Axl Mediates Resistance to Respiratory Syncytial Virus Infection Independent of Cell Attachment.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections in infants and young children. Axl, a TAM family receptor tyrosine kinase, has been demonstrated to be a receptor mediating enveloped virus infection. Here we show that Axl functions as a suppressor of antiviral response during RSV infection. Knockdown of Axl expression in human cells resulted in cell resistance to RSV infection, although the treatment did not significantly affect RSV binding or cell entry. Mice deficient in Axl showed resistance to RSV infection, including reduction in viral load and in pulmonary injury. Although T lymphocyte and macrophage infiltration was reduced, more IFN-γ-producing cells were present in BAL fluid in Axl-/- mice. Fewer alternatively activated alveolar macrophages were found in the lungs of Axl-/- mice. Axl-/- mouse embryonic fibroblasts and siRNA-treated human cells had more robust IFN-ß and IFN-stimulated gene induction of antiviral genes. Furthermore, reexpression of Axl using adenovirus-mediated Axl delivery repressed IFN-stimulated gene induction in Axl-null mouse embryonic fibroblasts by RSV infection. The results suggest that Axl, independent of being a virus entry receptor of RSV infection, negatively regulates IFN signaling to modulate host antiviral response against RSV infection.

Targeting entry into mitochondria for increased anticancer efficacy of BCL-XL-selective inhibitors in lung cancer.

The BCL-XL-selective inhibitors exhibit potential clinical application value when combined with chemotherapeutic drugs for the treatment of solid tumors. However, their efficacy in these settings is still low when treated with BCL-XL inhibitors alone in solid tumors. The mechanism responsible for the poor efficacy remains unclear. We show here that unable to interact with target of BCL-XL-selective inhibitors caused by invalid entry into mitochondria is essential for their inefficacy in solid tumors. We demonstrated in non-small-cell lung cancer (NSCLC) cells that the instability of A-1155463 in cells as well as invalid entry into mitochondria of A-1331852, two BCL-XL-selective inhibitors, accounted for their off-target problems. Furthermore, we found that a mitochondria-targeted, non-toxic small molecule NA-2a improved the on-target effect of A-1331852 to enhance its apoptotic regulatory activity, thereby increasing its anticancer activity in NSCLC. Our results indicated that NA-2a was selectively enriched in mitochondria transported by organic-anion-transporting polypeptide (OATP) transporters, which altered the permeability of the mitochondrial membrane, thereby promoting the entrance of A-1331852 to mitochondria and enhancing its disruption of the BIM-BCL-XL complex, which finally led to the increased anticancer activity in vitro and in vivo. Collectively, our data provided overwhelming evidence that the combination of NA-2a and A-1331852 could be used as a promising synergistic therapeutic agent in NSCLC therapy.

Grapevine U-Box E3 Ubiquitin Ligase VlPUB38 Negatively Regulates Fruit Ripening by Facilitating Abscisic-Aldehyde Oxidase Degradation.

The plant U-box E3 ubiquitin ligase-mediated ubiquitin/26S proteasome degradation system plays a key role in plant growth and development. Previously identified as a member of the grape PUB gene family, PUB38 was shown to participate in the berry-ripening progress. Here, we demonstrate that the E3 ligase VlPUB38 mediates abscisic acid (ABA) synthesis via 26S proteasome degradation and its involvement in regulating fruit-ripening processes. Strawberry-overexpressing VlPUB38 lines displayed obvious inhibition of mature phenotype, and this was rescued by exogenous ABA treatment and MG132. Post-ABA treatment, expression levels of ABA response-related genes in VlPUB38-overexpressed Arabidopsis significantly exceeded controls. Strawberry and Arabidopsis ectopic expression assays suggest that VlPUB38 negatively regulates fruit ripening in an ABA-dependent manner. Moreover, VlPUB38 has ubiquitin ligase activity, which depends on the U-box-conserved domain. VlPUB38 interacts with abscisic-aldehyde oxidase (VlAAO), targeting VlAAO proteolysis via the 26S proteasome system. These results indicate that VlPUB38 negatively regulates grape fruit ripening by mediating the degradation of key factor VlAAO in the ABA synthesis pathway.

Identification of C3H2C3-type RING E3 ubiquitin ligase in grapevine and characterization of drought resistance function of VyRCHC114.

BACKGROUND: RING is one of the largest E3 ubiquitin ligase families and C3H2C3 type is the largest subfamily of RING, which plays an important role in plant growth and development, and growth and responses to biotic and abiotic stresses. RESULTS: A total of 143 RING C3H2C3-type genes (RCHCs) were discovered from the grapevine genome and separated into groups (I-XI) according to their phylogenetic analysis, and these genes named according to their positions on chromosomes. Gene replication analysis showed that tandem duplications play a predominant role in the expansion of VvRCHCs family together. Structural analysis showed that most VvRCHCs (67.13 %) had no more than 2 introns, while genes clustered together based on phylogenetic trees had similar motifs and evolutionarily conserved structures. Cis-acting element analysis showed the diversity of VvRCHCs regulation. The expression profiles of eight DEGs in RNA-Seq after drought stress were like the results of qRT-PCR analysis. In vitro ubiquitin experiment showed that VyRCHC114 had E3 ubiquitin ligase activity, overexpression of VyRCHC114 in Arabidopsis improved drought tolerance. Moreover, the transgenic plant survival rate increased by 30 %, accompanied by electrolyte leakage, chlorophyll content and the activities of SOD, POD, APX and CAT were changed. The quantitative expression of AtCOR15a, AtRD29A, AtERD15 and AtP5CS1 showed that they participated in the response to drought stress may be regulated by the expression of VyRCHC114. CONCLUSIONS: This study provides valuable new information for the evolution of grapevine RCHCs and its relevance for studying the functional characteristics of grapevine VyRCHC114 genes under drought stress.

Glycyrrhizic Acid Inhibits SARS-CoV-2 Infection by Blocking Spike Protein-Mediated Cell Attachment.

Glycyrrhizic acid (GA), also known as glycyrrhizin, is a triterpene glycoside isolated from plants of Glycyrrhiza species (licorice). GA possesses a wide range of pharmacological and antiviral activities against enveloped viruses including severe acute respiratory syndrome (SARS) virus. Since the S protein (S) mediates SARS coronavirus 2 (SARS-CoV-2) cell attachment and cell entry, we assayed the GA effect on SARS-CoV-2 infection using an S protein-pseudotyped lentivirus (Lenti-S). GA treatment dose-dependently blocked Lenti-S infection. We showed that incubation of Lenti-S virus, but not the host cells with GA prior to the infection, reduced Lenti-S infection, indicating that GA targeted the virus for infection. Surface plasmon resonance measurement showed that GA interacted with a recombinant S protein and blocked S protein binding to host cells. Autodocking analysis revealed that the S protein has several GA-binding pockets including one at the interaction interface to the receptor angiotensin-converting enzyme 2 (ACE2) and another at the inner side of the receptor-binding domain (RBD) which might impact the close-to-open conformation change of the S protein required for ACE2 interaction. In addition to identifying GA antiviral activity against SARS-CoV-2, the study linked GA antiviral activity to its effect on virus cell binding.

Molecular cloning and characterization of a grapevine (Vitis vinifera L.) serotonin N-acetyltransferase (VvSNAT2) gene involved in plant defense.

BACKGROUND: Melatonin is a ubiquitous molecule and exists across kingdoms. Studies on melatonin in plants have mainly focused on its physiological influence on growth and development, and on its biosynthesis. A number of studies have been conducted on the melatonin content and exogenous melatonin treatment of grapevine (Vitis vinifera L.). However, key genes or enzymes of the melatonin biosynthetic pathway remain unclear. RESULTS: In this study, we cloned and identified the gene encoding serotonin N-acetyltransferase (SNAT) in grapevine (VvSNAT2). The VvSNAT2 protein was identified from a collection of 30 members of the grapevine GCN5-related N-acetyltransferase (GNAT) superfamily. Phylogenetic and protein sublocalization analyses showed that the candidate gene VvGNAT16 is VvSNAT2. Characterization of VvSNAT2 showed that its enzymatic activity is highest at a pH of 8.8 and a temperature of 45 °C. Analysis of enzyme kinetics showed the values of Km and Vmax of VvSNAT2 using serotonin were 392.5 µM and 836 pmol/min/mg protein, respectively. The expression of VvSNAT2 was induced by melatonin treatment and pathogen inoculation. Overexpression of VvSNAT2 in Arabidopsis resulted in greater accumulation of melatonin and chlorophyll and enhanced resistance to powdery mildew in the transgenic plants compared with the wild type (WT). Additionally, our data showed that the marker genes in the salicylic acid (SA) signaling pathway were expressed to higher levels in the transgenic plants compared with the WT. CONCLUSIONS: The VvSNAT2 gene was cloned and identified in grapevine for the first time. Our results indicate that VvSNAT2 overexpression activates the SA and JA signaling pathways; however, the SA pathway plays a central role in VvSNAT2-mediated plant defense.

The grapevine R2R3-type MYB transcription factor VdMYB1 positively regulates defense responses by activating the stilbene synthase gene 2 (VdSTS2).

BACKGROUND: Resveratrol is a naturally occurring plant stilbene that exhibits a wide range of valuable biological and pharmacological properties. Although the beneficial effects of trans-resveratrol to human health and plant protection against fungal pathogens and abiotic stresses are well-established, yet little is known about the molecular mechanisms regulating stilbene biosynthesis in plant defense progress. RESULTS: Here, we cloned and identified the Chinese wild grape (Vitis davidii) R2R3-MYB transcription factor VdMYB1, which activates defense responses against invading pathogen. VdMYB1 transcripts were significantly upregulated after inoculation with the grapevine powdery mildew fungus Erysiphe necator (Schw.) Burr. Transient expression analysis using onion epidermal cells and Arabidopsis thaliana protoplasts showed that VdMYB1 was localized in the nucleus. Yeast one-hybrid assays revealed that VdMYB1 acts as a transcriptional activator. Grapevine leaves transiently overexpressing VdMYB1 showed a lower number of fungal conidiophores compared with wild-type leaves. Overexpression of VdMYB1 in grapevine leaves did not alter the expression of genes in salicylic acid- and jasmonate-dependent pathways, but affected the expression of stilbene synthase (STS) genes, key regulators of flavonoid metabolism. Results of electrophoretic mobility shift assays and in vivo transcriptional activation assays showed that VdMYB1 binds to the MYB binding site (MYBBS) in the STS2 gene promoter, thus activating STS2 transcription. In heterologous expression assays using tobacco leaves, VdMYB1 activated STS2 gene expression and increased the accumulation of resveratrol. CONCLUSIONS: Our study showed that VdMYB1 activates STS2 gene expression to positively regulate defense responses, and increases the content of resveratrol in leaves.

Genome-wide identification of small heat-shock protein (HSP20) gene family in grape and expression profile during berry development.

BACKGROUND: Studies have shown that HSP20 (heat-shock protein 20) genes play important roles in regulating plant growth, development, and stress response. However, the grape HSP20 gene family has not been well studied. RESULTS: A total of 48 VvHSP20 genes were identified from the grape genome, which were divided into 11 subfamilies (CI, CII, CIII, CV, CVI, CVII, MI, MII, ER, CP and PX/Po) based on a phylogenetic analysis and subcellular localization. Further structural analysis showed that most of the VvHSP20 genes (93.8%) had no intron or only one intron, while genes that clustered together based on a phylogenetic tree had similar motifs and evolutionarily conserved structures. The HSP20s share a conservedα-crystalline domain (ACD) and the different components of the ACD domain suggest the functional diversity of VvHSP20s. In addition, the 48 VvHSP20 genes were distributed on 12 grape chromosomes and the majority of VvHSP20 genes were located at the proximal or distal ends of chromosomes. Chromosome mapping indicated that four groups of VvHSP20 genes were identified as tandem duplication genes. Phytohormone responsive, abiotic and biotic stress-responsive, and plant development-related cis-elements were identified from the cis-regulatory elements analysis of VvHSP20s. The expression profiles of VvHSP20s genes (VvHSP20-1, 11, 14, 17, 18, 19, 20, 24, 25, 28, 31, 39, 42, and 43) were largely similar between RNA-Seq and qRT-PCR analysis after hydrogen peroxide (H2O2) treatment. The results showed that most VvHSP20s were down-regulated by H2O2 treatment during fruit development. VvHSP20s genes were indeed found to be involved in the grape berry development and differences in their transcriptional levels may be the result of functional differentiation during evolution. CONCLUSIONS: Our results provide valuable information on the evolutionary relationship of genes in the VvHSP20 family, which is useful for future studies on the functional characteristics of VvHSP20 genes in grape.

Mitochondrion-Targeting Identification of a Fluorescent Apoptosis-Triggering Molecule by Mass Spectrometry Elucidates Drug Tracking.

The real-time tracking of localization and dynamics of small molecules in organelles helps to understand their function and identification of their potential targets at subcellular resolution. To identify the mitochondrion-targeting effects of small molecules (NA-17 and NA-2a) in cancer cells, we used mass spectrometry to study their distribution and accumulation in mitochondria and in the surrounding cytoplasm thus enabling tracing of action processes of therapeutic compounds. Colocalization analysis with the aid of imaging agents suggests that both NA-17 and NA-2a display mitochondrion-targeting effects. However, MS analysis reveals that only NA-2a displays both a mitochondrion-targeting effect and an accumulation effect, whereas NA-17 only distributes in the surrounding cytoplasm. A combination of mitochondrion imaging, immunoblotting, and MS analysis in mitochondria indicated that NA-17 neither has the ability to enter mitochondria directly nor displays any mitochondrion-targeting effect. Further studies revealed that NA-17 could not enter into mitochondria even when the mitochondrial permeability in cells changed after NA-17 treatment, as was evident from reactive oxygen species (ROS) generation and cytochrome c release. In the process of cellular metabolism, NA-17 itself is firmly restricted to the cytoplasm during the metabolic process, but its metabolites containing fluorophores could accumulate in mitochondria for cell imaging. Our studies have furnished new insights into the drug metabolism processes.

Functional Characterization of Resistance to Powdery Mildew of VvTIFY9 from Vitis vinifera.

Powdery mildew is a disease caused by fungal pathogens that harms grape leaves and fruits. The TIFY gene family is a plant-specific super-family involved in the process of plants' development and their biotic and abiotic stress responses. This study aimed to learn the function of the VvTIFY9 gene to investigate molecular mechanisms of grape resistance to powdery mildew. A VvTIFY9 protein encoding a conserved motif (TIF[F/Y]XG) was characterized in grape (Vitis vinifera). Sequence analysis confirmed that VvTIFY9 contained this conserved motif (TIF[F/Y]XG). Quantitative PCR analysis of VvTIFY9 in various grape tissues demonstrated that the expression of VvTIFY9 was higher in grape leaves. VvTIFY9 was induced by salicylic acid (SA) and methyl jasmonate (MeJA) and it also quickly responded to infection with Erysiphe necator in grape. Analysis of the subcellular localization and transcriptional activation activity of VvTIFY9 showed that VvTIFY9 located to the nucleus and had transcriptional activity. Arabidopsis that overexpressed VvTIFY9 were more resistant to Golovinomyces cichoracearum, and quantitative PCR revealed that two defense-related genes, AtPR1 and AtPDF1.2, were up-regulated in the overexpressing lines. These results indicate that VvTIFY9 is intimately involved in SA-mediated resistance to grape powdery mildew. This study provides the basis for exploring the molecular mechanism of grape resistance to disease resistance and candidate genes for transgenic disease resistance breeding of grape plants.

MicroRNA profiling analysis of developing berries for 'Kyoho' and its early-ripening mutant during berry ripening.

BACKGROUND: 'Fengzao' is an early-ripening bud mutant of 'Kyoho', which matures nearly 30 days earlier than 'Kyoho'. To gain a better understanding of the regulatory role of miRNAs in early-ripening of grape berry, high-throughput sequencing approach and quantitative RT-PCR validation were employed to identify miRNAs at the genome-wide level and profile the expression patterns of the miRNAs during berry development in 'Kyho' and 'Fengzao', respectively. RESULTS: Nine independent small RNA libraries were constructed and sequenced in two varieties from key berry development stages. A total of 108 known miRNAs and 61 novel miRNAs were identified. Among that, 159 miRNAs identified in 'Fengzao' all completely expressed in 'Kyoho' and there were 10 miRNAs specifically expressed in 'Kyoho'. The expression profiles of known and novel miRNAs were quite similar between two varieties. As the major differentially expressed miRNAs, novel_144, vvi-miR3626-3p and vvi-miR3626-5p only expressed in 'Kyoho', vvi-miR399b and vvi-miR399e were down-regulated in 'Fengzao', while vvi-miR477b-3p up-regulated in 'Fengzao'. According to the expression analysis and previous reports, miR169-NF-Y subunit, miR398-CSD, miR3626-RNA helicase, miR399- phosphate transporter and miR477-GRAS transcription factor were selected as the candidates for further investigations of miRNA regulation role in the early-ripening of grape. The qRT-PCR analyses validated the contrasting expression patterns for these miRNAs and their target genes. CONCLUSIONS: The miRNAome of the grape berry development of 'Kyoho', and its early-ripening bud mutant, 'Fengzao' were compared by high-throughput sequencing. The expression pattern of several key miRNAs and their target genes during grape berry development and ripening stages was examined. Our results provide valuable basis towards understanding the regulatory mechanisms of early-ripening of grape berry.

A Novel Naphthalimide Compound Restores p53 Function in Non-small Cell Lung Cancer by Reorganizing the Bak·Bcl-xl Complex and Triggering Transcriptional Regulation.

p53 inactivation is a hallmark in non-small-cell lung cancer (NSCLC). It is therefore highly desirable to develop tumor-specific treatment for NSCLC therapy by restoring p53 function. Herein, a novel naphthalimide compound, NA-17, was identified as a promising drug candidate in view of both its anticancer activity and mechanism of action. NA-17 exhibited strong anticancer activity on a broad range of cancer cell lines but showed low toxicity to normal cell lines, such as HL-7702 and WI-38. Moreover, NA-17 showed p53-dependent inhibition selectivity in different NSCLC cell lines due to the activation state of endogenous p53 in the background level. Further studies revealed that NA-17 caused cell cycle arrest at the G1 phase, changed cell size, and induced apoptosis and cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that targeted accumulation of phospho-p53 in mitochondria and nuclei induced by NA-17 resulted in activation of Bak and direct binding of phospho-p53 to the target DNA sequences, thereby evoking cell apoptosis and cell cycle arrest and eventually leading to irreversible cancer cell inhibition. This work provided new insights into the molecular interactions and anticancer mechanisms of phospho-p53-dependent naphthalimide compounds.

Comparative RNA-Seq profiling of berry development between table grape 'Kyoho' and its early-ripening mutant 'Fengzao'.

BACKGROUND: Early ripening is an important desirable attribute for fruit crops. 'Kyoho' is a popular table grape cultivar in many Asian countries. 'Fengzao' is a bud mutant of 'Kyoho' and ripens nearly 30 days earlier than 'Kyoho'. To identify genes controlling early fruit development and ripening in 'Fengzao', RNA-Seq profiles of the two cultivars were compared at 8 different berry developmental stages in both berry peel and flesh tissues. METHODS: RNA-Seq profiling of berry development between 'Kyoho' and 'Fenzhao' were obtained using the Illumina HiSeq system and analyzed using various statistical methods. Expression patterns of several selected genes were validated using qRT-PCR. RESULTS: About 447 millions of RNA-Seq sequences were generated from 40 RNA libraries covering various different berry developmental stages of 'Fengzao' and 'Kyoho'. These sequences were mapped to 23,178 and 22,982 genes in the flesh and peel tissues, respectively. While most genes in 'Fengzao' and 'Kyoho' shared similar expression patterns over different berry developmental stages, there were many genes whose expression were detected only in 'Fengzao' or 'Kyoho'. We observed 10 genes in flesh tissue and 22 genes in peel tissue were differentially expressed at FDR ≤ 0.05 when the mean expression of 'Fengzao' and 'Kyoho' were compared. The most noticeable one was VIT_214s0030g00950 (a superoxide dismutase gene). This ROS related gene showed lower expression levels in 'Fengzao' than 'Kyoho' in both peel and flesh tissues across various berry developmental stages with the only exception at véraison. VIT_200s0238g00060 (TMV resistance protein n-like) and VIT_213s0067g01100 (disease resistance protein at3g14460-like) were the two other noticeable genes which were found differentially expressed between the two cultivars in both peel and flesh tissues. GO functional category and KEGG enrichment analysis of DEGs indicated that gene activities related to stress and ROS were altered between the two cultivars in both flesh and peel tissues. Several differentially expressed genes of interest were successfully validated using qRT-PCR. CONCLUSIONS: Comparative profiling analysis revealed a few dozens of genes which were differentially expressed in the developing berries of 'Kyoho' and its early ripening mutant 'Fengzao'. Further analysis of these differentially expressed genes suggested that gene activities related to ROS and pathogenesis were likely involved in contributing to the early ripening in 'Fengzao'.

A planar Schiff base platinum(II) complex: crystal structure, cytotoxicity and interaction with DNA.

A new platinum(II) complex of salphen derivative, namely Schiff base ligand that derived from o-phenylenediamine and 5-chlorosalicylaldehyde was synthesized. The complex possessed a planar mononuclear structure. The in vitro cytotoxicities of the complex were evaluated by microculture tetrozolium (MTT) assay against seven human tumor cell lines with the IC50 values of ca. 11.61 µM. Cell cycle analysis indicated that the complex induced apoptosis and G1-phase arrest in A549 cells. The results of colony formation assay showed that the complex could suppress the proliferation and viability of A549 cells. The binding of the complex to potential target DNA were investigated by fluorescence spectroscopy, viscosity measurements, fluorescence polarization and agarose gel electrophoresis. The results suggest that the most probable binding mode of the complex is intercalation.

Identification of naphthalimide-derivatives as novel PBD-targeted polo-like kinase 1 inhibitors with efficacy in drug-resistant lung cancer cells.

Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29 µM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.

[Strategy for keeping efficient expression and pharmacodynamics in reducing rAAV gene medicine immune response based on the decrease of vector dosage].

How to reduce immune response is an unprecedented challenge for rAAV gene medicine. Recent studies suggested that lowering dosage of the vector used could reduce immune response caused by rAAV gene medicine. Nevertheless, it would also decrease the transgene expression, leading to failure of gene treatment. It is therefore important to take appropriate steps to maintain high gene expression level and pharmacodynamic, while the dosage of rAAV used is reduced. Here, steps to enhancing gene therapy, such as optimization of the administration, reconstruction of the viral vector and selection of the promoter, are discussed in order to achieve maximum outcome.

Post-traumatic hydrocephalus: An overview of classification, diagnosis, treatment, and post-treatment imaging evaluation.

The syndrome of post-traumatic hydrocephalus (PTH) has been recognized since Dandy's report in 1914. The pathogenesis of PTH has not been fully clarified. At present, it is believed that the obstacles of cerebrospinal fluid (CSF) secretion, absorption and circulation pathways are the reasons for the development of PTH. However, recent studies have also suggested that the osmotic pressure load of CSF and the pathological changes of CSF dynamics are caused by the development of hydrocephalus. Therefore, a better understanding of the definition, classification, diagnostic criteria, treatment, and evaluation of post-treatment effects of PTH is critical for the effective prevention and treatment of PTH. In this paper, we reviewed the classification and diagnosis of PTH and focused on the treatment and the imaging evaluation of post-treatment effects of PTH. This review might provide a judgment criterion for diagnosis of PTH and a basis for the effective prevention and treatment of PTH in the future.

Usability of Serum Stanniocalcin-1 as a Prognostic Biochemical Marker of Acute Supratentorial Intracerebral Hemorrhage: A Prospective Cohort Study.

Objective: Stanniocalcin-1 (STC1) may be neuroprotective. This study aimed to evaluate the prognostic role of serum STC1 levels in intracerebral hemorrhage (ICH). Methods: This prospective observational study was assigned in two parts. In the first part, blood samples of 48 patients with ICH were acquired on admission and on days 1, 2, 3, 5, and 7 after ICH, and those of 48 controls were collected at their entry into the study. In the second part, blood samples of 141 patients with ICH were obtained upon admission. Serum STC1 levels were measured, and the National Institutes of Health Stroke Scale (NIHSS), hematoma volume, and poststroke 6-month modified Rankin Scale (mRS) scores were recorded. Dynamic changes in serum STC levels and their correlation with disease severity and prognosis were investigated. Results: Serum STC1 levels were elevated after ICH, peaked on day 1, plateaued on day 2, declined gradually afterwards, and were significantly higher than those in controls. Serum STC1 levels were independently correlated with NIHSS scores, hematoma volume, and the 6-month post-injury mRS scores. Serum STC1 levels, NIHSS scores, and hematoma volume independently predicted a poor prognosis (mRS scores of 3-6). The model integrating serum STC1 levels, NIHSS scores, and hematoma volume was visually displayed using a nomogram and was relatively stable using the Hosmer-Lemeshow test and calibration curve analysis. Under the receiver operating characteristic curve, serum STC1 levels efficiently predicted a poor prognosis and showed similar prognostic ability to NIHSS scores and hematoma volume. The preceding model had significantly higher prognostic capability than NIHSS scores and hematoma volume alone and their combination. Conclusion: Substantial enhancement of serum STC1 levels after ICH, which is strongly correlated with severity, independently distinguished the risk of poor prognosis, assuming that serum STC1, as a prognostic parameter, may be clinically valuable in ICH.

Ultrasensitive detection of potassium ions based on target induced DNA conformational switch enhanced fluorescence polarization.

We have developed a simple, highly sensitive and selective fluorescence polarization assay for the detection of potassium ions based on target induced DNA conformational switch from hairpin to G-quadruplex enhanced fluorescence polarization. The assay was applied in the detection of low nM concentrations of potassium ions and was highly selective over other cations.

Small-molecule MX-C2/3 suppresses non-small cell lung cancer progression via p53 activation.

p53 inactivation is a common feature in non-small cell lung cancer (NSCLC) resulting in NSCLC malignant transformation. Targeting serine 392 phosphorylation to restore p53 anticancer activity has proven to be an effective therapeutic strategy against NSCLC. A synthetic p53 activator, NA-17, has been developed that shows promise in preclinical models of NSCLC. However, NA-17 exhibits limited therapeutic efficacy in oncogene-driven tumors as well as relatively high toxicity to normal cells. It is possible that high efficiency and low toxicity p53 activators can be obtained by optimizing the leading molecule. Here, we performed high-throughput screening of compounds optimized based on NA-17 to identify new p53 activators. Two promising candidates named MX-C2 and MX-C3 were identified, both exhibited considerable therapeutic efficacy in oncogene-driven tumor models. Similar to NA-17, MX-C2/3 induced p53 activation via phosphorylating serine-392 without DNA damage. Both compounds showed broad antitumor activity in NSCLC cells and limited toxicity in normal cell lines. Moreover, MX-C2/3 suppressed tumor progression by arresting the cell cycle at G2/M phase, exhibiting a different mechanism of cell cycle arrest than NA-17. In addition, MX-C2/3 promoted the enrichment of p-p53 (s392) in mitochondria, leading to the conformational activation of Bak for cell apoptosis, which is consistent with NA-17. Finally, we demonstrated that MX-C2 significantly inhibited tumor growth without obvious systemic toxicity in oncogene-driven HCC-827 xenograft models. Collectively, we report two p53 activators with high-efficiency and low-toxicity that target p53 serine 392 phosphorylation for anticancer translational investigation.