Synthesis, biological evaluation and mechanism studies of C-23 modified 23-hydroxybetulinic acid derivatives as anticancer agents

A series of C-23 modified 23-hydroxybetulinic acid (HBA) derivatives were synthesized and evaluated for their antiproliferative activity against a panel of cancer cell lines (A2780, A375, B16, MCF-7 and HepG2). The biological screening results showed that most of the derivatives exhibited more potent antiproliferative activity than HBA, and compound 6e exhibited the most potent activity with IC50 values of 2.14 μM, 2.89 μM, and 3.97 μM against A2780, B16, and MCF-7 cells, respectively. Further anticancer mechanism studies revealed that compound 6e induced the generation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential (MMP) of B16 cells in a dose-dependent manner. Moreover, western blot analysis indicated that compound 6e downregulated the expression of anti-apoptotic protein Bcl-2 and upregulated the expression of proapoptotic protein Bax, activation of caspase 3 to induce cell apoptosis. Meanwhile, compound 6e significantly inhibited the phosphorylation of MEK, ERK, and Akt without affecting the expression of MEK, ERK, and Akt. Furthermore, the in vivo anti-tumor activity of 6e was validated (tumor inhibitory ratio of 68.4% at the dose of 30 mg/kg) in mice with B16 melanoma

Assessment of left ventricular function in patients with type 2 diabetes mellitus by non-invasive myocardial work

BackgroundDiabetes mellitus (DM) is a chronic disease that poses a serious risk of cardiovascular diseases. Therefore, early detection of impaired cardiac function with non-invasive myocardial imaging is critical for improving the prognosis of patients with DM.PurposeThis study aimed to assess the left ventricular (LV) function in patients with type 2 diabetes mellitus (T2DM) by non-invasive myocardial work technique.Materials and methodsIn all, 67 patients with T2DM and 28 healthy controls were included and divided into a DM group and a control group. Two-dimensional dynamic images of apical three-chamber view, apical two-chamber view, and apical four-chamber view were collected from all subjects, consisting of at least three cardiac cycles. LV myocardial strain parameters, including global longitudinal strain (GLS) and peak strain dispersion (PSD), as well as myocardial work parameters, including global constructive work (GCW), global wasted work (GWW), global work index (GWI), and global work efficiency (GWE), were obtained and analyzed.ResultsA total of 15 subjects were randomly selected to assess intra-observer and inter-observer consistency of myocardial work parameters and strain parameters, which showed excellent results (intra-class correlation coefficients: 0.856 - 0.983, P<0.001). Compared with the control group, the DM group showed significantly higher PSD (37.59 ± 17.18 ms vs. 27.72 ± 13.52 ms, P<0.05) and GWW (63.98 ± 43.63 mmHg% vs. 39.28 ± 25.67 mmHg%, P<0.05), and lower GWE (96.38 ± 2.02% vs. 97.72 ± 0.98%, P<0.001). Furthermore, the PSD was positively correlated with GWW (r = 0.565, P<0.001) and negatively correlated with GWE (r = -0.569, P<0.001).ConclusionUncoordinated LV myocardial strain, higher GWW, and lower GWE in patients with T2DM may serve as indicators for the early assessment of cardiac impairment in T2DM

A map of human cancer signaling

We conducted a comprehensive analysis of a manually curated human signaling network containing 1634 nodes and 5089 signaling regulatory relations by integrating cancer-associated genetically and epigenetically altered genes. We find that cancer mutated genes are enriched in positive signaling regulatory loops, whereas the cancer-associated methylated genes are enriched in negative signaling regulatory loops. We further characterized an overall picture of the cancer-signaling architectural and functional organization. From the network, we extracted an oncogene-signaling map, which contains 326 nodes, 892 links and the interconnections of mutated and methylated genes. The map can be decomposed into 12 topological regions or oncogene-signaling blocks, including a few ‘oncogene-signaling-dependent blocks' in which frequently used oncogene-signaling events are enriched. One such block, in which the genes are highly mutated and methylated, appears in most tumors and thus plays a central role in cancer signaling. Functional collaborations between two oncogene-signaling-dependent blocks occur in most tumors, although breast and lung tumors exhibit more complex collaborative patterns between multiple blocks than other cancer types. Benchmarking two data sets derived from systematic screening of mutations in tumors further reinforced our findings that, although the mutations are tremendously diverse and complex at the gene level, clear patterns of oncogene-signaling collaborations emerge recurrently at the network level. Finally, the mutated genes in the network could be used to discover novel cancer-associated genes and biomarkers

Detection of sarcopenia using deep learning-based artificial intelligence body part measure system (AIBMS)

Background: Sarcopenia is an aging syndrome that increases the risks of various adverse outcomes, including falls, fractures, physical disability, and death. Sarcopenia can be diagnosed through medical images-based body part analysis, which requires laborious and time-consuming outlining of irregular contours of abdominal body parts. Therefore, it is critical to develop an efficient computational method for automatically segmenting body parts and predicting diseases.Methods: In this study, we designed an Artificial Intelligence Body Part Measure System (AIBMS) based on deep learning to automate body parts segmentation from abdominal CT scans and quantification of body part areas and volumes. The system was developed using three network models, including SEG-NET, U-NET, and Attention U-NET, and trained on abdominal CT plain scan data.Results: This segmentation model was evaluated using multi-device developmental and independent test datasets and demonstrated a high level of accuracy with over 0.9 DSC score in segment body parts. Based on the characteristics of the three network models, we gave recommendations for the appropriate model selection in various clinical scenarios. We constructed a sarcopenia classification model based on cutoff values (Auto SMI model), which demonstrated high accuracy in predicting sarcopenia with an AUC of 0.874. We used Youden index to optimize the Auto SMI model and found a better threshold of 40.69.Conclusion: We developed an AI system to segment body parts in abdominal CT images and constructed a model based on cutoff value to achieve the prediction of sarcopenia with high accuracy

Dynamic Succession of Microbial Communities in Soybean Paste Made with Broomcorn Millet as an Additive and Its Correlation with Flavor and Nutritional Properties during the Brewing Process

To obtain a full understanding the quality and microbial characteristics of soybean paste made from a mixture of soybean and broomcorn millet flour, its physicochemical properties (amino nitrogen and nitrite), and total phenols (TP), γ-aminobutyric acid (GABA), free amino acids (FAAs), volatile compounds, and microbial community composition were investigated. The results showed that the amino nitrogen content increased to 0.71%, and the nitrite content decreased to within the standard range (1.37 mg/kg). The contents of TP, key FAAs and volatile compounds increased significantly during the fermentation process. The core microbial communities included Enterobacter, Pseudomonas, Stenotrophomonas, Aspergillus, and Alternaria. The results of correlation analysis confirmed that bacteria (Bacillus, Knoellia, and Blastococcus) and fungi (Epicoccum and Saccharomyces) played a significant role in the bioactivity changes and flavor generation in soybean paste. This study will be of great significance for understanding the quality and flavor of novel soybean paste made with cereal flour as an additive

A new treatment for neurogenic inflammation caused by EV71 with CR2-targeted complement inhibitor

BACKGROUND: Enterovirus 71 (EV71), one of the most important neurotropic EVs, has caused death and long-term neurological sequelae in hundreds of thousands of young children in the Asia-Pacific region in the past decade. The neurological diseases are attributed to infection by EV71 inducing an extensive peripheral and central nervous system (CNS) inflammatory response with abnormal cytokine production and lymphocyte depletion induced by EV71 infection. In the absence of specific antiviral agents or vaccines, an effective immunosuppressive strategy would be valuable to alleviate the severity of the local inflammation induced by EV71 infection. PRESENTATION OF THE HYPOTHESIS: The complement system plays a pivotal role in the inflammatory response. Inappropriate or excessive activation of the complement system results in a severe inflammatory reaction or numerous pathological injuries. Previous studies have revealed that EV71 infection can induce complement activation and an inflammatory response of the CNS. CR2-targeted complement inhibition has been proved to be a potential therapeutic strategy for many diseases, such as influenza virus-induced lung tissue injury, postischemic cerebral injury and spinal cord injury. In this paper, a mouse model is proposed to test whether a recombinant fusion protein consisting of CR2 and a region of Crry (CR2-Crry) is able to specifically inhibit the local complement activation induced by EV71 infection, and to observe whether this treatment strategy can alleviate or even cure the neurogenic inflammation. TESTING THE HYPOTHESIS: CR2-Crry is expressed in CHO cells, and its biological activity is determined by complement inhibition assays. 7-day-old ICR mice are inoculated intracranially with EV71 to duplicate the neurological symptoms. The mice are then divided into two groups, in one of which the mice are treated with CR2-Crry targeted complement inhibitor, and in the other with phosphate-buffered saline. A group of mice deficient in complement C3, the breakdown products of which bind to CR2, are also infected with EV71 virus. The potential bioavailability and efficacy of the targeted complement inhibitor are evaluated by histology, immunofluorescence staining and radiolabeling. IMPLICATIONS OF THE HYPOTHESIS: CR2-Crry-mediated targeting complement inhibition will alleviate the local inflammation and provide an effective treatment for the severe neurological diseases associated with EV71 infection