Mitophagy Regulates the Circadian Rhythms by Degrading NR1D1 in Simulated Microgravity and Isolation Environments.

Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats' SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption.

IGF2BP2-Shox2 axis regulates hippocampal-neuronal senescence to alleviate microgravity-induced recognition disturbance.

During space travel, microgravity leads to disturbances in cognitive function, while the underlying mechanism is still unclear. Simulated microgravity mice showed neuronal age-like changes in the hippocampus of our study. In the context of microgravity, we discovered m6A modification reshapes in the hippocampal region. When paired with RNA-seq and MeRIP-seq, Shox2 was found to be a powerful regulator in hippocampal neuron that respondes to microgravity. Decreased expression of senescence-associated secretory phenotype factors and improved genes related to synapses led to the restoration of memory function in the hippocampus upon increased expression of Shox2. Moreover, we discovered that IGF2BP2 was required for the m6A modification of the Shox2, and overexpressed IGF2BP2 in the hippocampus protected against both neuronal senescence and learning and memory decline caused by loss of gravity. Accordingly, our research identified the hippocampal IGF2BP2-Shox2 axis as a possible therapeutic approach to maintaining cognitive function during space travel.

Study on the performance of sewage sludge biochar modified by nZVI to remove Cu(II) and Cr(VI) in water.

In this study, to simultaneously dispose of sludge and wastewater containing heavy metals, sludge biochar loaded with nano zero-valent-iron (nZVI) was prepared at 700 °C (nBC700) to remove Cr(VI) and Cu(II). The results showed the removal capacity of biochar was greatly improved by loading nZVI, and the adsorption capacities of biochar for Cu(II) and Cr(VI) increased by 251.96% and 205.18%. Pseudo-second-order kinetic and Sips isotherm models were fitted to the removal processes. Intraparticle diffusion models showed the removal process was controlled by surface diffusion and intraparticle diffusion. Competitive experiments showed Cr(VI) can compete with Cu(II) for active sites, but Cr(VI) was more easily removed by nBC700 through cation bridge. The removal mechanism illustrated removing Cu(II) mainly depended on complex precipitation, followed by reduction reaction, while Cr(VI) was on the contrary. This work provided effective data for sludge disposal and heavy metal removal.

Cathepsin F and Fibulin-1 as novel diagnostic biomarkers for brain metastasis of non-small cell lung cancer.

BACKGROUND: The lack of non-invasive methods for detection of early micro-metastasis is a major cause of the poor prognosis of non-small cell lung cancer (NSCLC) brain metastasis (BM) patients. Herein, we aimed to identify circulating biomarkers based on proteomics for the early diagnosis and monitoring of patients with NSCLC BM. METHODS: Upregulated proteins were detected by secretory proteomics in the animal-derived high brain metastatic lung cancer cell line. A well-designed study composed of three independent cohorts was then performed to verify these blood-based protein biomarkers: the serum discovery and verification cohorts (n = 80; n = 459), and the tissue verification cohort (n = 76). Logistic regression was used to develop a diagnostic biomarker panel. Model validation cohort (n = 160) was used to verify the stability of the constructed predictive model. Changes in serum Cathepsin F (CTSF) levels of patients were tracked to monitor the treatment response. Progression-free survival (PFS) and overall survival (OS) were analysed to assess their prognostic relevance. RESULTS: CTSF and Fibulin-1 (FBLN1) levels were specifically upregulated in sera and tissues of patients with NSCLC BM compared with NSCLC without BM and primary brain tumour. The combined diagnostic performance of CTSF and FBLN1 was superior to their individual ones. CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of progression were detected earlier than the magnetic resonance imaging changes. Elevated expression of CTSF in NSCLC BM tissues was associated with poor PFS, and was found to be an independent prognostic factor. CONCLUSIONS: We report a novel blood-based biomarker panel for early diagnosis, monitoring of therapeutic response, and prognostic evaluation of patients with NSCLC BM.

MET inhibition enhances PARP inhibitor efficacy in castration-resistant prostate cancer by suppressing the ATM/ATR and PI3K/AKT pathways.

Up to 30% of patients with metastatic castration-resistant prostate cancer (CRPC) patients carry altered DNA damage response genes, enabling the use of poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in advanced CRPC. The proto-oncogene mesenchymal-epithelial transition (MET) is crucial in the migration, proliferation, and invasion of tumour cells. Aberrant expression of MET and its ligand hepatocyte growth factor is associated with drug resistance in cancer therapy. Here, we found that MET was highly expressed in human CRPC tissues and overexpressed in DU145 and PC3 cells in a drug concentration-dependent manner and is closely related to sensitivity to PARP inhibitors. Combining the PARP inhibitor olaparib with the MET inhibitor crizotinib synergistically inhibited CRPC cell growth both in vivo and in vitro. Further analysis of the underlying molecular mechanism underlying the MET suppression-induced drug sensitivity revealed that olaparib and crizotinib could together downregulate the ATM/ATR signaling pathway, inducing apoptosis by inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, enhancing the olaparib-induced antitumour effect in DU145 and PC3 cells. In conclusion, we demonstrated that MET inhibition enhances sensitivity of CRPC to PARP inhibitors by suppressing the ATM/ATR and PI3K/AKT pathways and provides a novel, targeted therapy regimen for CRPC.

Targeting c-MET to Enhance the Efficacy of Olaparib in Prostate Cancer.

PURPOSE: Prostate cancer is the second leading cause of cancer death in men worldwide. Olaparib is clinically approved for the treatment prostate cancer, but cytotoxicity and off-target effects including DNA damage limit its clinical applications. In the current study, new strategies to improve the therapeutic efficacy of olaparib for the treatment of prostate cancer were investigated. METHODS: Two prostate cancer cell lines were exposed to the c-MET inhibitor PHA665752 and/or the PARP inhibitor olaparib. Cell counting kit-8, colony formation assays, and transwell assays were conducted to evaluate the cytotoxicity of olaparib alone or in combination with PHA665752 in prostate cancer cell lines. Western blotting, immunofluorescence staining, and the comet assay were used to assess the effects of PHA665752 on olaparib-induced DNA damage. RESULTS: Combined inhibition of c-MET and PARP resulted in effective and synergistic blocking of the growth of prostate cancer cell lines. Invasion and migration were significantly suppressed when the agents were combined. Mechanistically, dual blocking of PARP and c-MET in prostate cancer cell lines was associated with an impaired DNA damage response. Interestingly, immunofluorescence staining analysis of RAD51 protein indicated that the c-MET inhibitor PHA665752 significantly impaired homologous repair via downregulated translocation of RAD51 into the nucleus in prostate cancer cells. CONCLUSION: The combination of the c-MET inhibitor PHA665752 and the PARP inhibitor olaparib may be a promising therapeutic strategy in patients with prostate cancer.

MicroRNA-125b reduces glucose uptake in papillary thyroid carcinoma cells.

Previous studies have shown that microRNA (miR)-125b plays important roles in several human cancer types. The aim of the present study was to analyze the potential roles of miR-125b in papillary thyroid carcinoma (PTC). It was found that miR-125b was downregulated in PTC and its expression was affected by clinical stages. Glucose transporter 1 (GLUT1) was upregulated in PTC and was negatively correlated with miR-125b. In PTC cells, overexpression of miR-125b suppressed glucose uptake and downregulated GLUT1. Furthermore, GLUT1 overexpression reduced the effects of miR-125b overexpression on glucose uptake. Moreover, miR-125b overexpression suppressed PTC cell proliferation. GLUT1 overexpression promoted the proliferation of PTC cells and reduced the effects of miR-125b overexpression on cancer cell proliferation. Overall, miR-125b decreased glucose uptake in PTC cells by downregulating GLUT1.

Effect of pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer: A meta-analysis
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INTRODUCTION: Pertuzumab, as an adjunctive therapy to trastuzumab and docetaxel, has been reported to be potentially beneficial for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, the results remain controversial. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of pertuzumab supplementation in patients with HER2-positive metastatic breast cancer. METHODS: Medline, SCOPUS, Google Scholar, Cochrane library databases, EMBASE, Springer, and Science Direct were systematically searched. Randomized controlled trials (RCTs) assessing the effect of pertuzumab + trastuzumab + docetaxel vs. trastuzumab + docetaxel on the treatment of HER2-positive metastatic breast cancer were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcomes were death, overall survival, and progression-free survival. Meta-analysis was performed using fixed- or random-effect model. RESULTS: Five RCTs involving 3,742 patients were included in the meta-analysis. Overall, compared with placebo and trastuzumab + docetaxel treatment, combination treatment of pertuzumab + trastuzumab + docetaxel treatment was associated with the significantly reduced death (hazard ratio (HR) = 0.67; 95% confidence interval (CI) = 0.57 - 0.78; p < 0.005) as well as improved overall survival (HR = 0.66; 95% CI = 0.35 - 0.67; p = 0.98) and progression-free survival (HR = 0.64; 95% CI = 0.58 - 0.71; p < 0.005). Moreover, pertuzumab supplementation did not increase the number of patients with reductions in the left ventricular ejection fraction (LVEF) of 10% or more (risk ratio (RR) = 0.70; 95% CI = 0.47 - 1.04; p = 0.07). CONCLUSION: Pertuzumab + trastuzumab + docetaxel treatment significantly reduced death, increased overall survival, and progression-free survival in patients with HER2-positive metastatic breast cancer compared to placebo and trastuzumab + docetaxel treatment, but showed no increased adverse events.
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Influence of nanocrystalline boron precursor powder on superconductivity in MgB2 bulk.

In this report, high-purity nanocrystalline boron powders processed by ball-milling were used as the precursor powders to fabricate MgB2 superconductor. The transport properties and the critical current density in the samples made from ball-milled boron powders and as-supplied boron powders were investigated. It was found that the ball-milled boron powders led to a significant enhancement of the critical current density in MgB2 sintered at 650 degrees C. The reason can be attributed to the small MgB2 grain size caused by the ball-milled boron precursor powders. The resistivity of the samples made from the ball-milled boron powder was lower than that of the sample from as-supplied boron powder. As the sintering temperature increased, both resistivity and upper critical field decreased in the samples using the ball-milled boron powders as a precursor. Poor connectivity and large strain are responsible for the high resistivity.

GATA4 and NKX2.5 gene analysis in Chinese Uygur patients with congenital heart disease.

BACKGROUND: Congenital heart disease (CHD) is the most common developmental anomaly in newborns. The germline mutations in GATA4 and NKX2.5 genes have been identified as responsible for CHD. The frequency of GATA4 and NKX2.5 mutations in Chinese Uygur patients with CHD and the correlation between their genotype and CHD phenotype are unknown. METHODS: We examined the coding region of GATA4 and NKX2.5 genes in 62 Chinese Uygur patients with CHD and 117 Chinese Uygur individuals as the controls by denaturing high performance liquid chromatography (DHPLC) and sequencing. RESULTS: Two heterozygous missense mutations of c.1220C > A and c.1273G > A in GATA4 gene, which cause the amino acid residue changes of P407Q and D425N in GATA4, were found in a patient with tetralogy of Fallot and a patient with ventricular septal defect, respectively. The two patients did not have atrioventricular conduct defects or non-cardiac abnormalities. The two mutations are expected to affect the protein function. There were no reported NKX2.5 mutations in the patients. CONCLUSION: Our results provided the primary data on CHD phenotype associated with GATA4 mutation in the Chinese Uygur population.