Integrated physio-biochemical and transcriptomic analysis reveals the joint toxicity mechanisms of two typical antidepressants fluoxetine and sertraline on Microcystis aeruginosa.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are of increasing concern worldwide due to their ubiquitous occurrence and detrimental effects on aquatic organisms. However, little is known regarding their effects on the dominant bloom-forming cyanobacterium, Microcystis aeruginosa. Here, we investigated the individual and joint effects of two typical SSRIs fluoxetine (FLX) and sertraline (SER) on M. aeruginosa at physio-biochemical and molecular levels. Results showed that FLX and SER had strong growth inhibitory effects on M. aeruginosa with the 96-h median effect concentrations (EC50s) of 362 and 225 µg/L, respectively. Besides, the mixtures showed an additive effect on microalgal growth. Meanwhile, both individual SSRIs and their mixtures can inhibit photosynthetic pigment synthesis, cause oxidative damage, destroy cell membrane, and promote microcystin-leucine-arginine (MC-LR) synthesis and release. Moreover, the mixtures enhanced the damage to photosynthesis, antioxidant system, and cell membrane and facilitated MC-LR synthesis and release compared to individuals. Furthermore, transcriptomic analysis revealed that the dysregulation of the key genes related to transport, photosystem, protein synthesis, and non-ribosomal peptide structures was the fundamental molecular mechanism underlying the physio-biochemical responses of M. aeruginosa. These findings provide a better understanding of the toxicity mechanisms of SSRIs to microalgae and their risks to aquatic ecosystems.

Persistent immune injury induced by short-term decabromodiphenyl ether (BDE-209) exposure to female middle-aged Balb/c mice.

Decabromodiphenyl ether (BDE-209), widely used in various industries for its excellent flame-retardant performance, could be enriched in humans and is closely associated with immune impairment. In addition, immune system is gradually declined and becoming more sensitive to environmental pollutants in the ageing process. Therefore, the immunotoxicity of BDE-209 (4, 40, and 400 mg/kg/day) to middle-aged mice and its recovery and susceptibility was first to be comprehensively investigated in this study. The results showed that BDE-209 exposure could lead to oxidative injury to immune organs (spleen, thymus, and liver), impair humoral (immunoglobulins), cellular (lymphopoiesis), and non-specific immunity, and disturb the expressions of the genes related to Th1/Th2 balance (T helper cells) in the middle-aged mice. In addition, Integrated Biomarker Response (IBR) indicated that BDE-209-induced immune impairment was challenging to self-regulated, and even exacerbated after 21 days of recovery and oxidative injury in immune organs could be the main reason. Furthermore, factorial analysis showed that middle-aged mice exposed to BDE-209 suffered from greater immune impairment than adult mice, and the immune impairment in aged mice is more difficult to be self-repaired than that in adult mice. It can be seen that the aged tend to suffer from BDE-209-induced persistent immune impairment and health threats.

Metabolic Intervention Liposome Boosted Lung Cancer Radio-Immunotherapy via Hypoxia Amelioration and PD-L1 Restraint.

At present, radiotherapy (RT) still acquires limited success in clinical due to the lessened DNA damage under hypoxia and acquired immune tolerance owing to the amplified programmed death ligand-1 (PD-L1) expression. Incredibly, intracellular PD-L1 expression depression is proven to better sensitize RT by inhibiting DNA damage repair. However, the disability of the clinically used antibodies in disrupting the extracellular PD-L1function still limits the effectiveness of radio-immunotherapy. Therefore, better PD-L1 regulation strategies are still urgently needed to better sensitize radio-immunotherapy. Hence, for this purpose, TPP-LND is synthesized by linking mitochondrial-targeted triphenylphosphine cations (TPP+ ) to the antineoplastic agent lonidamine (LND), which significantly reduces the dose needed for LND to induce effective oxidative phosphorylation inhibition (2 vs 300 µM). Then, TPP-LND is wrapped with liposomes to form TPP-LND@Lip nanoparticles. By doing this, TPP-LND@Lip nanoparticles can sensitize RT by reversing the hypoxic microenvironment of tumors to generate more DNA damage and reducing the expression of PD-L1 via enhancing the adenosine 5'-monophosphate-activated protein kinase activation. As expected, these well-designed economical TPP-LND@Lip nanoparticles are more effective than conventional anti-PD-L1 antibodies to some extent.

Molecular insights of 2,6-dichlorobenzoquinone-induced cytotoxicity in zebrafish embryo: Activation of ROS-mediated cell cycle arrest and apoptosis.

2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), as an emerging disinfection by-product, has been frequently detected in waters, posing potential health risk on public health. Although some studies have pointed out that 2,6-DCBQ exposure can induce cytotoxicity, limited information is available for underlying mechanism for 2,6-DCBQ-induced cytotoxicity. To explore this mechanism, we assessed the levels of reactive oxygen species (ROS), acridine orange (AO) staining, and the mRNA transcriptions of genes (Chk2, Cdk2, Ccna, Ccnb and Ccne) involved in cell-cycle and genes (p53, bax, bcl-2 and caspase 3) involved in apoptosis in zebrafish embryo, after exposed to different concentrations (10, 30, 60, 90 and 120 µg/L) of 2,6-DCBQ for 72 h. Our results indicated that 2,6-DCBQ exposure induced ROS generation and cell apoptosis, and disturbed the mRNA transcription of genes related to cell cycle and apoptosis in zebrafish embryo. Moreover, we also found that 30 ~ 60 µg/L 2,6-DCBQ is the important transition from cell-cycle arrest to cell apoptosis. These results provided novel insight into 2,6-DCBQ-induced cytotoxicity.

Recent research on the mechanism of mesenchymal stem cells in the treatment of bronchopulmonary dysplasia. / 间å è´¨å¹²ç»†èƒžæ²»ç–—æ”¯æ°”ç®¡è‚ºå‘è‚²ä¸è‰¯ä½œç”¨æœºåˆ¶çš„ç ”ç©¶è¿›å±•.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease due to impaired pulmonary development and is one of the main causes of respiratory failure in preterm infants. Preterm infants with BPD have significantly higher complication and mortality rates than those without BPD. At present, comprehensive management is the main intervention method for BPD, including reasonable respiratory and circulatory support, appropriate enteral nutrition and parenteral nutrition, application of caffeine/glucocorticoids/surfactants, and out-of-hospital management after discharge. The continuous advances in stem cell medicine in recent years provide new ideas for the treatment of BPD. Various pre-clinical trials have confirmed that stem cell therapy can effectively prevent lung injury and promote lung growth and damage repair. This article performs a comprehensive analysis of the mechanism of mesenchymal stem cells in the treatment of BPD, so as to provide a basis for clinical applications.

Preparation and Characterization of Paraffin/Mesoporous Silica Shape-Stabilized Phase Change Materials for Building Thermal Insulation.

The use of phase change materials (PCMs) is an attractive method for energy storage and utilization in building envelopes. Here, shape-stabilized phase change materials (SS-PCMs) were prepared via direct adsorption using mesoporous silica (MS) with different pore diameters as the support matrix. The leakage properties, microstructure, chemical structure, thermophysical properties, activation energy, thermal stability and thermal storage-release characteristics of paraffin and SS-PCMs were investigated. The results show that the maximum mass proportion of paraffin in SS-PCMs is 70% when the average pore diameter of mesoporous silica is 15 nm, and the phase change temperature and latent heat of the corresponding SS-PCM are 23.6 °C and 135.4 kJ/kg, respectively. No chemical reaction occurs between mesoporous silica and paraffin and the SS-PCMs exhibit high thermal stability. The high activation energy of the paraffin (70%)/MS1 SS-PCM verifies that the shape and thermal properties can be maintained stably during phase change conversions. The time required for SS-PCMs to complete the thermal storage and release process is reduced by up to 34.0% compared with that for pure paraffin, showing a decline in the thermal conductivity of SS-PCMs after the addition of mesoporous silica. Hence, the prepared paraffin/MS SS-PCMs, in particular paraffin (70%)/MS1 SS-PCM, can be used for storing thermal energy and regulating indoor temperature in buildings.

Fast identification of the geographical origin of Gastrodia elata using excitation-emission matrix fluorescence and chemometric methods.

Geographical origin is an important factor affecting the quality of traditional Chinese medicine. In this paper, the identification of geographical origin of Gastrodia elata was performed by using excitation-emission matrix fluorescence and chemometric methods. Firstly, excitation-emission matrix (EEM) fluorescence spectra of Gastrodia elata samples from different geographical origins were obtained. And then three chemometric methods, including multilinear partial least squares discriminant analysis (N-PLS-DA), unfold partial least squares discriminant analysis (U-PLS-DA), and k-nearest neighbor (kNN) method, were applied to build discriminant models. Finally, 45 Gastrodia elata samples could be differentiated from each other by these classification models according to their geographical origins. The results showed that all models obtained good classification results. Compared with the N-PLS-DA and U-PLS-DA, kNN got more accurate and reliable classification results and could identify Gastrodia elata samples from different geographical origins with 100% accuracy on the training and test set. Therefore, the proposed method was available for easily and quickly distinguishing the geographical origin of Gastrodia elata, which can be considered as a promising alternative method for determining the geographic origin of other traditional Chinese medicines.

Long non-coding RNA Hsp4 alleviates lipopolysaccharide-induced apoptosis of lung epithelial cells via miRNA-466m-3p/DNAjb6 axis.

Acute lung injury (ALI), as a life-threatening syndrome, is mainly characterized with diffuse alveolar injury, excessive pulmonary inflammation, edema and apoptosis of lung epithelial cells. This study investigated the effects of LncRNA Hsp4 (Hsp4, ENSMUST00000175718) on lipopolysaccharide (LPS)-induced apoptosis of MLE-12 cells. In our research, we found that LPS treatment remarkably induced apoptosis of MLE-12 cells and decreased the expression of Hsp4. Overexpression of Hsp4 significantly reversed LPS-induced cell apoptosis through inhibiting mTOR signaling, while suppression of Hsp4 presented opposite effects. Further results showed that Hsp4 positively regulated the expression of miR-466m-3p. Knockdown of miR-466m-3p reversed LPS-induced cell apoptosis via increasing the levels of DNAjb6 which was confirmed to be the target gene of miR-466m-3p. This finding will be helpful for further understanding the critical roles of Hsp4 in ALI and may provide potential targets for ALI diagnosis and treatment.

Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity.

The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.

Functional characterization of a rice de novo DNA methyltransferase, OsDRM2, expressed in Escherichia coli and yeast.

DNA methylation of cytosine nucleotides is an important epigenetic modification that occurs in most eukaryotic organisms and is established and maintained by various DNA methyltransferases together with their co-factors. There are two major categories of DNA methyltransferases: de novo and maintenance. Here, we report the isolation and functional characterization of a de novo methyltransferase, named OsDRM2, from rice (Oryza sativa L.). The full-length coding region of OsDRM2 was cloned and transformed into Escherichia coli and Saccharomyces cerevisiae. Both of these organisms expressed the OsDRM2 protein, which exhibited stochastic de novo methylation activity in vitro at CG, CHG, and CHH di- and tri-nucleotide patterns. Two lines of evidence demonstrated the de novo activity of OsDRM2: (1) a 5'-CCGG-3' containing DNA fragment that had been pre-treated with OsDRM2 protein expressed in E. coli was protected from digestion by the CG-methylation-sensitive isoschizomer HpaII; (2) methylation-sensitive amplified polymorphism (MSAP) analysis of S. cerevisiae genomic DNA from transformants that had been introduced with OsDRM2 revealed CG and CHG methylation levels of 3.92-9.12%, and 2.88-6.93%, respectively, whereas the mock control S. cerevisiae DNA did not exhibit cytosine methylation. These results were further supported by bisulfite sequencing of the 18S rRNA and EAF5 genes of the transformed S. cerevisiae, which exhibited different DNA methylation patterns, which were observed in the genomic DNA. Our findings establish that OsDRM2 is an active de novo DNA methyltransferase gene with conserved activity in both prokaryotic and eukaryotic non-host species.

[Direct determination of isocarbophos by using oil-soluble CdSe quantum dots as fluorescence probe].

A simple, rapid and direct approach to isocarbophos determination was developed based on the fluorescence quenching of oil-soluble CdSe quantum dots by isocarbophos. Under the optimized conditions, the linear range of oil-soluble CdSe QDs fluorescence intensity versus the concentration of isocarbophos was 2.30 x 10(-1) - 1.09 x 10(-5) mol x L(-1), with a correlation coefficient of 0.999 9 and a limit of detection of 1.1 x 10(-7) mol x L(-1). The proposed method has been applied to the determination of isocarbophos in rice and wheat flour with standard recoveries of 93.3%-105.0%. The fluorescence quenching mechanism was further investigated by using UV-Vis absorption spectra and time-resolved fluorescence spectrum. The results indicated that the fluorescence quenching of oil-soluble CdSe QDs by isocarbophos was caused by the change of the surface state which resulted in the enhancement of the surface defect and the occurrence of the non-radiational recombination.

Expectant management of heterotopic cesarean scar pregnancy.

BACKGROUND: Heterotopic cesarean scar pregnancy (HCSP) is a very rare but life-threatening entity and there is no optimal management strategy. Here we report a successfully managed case of HCSP with expectant treatment in a tertiary referral hospital. METHODS: A woman with HCSP after in vitro fertilization-embryo transfer opted for expectant treatment after five days of mild bleeding and ultrasound demonstrated cardiac activity disappearance of the scar pregnancy at 8(+4) weeks of gestation. RESULTS: The patient had mild to moderate bleeding during close monitoring. Three days later, speculum examination revealed the gestational mass was partly protruding at the os of the cervix and it was removed with forceps without massive hemorrhage. A healthy male baby was delivered by cesarean section at gestational age of 36(+4) weeks. CONCLUSIONS: The expectant method might be an alternative option for a HCSP with loss of cardiac activity of the scar pregnancy, when applied under supportive management and with available emergency surgery facilities.

Downregulative effects of nitric oxide on oocyte fertilization and embryo development: possible roles of nitric oxide in the pathogenesis of endometriosis-associated infertility.

AIMS: To investigate the effects of elevated nitric oxide (NO) levels in peritoneal fluids (PF) on oocyte fertilization and pre-implantation embryo development, and the relation of those effects to endometriosis-associated infertility. METHODS: PF from women undergoing laparoscopy for infertility of minor endometriosis, tubal blockage and operation for tubal ligation was aspired at the pouch of the cul-de-sac during surgery. Oocytes and embryos of adult ICR mice were cultured in vitro with or without endometriotic PF. The fertilization rate of oocyte and the cleavage rate of 2-cell embryos were examined. Also, the clinical indexes of IVF-ET of women with minor endometriosis and tubal infertility were analyzed. RESULTS: Oocyte fertilization rate of endometriotic women with IVF-ET treatment was significantly lower than that of tubal block women. The dose-related adverse effects of endometriotic PF and SNP (NO donor) in culture medium on oocyte fertilization and embryos development were confirmed. CONCLUSION: Increased NO levels in PF play an important role in mediating the effects of endometriotic PF on oocyte fertilization and embryo development. IVF might serve as an alternative treatment for endometriosis-associated infertility.