled carbon nanotubes (SWNTs) with various unique properties have attracted great attention in cancer theranostics. Herein, SWNTs are coated with a shell of polydopamine (PDA), which is further modified by polyethylene glycol (PEG). The PDA shell in the obtained SWNT@PDA-PEG could chelate Mn(2+), which together with metallic nanoparticulate impurities anchored on SWNTs offer enhanced both T1 and T2 contrasts under magnetic resonance (MR) imaging. Meanwhile, also utilizing the PDA shell, radionuclide (131)I could be easily labeled onto SWNT@PDA-PEG, enabling nuclear imaging and radioisotope cancer therapy. As revealed by MR & gamma imaging, efficient tumor accumulation of SWNT@PDA-(131)I-PEG is observed after systemic administration into mice. By further utilizing the strong near-infarared (NIR) absorbance of SWNTs, NIR-triggered photothermal therapy in combination with (131)I-based radioisotope therapy is realized in our animal experiments, in which a remarkable synergistic antitumor therapeutic effect is observed compared to monotherapies. Our work not only presents a new type of theranostic nanoplatform based on SWNTs, but also suggests the promise of PDA coating as a general approach to modify nano-agents and endow them with highly integrated functionalities.

High recurrence rates of non-muscle invasive bladder cancer (NMIBC) in patients require lifelong testing and monitoring. The aim of this study is to develop a simplified RT-qPCR method (RT-qPCR-D) which directly quantifies cell-free miR-155 in urine without RNA extraction, and assess it as a potential tool in NMIBC detection. A pilot study including 60 urine samples was used to investigate the feasibility of RT-qPCR-D in detecting cell-free miR-155. Then, miR-155 levels were quantified in a large independent cohort of urine from 162 NIMBC patients, 76 cystitis patients, and 86 healthy donors using the RT-qPCR-D method. Changes of cell-free miR-155 before and after operation were also analyzed in 32 NIMBC patients. In pilot study, we found a significant linear association between RT-qPCR and RT-qPCR-D in urinary miR-155 detection. Both methods showed cell-free miR-155 were significantly increased in NMIBC patients, and could reflect their expression in tissues. Then, the increased expression of cell-free miR-155 was successfully validated in 162 NIMBC patients when compared with cystitis patients and healthy donors. Moreover, it distinguished NMIBC patients from others with 80.2% sensitivity and 84.6% specificity, which was superior to urine cytology. Cell-free miR-155 correlated with NMIBC stage and grade, and was an independent factor for predicting recurrence and progression to muscle invasion. In addition, cell-free miR-155 was significantly decreased after NMIBC patients underwent transurethral bladder resection. In conclusion, detection of cell-free miR-155 in urine using RT-qPCR-D is a simple and noninvasive approach which may be used for NMIBC diagnosis and prognosis prediction.

Salvianolic acids are among the main bioactive components in Salvia miltiorrhiza, and their biosynthesis has attracted widespread interest. However, previous studies on the biosynthesis of phenolic acids using next-generation sequencing platforms are limited with regard to the assembly of full-length transcripts. Based on hybrid-seq (next-generation and single molecular real-time sequencing) of the S. miltiorrhiza root transcriptome, we experimentally identified 15 full-length transcripts and four alternative splicing events of enzyme-coding genes involved in the biosynthesis of rosmarinic acid. Moreover, we herein demonstrate that lithospermic acid B accumulates in the phloem and xylem of roots, in agreement with the expression patterns of the identified key genes related to rosmarinic acid biosynthesis. According to co-expression patterns, we predicted that six candidate cytochrome P450s and five candidate laccases participate in the salvianolic acid pathway. Our results provide a valuable resource for further investigation into the synthetic biology of phenolic acids in S. miltiorrhiza.

The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53.

Differential methylation of the homologous chromosomes, a well-known mechanism leading to genomic imprinting and X-chromosome inactivation, is widely reported at the non-imprinted regions on autosomes. To evaluate the transgenerational DNA methylation patterns in human, we analyzed the DNA methylomes of somatic and germ cells in a four-generation family. We found that allelic asymmetry of DNA methylation was pervasive at the non-imprinted loci and was likely regulated by cis-acting genetic variants. We also observed that the allelic methylation patterns for the vast majority of the cis-regulated loci were shared between the somatic and germ cells from the same individual. These results demonstrated the interaction between genetic and epigenetic variations and suggested the possibility of widespread sequence-dependent transmission of DNA methylation during spermatogenesis.

The artemisinin (ART), discovered in China, has been widely used against malaria in China over the last 30 years. Understanding the emergence and origin of ART resistance in China is therefore of great interest. We analyzed 111 culture-adapted isolates of P. falciparum from China-Myanmar (CM) border for their susceptibility to dihydroartemisinin using the ring stage survival assay (RSA0-3h) and genotyped their K13 genes. Of the isolates, 59 had a wild type of the K13 marker and a median ring survival rate of 0.26% (P95 = 1.005%). Among the remaining isolates harboring single mutations in the K13 marker, 26 survived at >P95(median survival rate = 2.95%). Further, we genotyped the K13 gene of 693 isolates collected from different regions in China and China-Myanmar/Thai-Cambodia/Thai-Myanmar (CM/TC/TM) borders, 308 (44.4%) had K13 mutations and marked differences in the patterns of K13 mutations were observed between the CM and the TC/TM borders. A network diagram showed that majority of the K13 mutant alleles from the CM border clustered together including those harboring the high resistant-associated R539T mutations. The resistant parasites carrying distinct halplotypes suggested the multiple indigenous origins of the resistant alleles, which highlight the importance of surveillance of resistance in all malaria endemic areas where ART has been introduced.