Lung cancer is the most common cause of cancer-related deaths worldwide. Natural phytochemicals from traditional medicinal plants such as solamargine have been shown to have anticancer properties. The prostaglandin E2 receptor EP4 is highly expressed in human cancer, however, the functional role of EP4 in the occurrence and progression of non small cell lung cancer (NSCLC) remained to be elucidated.

Lung cancer is the most common cancer and the leading cause of cancer deaths worldwide. We previously showed that solamargine, one natural phytochemicals from traditional plants, inhibited the growth of lung cancer cells through inhibition of prostaglandin E2 (PGE2 ) receptor EP4. However, the potential downstream effectors of EP4 involving in the anti-lung cancer effects of solamargine still remained to be determined. In this study, we further verified that solamargine inhibited growth of non-small-cell lung cancer (NSCLC) cells in multiple cell lines. Mechanistically, solamargine increased phosphorylation of ERK1/2. Moreover, solamargine inhibited the protein expression of DNA methyltransferase 1 (DNMT1) and c-Jun, which were abrogated in cells treated with MEK/ERK1/2 inhibitor (PD98059) and transfected with exogenously expressed DNMT1 gene, respectively. Interestingly, overexpressed DNMT1 gene antagonized the effect of solamargine on c-Jun protein expression. Intriguingly, overexpressed c-Jun blocked solamargine-inhibited lung cancer cell growth, and feedback resisted the solamargine-induced phosphorylation of ERK1/2. A nude mouse xenograft model implanted with lung cancer cells in vivo confirmed the results in vitro. Collectively, our results show that solamargine inhibits the growth of human lung cancer cells through reduction of EP4 protein expression, followed by increasing ERK1/2 phosphorylation. This results in decrease in DNMT1 and c-Jun protein expressions. The inter-correlations between EP4, DNMT1 and c-Jun and feedback regulation of ERK1/2 by c-Jun contribute to the overall responses of solamargine in this process. This study uncovers an additional novel mechanism by which solamargine inhibits growth of human lung cancer cells.

Prostate cancer is one of the most common malignancies in men. The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features, resulting in a poor outcome. However, the functional role for MUC1 C-terminal domain (MUC1-C) in androgen-independent prostate cancer occurrence and development has remained unclear.

The injection of rabies immune globulin (RIG) is of the utmost importance in the management of category III exposures to rabies-suspect animals. Because of the high cost and limited availability of existing RIG, one possible replacement for RIG is monoclonal antibodies (MAbs) against the rabies virus (RABV). Consequently, it is necessary to determine the neutralizing activity of the MAbs against rabies viruses, especially street rabies virus. However, the method to detect the neutralizing activity of MAbs against street rabies virus remains undefined.

Apoptosis of cardiomyocytes and oxidant stress are considered essential processes in the progression of cardiovascular diseases. A hypoxic stress which causes apoptosis of cardiomyocytes is the main problem in ischemic heart disease. The aim of the present study was to explore the functional role and potential mechanisms of miR-223-3p in hypoxia-induced cardiomyocyte apoptosis and oxidative stress. Here, we observed a increment of miR-223-3p level accompanied by the decrease of Krüppel-like zinc-finger transcription factor 15 (KLF15) expression in response to hypoxia. Additionally, absence of miR-223-3p manifestly dampened hypoxia-induced cardiomyocyte injury in H9c2 cells, including improving cell viability, attenuating the LDH leakage and preventing cardiomyocyte apoptosis accompanied by an increase in the expression of Bcl-2 and a decrease in the expression of Bax and C-caspase 3 in the setting of hypoxia. Moreover, depletion of miR-223-3p evidently retarded oxidant stress by inhibiting reactive oxygen species generation and lipid peroxidation, as well as enhancing antioxidant enzyme activity in H9c2 cells following exposure to hypoxia. More importantly, KLF15 was a direct and functional target of miR-223-3p. Further data validated that miR-223-3p negatively regulated the expression of KLF15. Mechanistically, deletion of KLF15 partly abrogated the suppressive effects of miR-223-3p deletion on hypoxia-induced cardiomyocyte apoptosis and oxidative stress. Taken all data together, our findings established that our study defines a novel mechanism by which miR-223-3p protects against cardiomyocyte apoptosis and oxidative stress by targeting KLF15, suggesting that the miR-223-3p/KLF15 may be a potential therapeutic target for ischemic heart conditions.

β-Elemene, an active component of natural plants, has been shown to exhibit anticancer properties. However, the detailed mechanism underlying these effects has yet to be determined. In this study, we show that β-elemene inhibits the growth of lung cancer cells. Mechanistically, we found that β-elemene decreased the phosphorylation of signal transducer and activator of transcription 3 (Stat3) and miRNA155-5p mRNA but induced the protein expression of human forkhead box class O (FOXO)3a; the latter two were abrogated in cells with overexpressed Stat3. Notably, miRNA155-5p mimics reduced FOXO3a luciferase reporter activity in the 3-UTR region and protein expression, whereas overexpressed FOXO3a countered the reduction of the miRNA155-5p levels by β-elemene. Moreover, β-elemene increased the mRNA and protein expression levels as well as promoter activity of insulin-like growth factor-binding protein 1 (IGFBP1); this finding was not observed in cells with a silenced FOXO3a gene and miRNA155-5p mimics. Finally, silencing of IGFBP1 blocked β-elemene-inhibited cell growth. Similar findings were observed in vivo. In summary, our results indicate that β-elemene increases IGFBP1 gene expression via inactivation of Stat3 followed by a reciprocal interaction between miRNA155-5p and FOXO3a. This effect leads to inhibition of human lung cancer cell growth. These findings reveal a novel molecular mechanism underlying the inhibitory effects of β-elemene on lung cancer cells.

Yunnan Province in China borders 3 countries (Vietnam, Laos, and Myanmar) in Southeast Asia. In the 1980s, a large-scale rabies epidemic occurred in this province, which subsided by the late 1990s. However, 3 human cases of rabies in 2000 indicated reemergence of the disease in 1 county. In 2012, rabies was detected in 77 counties; 663 persons died of rabies during this new epidemic. Fifty two rabies virus strains obtained during 2008-2012 were identified and analyzed phylogenetically by sequencing the nucleoprotein gene. Of the 4 clades identified, clades YN-A and YN-C were closely related to strains from neighboring provinces, and clade YN-B was closely related to strains from Southeast Asia, but formed a distinct branch. Rabies virus diversity might be attributed to dog movements among counties, provinces, and neighboring countries. These findings suggest that Yunnan Province is a focal point for spread of rabies between Southeast Asia and China.

Catalpol and puerarin are two monomers of Rehmannia glutinosa and Lobed Kudzuvine Root, which are two herbs commonly used together in ancient prescriptions of traditional Chinese medicine for cerebral ischemia. Our previous study shows that the lyophilized powder of the two monomers improved the outcome of cerebral ischemia excellently in rodents. However, if it protects vessels from ischemia is unknown. The present research studied the protection of lyophilized powder of catalpol and puerarin (CP) on endothelial cells and the relative mechanism in vivo and in vitro. Middle cerebral artery occlusion (MCAO) rats were used to study the improvement of CP on neurological deficiency, regional cerebral blood flow (rCBF), and infarct volume. The morphology of vessels and the apoptosis of brain vascular endothelial cells (BVECs) were observed and detected by immunohistochemistry approaches. To study how CP protected primary BVECs (pBVECs) from ischemic penumbra, oxygen glucose deprivation (OGD)-damaged pBVECs were cultured in the condition of insufficient nutrition and low oxygen which recapitulate the low perfusion of ischemic penumbra. Using the cell model, the mechanism by which CP protected pBVECs was studied by shRNA and pathway inhibitors. CP at the dose of 65.4 mg/kg increased regional cerebral blood flow (rCBF), reduced infarct volume, protected vessel integrity and inhibited endothelial cell apoptosis in vivo. But it only improved rCBF, vessel integrity and BVECs apoptosis at the dose of 32.7 mg/kg. In vitro, the protection of CP on pBVECs was proved to be ERK/HIF-1a- and PI3K/AKT/mTOR/HIF-1a-dependent. This study indicates a possibility of CP being a new drug for cerebral ischemia. Besides, this research provides an alternative cell model for penumbra ECs study.

Sedimentary hydrocarbon remnants of eukaryotic C26-C30 sterols can be used to reconstruct early algal evolution. Enhanced C29 sterol abundances provide algal cell membranes a density advantage in large temperature fluctuations. Here, we combined a literature review with new analyses to generate a comprehensive inventory of unambiguously syngenetic steranes in Neoproterozoic rocks. Our results show that the capacity for C29 24-ethyl-sterol biosynthesis emerged in the Cryogenian, that is, between 720 and 635 million years ago during the Neoproterozoic Snowball Earth glaciations, which were an evolutionary stimulant, not a bottleneck. This biochemical innovation heralded the rise of green algae to global dominance of marine ecosystems and highlights the environmental drivers for the evolution of sterol biosynthesis. The Cryogenian emergence of C29 sterol biosynthesis places a benchmark for verifying older sterane signatures and sets a new framework for our understanding of early algal evolution.

Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG) have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC). Two kinds of chimeric human antibodies (chimeric #7 and #17) were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

China has seen a massive resurgence of rabies cases in the last 15 years with more than 25,000 human fatalities. Initial cases were reported in the southwest but are now reported in almost every province. There have been several phylogenetic investigations into the origin and spread of the virus within China but few reports investigating the impact of the epidemic on neighboring countries. We therefore collected nucleoprotein sequences from China and South East Asia and investigated their phylogenetic and phylogeographic relationship. Our results indicate that within South East Asia, isolates mainly cluster according to their geographic origin. We found evidence of sporadic exchange of strains between neighboring countries, but it appears that the major strain responsible for the current Chinese epidemic has not been exported. This suggests that national geographical boundaries and border controls are effective at halting the spread of rabies from China into adjacent regions. We further investigated the geographic structure of Chinese sequences and found that the current epidemic is dominated by variant strains that were likely present at low levels in previous domestic epidemics. We also identified epidemiological linkages between high incidence provinces consistent with observations based on surveillance data from human rabies cases.

Historically, Japanese Encephalitis virus (JEV) genotype III (GIII) has been responsible for human diseases. In recent years, JEV genotype I (GI) has been isolated from mosquitoes collected in numerous countries, but has not been isolated from patients with encephalitis. In this study, we report recovery of JEV GI live virus and identification of JEV GI RNA from cerebrospinal fluid (CSF) of encephalitis patients in JE endemic areas of China. Whole-genome sequencing and molecular phylogenetic analysis of the JEV isolate from the CSF samples was performed. The isolate in this study is highly similar to other JEV GI strains which isolated from mosquitoes at both the nucleotide and deduced amino acid levels. Phylogenetic analysis based on the genomic sequence showed that the isolate belongs to JEV GI, which is consistent with the phylogenetic analysis based on the pre-membrane (PrM) and Glycoprotein genes. As a conclusion, this is the first time to isolate JEV GI strain from CSF samples of encephalitis patients, so continuous survey and evaluate the infectivity and pathogenecity of JEV GI strains are necessary, especially for the JEV GI strains from encephalitis patients. With respect to the latter, because all current JEV vaccines (live and inactivated are derived from JEV GIII strains, future studies should be aimed at investigating and monitoring cross-protection of the human JEV GI isolates against widely used JEV vaccines.

We recently determined that Nanjianyin virus, isolated from serum of a patient in Yunnan Province, China, in 1989, is a type of Kyasanur Forest disease virus. Results of a 1987-1990 seroepidemiologic investigation in Yunnan Province had shown that residents of the Hengduan Mountain region had been infected with Nanjianyin virus.

Polyphyllin I (PPI), one of the steroidal saponins in paris polyphylla, has been reported to exhibit antitumor effects. However, the detailed molecular mechanism underlying this has not been elucidated.

Drought stress results in significant crop yield losses. Comparative transcriptome analysis between tolerant and sensitive species can provide insights into drought tolerance mechanisms in jute. We present a comprehensive study on drought tolerance in two jute species-a drought tolerant species (Corchorus olitorius L., GF) and a drought sensitive species (Corchorus capsularis L., YY). In total, 45,831 non-redundant unigenes with average sequence length of 1421 bp were identified. Higher numbers of differentially expressed genes (DEGs) were discovered in YY (794) than in GF (39), implying that YY was relatively more vulnerable or hyper-responsive to drought stress at the molecular level; the two main pathways, phenylpropanoid biosynthesis and peroxisome pathway, significantly involved in scavenging of reactive oxygen species (ROS) and 14 unigenes in the two pathways presented a significant differential expression in response to increase of superoxide. Our classification analysis showed that 1769 transcription factors can be grouped into 81 families and 948 protein kinases (PKs) into 122 families. In YY, we identified 34 TF DEGs from and 23 PK DEGs, including 19 receptor-like kinases (RLKs). Most of these RLKs were downregulated during drought stress, implying their role as negative regulators of the drought tolerance mechanism in jute.

The object of this study was to develop a thermally and reactive oxygen species-responsive nanocarrier system for cancer therapy.

Kdp-ATPase is an inducible high affinity potassium uptake system that is widely distributed in bacteria, and is generally regulated by the KdpD/KdpE two-component system (TCS). In this study, conducted on Mycobacterium smegmatis, the kdpFABC (encoding Kdp-ATPase) expression was found to be affected by low concentration of K+, high concentrations of Na+, and/or [Formula: see text] of the medium. The KdpE was found to be a transcriptional regulator that bound to a specific 22-bp sequence in the promoter region of kdpFABC operon to positively regulate kdpFABC expression. The KdpE binding motif was highly conserved in the promoters of kdpFABC among the mycobacterial species. 5'-RACE data indicated a transcriptional start site (TSS) of the kdpFABC operon within the coding sequence of MSMEG_5391, which comprised a 120-bp long 5'-UTR and an open reading frame of the 87-bp kdpF gene. The kdpE deletion resulted in altered growth rate under normal and low K+ conditions. Furthermore, under K+ limiting conditions, a single transcript (kdpFABCDE) spanning kdpFABC and kdpDE operons was observed. This study provided the first insight into the regulation of kdpFABC operon by the KdpD/KdpE TCS in M. smegmatis.

MicroRNAs (miRNAs) play an important role in regulating immune system function by mRNA destabilisation or inhibition of translation. Recently, miR-155 was detected to be significantly up-regulated in colonic tissues of patients with active UC. However, it is unknown whether miR-155 is involved in the pathogenesis of UC and how it influences immune response in dextran sulfate sodium (DSS)-induced colitis mice. Here, we investigated the role of miR-155 in UC. Firstly, through bioinformatics analysis and luciferase report assay, we found Jarid2 was a direct target of miR-155; then, we carried out in situ hybridization, immunofluorescence and flow cytometry, and revealed that miR-155 levels were increased, Jarid2 levels were decreased and the frequency of Th17 cells was elevated in DSS-induced mice; we also used lentiviral vector to deliver miR-155 inhibition sequences to silence miR-155 that was effectively taken up by epithelial cells. MiR-155 inhibition attenuated DSS-induced colonic damage and inhibited Th17 cells differentiation. This study suggests that miR-155 plays a host-damaging role during DSS-induced colitis mice and induces Th17 differentiation by targeting Jarid2.

An aging-induced decrease in Schwann cell viability can affect regeneration following peripheral nerve injury in mammals. It is therefore necessary to investigate possible age-related changes in gene expression that may affect the biological function of peripheral nerves. Ten 1-week-old and ten 12-month-old healthy male Sprague-Dawley rats were divided into young (1 week old) and adult (12 months old) groups according to their ages. mRNA expression in the sciatic nerve was compared between young and adult rats using next-generation sequencing (NGS) and bioinformatics (n = 4/group). The 18 groups of differentially expressed mRNA (DEmRNAs) were also tested by quantitative reverse transcription polymerase chain reaction (n = 6/group). Results revealed that (1) compared with young rats, adult rats had 3608 groups of DEmRNAs. Of these, 2684 were groups of upregulated genes, and 924 were groups of downregulated genes. Their functions mainly involved cell viability, proliferation, differentiation, regeneration, and myelination. (2) The gene with the most obvious increase of all DEmRNAs in adult rats was Thrsp (log2FC = 9.01, P < 0.05), and the gene with the most obvious reduction was Col2a1 (log2FC = -8.89, P < 0.05). (3) Gene Ontology analysis showed that DEmRNAs were mainly concentrated in oligosaccharide binding, nucleotide-binding oligomerization domain containing one signaling pathway, and peptide-transporting ATPase activity. (4) Analysis using the Kyoto Encyclopedia of Genes and Genomes showed that, with increased age, DEmRNAs were mainly enriched in steroid biosynthesis, Staphylococcus aureus infection, and graft-versus-host disease. (5) Spearman's correlation coefficient method for evaluating NGS accuracy showed that the NGS results and quantitative reverse transcription polymerase chain reaction results were positively correlated (rs = 0.74, P < 0.05). These findings confirm a difference in sciatic nerve gene expression between adult and young rats, suggesting that, in peripheral nerves, cells and the microenvironment change with age, thus influencing the function and repair of peripheral nerves.

Nephrotoxicity is a major side effect of cisplatin (CP)- and platinum-related chemotherapy, and inflammation contributes to disease pathogenesis. Interleukin-9 (IL-9) is a pleiotropic cytokine associated with inflammation. Here, we investigated the key role of IL-9 as a regulator of protective mechanisms in CP-induced acute kidney injury (AKI). We observed that IL-9 was decreased not only in a CP-induced AKI mouse model but also in THP-1 and RAW264.7 cell lines. Seventy-two hours post-CP injection, renal dysfunction and tubule injury were significantly attenuated in IL-9 overexpression adeno-associated virus 9 (AAV9)-treated mice. The levels of serum urea, serum creatinine, kidney injury molecule-1 (KIM-1), and histological damage were partially diminished following treatment with IL-9. The renoprotective effects of IL-9 may be attributed to the regulation of cytokines, and we found that IL-9 acted on macrophages in a regulatory manner, promoting an anti-inflammatory phenotype. Furthermore, IL-9 enhanced the suppression of macrophage-driven renal inflammation. Inhibition of H3K27 acetylation orchestrated IL-9-mediated renoprotection in CP-induced AKI. Thus, our findings indicate novel and potent anti-inflammatory properties of IL-9 that confer preservation of kidney function and structure in CP-induced AKI, which may counteract kidney disease procession.