BMAL1 alleviates myocardial damage in sepsis by activating SIRT1 signaling and promoting mitochondrial autophagy.

BACKGROUND: Brain and muscle arnt-like protein-1 (BMAL1) deficiency is associated with myocardial dysfunction and suppressed sirtuin 1 (SIRT1). However, whether BMAL1 promotes mitophagy via SIRT1 to alleviate myocardial injury in sepsis remains unknown. METHODS: An in vitro myocardial injury model was established using lipopolysaccharide (LPS)-treated H9C2 cells. Knockdown or overexpression of genes was performed using plasmid transfection. Gene and protein expression was assessed by qRT-PCR and Western blot, respectively. Cell proliferation was evaluated using cell counting kit-8, and cellular apoptosis and reactive oxygen species (ROS) levels were analyzed using flow cytometry. An in vivo myocardial injury model of sepsis was established by cecal ligation and puncture in rats. Myocardial function was characterized by analyzing the damage-associated proteins, inflammatory factors, ejection fraction, and fraction shortening. RESULTS: sgBMAL1 significantly decreased BMAL1 levels and remarkably increased the sensitivity of H9C2 cells to LPS stimulation, consequently enhancing LPS-induced apoptosis, inflammation, and ROS levels. These effects were further attenuated by BMAL1 overexpression. BMAL1 knockdown inhibited the expression of SIRT1 and mitophagy-associated proteins. SIRT1 overexpression reversed the enhancement of shBMAL1 on cell proliferation and inflammation. In the rat model of sepsis, BMAL1 overexpression decreased the myocardial injury-associated proteins to recover the myocardial function and suppressed inflammatory activities by promoting mitophagy via SIRT1. CONCLUSION: BMAL1 enhances mitophagy dependent on SIRT1, thereby alleviating myocardial injury in sepsis.

IL-17A inhibits the degradation of RANKL in osteoblasts by inhibiting BCL2-Beclin1-autophagy signaling.

The inflammatory cytokine IL-17A is known to have the capacity to promote osteoclastogenesis, thereby enhancing bone loss. Moreover, IL-17A can promote the expression of RANKL in osteoblasts, contributing to its pro-osteoclastogenic effect. IL-17A is an autophagy regulator, which is also responsible for its regulation on RANKL expression. However, the specific role of autophagy in IL-17A-regulated RANKL expression and the underlying mechanism of IL-17A-regulated osteoblast autophagy remain unclear. IL-17A is known to inhibit autophagy by preventing BCL2 degradation. This study aimed to explore the significance of BCL2-dependent autophagy in IL-17A-regulated RANKL expression. Our results showed that IL-17A at 50 ng/mL could inhibit autophagic activity and promote RANKL protein expression in MC3T3-E1 osteoblast line. Moreover, the corresponding concentration of IL-17A could enhance BCL2 protein expression and the protein interaction between BCL2 and Beclin1 in MC3T3-E1 cells. However, the protein expression of RANKL and BCL2 promoted by 50 ng/mL of IL-17A was blocked by autophagy activation with Beclin1 pharmacological upregulation. Furthermore, RANKL protein expression promoted by 50 ng/mL of IL-17A was also reversed by autophagy activation with BCL2 knockdown. Importantly, the supernatant from osteoblasts treated with 50 ng/mL of IL-17A made osteoclast precursors (OCPs) form larger osteoclasts, which was reversed by BCL2 knockdown in osteoblasts. In conclusion, high levels of IL-17A prevent the degradation of RANKL by inhibiting BCL2-Beclin1-autophagy activation signal transduction in osteoblasts, thereby indirectly promoting osteoclastogenesis.

Transcriptomic analysis of the effect of deferoxamine exposure on the growth, photosynthetic activity and iron transfer of Microcystis aeruginosa.

Deferoxamine (DFB) is a trihydroxamic acid siderophore that chelates with iron (Fe) to form iron-siderophore complexes. The existence of siderophores in nature changes the form of iron and affects the absorption and utilization of iron by organisms. However, the relationship between siderophores and the growth of Cyanobacteria is largely unknown. In this study, the cellular and transcriptomic responses to the addition of DFB were investigated. A high concentration of DFB (12 mg/L) significantly inhibited the growth of Cyanobacteria cells, reduced photosynthetic activity, and induced the production of peroxidase, with the highest inhibition rate of algal growth of 74.82%. These indexes were also affected for the low (3 mg/L) and medium concentration (6 mg/L) groups, but this difference is closely related to the growth stage of Cyanobacteria cells. This may be due to competition between the cell-associated iron-binding part/system and the extracellular Fe (Ⅲ)-DFB ligand. Transcriptome results showed that most of the genes involved in iron uptake and transport were down-regulated, and only the fur gene encoding the iron uptake regulator protein was significantly up-regulated. Most genes related to photosynthesis, glycolysis, and fatty acid metabolism were also down-regulated, while the obvious up-regulation of a few genes may be a complex regulation in response to the down-regulation of most genes. These findings will provide important insights into the effects of siderophores on iron bioavailability in algae.

Preliminary results of randomized phase II study of etoposide plus lobaplatin or etoposide plus cisplatin with concurrent thoracic radiotherapy in the treatment of limited-stage small cell lung cancer.

The purpose is to compare the clinical efficacy and toxicity of etoposide plus lobaplatin (EL) or etoposide plus cisplatin (EP) with concurrent thoracic radiotherapy during the treatment of limited-stage small cell lung cancer (LS-SCLC). Forty-two patients with LS-SCLC were randomly divided into EL ( n = 19) or EP ( n = 23) regimens combined with thoracic intensity-modulated radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The 1-, 2-, and 3-year PFS rates in the EL and EP cohorts were 50.8, 38.1, and 12.7%; and 56.5, 43.5, and 29.0%, respectively ( P = 0.527), whereas the 1-, 2-, and 3-year overall survival (OS) rates were 72.2, 52.5, and 43.8%; and 73.9, 48.4, and 48.4%, respectively ( P = 0.923). The hematological toxicities were similar in two cohorts. However, gastrointestinal reactions were more severe in the EP group. The incidence of nausea and vomiting in EL and EP cohorts were 31.6% vs. 73.9% ( P = 0.006) and 20.1% vs. 60.9% ( P = 0.009), respectively. The two cohorts did not show ≥grade 4 radiation esophagitis and ≥grade 3 radiation pneumonitis. The incidence of acute radiation esophagitis in EL group was lower ( P = 0.038), both groups showed a similar incidence of radiation pneumonitis ( P = 1.000). EL or EP chemotherapy with concurrent thoracic radiotherapy showed similar PFS and OS. The EL group showed milder gastrointestinal toxicity and radiation esophagitis. Radiation pneumonitis and hematological toxicity were similar in the two regimens, which can be tolerated by patients.

Investigation of the conversion mechanism of endogenous semicarbazide in shrimp on the amino acid level.

Semicarbazide (SEM), the metabolite of antibiotic nitrofurazone, is often used as the biomarker to determine the use of nitrofurazone. Frequent false-positive events of SEM have brought great trouble to the aquatic industry in international trade. In this paper, the situation of endogenous SEM in aquatic products was investigated, and the possible mechanism of amino acid conversion into SEM was studied by establishing a simulated oxidation system and a urea system. The results revealed the presence of endogenous SEM in the muscle tissue of shrimps, and the content of SEM ranged from 0.56 to 5.28 ng/g, which presented as Macrobrachium nipponense>Macrobrachium rosenbergii>Procambarus clarkii. The increase in SEM production of control lysine under natural oxidation conditions suggests that oxidation has an effect on the conversion of SEM. Under the action of the simulated oxidation system, the SEM of Arginine, Lysine, Citrulline and Glutamine among the 21 amino acids were increased, and the polymer azine was formed. In combination with the structure of four amino acids, it was presumed that the group of amide is a key intermediate structure for the formation of endogenous SEM. In addition, under the urea system, the content of SEM produced by amino acids increased after the addition of urea, and the concentration of urea had a significant correlation with the content of SEM. Taken together, the production of endogenous SEM in shrimps is related to amino acids and urea, and the urea cycle and other substances containing amide structures should also be considered in future explorations.

RNA sequencing-based identification of microRNAs in the antler cartilage of Gansu red deer (Cervus elaphus kansuensis).

Background: The velvet antler is a complex mammalian bone organ with unique biological characteristics, such as regeneration. The rapid growth stage (RGS) is a special period in the regeneration process of velvet antler. Methods: To elucidate the functions of microRNAs (miRNAs) at the RGS of antler development in Gansu red deer (Cervus elaphus kansuensis), we used RNA sequencing (RNA-seq) to analyze miRNA expression profiles in cartilage tissues of deer antler tips at three different growth stages. Results: The RNA-seq results revealed 1,073 known and 204 novel miRNAs, including 1,207, 1,242, and 1,204 from 30-, 60-, and 90-d antler cartilage tissues, respectively. To identify key miRNAs controlling rapid antler growth, we predicted target genes of screened 25 differentially expressed miRNAs (DEMs) and specifically expressed miRNAs (SEMs) in 60 d and annotated their functions. The KEGG results revealed that target genes of 25 DEMs and 30 SEMs were highly classified in the "Metabolic pathways", "Pathways in cancer", "Proteoglycans in cancer" and "PI3K-Akt signaling pathway". In addition, a novel miRNA (CM008039.1_315920), highly enriched in "NF-kappa B signaling pathway", may need further study. Conclusions: The miRNAs identified in our study are potentially important in rapid antler growth. Our findings provide new insights to help elucidate the miRNA-mediated regulatory mechanisms involved during velvet antler development in C. elaphus kansuensis.

[Effects of silence information regulator 7 on proliferation and apoptosis of mouse renal podocytes under high glucose environment].

Objective: To investigate the effects and its mechanisms of silence information regulator 7(SIRT7)on mouse renal podocytes proliferation and apoptosis under high glucose environment. Methods: Mouse renal podocytes cultured with high glucose and treated with different methods were divided into the following groups:control group(Control),high glucose group(HG),high glucose+transfecting with SIRT7 overexpression vetor(pcDNA3.1-SIRT7) group(SIRT7 OE+HG),high glucose+transfecting with the negative control vetor(pcDNA3.1)group(SIRT7 OE-NC+HG),high glucose+transfecting with small interfering RNA-SIRT7 (siRNA-SIRT7) group (siRNA-SIRT7+HG), high glucose+ transfecting with siRNA-SIRT7 control group (siRNA-SIRT7-NC+ HG). Viability of proliferation was examined by CCK-8 method.Rate of apoptosis was detected by flow cytometry. The level of SIRT7 mRNA expression was measured by qRT-PCR. Western blot was performed to detect the protein expression of Nephrin and key factors of Wnt/ß-catenin signaling pathway. Results: The CCK-8 result showed that,compared with control group, the proliferative activity of mouse renal podocytes in HG group was decreased (P＜0.05). After transfected with SIRT7 overexpression vetor or small interfering RNA-SIRT7,compared to HG group,the cell proliferation activity was further decreased in siRNA-SIRT7 group(P＜0.05),but it was enhanced in SIRT7 OE+HG group (P＜0.05). The results of flow cytometry showed that compared with the control group, the apoptosis rate of cells in the HG group was increased (P＜0.05). Compared with the HG group, the apoptosis rate of cells in the siRNA SIRT7+HG group was increased significantly(P＜0.05), while that in the SIRT7 OE+HG group was decreased (P＜0.05). Compared with control group,the expressions of Nephrin, Wnt5a and ß-catenin were inhibited in HG group (P＜0.05). compared to HG group,siRNA-SIRT7 could down-regulate the expression levels of Nephrin, Wnt5a and ß-catenin in siRNA-SIRT7 group (P＜0.05), SIRT7 overexpression could up-regulate the expression levels of Nephrin, Wnt5a and ß-catenin in SIRT7 OE+HG group (P＜0.05). Conclusion: The findings suggest that high glucose environment is an important factor to inhibit the proliferation and induce apoptosis of mouse renal podocytes.Overexpression of SIRT7 can reverse the effects by activating Wnt/ß-catenin signaling pathway and up-regulating ß-catenin expression.

Reasonable Timing of Radiotherapy for Stage IV Non-Small-Cell Lung Cancer During Targeted Therapy Based on Tumour Volume Change.

PURPOSE: The aim of this study was to investigate the reasonable timing of radiotherapy for stage IV non-small-cell lung cancer (NSCLC) with EGFR-positive mutations during targeted therapy based on tumour volume change (TVC). PATIENTS AND METHODS: Simulation Computed Tomography Scan (SCTS) measurements were taken to test TVC in patients with stage IV NSCLC during targeted therapy at intervals of 10 days. The SCTS measurement was terminated when the tumour volume shrinkage rate in the latter simulation compared with the previous simulation was ≤5% or when the time after treatment was 90 days. Then, primary tumour radiotherapy was performed. Related parameters of the radiotherapy plan were compared between the implementation and simulation plans. RESULTS: Twenty-seven patients were enrolled in the analysis. After treatment, shrinkage of the primary tumour was observed in all patients, but the rate and speed were inconsistent. The average tumour volume decreased obviously within 40 days and was significantly different every 10 days (P ≤ 0.001). The average volume decreased slowly and tended to be stable (P>0.05) after 40 days. After the termination of SCTSs, 21 patients accepted primary tumour radiotherapy. No patients experienced grade 3+ acute radiation toxicity. The implementation radiotherapy plan was significantly better than that before treatment (all P<0.05) but not better than that on the 40th day after treatment (all P>0.05). CONCLUSIONS: To obtain a high radiation dose and control radiation toxicity, the 40th day after targeted therapy may be a reasonable time to start radiotherapy for stage IV NSCLC with EGFR-positive mutations. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/ct2/show/NCT03258671, identifier, NCT03258671.

Effects of music therapy on cancer-related fatigue, anxiety, and depression in patients with digestive tumors: A protocol for systematic review and meta-analysis.

BACKGROUND: Digestive tumor is one of the most common cancers, its symptoms and treatment will bring patients with anxiety, depression and other negative emotions, and cause cancer-related fatigue. As a new complementary replacement therapy, music therapy can greatly reduce cancer-related fatigue, anxiety and depression, and achieve good clinical results, but there is a lack of evidence-based medicine. The purpose of this study is to evaluate the effect of music therapy on cancer-related fatigue, anxiety, and depression in patients with digestive tumors by meta-analysis. METHOD: Computer search of Chinese and English databases: Wanfang, VP Information Chinese Journal Service Platform, China National Knowledge Infrastructure, Chinese BioMedicine Literature Database and pubmed, embase, cochrane, web of science. A comprehensive collection of relevant studies on the effects of music therapy on digestive tract cancer-related fatigue, anxiety and depression, the retrieval time is from the date of establishment to March 2021. According to the inclusion and exclusion criteria, the literature is selected, the quality of the literature is evaluated and the data are extracted. The data are analyzed by meta-analysis. RESULT: The purpose of this study is to evaluate the effect of music therapy on digestive tract cancer-related fatigue, anxiety, and depression by European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire, Hamilton Depression Scale, and Hamilton Anxiety Scale . CONCLUSION: This study will provide reliable evidence-based evidence for the clinical application of music therapy in the treatment of digestive tract cancer-related fatigue and anxiety and depression. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/UR4GV.

Prognostic Model to Predict Overall Survival for Metastatic Non-Small Cell Lung Cancer Patients Treated With Chemotherapy Combined With Concurrent Radiation Therapy to the Primary Tumor: Analysis From Two Prospective Studies.

PURPOSE: The role of radiotherapy, in addition to chemotherapy, has not been thoroughly determined in metastatic non-small cell lung cancer (NSCLC). The purpose of the study was to investigate the prognostic factors and to establish a model for the prediction of overall survival (OS) in metastatic NSCLC patients who received chemotherapy combined with the radiation therapy to the primary tumor. METHODS: The study retrospectively reviewed 243 patients with metastatic NSCLC in two prospective studies. A prognostic model was established based on the results of the Cox regression analysis. RESULTS: Multivariate analysis showed that being male, Karnofsky Performance Status score < 80, the number of chemotherapy cycles <4, hemoglobin level ≤120 g/L, the count of neutrophils greater than 5.8 ×109/L, and the count of platelets greater than 220 ×109/L independently predicted worse OS. According to the number of risk factors, patients were further divided into one of three risk groups: those having ≤ 2 risk factors were scored as the low-risk group, those having 3 risk factors were scored as the moderate-risk group, and those having ≥ 4 risk factors were scored as the high-risk group. In the low-risk group, 1-year OS is 67.7%, 2-year OS is 32.1%, and 3-year OS is 19.3%; in the moderate-risk group, 1-year OS is 59.6%, 2-year OS is 18.0%, and 3-year OS is 7.9%; the corresponding OS rates for the high-risk group were 26.2%, 7.9%, and 0% (P<0.001) respectively. CONCLUSION: Metastatic NSCLC patients treated with chemotherapy in combination with thoracic radiation may be classified as low-risk, moderate-risk, or high-risk group using six independent prognostic factors. This prognostic model may help design the study and develop the plans of individualized treatment.

Light Pollution Changes the Toxicological Effects of Cadmium on Microbial Community Structure and Function Associated with Leaf Litter Decomposition.

Artificial light at night (ALAN/A) can not only alter the behavior and communication of biological organisms, it can also interact with other stressors. Despite its widespread use and the numerous potential ecological effects, little is known about the impact of ALAN on plant litter decomposition under cadmium (Cd) pollution in aquatic ecosystems. In an indoor microcosm experiment, we tested single and combined effects of ALAN and Cd on the activities and community structure of fungi associated with plant litter. The results showed that ALAN and/or Cd can change both water and leaf litter characteristics. ALAN exposure not only altered fungal community structure and their correlations, but also increased the activities of alkaline phosphatase, ß-glucosidase, and cellobiohydrolase. The leaf litter decomposition rate was 71% higher in the A-Cd treatment than that in the N-Cd treatment, indicating that the presence of ALAN weakened the negative impact of Cd on leaf litter decomposition. These results suggested that ALAN exposure mitigated the negative effect of Cd on leaf litter decomposition, contributing to the duel effect of ALAN on leaf litter decomposition. Overall, the results expand our understanding of ALAN on the environment and highlight the contribution of ALAN to Cd toxicity in aquatic ecosystems.

Artificial light at night alter the impact of arsenic on microbial decomposers and leaf litter decomposition in streams.

Artificial light at night (ALAN, also known as light pollution) has been proved to be a contributor to environmental change and a biodiversity threat worldwide, yet little is known about its potential interaction with different metal pollutants, such as arsenic (As), one of the largest threats to aquatic ecosystems. To narrow this gap, an indoor microcosm study was performed using an ALAN simulation device to examine whether ALAN exposure altered the impact of arsenic on plant litter decomposition and its associated fungi. Results revealed that microbial decomposers involved in the conversion of As(III) to As(V), and ALAN exposure enhanced this effect; ALAN or arsenic only exposure altered fungal community composition and the correlations between fungi species, as well as stimulated or inhibited litter decomposition, respectively. The negative effects of arsenic on the decomposition of Pterocarya stenoptera leaf litter was alleviated by ALAN resulting in the enhanced photodegradation of leaf litter lignin and microbiological oxidation of As(III) to As(V), the increased microbial biomass and CBH activity, as well as the enhanced correlations between CBH and litter decomposition rate. Overall, results expand our understanding of ALAN on environment and highlight the contribution of ALAN to the toxicity of arsenic in aquatic ecosystems.

Artificial Light at Night Alleviates the Negative Effect of Pb on Freshwater Ecosystems.

Artificial light at night (ALAN) is an increasing phenomenon worldwide that can cause a series of biological and ecological effects, yet little is known about its potential interaction with other stressors in aquatic ecosystems. Here, we tested whether the impact of lead (Pb) on litter decomposition was altered by ALAN exposure using an indoor microcosm experiment. The results showed that ALAN exposure alone significantly increased leaf litter decomposition, decreased the lignin content of leaf litter, and altered fungal community composition and structure. The decomposition rate was 51% higher in Pb with ALAN exposure treatments than in Pb without ALAN treatments, resulting in increased microbial biomass, ß-glucosidase (ß-G) activity, and the enhanced correlation between ß-G and litter decomposition rate. These results indicate that the negative effect of Pb on leaf litter decomposition in aquatic ecosystems may be alleviated by ALAN. In addition, ALAN exposure also alters the correlation among fungi associated with leaf litter decomposition. In summary, this study expands our understanding of Pb toxicity on litter decomposition in freshwater ecosystems and highlights the importance of considering ALAN when assessing environmental metal pollutions.

[Expression of monocyte chemotactic protein-1 and its receptor in sudden coronary death].

OBJECTIVE: To investigate the expression of monocyte chemotactic protein-1 (MCP-1) and its receptor CC chemokine receptor-2 (CCR-2) in coronary atherosclerosis plaques between sidden coronary death (SCD) and non-SCD. Methods The expression levels of MCP-1 and CCR-2 in SCD group, coronary atherosclerosis group (non-SCD), control group (normal coronary artery) were detected by immunohistochemistry. RESULTS: Positive rates of MCP-1 among the three groups were 78%, 47%, and 0%, respectively, with significant expressing differences between each two groups (P<0.05). Positive rates of CCR-2 among three groups were 72%, 47%, and 0%, respectively, with significant expressing differences between the SCD group and coronary atherosclerosis group as well as between the SCD group and control group (P<0.05), but with no significant expressing difference between coronary atherosclerosis group and control group (P>0.05). CONCLUSION: Overexpression of MCP-1 and CCR-2 in coronary atherosclerotic plaques is closely correlated with SCD.