G-quadruplex stabilizer Tetra-Pt(bpy) disrupts telomere maintenance and impairs FAK-mediated migration of telomerase-positive cells.

G-quadruplex regulates a wide spectrum of biological processes, including telomere maintenance, DNA replication and transcription. The development of small molecules to selectively target G-quadruplex and their application remain hotspots in cancer therapy. Here, we explored the biological effect of G-quadruplexes stabilizer Tetra-Pt(bpy) in telomerase-positive cancer cells. Telomere maintenance was evaluated by telomerase repeat amplification protocol, chromosome orientation fluorescence in situ hybridization and telomere restriction fragment assays. We found that Tetra-Pt(bpy) accelerates telomere shortening through dual inhibition of telomerase activity and telomere sister chromatin exchanges mediated by telomeric G-quadruplexes. Consequently, Tetra-Pt(bpy)-treated cancer cells became enriched with extremely short telomeres and produced a strong telomeric DNA damage response following long-term treatment, leading to cell proliferation inhibition and senescence. Experimental evidence from RNA seq and cell migration-related assays showed that Tetra-Pt(bpy) decreased cell-matrix adhesion and inhibited the migration of non-senescent tumor cells. Mechanistically, Tetra-Pt(bpy) induced the formation of G-quadruplexes in focal adhesion kinase (FAK)-encoding gene PTK2, resulting in FAK transcription inhibition. Tetra-Pt(bpy) reduced xenograft tumor formation and inhibited tumor cell growth and migration in mice. This study further elucidates the function of G-quadruplexes in the human genome and reveals the potential of Tetra-Pt(bpy) as a novel chemotherapeutic agent for targeting telomerase-positive cancer cells.

A chalcone-syringaldehyde hybrid inhibits triple-negative breast cancer cell proliferation and migration by inhibiting CKAP2-mediated FAK and STAT3 phosphorylation.

BACKGROUND: Although triple-negative breast cancer (TNBC) accounts for only 15% of breast cancer cases, it is associated with a high relapse rate and poor outcome after standard treatment. Currently, the effective drugs and treatment strategies for TNBC remain limited, and thus, developing effective treatments for TNBC is pressing. Several studies have demonstrated that both chalcone and syringaldehyde have anticancer effect, but their potential anti-TNBC bioactivity are still unknown. PURPOSE: The present study aimed to synthesize a chalcone-syringaldehyde hybrid (CSH1) and explore its potential anti-TNBC effects and the underlying molecular mechanism. METHODS: Cell cytotoxicity was determined by 3-(4,5-dimethythiazol)-2,5-diphenyltetrazolium bromide (MTT). The activity of cell proliferation was measured by colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) staining assay. Cell cycle distribution and cell apoptosis were determined by fluorescence-activated cell sorter (FACS). The situation of DNA damage was observed using fluorescence microscopy. The ability of cell-matrix adhesion, migration and invasion was detected using cell adhesion assay and transwell assay. Transcriptome sequencing was performed to find out the changed genes. Levels of various signaling proteins were assessed by western blotting. RESULTS: CSH1 treatment triggered DNA damage and inhibited DNA replication, cell cycle arrest, and cell apoptosis via suppressing signal transducer and activator of transcription 3 (STAT3) phosphorylation. Whole genome RNA-seq analysis suggested that 4% of changed genes were correlated to DNA damage and repair, and nearly 18% of changed genes were functionally related to cell adhesion and migration. Experimental evidence indicated that CSH1 treatment significantly affected the distribution of focal adhesion kinase (FAK) and its phosphorylation, resulting in cell-matrix-adhesion reduction and migration inhibition of TNBC cells. Further mechanistic studies indicated that CSH1 inhibited TNBC cell proliferation, adhesion, and migration by inhibiting cytoskeleton-associated protein 2 (CKAP2)-mediated FAK and STAT3 phosphorylation signaling. CONCLUSION: These results suggest that CKAP2-mediated FAK and STAT3 phosphorylation signaling is a valuable target for TNBC treatment, and these findings also reveal the potential of CSH1 as a prospective TNBC drug.

Bristled-wing design of materials, microstructures, and aerodynamics enables flapping flight in tiny wasps.

Parasitoid wasps of the smallest flying insects with bristled wings exhibit sophisticated flight behaviors while challenging biomechanical limitations in miniaturization and low-speed flow regimes. Here, we investigate the morphology, material composition, and mechanical properties of the bristles of the parasitoid wasps Anagrus Haliday. The bristles are extremely stiff and exhibit a high-aspect-ratio conical tubular structure with a large Young's modulus. This leads to a marginal deflection and uniform structural stress distribution in the bristles while they experience high-frequency flapping-induced aerodynamic loading, indicating that the bristles are robust to fatigue. The flapping aerodynamics of the bristled wings reveal that the wing surfaces act as porous flat paddles to reduce the overall inertial load while utilizing a passive shear-based aerodynamic drag-enhancing mechanism to generate the requisite aerodynamic forces. The bristled wing may have evolved as a novel design that achieves multiple functions and provides innovative ideas for developing bioinspired engineering microdevices.

C1632 suppresses the migration and proliferation of non-small-cell lung cancer cells involving LIN28 and FGFR1 pathway.

Chemoresistance and migration represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients in clinic. In the present study, we report that the compound C1632 is preferentially distributed in the lung after oral administration in vivo with high bioavailability and limited inhibitory effects on CYP450 isoenzymes. We found that C1632 could simultaneously inhibit the expression of LIN28 and block FGFR1 signalling transduction in NSCLC A549 and A549R cells, resulting in significant decreases in the phosphorylation of focal adhesion kinase and the expression of matrix metalloproteinase-9. Consequently, C1632 effectively inhibited the migration and invasion of A549 and A549R cells. Meanwhile, C1632 significantly suppressed the cell viability and the colony formation of A549 and A549R cells by inhibiting DNA replication and inducing G0/G1 cell cycle arrest. Interestingly, compared with A549 cells, C1632 possesses the same or even better anti-migration and anti-proliferation effects on A549R cells, regardless of drug resistance. In addition, C1632 also displayed the capacity to inhibit the growth of A549R xenograft tumours in mice. Altogether, these findings reveal the potential of C1632 as a promising anti-NSCLC agent, especially for chemotherapy-resistant NSCLC treatment.

The different biological effects of TMPyP4 and cisplatin in the inflammatory microenvironment of osteosarcoma are attributed to G-quadruplex.

OBJECTIVE: Osteosarcoma (OS) is characterized by high levels of the tumour-associated inflammatory microenvironment. Moreover, in approximately 60% of OS, telomere length is maintained by alternative lengthening of telomeres (ALT) pathway. Whether the ALT pathway can be exploited for OS therapeutic treatment and how the OS inflammatory microenvironment influences the anti-cancer drug effect remains unknown. Here, we examined the biological effects of TMPyP4 and cisplatin in the inflammatory microenvironment of OS cells. MATERIALS AND METHODS: Immunofluorescence in situ hybridization (IF-FISH) and C-circle experiments were used to detect the G-quadruplex and ALT activity. The redox potential of single guanine, G-quadruplex and G-quadruplex/TMPyP4 was evaluated by the lowest unoccupied molecular orbital energy (LUMO), zeta potential and cyclic voltammetry. Cell viability, flow cytometry and apoptosis, Western blot, comet assay, adhesion, transwell and scratch experiments were performed to compare the anti-tumour proliferation and migration effects of TMPyP4 and cisplatin in the inflammatory microenvironment. RESULTS: This study indicated that compared with cisplatin, TMPyP4 could induce the formation of human telomeres and FAK G-quadruplex in vitro and in vivo, and TMPyP4-treated OS cells showed fewer extrachromosomal C-circles and fewer ALT-associated promyelocytic leukaemia bodies. Consequently, the ALT activity and FAK-related cell migration were suppressed by TMPyP4. Mechanistically, the formation of G-quadruplex resulted in both lower redox potential than G within the genome and FAK transcription inhibition, and TMPyP4 could enhance this phenomenon, especially in the inflammatory microenvironment. CONCLUSIONS: Our results reveal that TMPyP4 is more suitable for OS treatment than cisplatin.

Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage.

BACKGROUND: Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes. METHODS: The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), ß-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay. RESULTS: The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells. CONCLUSION: Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.

H2O2 enhances the anticancer activity of TMPyP4 by ROS-mediated mitochondrial dysfunction and DNA damage.

Cancer is one of the diseases that threatens human health and is a leading cause of mortality worldwide. High levels of reactive oxygen species (ROS) have been observed in cancer tissues compared with normal tissues in vivo, and it is not yet known how this influences chemotherapeutic drug action. Cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) is a photosensitizer used in photodynamic therapy (PDT) and a telomerase inhibitor used in the treatment of telomerase-positive cancer. Here, we investigated the anticancer activity of TMPyP4 in A549 and PANC cells cultured in H2O2. The results showed that compared to TMPyP4 alone, the combination of TMPyP4 and H2O2 exhibited sensitization effects on cell viability and colony formation inhibition and apoptosis in A549 and PANC cells, but had no effect in human normal MIHA cells. Mechanistically, the combination of TMPyP4 and H2O2 activates high ROS and mitochondrial membrane potential in A549 and PANC cells, resulting in intense DNA damage and DNA damage responses. Consequently, compared to TMPyP4 alone, TMPyP4 and H2O2 combined treatment upregulates the expression of BAX, cleaved caspase 3, and p-JNK and downregulates the expression of Bcl-2 in A549 and PANC cells. Taken together, these data suggested that H2O2 enhanced the anticancer activity of TMPyP4-mediated ROS-dependent DNA damage and related apoptotic protein regulation, revealing that the high ROS tumor microenvironment plays an important role in chemotherapeutic drug action.

Sequencing and analysis of the complete mitochondrial genome of Habrobracon hebetor (Hymenoptera: Braconidae).

We determined the complete mitochondrial genome sequence of Habrobracon hebetor (Say). The complete mitogenome sequence of H. hebetor was observed to be a circular molecule 15,708 bp long and consists of 13 protein-coding genes (PCG), 2 ribosomal RNA (rRNA) genes, and 22 transfer RNA (tRNA) genes (GenBank accession no. MN842279). This nucleotide composition is biased toward adenine and thymine (85.2% A + T). The A + T-rich region is found between trnM and trnQ, and this entire region was 864 bp long.

The complete mitochondrial genome of large odorous frog, Odorrana graminea (Amphibia: Ranidae) and phylogenetic analysis.

The mitochondrial genome of Odorrana graminea was sequenced and analyzed. The complete mitochondrial genome is 18,106 bp in length, including 13 protein-coding genes (PCGs), 2 ribosomal RNA genes, 21 transfer RNA genes, and a control region (D-loop). All PCGs are initiated by ATN codons, except for GTG for COI and ND5. Five PCGs use a common stop codon of TAA or TAG, whereas COI terminats with AGG as stop codon; ND6 with AGA; the other six ends with an incomplete stop codon (a single stop nucleotide T). The analysis results based on Bayesian inference method provide a useful resource for the phylogenetic studies of superfamily Ranoidea.

Clinical characteristics and risk factors of severe hyponatremia in cirrhotic patients treated with terlipressin.

WHAT IS KNOWN AND OBJECTIVE: As terlipressin becomes more widely used in clinical practice, more papers had reported the correlation between hyponatremia and terlipressin treatment. This study was performed to evaluate the clinical characteristics and risk factors of severe hyponatremia in cirrhotic patients treated with terlipressin and the effects of concomitant drugs. METHODS: We conducted a retrospective evaluation of patients with cirrhosis treated with terlipressin at the gastroenterology department of Hospital between 1 January 2016 and 30 June 2018. Patients treated with terlipressin for gastrointestinal bleeding due to peptic ulcer and other non-hepatic factors were excluded. RESULTS AND DISCUSSION: After the patients received terlipressin, their serum sodium concentrations decreased from 138.2 ± 4.3 mmol/L to 129.3 ± 7.2 mmol/L. Statistically significant differences were observed with respect to sex, initial serum sodium concentration, lowest serum sodium concentration, hyponatremia duration and total drug dose. Among the patients with hyponatremia, statistically significant differences in albumin level, serum creatinine level, hyponatremia duration and total drug dose were found between the patients with severe hyponatremia and those with non-severe hyponatremia. Logistic regression analysis revealed that initial serum sodium concentration (odds ratio, 95% confidence interval: 18.475, 3.967-86.035; P = .000) was a risk factor for reduced serum concentration, and that albumin level (1.105, 1.012-1.207; P = .026), serum creatinine level (0.975, 0.952-0.997; P = .028) and hyponatremia duration (1.297, 1.064-1.583; P = .010) were risk factors of severe hyponatremia. WHAT IS NEW AND CONCLUSION: The incidence of severe hyponatremia among patients with cirrhosis who are treated with terlipressin is high. Moreover, higher initial serum sodium concentrations and increased duration of terlipressin administration are associated with a higher the incidence of severe hyponatremia. The initial albumin level is a risk factor for severe hyponatremia as is serum creatinine, although the latter is negatively correlated with the occurrence of the condition.

Mutation in cyp51A and high expression of efflux pump gene of Aspergillus fumigatus induced by propiconazole in liquid medium and soil.

Triazole resistance in Aspergillus fumigatus is a major cause of clinical inefficacy in the treatment of invasive aspergillosis (IA). The hypothesis that triazole fungicides have driven the development of resistance in A. fumigatus has garnered substantial attention due to the similar structure and global detection of antifungal resistant A. fumigatus (ARAF) isolates in the soil. However, there is little evidence linking the application of triazole fungicides to the emergence of ARAF in the soil. This study was conducted to test if the resistance in A. fumigatus and its associated mutations in cyp51A could be induced by propiconazole in liquid medium and soil. The results indicate that propiconazole can induce resistance by alteration of G138S in cyp51A, and the overexpression of cyp51A, AfuMDR3 and AfuMDR4. G138S in cyp51A was first detected in the soil and associated with resistance. The emergence of the ARAFs in the soil may depends upon the level of propiconazole, and the number of ARAFs in soil treated with propiconazole at 2- and 5-fold dose was much greater than those in soil treated at the recommended dosage. The current data indicate that propiconazole can induce triazole resistance in A. fumigatus and should be applied for agricultural purposes at levels at or below the recommended dosage to avoid the emergence of ARAF in the soil.

Fungicides induced triazole-resistance in Aspergillus fumigatus associated with mutations of TR46/Y121F/T289A and its appearance in agricultural fields.

Azole resistance in Aspergillus fumigatus is a growing public health problem. The sources of this resistance have been gained much attention. The present study was conducted to assess if resistant strain of A. fumigatus and its associated mutations in cyp51A could be induced by triazole fungicides and whether the resistant strain of A. fumigatus exist in agricultural fields. The results indicated that the resistance in A. fumigatus with mutations of TR46/Y121F/T289A, A284T, G448S and P222Q could be induced by agricultural triazoles (epoxiconazole, tebuconazole, propiconazole, hexaconazole, and metconazole). TR46/Y121F/T289A was the most common mutation in the induced resistant strain of A. fumigatus. A total of 144 soil samples were collected from different greenhouses for vegetables and fruits in Zhejiang, China. Among them, 2 voriconazole-resistant strains (No. 15 and 44) harboring the mutation of TR46/Y121F/T289A and 1 itraconazole-resistant strain (No. 51) harboring the mutation of TR34/L98H/S297T/F495I were isolated and identified. This implies that resistant strain of A. fumigatus has already distributed at least in 5.8% of the greenhouses. These findings might imply that there is a direct link between the agricultural use of triazoles and the appearance of the resistance in A. fumigatus to triazole medicals and its associated mutations in cyp51A.

Description of three new species of Arescon Walker (Hymenoptera, Mymaridae) from China.

Three new species of Arescon Walker, 1846, Arescon gaoligongensis Jin & Li, sp. n., Arescon sparsiciliatus Jin & Li, sp. n. and Arescon stenopterus Jin & Li, sp. n. are described. A key to the Chinese species is given and photomicrographs are provided to illustrate morphological characters. All the specimens are deposited in the insect collections of Northeast Forestry University, China.

Reduced mobility of fomesafen through enhanced adsorption in biochar-amended soil.

The residual soil material resulting from biomass thermochemical transformation during carbon separation, known as biochar, has been introduced as a soil amendment because of its numerous environmental benefits, including uses for contaminated land management. Adsorption and leaching of fomesafen in soils amended with 3 different rates of rice hull biochar (0.5%, 1%, and 2% w/w) under laboratory conditions were investigated, and studies were performed following a batch equilibration adsorption-desorption procedure and a column experiment for leaching. Adsorption-desorption data fit with the Freundlich equation well. The adsorption coefficient of fomesafen sharply increased from 0.59 to 0.99 to 8.02 to 22.23 when the amount of biochar amendment in the soil increased from 0% to 2% (w/w). In addition, a strong correlation was found between the amount of adsorbed fomesafen and the rate of amended biochar (r > 0.992, p < 0.01). Furthermore, biochar amendments reduced the desorption percentage of fomesafen in the soils. The outcomes of the leaching experiment also illustrated that the lowest fomesafen concentration in the leachate (21.4%) occurred in the soil amended with 2% (w/w) biochar. Moreover, the adsorption coefficients (K(f)(ads)) of the soil were positively correlated with the total amount of adsorbed fomesafen in the corresponding soil columns (r = 0.990, p < 0.01) and negatively correlated with the leachate percentage (r = 0.987, p < 0.05). The results of the present study suggest that biochar amendments in agricultural soils likely alter the fate of herbicides by decreasing their transport through enhanced adsorption.

A taxonomic study of Ooctonus (Hymenoptera, Mymaridae) from Heilongjiang, China.

Five species of Ooctonus Haliday (Hymenoptera, Mymaridae) from Heilongjiang Province, China, are reviewed. One species, Ooctonushuberi sp. n., is described as new, and four species, Ooctonusorientalis Doutt, Ooctonussaturn Triapitsyn, Ooctonussublaevis Förster and Ooctonusvulgatus Haliday are reported as new to China. A key to the females of the 10 described Chinese species is given. All the specimens are deposited in the insect collections of Northeast Forestry University, China.

Bioaugmentation of DDT-contaminated soil by dissemination of the catabolic plasmid pDOD.

A plasmid transfer-mediated bioaugmentation method for the enhancement of dichlorodiphenyltrichloroethane (DDT) degradation in soil was developed using the catabolic plasmid pDOD from Sphingobacterium sp. D-6. The pDOD plasmid could be transferred to soil bacteria, such as members of Cellulomonas, to form DDT degraders and thus accelerate DDT degradation. The transfer efficiency of pDOD was affected by the donor, temperature, moisture, and soil type. Approximately 50.7% of the DDT in the contaminated field was removed 210 days after the application of Escherichia coli TG I (pDOD-gfp). The results suggested that seeding pDOD into soil is an effective bioaugmentation method for enhancing the degradation of DDT.

A new species of Ptilomymar (Hymenoptera, Mymaridae) and a key to the described species.

Ptilomymar dianensis sp. n. (Hymenoptera, Mymaridae) from southwest China is described and illustrated. A key to the six described species is given. The type specimens are deposited in the insect collections of Northeast Forestry University, China.

First record of Eubroncus (Hymenoptera, Mymaridae) from China, with description of three new species.

The genus Eubroncus Yoshimoto, Kozlov & Trjapitzin is first recorded from China, and three species, E. hani sp. n., E. tibetanus sp. n. and E. vertexus sp. n. are described as new. A key to the six described species is given, with photomicrographs to illustrate morphological characters.

Soil genotoxicity induced by successive applications of chlorothalonil under greenhouse conditions.

Greenhouse production of vegetables has been developed rapidly in China. High temperature and humidity inside the greenhouse make this environment more suitable for fast reproduction of fungal diseases. Fungicides are among the chemicals used extensively in the greenhouse to prevent crops from invasive infections by phytopathogens; however, little is known about the accumulation of fungicides in soil and their effect on soil quality under greenhouse conditions. In the present study, the accumulation of the fungicide chlorothalonil (CT) and its toxic metabolite hydroxy-chlorothalonil (HCT) in soil as well as their related soil genotoxicity under greenhouse conditions was investigated. The results indicated that both CT and HCT accumulated in soil with repeated applications of CT, and the accumulation level was strongly correlated to application dosage and its frequency. In addition, soil genotoxicity, which was measured by Vicia faba, also increased with the accumulation of CT and HCT, and the main contributor to this phenomenon was CT rather than HCT. The data demonstrated that successive applications of fungicides may result in their accumulation in soil and thus a decline in soil quality.

Impact of coexistence of carbendazim, atrazine, and imidacloprid on their adsorption, desorption, and mobility in soil.

The effect of coexisting pesticide on adsorption/desorption and mobility of another one was investigated with carbendazim (CBD), imidacloprid (IDP), and atrazine (ATR). The data indicated that adsorption of CBD, ATR, and IDP on the tested soil was fitted well by Freundlich equation and increased with an order of IDP < ATR ≪ CBD. Adsorption of a pesticide was decreased by the coexistence of another one through their competitive adsorption. The presence of coexisting solute of the more adsorbability played a more important role than that of the lesser adsorbability. The adsorption of IDP and ATR was easier to be affected by 28.9-52.0 % and 31.1-60.7 % with the addition of CBD, while that of CBD was much less influenced by 3.4-18.1 % and 6.9-31.8 % with the presence of ATR and IDP, respectively. An adsorbability-related enhancement in desorption of the three pesticides by the co-adsorbed solute was also observed. As a result of competitive adsorption/desorption, the mobility of the pesticides estimated from soil thin-layer chromatography was altered. The results clearly illustrated that adsorbability and concentration-related alteration in adsorption/desorption and mobility will be caused by the coexistence of pesticides.