Role of non-coding RNAs and RNA modifiers in cancer therapy resistance.

As the standard treatments for cancer, chemotherapy and radiotherapy have been widely applied to clinical practice worldwide. However, the resistance to cancer therapies is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complicated and result from multiple factors. Among them, non-coding RNAs (ncRNAs), along with their modifiers, have been investigated to play key roles in regulating tumor development and mediating therapy resistance within various cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, gastric cancer, etc. In this review, we attempt to elucidate the mechanisms underlying ncRNA/modifier-modulated resistance to chemotherapy and radiotherapy, providing some therapeutic potential points for future cancer treatment.

Identification of Target Genes and Transcription Factors in Mice with LMNA-Related Dilated Cardiomyopathy by Integrated Bioinformatic Analyses.

BACKGROUND Dilated cardiomyopathy (DCM), which is characterized by enlarged ventricular dimensions and systolic dysfunction, is the most common type of cardiomyopathy. Mutations in the LMNA gene are reported in approximately 10% of familial DCM cases. However, the mechanism of LMNA mutations in human DCM remains unclear. MATERIAL AND METHODS We used the GSE36502 and GSE123916 datasets to obtain gene expression profiles from LMNA-related DCM mice and to identify differentially expressed genes (DEGs). Crucial function and pathway enrichment analyses of DEGs were performed. Protein-protein interaction (PPI) network analysis was carried out to identify the top 10 hub genes, which were validated using reverse transcription-polymerase chain reaction (RT-PCR) to find target genes. Weighted gene co-expression network analysis (WGCNA) was used to explore the module relevant to external traits of LMNA-related DCM mice. Transcription factors (TFs) for the selected genes were analyzed using NetworkAnalyst. RESULTS A total of 156 common DEGs (co-DEGs) were identified, including 80 up-regulated and 76 down-regulated genes. The enriched biological functions and pathways were oxidative stress, regulation of apoptosis, regulation of fibrosis, and MAPK pathways. Five target genes (Timp1, Hmox1, Spp1, Atf3, and Adipoq) were verified after RT-PCR. Most co-DEGs were discovered to be related to the development of external traits. Three TFs (ELF1, ETS1, and NRF1) showed close interactions with the hub genes. CONCLUSIONS Our study used integrated bioinformatic analyses and revealed some important genes in mice with LMNA-related DCM, which could provide novel insights into the mechanism underlying human LMNA-related DCM.

Administration of anti-CTLA-4 monoclonal antibody augments protective immunity induced by Schistosoma japonicum glutathione-S-transferase.

AIMS: The aim of this study was to evaluate the effect of anti-CTLA-4 monoclonal antibody (mAb) on 26-kDa glutathione-S-transferase (GST) vaccine-induced immunity against Schistosoma japonicum infection. METHODS AND RESULTS: Mice immunized with GST before infection with S japonicum cercariae were injected with anti-CTLA-4 mAb. Worm reduction rate of GST was increased from 25.41% in mice with GST immunization to 52.48% in mice with GST plus anti-CTLA-4 mAb. The percentages of regulatory T cells (Tregs) were significantly higher following administration of both GST and anti-CTLA-4 mAb, or anti-CTLA-4 mAb alone. Elevated levels of IFN-γ, IL-2, IL-4 and IL-5 were observed. CONCLUSION: These results demonstrated that CTLA-4 may inhibit the protective effect of GST vaccine, and anti-CTLA-4 mAb may be used as an adjuvant to enhance the immune protection conferred by the GST vaccine by enhancing Th1- and Th2-type immune response.

Anti-CTLA-4 monoclonal antibody improves efficacy of the glyceraldehyde-3-phosphate dehydrogenase protein vaccine against Schistosoma japonicum in mice.

Schistosomiasis is a devastating disease caused by Schistosoma infection. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has emerged as a candidate vaccine component against Schistosoma japonicum, but only confers partial protection. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates T cell activation and shows negative effects on vaccine-induced immune protection; however, its potential influence on the protective effects of a GAPDH vaccine against S. japonicum and the underlying mechanism remain unclear. In this study, we established a mouse model of S. japonicum infection, and the mice were randomly divided into uninfected, infected control, anti-CTLA-4 monoclonal antibody (anti-CTLA-4 mAb), GAPDH, and GAPDH combined with anti-CTLA-4 mAb groups to compare the protective effects against infection and the consequent tissue damage. The worm reduction rate in the GAPDH-treated infected mice was 26.58%, which increased to 54.61% when combined with anti-CTLA-4 mAb. The frequency of regulatory T cells (Tregs) was significantly higher in the anti-CTLA-4 mAb group and was lower in the GAPDH group. However, both anti-CTLA-4 mAb and GAPDH elevated the levels of the cytokines IFN-γ, IL-2, IL-4, and IL-5 in the spleens of infected mice, and their combination further enhanced cytokine production. The diameter of egg granuloma in the anti-CTLA-4 mAb group and combined treatment group increased significantly compared to that of the other groups. These results suggest that anti-CTLA-4 mAb can be used as an adjuvant to enhance the immune protection of the GAPDH vaccine via inducing the Th1 immune response, although this comes at the cost of enhanced body injury.

Experimental study on water transport observations of desert riparian forests in the lower reaches of the Tarim River in China.

Studying the water use processes of desert riparian vegetation in arid regions and analyzing the response and adaptation strategies of plants to drought stress are of great significance for developing ecological restoration measures. Based on field monitoring and test analyses of physiological ecological indicators of dominant species (Populus euphratica and Tamarix chinensis) in the desert riparian forest in the lower reaches of the Tarim River, the water relations of P. euphratica and T. chinensis under drought stress are discussed and some water use strategies put forward. The results show that (1) concerning plant water uptake, desert riparian forests depend mainly on groundwater to survive under long-term water stress. (2) Concerning plant water distribution, the survival of P. euphratica and nearby shallow root plants is mainly due to the hydraulic lift and water redistribution of P. euphratica under drought stress. (3) Concerning plant water transport, P. euphratica sustains the survival of competitive and advantageous branches by improving their ability to acquire water while restraining the growth of inferior branches. (4) Concerning plant transpiration, the sap flow curves of daily variations of P. euphratica and T. chinensis were wide-peak sin and narrower-peak respectively. T. chinensis has better environmental adaptability.

[Role of nitrative stress in nano nickel oxide-induced lung injury in rats].

OBJECTIVE: To investigate the subchronic lung injury induced by nano nickel oxide( nano NiO) and its mechanism from the view of nitrative stress in rats. METHODS: A total of 40 adult male Wistar rats were randomly divided into 5 groups, control group( normal saline), 0. 015, 0. 06 and 0. 24 mg / kg nano NiO groups and 0. 24 mg / kg micro NiO group. Rats received intratracheally instilled nano NiO, micro NiO and normal saline twice a week for 6 weeks, respectively. All rats were sacrificed after the exposure to obtain lung tissues. HE staining was used to observe the lung pathological changes. The content of nitric oxide, and the activities of total nitric oxide synthase( TNOS) and inducible nitric oxide synthase( iNOS) in pulmonary tissue homogenate were measured by microplate reader. The levels of interleukin-2( IL-2), transforminggrowth factor-beta( TGF-ß), interferon-gamma( IFN-γ) and 8-hydroxy-2'-deoxyguanosine( 8-OHd G) in serum were detected by enzyme-linked immunosorbent assay( ELISA). RESULTS: The results of lung histopathology showed that the widened alveolar speta, inflammatory infiltration and nanoparticles deposition increased with the increasing dosage of nano NiO. Compared to control group, the content of NO and the activities of TNOS and iNOS in 0. 24 mg / kg nano NiO group increased in lung homogenate( P < 0. 05). The levels of IL-2, TGF-ß and IFN-γ in nano NiO 0. 06 and 0. 24 mg /kg group were higher than that of control group, and the level of 8-OHd G increased in nano NiO 0. 24 mg / kg group when compared to control group in serum( P < 0. 05). Compared to micro NiO group, the levels of NO and iNOS in lung homogenate, and the serum levels of IL-2 and 8-OHd G increased after exposed to 0. 24 mg / kg nano NiO in rats( P < 0. 05). CONCLUSION: Nano NiO can lead to lung injury in rats which may be related with nitrative stress reaction based on pulmonary inflammation.

Drought Stress Might Induce Sexual Spatial Segregation in Dioecious Populus euphratica-Insights from Long-Term Water Use Efficiency and Growth Rates.

P. euphratica stands as the pioneering and dominant tree within desert riparian forests in arid and semi-arid regions. The aim of our work was to reveal why dioecious P. euphratica in natural desert riparian forests in the lower Tarim River exhibits sexual spatial distribution differences combined with field investigation, tree ring techniques, isotope analysis techniques, and statistical analyses. The results showed that P. euphratica was a male-biased population, with the operational sex ratio (OSR) exhibiting spatial distribution differences to variations in drought stress resulting from groundwater depth change. The highest OSR was observed under mild drought stress (groundwater depth of 6-7 m), and it was reduced under non-drought stress (groundwater depth below 6 m) or severe drought stress (groundwater depth exceeding 7 m). As drought stress escalated, the degradation and aging of the P. euphratica forest became more pronounced. Males exhibited significantly higher growth rates and WUEi than females under mild drought stress. However, under severe drought stress, males' growth rates significantly slowed down, accompanied by significantly lower WUEi than in females. This divergence determined the sexual spatial segregation of P. euphratica in the natural desert riparian forests of the lower Tarim River. Furthermore, the current ecological water conveyance project (EWCP) in the lower Tarim River was hard to fundamentally reverse the degradation and aging of the P. euphratica forest due to inadequate population regeneration. Consequently, we advocated for an optimized ecological water conveyance mode to restore, conserve, and rejuvenate natural P. euphratica forests.

An approach of multi-element fusion method for harmful algal blooms prediction.

The harmful algal blooms (HABs) are an issue of concern for water management worldwide. Effective strategies for monitoring and predicting of HAB spatio-temporal variability in waterbodies are more essential. To promote the monitoring and predicting of HABs, we proposed a multi-element fusion prediction (MEFP) method for cyanobacteria bloom. Considering the impact of surrounding factors for HAB occurrence, the proposed MEFP fuses multiple exogenous factors to enhance the prediction accuracy in different environments. Specifically, MEFP adopts a dual-sides network that parallelly captures the potential outbreak patterns on the numerous input features. The restricted Boltzmann machine is utilized to optimize the processing of parameter initialization. Subsequently, the attention mechanism is introduced in the post-network stage to establish the contextual relationship between the current and historical temporal information. The experimental results on the real-world dataset demonstrate the proposed MEFP model outperforms other benchmark methods.

The effects of ecological rehabilitation projects on the resilience of an extremely drought-prone desert riparian forest ecosystem in the Tarim River Basin, Xinjiang, China.

The Tarim River Basin in Xinjiang, China, has a typical desert riparian forest ecosystem. Analysis of the resilience of this type of ecosystem under extreme drought conditions and ecological rehabilitation projects could provide a theoretical basis for understanding ecosystem stability and resistance, and provide new ecological rehabilitation measures to improve ecosystem resilience. We employed a quantitative framework to assess net primary productivity (NPP) resilience, emphasizing four aspects of NPP dynamics: NPP, NPP stability, NPP resistance, and maximum NPP potential. We compared ecosystem resilience across four time periods: before the implementation of ecological rehabilitation projects (1990-2000), during construction and partial implementation of ecological rehabilitation projects (2001-2012), during the initial project stage of ecological rehabilitation (2013-2015), and during the late project stage of ecological rehabilitation (2016-2018). There are three main finding of this research. (1) Mean NPP was increased significantly from 2013 and was decreased from 2016, especially in the main stream of the Tarim River and in the basins of eight of its nine tributary rivers. (2) Ecosystem resilience in 2013-2018 was greater than in 1990-2012, with the greatest NPP stability, mean NPP and NPP resistance, especially in part one of the river basin (the Aksu River, the Weigan-Kuche River, the Dina River, the Kaidu-Konqi River, and the main stream of the Tarim River). Ecosystem resilience in 2001-2012 was lowest when compared to 1990-2000 and 2013-2018, with lowest mean NPP, NPP stability, NPP resistance and maximum NPP potential, particularly in part two of the river basin (the Kashigr River, the Yarkand River and the Hotan River basins). Therefore, part one was most affected by ecological restoration projects. When 2013-2018 was divided into two distinct stages, 2013-2015 and 2016-2018, resilience in the latter stage was the lowest, with lowest mean NPP, NPP resistance and maximum NPP potential, especially in the main stream of the Tarim River. This may be due to unreasonable water conveyance in 2014-2015. (3) Ecological resilience has increased significantly in 2013-2015 after the implementation of ecological water transfer projects, river regulation, and natural vegetation enclosure projects. Ecosystem resilience could continue to increase even more in the future with the continued implementation of reasonable ecological water transfer projects.

PXDN reduces autophagic flux in insulin-resistant cardiomyocytes via modulating FoxO1.

Autophagy, a well-observed intracellular lysosomal degradation process, is particularly important to the cell viability in diabetic cardiomyopathy (DCM). Peroxidasin (PXDN) is a heme-containing peroxidase that augments oxidative stress and plays an essential role in cardiovascular diseases, while whether PXDN contributes to the pathogenesis of DCM remains unknown. Here we reported the suppression of cell viability and autophagic flux, as shown by autophagosomes accumulation and increased expression level of LC3-II and p62 in cultured H9C2 and human AC16 cells that treated with 400 µM palmitate acid (PA) for 24 h. Simultaneously, PXDN protein level increased. Moreover, cell death, autophagosomes accumulation as well as increased p62 expression were suppressed by PXDN silence. In addition, knockdown of PXDN reversed PA-induced downregulated forkhead box-1 (FoxO1) and reduced FoxO1 phosphorylation, whereas did not affect AKT phosphorylation. Not consistent with the effects of si-PXDN, double-silence of PXDN and FoxO1 significantly increased cell death, suppressed autophagic flux and declined the level of FoxO1 and PXDN, while the expression of LC3-II was unchanged under PA stimulation. Furthermore, inhibition of FoxO1 in PA-untreated cells induced cell death, inhibited autophagic flux, and inhibited FoxO1 and PXDN expression. Thus, we come to conclusion that PXDN plays a key role in PA-induced cell death by impairing autophagic flux through inhibiting FoxO1, and FoxO1 may also affect the expression of PXDN. These findings may develop better understanding of potential mechanisms regarding autophagy in insulin-resistant cardiomyocytes.

Glutathione S-transferase influences the fecundity of Schistosoma japonicum.

The aim of this study was to investigate the effect of Schistosoma japonicum glutathione S-transferase (SjGST) on the developmental stages of the parasite. We found that the mRNA levels of GST were higher in schistosomula obtained from the host and the eggs than that in other developmental stages. SjGST was mainly distributed in the egg shells, teguments of the worms, and part of the parenchyma of the worms. GST knockdown with RNA interference in S. japonicum worms resulted in a silencing rate higher than 80%. The egg reduction rate (18%) and abnormal egg ratio (28%) were significantly higher (P < 0.05) in the GST-silenced group than in the negative control group. These results indicate that SjGST plays an important role in the fecundity of S. japonicum, specifically in egg formation.

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal-regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms.

Background Hydrogen peroxide (H2O2) is a critical molecular signal in the development of abdominal aortic aneurysm ( AAA ) formation. Vascular peroxidase 1 ( VPO 1) catalyzes the production of hypochlorous acid ( HOC l) from H2O2 and significantly enhances oxidative stress. The switch from a contractile phenotype to a synthetic one in vascular smooth muscle cells ( VSMC s) is driven by reactive oxygen species and is recognized as an early and important event in AAA formation. This study aims to determine if VPO 1 plays a critical role in the development of AAA by regulating VSMC phenotypic switch. Methods and Results VPO 1 is upregulated in human and elastase-induced mouse aneurysmal tissues compared with healthy control tissues. Additionally, KLF 4, a nuclear transcriptional factor, is upregulated in aneurysmatic tissues along with a concomitant downregulation of differentiated smooth muscle cell markers and an increase of synthetic phenotypic markers, indicating VSMC phenotypic switch in these diseased tissues. In cultured VSMC s from rat abdominal aorta, H2O2 treatment significantly increases VPO 1 expression and HOC l levels as well as VSMC phenotypic switch. In support of these findings, depletion of VPO 1 significantly attenuates the effects of H2O2 and HOC l treatment. Furthermore, HOC l treatment promotes VSMC phenotypic switch and ERK 1/2 phosphorylation. Pretreatment with U0126 (a specific inhibitor of ERK 1/2) significantly attenuates HOC l-induced VSMC phenotypic switch. Conclusions Our results demonstrate that VPO 1 modulates VSMC phenotypic switch through the H2O2/ VPO 1/ HOC l/ ERK 1/2 signaling pathway and plays a key role in the development of AAA . Our findings also implicate VPO 1 as a novel signaling node that mediates VSMC phenotypic switch and plays a key role in the development of AAA . Clinical Trial Registration URL : www.chictr.org.cn . Unique identifier: Chi CTR 1800016922.

[Impurity analysis and their structure determination of gatifloxacin].

AIM: To analyse the impurities of gatifloxacin. METHODS: The impurity of gatifloxacin were analysized and determinated by RP-HPLC/electrospray ionization mass spectrometry with a Zorbax SB-C18(4.6 mm x 150 mm ID, 5 microns). The mobile phase was 3% acetic acid/acetonitrile-3% acetic acid/water (15:85). The two compounds were synthesized: 1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (DMP) and 1-cyclopropyl-6-fluoro-1, 4-dihydro-8-hydro-7-(3-methy-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (DMO). Their liquid chromatogram, UV, MS were compared with those of the impurity of gatifloxacin. RESULTS: The mass of the impurity was 14 less than that of gatifloxacin. It means the impurity was CH2 less than gatifloxacin. The tR (HPLC), UV and MS of DMP were the same as those of the impurity of gatifloxacin. CONCLUSION: Based on the tR (HPLC), UV and MS, the impurity of gatifloxacin is confirmed as DMP.

[Determination of first-order structure of somatostatin by electrospray ionization mass spectrometry].

AIM: To determine the molecular weight and first-order structure of somatostatin. METHODS: The molecular weight of somatostatin was determined by electrospray ionization mass spectrometry. Somatostatin was deoxidized by 2-mercaptoethanol. A series of typical fragment ions of deoxidized product were obtained by insource collision-induced dissociation (CID). RESULTS: The m/z of quasi-molecular ion [M + H]+ of somatostatin was 1,637.8 and [M + Na]+ was 1,659.5. The m/z of double-charge ion [M + 2H]2+ was 819.5 and [M + H + Na]2+ was 830.3. It showed that the molecular weight of somatostatin was 1,636.7. The y and b series of fragment ions of deoxidized product were obtained by adjusting the fragmentor voltage. It was determined that the first-order structure of deoxidized product of somatostatin was A-G-C-K-N-F-F-W-K-T-F-T-S-C. CONCLUSION: The molecular weight and first-order structure of somatostatin were confirmed.

[Analysis of impurity in caderofloxacin].

AIM: To analyse the main impurity of caderofloxacin. METHODS: The impurity of caderofloxacin was analysed and determinated by RP-HPLC/ESI/MS with a Zorbax SB-C18 (150 mm x 4.6 mm ID, 5 microns) column. The mobile phase was acetonitrile-0.5% acetic acid solution (17:83). A compound was synthesized: 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-1, 4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid (DMCA). Its HPLC chromatogram, UV and MS spectrum were compared with those of the impurity in caderofloxacin. RESULTS: The molecular weight of the impurity was 14 less than that of caderofloxacin. It means the impurity was a CH2-group less than caderoflixacin. The tR, UV and MS of DMCA were the same as those of the impurity in caderofloxacin. CONCLUSION: Based on the tR (HPLC), UV and MS, the impurity of caderofloxacin is confirmed as DMCA.

[Detection of hepatotoxic pyrrolizidine alkaloids in Ligularia Cass. with LC/MSn].

AIM: To detect the hepatotoxic pyrrolizidine alkaloids (HPA) in the genus Ligularia Cass.. METHODS: The alkaloid extracts of Ligularia plant materials were detected and analyzed by the method of combination of TLC, and LC/MSn. RESULTS: Among 22 species of Ligularia Cass., HPA were detected in 18 species with LC/MSn, and no HPA was detected in the remaining 4 species. CONCLUSION: HPA was first detected with LC/MSn in L. tongelensis and other 15 species of Ligularia Cass.; HPA from these plants should be isolated, separated and identified and it is necessary to study the activities and toxicities of the HPA. The types and kinds of HPA from different species and sources are different, they should be detected separately.

[Study on the fingerprints of the alkaloids in Sophora flavescens].

OBJECTIVE: To establish a method for HPLC fingerprint determination of the alkaloids in S. flavescens. METHOD: RP-HPLC, linear gradient elution, LC/MS, etc. were used to determine the fingerprint and identify the main peaks in the HPLC fingerprint. RESULT: A satisfactory method for HPLC fingerprint determination of the alkaloids in S. flavescens. was established, and 5 peaks in the HPLC fingerprint were identified. CONCLUSION: The perfect fingerprint can be obtained and the method can be used for quality control of S. flavescens.

Liquid chromatographic-mass spectrometry analysis and pharmacokinetic studies of erianin for intravenous injection in dogs.

The purpose of the present study was to examine the pharmacokinetic characteristics of erianin (2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)-ethyl]-phenol, CAS 95041-90-0), a nature product extracted from Dendrobium chrysotoxum, having notable antitumour activity, after intravenous injection of erianin fat emulsion to beagle dogs. An HPLC-MS method was developed to analyze the erianin levels in dog plasma and validated in a pharmacokinetic study. Plasma profiles were obtained after intravenous injection of erianin fat emulsion at the doses 7.5, 15 and 30 mg/kg. The elimination half-life (t(1/2)) values for erianin were estimated to be 1.41+/- 0.31, 1.66 +/- 0.19, 1.60 0.28 h, while the mean area under concentration-time curve (AUC(0-infinity)) values were 1021.3 +/- 373.7, 2305.1 +/- 597.0 and 3952.1 +/- 378.2 ng x h/ml, respectively. In conclusion, the present observations indicated that erianin plasma concentrations were clearly dose-proportional for the dose range studied. There was no gender difference in pharmacokinetics for erianin in male and female dogs.