MiR-383-5p inhibits the proliferation and migration of lung adenocarcinoma cells by targeting SHMT2.

Purpose: To explore the effects of miR-383-5p and serine hydroxymethyltransferase 2 (SHMT2) on the proliferation and migration of lung adenocarcinoma cells. Methods: SHMT2 expression in lung adenocarcinoma and normal tissues was investigated using The Cancer Genome Atlas database. Immunohistochemical analysis was performed to confirm SHMT2 expression in lung adenocarcinoma and adjacent normal lung tissues. Bioinformatics analysis and luciferase reporter assays were used to analyze the relationship between miR-383-5p and SHMT2 expression. The protein expression levels of SHMT2, vimentin, N-cadherin, E-cadherin, Bcl-2, and cyclinD1 were analyzed using western blotting. The reverse transcription-quantitative polymerase chain reaction was used to detect SHMT2 knockdown efficiency, miR-383-5p overexpression, and inhibition efficiency. The proliferative ability of cells was detected using the Cell Counting Kit-8 assay. The Transwell assay was used to detect the migration ability of cells. Results: SHMT2 expression was significantly increased in patients with lung adenocarcinoma compared to that in control patients; the higher the SHMT2 expression the worse the outcomes were in patients with lung adenocarcinoma. SHMT2 knockdown inhibited the proliferation, migration, and epithelial-mesenchymal transition of lung adenocarcinoma A549 and H1299 cells. MiR-383-5p directly targeted and downregulated SHMT2 in A549 and H1299 cells. The effects of miRNA-383-5p on the proliferation and migration of these cells differed from those of SHMT2. Exogenous overexpression of SHMT2 reversed the miR-383-5p-induced proliferation and migration inhibition in A549 and H1299 cells. Conclusion: MiR-383-5p inhibits the proliferation and migration of lung adenocarcinoma cells by targeting and downregulating SHMT2.

Combination of epidrugs with immune checkpoint inhibitors in cancer immunotherapy: From theory to therapy.

Immunotherapy based on immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in multiple types of cancer. However, the resistance and relapse as associated with the extreme complexity of cancer-immunity interactions remain a major challenge to be resolved. Owing to the epigenome plasticity of cancer and immune cells, a growing body of evidence has been presented indicating that epigenetic treatments have the potential to overcome current limitations of immunotherapy, thus providing a rationalefor the combination of ICIs with epigenetic agents (epidrugs). In this review, we first make an overview about the epigenetic regulations in tumor biology and immunodevelopment. Subsequently, a diverse array of inhibitory agents under investigations targeted epigenetic modulators (Azacitidine, Decitabine, Vorinostat, Romidepsin, Belinostat, Panobinostat, Tazemetostat, Enasidenib and Ivosidenib, etc.) and immune checkpoints (Atezolizmab, Avelumab, Cemiplimab, Durvalumb, Ipilimumab, Nivolumab and Pembrolizmab, etc.) to increase anticancer responses were described and the potential mechanisms were further discussed. Finally, we summarize the findings of clinical trials and provide a perspective for future clinical studies directed at investigating the combination of epidrugs with ICIs as a treatment for cancer.

Toxicity Effects of Combined Mixtures of BDE-47 and Nickel on the Microalgae Phaeodactylum tricornutum (Bacillariophyceae).

Nickel and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) are two environmental pollutants commonly and simultaneously present in aquatic systems. Nickel and BDE-47 are individually toxic to various aquatic organisms. However, their toxicity mechanisms are species-dependent, and the toxic effects of combined mixtures of BDE-47 and nickel have not yet been investigated. The present study investigated the toxic effects of combined mixtures of BDE-47 and nickel in the diatom Phaeodactylum tricornutum. BDE-47 and nickel mixtures significantly decreased cell abundance and photosynthetic efficiency, while these cells' reactive oxygen species (ROS) production significantly increased. The EC50-72 h for BDE-47 and mixtures of BDE-47 and nickel were 16.46 ± 0.93 and 1.35 ± 0.06 mg/L, respectively. Thus, combined mixtures of the two pollutants enhance their toxic effects. Interactions between BDE-47 and nickel were evaluated, revealing synergistic interactions that contributed to toxicity in P. tricornutum. Moreover, transcriptomic analyses revealed photosynthesis, nitrogen metabolism, the biosynthesis of amino acids, the biosynthesis of secondary metabolites, oxoacid metabolism, organic acid metabolism, carboxylic acid metabolism, and oxidation-reduction processes were considerably affected by the mixtures. This study provides evidence for the mechanisms of toxicity from combined BDE-47 and nickel exposure while also improving our understanding of the ecological risks of toxic chemicals on microalgae.

Toxic effect of nickel on microalgae Phaeodactylum tricornutum (Bacillariophyceae).

Nickel acts as an essential trace nutrient or toxicant for organisms, depending on its concentration. The increased concentrations of nickel, due to anthropogenic activity, in the aquatic environment are potential threats to aquatic organisms. However, the knowledge on toxic mechanisms of nickel to microalgae remains incompletely understood. In the present study, we investigated the toxic effects of nickel in the cosmopolitan diatom Phaeodactylum tricornutum via evaluation of physiological and transcriptome responses. The results showed that the median effective concentration-72 h (EC50-72 h) and EC50-96 h of nickel was 2.48 ± 0.33 and 1.85 ± 0.17 mg/L, respectively. The P. tricornutum cell abundance and photosynthesis significantly decreased by 1 mg/L of nickel. Results from photosynthetic parameters including efficiency of the oxygen evolving complex (OEC) of photosystem II (PSII) (Fv/F0), maximum photosynthetic efficiency of PS II (Fv/Fm), electron transport rate (ETR), actual photosynthetic efficiency of PS II (Y(II)), non-photochemical quenching (NPQ), and photochemical quenching (qP) indicated that OEC of PS II might be impaired by nickel. The transcriptome data also reveal that OEC apparatus coding gene PS II oxygen-evolving enhancer protein 2 (PsbP) was regulated by nickel. Moreover, induced reactive oxygen species (ROS) production and chlorophyll a content were also detected under nickel stress. Transcriptome analysis revealed that nickel affected a variety of differentially expressed genes (DEGs) that involved in redox homeostasis, nitrogen metabolisms, fatty acids, and DNA metabolism. However, thiol-disulfide redox system might play important roles in nickel-induced oxidative stress resistance. This study improved the understanding of the toxic effect of nickel on the diatom P. tricornutum.

Great future or greedy venture: Precision medicine needs philosophy.

INTRODUCTION: Over the past decade, we have witnessed the initiation and implementation of precision medicine (PM), a discipline that promises to individualize and personalize medical management and treatment, rendering them ultimately more precise and effective. Despite of the continuing advances and numerous clinical applications, the potential of PM remains highly controversial, sparking heated debates about its future. METHOD: The present article reviews the philosophical issues and practical challenges that are critical to the feasibility and implementation of PM. OUTCOME: The explanation and argument about the relations between PM and computability, uncertainty as well as complexity, show that key foundational assumptions of PM might not be fully validated. CONCLUSION: The present analysis suggests that our current understanding of PM is probably oversimplified and too superficial. More efforts are needed to realize the hope that PM has elicited, rather than make the term just as a hype.

Physiological and biochemical responses of the freshwater green algae Closterium ehrenbergii to the common disinfectant chlorine.

Chlorine (Cl2) is widely used as a disinfectant in water treatment plants and for cleaning swimming pools; it is finally discharged into aquatic environments, possibly causing damage to the non-target organisms in the receiving water bodies. Present study evaluated the effects of the biocide Cl2 to the green alga Closterium ehrenbergii (C. ehrenbergii). Growth rate, chlorophyll a levels, carotenoids, chlorophyll autofluorescence, and antioxidant enzymes were monitored up to 72-h after Cl2 exposure. C. ehrenbergii showed dose-dependent decrease in growth rate and cell division after exposure to Cl2. By using cell counts, the median effective concentration (EC50)-72-h was calculated to be 0.071mgL(-1). Cl2 significantly decreased the pigment levels and chlorophyll autofluorescence intensity, indicating that the photosystem was damaged in C. ehrenbergii. In addition, it increased the production of reactive oxygen species (ROS) in the cells. This stressor significantly increased the activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase, and glutathione, and affected the physiology of the cells. These results indicate that Cl2 induces oxidative stress in the cellular metabolic process and leads to physiological and biochemical damages in the green algae. Cl2 discharged in industrial effluents and from water treatment plants may cause harmful effects to the C. ehrenbergii a common freshwater microalgae and other non-target organisms.

Characterization of a novel catalase-peroxidase (KATG) gene from the dinoflagellate Prorocentrum minimum.

Dinoflagellates are a group of eukaryotic microalgae that have many unusual cytological and genomic characteristics. Here, we report the detection of a novel catalase-peroxidase (KatG) gene from the dinoflagellate Prorocentrum minimum, and its transcript levels under copper sulfate (CuSO4 ) treatment. cDNA analysis yielded a 1,293 bp complete open reading frame (ORF) encoding a 431-amino acid (aa) polypeptide (46.6 kDa). The conserved dinoflagellate splice leader (DinoSL) indicates that this gene is nucleus encoded, and a signal sequence at the N-terminus of the deduced protein indicates that the KatG protein may pass across the endoplasmic reticulum or cytoplasmic membrane, but its precise subcellular location is not known. Unlike the typical KatG proteins, P. minimum KatG (PmKatG) only has one conserved domain (N-domain). Gene expression of PmKatG dramatically increased with increasing concentrations of CuSO4 , suggesting that it functions in the defense mechanisms associated with oxidative stress.

Differential transcription of heat shock protein 90 (HSP90) in the dinoflagellate Prorocentrum minimum by copper and endocrine-disrupting chemicals.

The dinoflagellate algae survive variations in water temperature as well as sudden exposures to toxic substances; heat shock proteins (HSPs) seem to function as part of their cell survival strategy. In the present study, we determined the complete open reading frame (ORF) of HSP90 gene in the dinoflagellate Prorocentrum minimum (PmHSP90), and examined the expression levels of the gene after exposure to thermal stressors, copper metal, and endocrine-disrupting chemicals, including bisphenol A (BPA) and polychlorinated biphenyl (PCB). The complete ORF of PmHSP90 was 2,130-bp long, encoding a 709-amino acid-long polypeptide (81.62 kDa), and bearing characteristics of the HSP90 family and conserved domains. Real-time (RT)-PCR analyses revealed different expression patterns after exposure to heat, metals, and chemicals. The expression of PmHSP90 was significantly upregulated by increased thermal stresses, with the highest changes of 2.4-fold and 1.9-fold occurring after 24 h at 25 °C and 30 °C, respectively. The gene expression dramatically increased (2.1 to 8.9-fold changes) with increasing concentrations of copper (one-way ANOVA, P < 0.01). Treatment with BPA or PCB, however, did not induce significant changes in PmHSP90 expression. These data suggest that the dinoflagellate HSP90 responds to thermal stressors, but may differentially respond to toxic substances such as metals and endocrine-disrupting chemicals.