Exploring the active mechanism of berberine against HCC by systematic pharmacology and experimental validation

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Berberine (BBR) is the main component of Coptidis rhizoma, the dried rhizome of Coptis chinensis and is a potential plant alkaloid used for the treatment of cancer due to its high antitumor activity. The present study examined the therapeutic potential and molecular mechanism of action of BBR against HCC, using systematic pharmacology combined with a molecular docking approach and experimental validation in vitro. Through systematic pharmacological analysis, it was found that BBR serves a significant role in inhibiting HCC by affecting multiple pathways, especially the PI3K/AKT signaling pathway. Furthermore, the docking approach indicated that the binding of BBR to AKT could lead to the suppression of AKT activity. The present study examined the inhibitory effect of BBR on the PI3K/AKT pathway in HCC and identified that BBR downregulated the expressions of phosphorylated AKT and PI3K in MHCC97‑H and HepG2 cells, inhibiting their growth, cell migration and invasion in a dose‑dependent manner. In addition, inhibition of the AKT pathway by BBR also contributed to cell apoptosis in MHCC97‑H and HepG2 cells. Taken together, the results of the present study suggested that BBR may be a promising antitumor drug for HCC that acts by inhibiting the PI3K/AKT pathway

Insolation driven biomagnetic response to the Holocene Warm Period in semi-arid East Asia

The Holocene Warm Period (HWP) provides valuable insights into the climate system and biotic responses to environmental variability and thus serves as an excellent analogue for future global climate changes. Here we document, for the first time, that warm and wet HWP conditions were highly favourable for magnetofossil proliferation in the semi-arid Asian interior. The pronounced increase of magnetofossil concentrations at ~9.8 ka and decrease at ~5.9 ka in Dali Lake coincided respectively with the onset and termination of the HWP, and are respectively linked to increased nutrient supply due to postglacial warming and poor nutrition due to drying at ~6 ka in the Asian interior. The two-stage transition at ~7.7 ka correlates well with increased organic carbon in middle HWP and suggests that improved climate conditions, leading to high quality nutrient influx, fostered magnetofossil proliferation. Our findings represent an excellent lake record in which magnetofossil abundance is, through nutrient availability, controlled by insolation driven climate changes.This research was supported by the NSFC grant 41330104 and the 973 program grant 2012CB821900. J.X. was supported by the 973 program grant 2010CB833400 and the NSFC grant 41130101. J.L. received support from the NSFC grant 41374004. C.D. acknowledges further support from the NSFC grant 40925012 and the CAS Bairen Program

Benchmarking Component Analysis of Remanent Magnetization Curves With a Synthetic Mixture Series: Insight into the Reliability of Unmixing Natural Samples

Geological samples often contain several magnetic components associated with different geological processes. Component analysis of remanent magnetization curves has been widely applied to decompose convoluted information. However, the reliability of commonly used methods is poorly assessed as independent verification is rarely available. For this purpose, we designed an experiment using a series of mixtures of two endmembers to benchmark unmixing methods for isothermal remanent magnetization (IRM) acquisition curves. First‐order reversal curves (FORC) diagrams were analyzed for comparison. It is demonstrated that the parametric method, which unmixes samples using specific probability distributions, may result in biased estimates. In contrast, an endmember‐based IRM unmixing approach yielded better quantitative results, which are comparable to the results obtained by FORC analysis based on principle component analysis (FORC‐PCA). We demonstrate that endmember‐based methods are in principle more suitable for unmixing a collection of samples with common endmembers; however, the level of decomposition will vary depending on the difference between the true endmembers that are associated with distinctive processes and the empirical endmembers used for unmixing. When it is desired to further decompose endmembers, the parametric unmixing approach remains a valuable means of inferring their underlying components. We illustrate that the results obtained by endmember‐based and parametric methods can be quantitatively combined to provide improved unmixing results at the level of parametric model distributions.The work was supported by the National Natural Science Foundation of China (41621004 and 41904070) and the Strategic Priority Research Program of Chinese Academy of Sciences (XDB18010000). This study was also supported by the National Institute of Polar Research (NIPR) through Advanced Project (KP‐7 and KP306) and JSPS KAKENHI grants (15K13581, 16H04068, 17H06321, and 18K13638). X. Z. acknowledges the Australian Research Council Discovery Projects DP200100765 and the National Natural Science Foundation of China (grant 41920104009) for financial supports

Ethnic disparities in the risk of colorectal adenomas associated with aspirin and statin use: a retrospective multiethnic study

BACKGROUND: Although data on the inverse association between colorectal adenomas (CRA) and daily aspirin or statin therapy exists in white and black patients, scarce data exists on these associations in the Hispanic population. With a rapidly increasing Hispanic population in the United States, defining the association in Hispanics is crucial. METHODS: The study sample included 1,843 consecutive patients who underwent a colonoscopy (screening or diagnostic) from 2009 to 2011 at a community hospital in East Meadow, New York. Data was then extracted from patient charts regarding aspirin and/or statin use. Adjusted odds ratios (OR) and their 95% confidence intervals (CI) were calculated to assess the association between colonoscopy findings and aspirin, statin, or aspirin/statin use. RESULTS: In our total population including all races, aspirin user had an increased risk for having two or more adenomas (OR =1.73, 95% CI: 1.00, 2.99, P=0.05) and presence of an adenoma in the proximal colon (OR =1.66, 95% CI: 1.07, 2.58, P=0.02). In the total study population, those who used both statin and aspirin had an increased risk for having two or more adenomas (OR =2.56, 95% CI: 1.21, 5.39, P=0.01). In the Hispanic population, users of both medications had an increased risk for having two or more adenomas (OR =19.04, 95% CI: 1.30, 280.09, P=0.03), adenoma present in the distal colon (OR =5.75, 95% CI: 1.64, 20.21, P=0.01) and largest adenoma in distal colon (OR =5.75, 95% CI: 1.64, 20.21, P=0.01). CONCLUSIONS: Aspirin use and aspirin/statin use was associated with abnormal colonoscopy findings, particularly in the Hispanic population. These findings may be due to environmental factors such as dietary, colonic flora, or genetic susceptibility. The findings warrant further investigational research, particularly in Hispanics

Cell transcriptomic atlas of the non-human primate Macaca fascicularis.

Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell-cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M. fascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.We thank W. Liu and L. Xu from the Huazhen Laboratory Animal Breeding Centre for helping in the collection of monkey tissues, D. Zhu and H. Li from the Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) for technical help, G. Guo and H. Sun from Zhejiang University for providing HCL and MCA gene expression data matrices, G. Dong and C. Liu from BGI Research, and X. Zhang, P. Li and C. Qi from the Guangzhou Institutes of Biomedicine and Health for experimental advice or providing reagents. This work was supported by the Shenzhen Basic Research Project for Excellent Young Scholars (RCYX20200714114644191), Shenzhen Key Laboratory of Single-Cell Omics (ZDSYS20190902093613831), Shenzhen Bay Laboratory (SZBL2019062801012) and Guangdong Provincial Key Laboratory of Genome Read and Write (2017B030301011). In addition, L.L. was supported by the National Natural Science Foundation of China (31900466), Y. Hou was supported by the Natural Science Foundation of Guangdong Province (2018A030313379) and M.A.E. was supported by a Changbai Mountain Scholar award (419020201252), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030502), a Chinese Academy of Sciences–Japan Society for the Promotion of Science joint research project (GJHZ2093), the National Natural Science Foundation of China (92068106, U20A2015) and the Guangdong Basic and Applied Basic Research Foundation (2021B1515120075). M.L. was supported by the National Key Research and Development Program of China (2021YFC2600200).S

LINC00941 Promotes Cell Malignant Behavior and Is One of Five Costimulatory Molecule-Related lncRNAs That Predict Prognosis in Renal Clear Cell Carcinoma

Background and Objectives: A significant role was played by costimulatory molecules in renal cancer. However, the lncRNAs regulating costimulatory molecules have not been fully investigated. Materials and Methods: Data from the next-sequence file and clinical data were downloaded from the Cancer Genome Atlas (TCGA) database. All analyses were conducted using the R and GraphPad Prism software. Results: A total of 1736 costimulatory molecule-related lncRNAs were determined under the threshold of |Cor| > 0.5 and p-value Conclusions: Our study established a costimulatory molecule-related lncRNAs-based prognosis model with a great prediction prognosis. In addition, LINC00941 could enhance the malignant biological behaviors of renal cancer cells

LINC00941 Promotes Cell Malignant Behavior and Is One of Five Costimulatory Molecule-Related lncRNAs That Predict Prognosis in Renal Clear Cell Carcinoma

Background and Objectives: A significant role was played by costimulatory molecules in renal cancer. However, the lncRNAs regulating costimulatory molecules have not been fully investigated. Materials and Methods: Data from the next-sequence file and clinical data were downloaded from the Cancer Genome Atlas (TCGA) database. All analyses were conducted using the R and GraphPad Prism software. Results: A total of 1736 costimulatory molecule-related lncRNAs were determined under the threshold of |Cor| > 0.5 and p-value < 0.001. Furthermore, a prognosis prediction signature consisting of five lncRNAs: LINC00941, AC016773.1, AL162171.1, HOTAIRM1, and AL109741.1 was established with great prediction ability. By combining risk score and clinical parameters, a nomogram plot was constructed for better clinical practice. A biological enrichment analysis indicated that E2F targets, coagulation, IL6/JAK/STAT3 signaling, G2/M checkpoint, and allograft rejection pathways were activated in high-risk patients. Furthermore, a higher infiltration level of resting CD4+ T cell, M2 macrophage, and resting mast cells, while a lower CD8+ T cell infiltration was observed in high-risk patients. It is worthy of note that, low-risk patients might respond better to PD-1 checkpoint therapy. A correlation analysis of LINC00941 revealed that it was positively correlated with Th2 cells, Th1 cells, macrophages, and Treg cells, but negatively correlated with Th17 cells. A pathway enrichment analysis indicated that the pathways of the inflammatory response, G2M checkpoint, and IL6/JAK/STAT3 signaling were significantly activated in patients with high LINC00941 expression. In vitro experiments indicated that LINC00941 can enhance the malignant biological behaviors of renal cancer cells. Conclusions: Our study established a costimulatory molecule-related lncRNAs-based prognosis model with a great prediction prognosis. In addition, LINC00941 could enhance the malignant biological behaviors of renal cancer cells