Florofangchinoline inhibits proliferation of osteosarcoma cells via targeting of histone H3 lysine 27 trimethylation and AMPK activation

Purpose: To investigate the effect of florofangchinoline on osteosarcoma cell growth in vitro, and the underlying mechanism of action.Methods: Changes in the viability of KHOS and Saos-2 cells were measured using water soluble tetrazolium salt (WST) assay, while apoptosis was determined using Annexin V/PI staining and flow cytometry. Increases in mtDNA, and expressions of PGC-1α and TFAM were assayed with immunoblot analysis and quantitative real-time polymerase chain reaction (qPCR), respectively.Results: Microscopic examination of florofangchinoline-treated cells showed significant decrease in cell density, relative to control cells (p < 0.05). Treatment with 10 μM florofangchinoline increased apoptosis in KHOS and Saos-2 cells to 56.32 and 63.75 %, respectively (p < 0.05). Florofangchinoline treatment markedly enhanced cleavage of caspase-3, caspase-8, caspase-9 and PARP. It elevated Bax level and reduced Bcl-2 in KHOS and Saos-2 cells. Moreover, florofangchinoline increased p21 and p-AMPKα levels, and mtDNA counts in KHOS and Saos-2 cells (p < 0.05). Moreover, in florofangchinoline-treated KHOS cells, the expressions of EED, EZH2 and SUZ12 were significantly suppressed (p < 0.05).Conclusion: Florofangchinoline inhibits osteosarcoma cell viability by activation of apoptosis. Moreover, it activates AMPK and down-regulates  histone H3 lysine 27 trimethylation in osteosarcoma cells. Therefore, florofangchinoline has potentials for development as a therapeutic drug forosteosarcoma. Keywords: Osteosarcoma, Histone H3, Florofangchinoline, Apoptosis, Chemotherapeuti

Genomic and Transcriptomic Evidence for Carbohydrate Consumption among Microorganisms in a Cold Seep Brine Pool

The detailed lifestyle of microorganisms in deep-sea brine environments remains largely unexplored. Using a carefully calibrated genome binning approach, we reconstructed partial to nearly-complete genomes of 51 microorganisms in biofilms from the Thuwal cold seep brine pool of the Red Sea. The recovered metagenome-assembled genomes (MAGs) belong to six different phyla: Actinobacteria, Proteobacteria, Candidatus Cloacimonetes, Candidatus Marinimicrobia, Bathyarchaeota and Thaumarchaeota. By comparison with close relatives of these microorganisms, we identified a number of unique genes associated with organic carbon metabolism and energy generation. These genes included various glycoside hydrolases, nitrate and sulfate reductases, putative bacterial microcompartment biosynthetic clusters (BMC), and F420H2 dehydrogenases. Phylogenetic analysis suggested that the acquisition of these genes probably occurred through horizontal gene transfer (HGT). Metatranscriptomics illustrated that glycoside hydrolases are among the most highly expressed genes. Our results suggest that the microbial inhabitants are well adapted to this brine environment, and anaerobic carbohydrate consumption mediated by glycoside hydrolases and electron transport systems (ETSs) is a dominant process performed by microorganisms from various phyla within this ecosystem

Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury.

AIMS: Mesenchymal stem cells (MSCs) can ameliorate myocardial infarction (MI) injury. However, older-donor MSCs seem less efficacious than those from younger donors, and the contributing underlying mechanisms remain unknown. Here, we determine how age-related expression of pigment epithelium-derived factor (PEDF) affects MSC therapeutic efficacy for MI. METHODS AND RESULTS: Reverse transcriptase-polymerized chain reaction and enzyme-linked immunosorbent assay analyses revealed dramatically increased PEDF expression in MSCs from old mice compared to young mice. Morphological and functional experiments demonstrated significantly impaired old MSC therapeutic efficacy compared with young MSCs in treatment of mice subjected to MI. Immunofluorescent staining demonstrated that administration of old MSCs compared with young MSCs resulted in an infarct region containing fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts. Pigment epithelium-derived factor overexpression in young MSCs impaired the beneficial effects against MI injury, and induced cellular profile changes in the infarct region similar to administration of old MSCs. Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration. Studies in vitro showed that PEDF secreted by MSCs regulated the proliferation and migration of cardiac fibroblasts. CONCLUSIONS: This is the first evidence that paracrine factor PEDF plays critical role in the regulatory effects of MSCs against MI injury. Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion. These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy

Association between short-term exposure to ambient air pollution and heart failure: An updated systematic review and meta-analysis of more than 7 million participants

IntroductionExposure to air pollution has been linked to the mortality of heart failure. In this study, we sought to update the existing systematic review and meta-analysis, published in 2013, to further assess the association between air pollution and acute decompensated heart failure, including hospitalization and heart failure mortality.MethodsPubMed, Web of Science, EMBASE, and OVID databases were systematically searched till April 2022. We enrolled the studies regarding air pollution exposure and heart failure and extracted the original data to combine and obtain an overall risk estimate for each pollutant.ResultsWe analyzed 51 studies and 7,555,442 patients. Our results indicated that heart failure hospitalization or death was associated with increases in carbon monoxide (3.46% per 1 part per million; 95% CI 1.0233–1.046, P < 0.001), sulfur dioxide (2.20% per 10 parts per billion; 95% CI 1.0106–1.0335, P < 0.001), nitrogen dioxide (2.07% per 10 parts per billion; 95% CI 1.0106–1.0335, P < 0.001), and ozone (0.95% per 10 parts per billion; 95% CI 1.0024–1.0166, P < 0.001) concentrations. Increases in particulate matter concentration were related to heart failure hospitalization or death (PM2.5 1.29% per 10 μg/m3, 95% CI 1.0093–1.0165, P < 0.001; PM10 1.30% per 10 μg/m3, 95% CI 1.0102–1.0157, P < 0.001).ConclusionThe increase in the concentration of all pollutants, including gases (carbon monoxide, sulfur dioxide, nitrogen dioxide, ozone) and particulate matter [(PM2.5), (PM10)], is positively correlated with hospitalization rates and mortality of heart failure.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42021256241

Raw Garlic Consumption and Risk of Liver Cancer: A Population-Based Case-Control Study in Eastern China.

Although the major risk factors for liver cancer have been established, preventive factors for liver cancer have not been fully explored. We evaluated the association between raw garlic consumption and liver cancer in a large population-based case-control study in Eastern China. The study was conducted in Jiangsu, China, from 2003 to 2010. A total of 2011 incident liver cancer cases and 7933 randomly selected population-controls were interviewed. Epidemiological data including raw garlic intake and other exposures were collected, and serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were assayed. Overall, eating raw garlic twice or more per week was inversely associated with liver cancer, with an adjusted odds ratio (aOR) of 0.77 (95% confidence interval (CI): 0.62-0.96) compared to those ingesting no raw garlic or less than twice per week. In stratified analyses, high intake of raw garlic was inversely associated with liver cancer among Hepatitis B surface antigen (HBsAg) negative individuals, frequent alcohol drinkers, those having history of eating mold-contaminated food or drinking raw water, and those without family history of liver cancer. Marginal interactions on an additive scale were observed between low raw garlic intake and HBsAg positivity (attributable proportion due to interaction (AP) = 0.31, 95% CI: -0.01-0.62) and heavy alcohol drinking (AP = 0.28, 95% CI: 0.00-0.57). Raw garlic consumption is inversely associated with liver cancer. Such an association shed some light on the potential etiologic role of garlic intake on liver cancer, which in turn might provide a possible dietary intervention to reduce liver cancer in Chinese population

Decreased default mode network functional connectivity with visual processing regions as potential biomarkers for delayed neurocognitive recovery: A resting-state fMRI study and machine-learning analysis

ObjectivesThe abnormal functional connectivity (FC) pattern of default mode network (DMN) may be key markers for early identification of various cognitive disorders. However, the whole-brain FC changes of DMN in delayed neurocognitive recovery (DNR) are still unclear. Our study was aimed at exploring the whole-brain FC patterns of all regions in DMN and the potential features as biomarkers for the prediction of DNR using machine-learning algorithms.MethodsResting-state functional magnetic resonance imaging (fMRI) was conducted before surgery on 74 patients undergoing non-cardiac surgery. Seed-based whole-brain FC with 18 core regions located in the DMN was performed, and FC features that were statistically different between the DNR and non-DNR patients after false discovery correction were extracted. Afterward, based on the extracted FC features, machine-learning algorithms such as support vector machine, logistic regression, decision tree, and random forest were established to recognize DNR. The machine learning experiment procedure mainly included three following steps: feature standardization, parameter adjustment, and performance comparison. Finally, independent testing was conducted to validate the established prediction model. The algorithm performance was evaluated by a permutation test.ResultsWe found significantly decreased DMN connectivity with the brain regions involved in visual processing in DNR patients than in non-DNR patients. The best result was obtained from the random forest algorithm based on the 20 decision trees (estimators). The random forest model achieved the accuracy, sensitivity, and specificity of 84.0, 63.1, and 89.5%, respectively. The area under the receiver operating characteristic curve of the classifier reached 86.4%. The feature that contributed the most to the random forest model was the FC between the left retrosplenial cortex/posterior cingulate cortex and left precuneus.ConclusionThe decreased FC of DMN with regions involved in visual processing might be effective markers for the prediction of DNR and could provide new insights into the neural mechanisms of DNR.Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR-DCD-15006096

Diagnostic Role of Prostate-Specific Membrane Antigen in Adrenocortical Carcinoma

Objective: To investigate the role of PSMA in the differential diagnosis of adrenocortical carcinoma samples (ACCs) and adrenocortical adenoma samples (ACAs), to validate the prognostic role of PSMA in patients with ACCs, and to explore the possibility that this marker can differentiate localized ACCs from adrenal metastases from other sites.Methods: PSMA protein expression in tissue samples from 50 ACCs, 90 ACAs (including 20 from patients who presented with Cushing's syndrome, 20 aldosterone-producing adenomas and 50 non-functional tumors) and 10 tissues that were metastases from other primary sites was assessed by immunohistochemistry. The clinical and pathological characteristics were compared, the intensity and density were analyzed, and the prognostic role was evaluated.Results: The analysis of clinical and pathological features revealed that the size of ACCs was greater than that of benign tissues and the ACC patients were older than the ACA patients (p < 0.01). The percentage of PSMA-positive vessels, the mean intensity and the degree of staining density were found to be significantly lower in ACAs than in ACCs (p < 0.01). In these 140 samples, 60% of the ACCs were grouped in the positive category. The samples were negative for metastases that were from other primary sites. The ENSAT stage and Ki-67 were correlated with PSMA expression. The survival distribution revealed that high PSMA expression did not show any prognostic relevance in the current ACCs series. Those samples with a score of > 3.5 were 75 times more likely to be malignant (OR = 75). We established a cut-off score of 3.5 (p < 0.05), which had 46% sensitivity and 99% specificity. Paralleling PSMA and Ki-67 maximized the area under the curve, with 72% sensitivity and 100% specificity.Conclusions: Our results strongly confirm that PSMA is helpful for distinguishing benign from malignant tumors and that its high expression levels correlate with a high ENSAT stage and high proliferation. The combination of PSMA and Ki-67 can be particularly useful. Furthermore, PSMA might be a useful tool for the identification of localized adrenal carcinoma and metastatic carcinoma

PSR J1926-0652: A Pulsar with Interesting Emission Properties Discovered at FAST

We describe PSR J1926-0652, a pulsar recently discovered with the Five-hundred-meter Aperture Spherical radio Telescope (FAST). Using sensitive single-pulse detections from FAST and long-term timing observations from the Parkes 64-m radio telescope, we probed phenomena on both long and short time scales. The FAST observations covered a wide frequency range from 270 to 800 MHz, enabling individual pulses to be studied in detail. The pulsar exhibits at least four profile components, short-term nulling lasting from 4 to 450 pulses, complex subpulse drifting behaviours and intermittency on scales of tens of minutes. While the average band spacing P3 is relatively constant across different bursts and components, significant variations in the separation of adjacent bands are seen, especially near the beginning and end of a burst. Band shapes and slopes are quite variable, especially for the trailing components and for the shorter bursts. We show that for each burst the last detectable pulse prior to emission ceasing has different properties compared to other pulses. These complexities pose challenges for the classic carousel-type models.Comment: 13pages with 12 figure

The Nearest Neutron Star Candidate in a Binary Revealed by Optical Time-domain Surveys

Recent studies have revealed the global deposition on Earth of radioactive elements (e.g., $^{60}$Fe) resulting from the metal-enriched ejecta of nearby (within $\sim 100$ pc) supernova explosions. The majority of neutron stars in our Solar neighborhood remain to be discovered. Here we report the discovery of the nearest ($127.7 \pm 0.3$ pc) neutron star candidate in the single-lined spectroscopic binary LAMOST J235456.76+335625.7 (hereafter J2354). Utilizing the multi-epoch spectra and high-cadence periodic light curves, we measure the mass of the visible star ($M_{\rm vis}=0.70\pm 0.05\ M_{\odot}$) and determine the mass function of the invisible object $f(M)=0.525 \pm 0.004\ M_{\odot}$, i.e., the mass of the unseen compact object is $M_{\rm inv} \geq 1.26 \pm 0.03\ M_{\odot}$. The excess UV emission due to a hot supramassive white dwarf is absent. Hence, it is likely that J2354 harbors a neutron star. J2354 is X-ray dim (the$0.1$--$2.4$keV luminosity$<10^{30}\ {\rm erg\ s^{-1}}$) since it is not detected in the ROSAT all-sky surveys in X-ray. One-hour exceptionally sensitive radio follow-up observations with FAST, the largest single-dish radio telescope, failed to reveal any radio pulsating signals (the potential pulse power at$1.4$GHz is$<6.8\times 10^{23}\ {\rm erg\ s^{-1}}$). Hence, the neutron star candidate in J2354 can only be discovered via our time-resolved observations. The alternative scenario involving a nearby supramassive cold white dwarf cannot be fully excluded. Our discovery demonstrates a promising way to unveil the missing population of backyard inactive neutron stars or supramassive cold white dwarfs in binaries by exploring the optical time domain, thereby facilitating understanding of the supernovae explosion and metal-enrichment history in our Solar neighborhood.Comment: 35 pages, 8 figures, to be submitte