Polypharmacology of Berberine Based on Multi-Target Binding Motifs

Background: Polypharmacology is emerging as the next paradigm in drug discovery. However, considerable challenges still exist for polypharmacology modeling. In this study, we developed a rational design to identify highly potential targets (HPTs) for polypharmacological drugs, such as berberine.Methods and Results: All the proven co-crystal structures locate berberine in the active cavities of a redundancy of aromatic, aliphatic, and acidic residues. The side chains from residues provide hydrophobic and electronic interactions to aid in neutralization for the positive charge of berberine. Accordingly, we generated multi-target binding motifs (MBM) for berberine, and established a new mathematical model to identify HPTs based on MBM. Remarkably, the berberine MBM was embodied in 13 HPTs, including beta-secretase 1 (BACE1) and amyloid-β1-42 (Aβ1-42). Further study indicated that berberine acted as a high-affinity BACE1 inhibitor and prevented Aβ1-42 aggregation to delay the pathological process of Alzheimer’s disease.Conclusion: Here, we proposed a MBM-based drug-target space model to analyze the underlying mechanism of multi-target drugs against polypharmacological profiles, and demonstrated the role of berberine in Alzheimer’s disease. This approach can be useful in derivation of rules, which will illuminate our understanding of drug action in diseases

Pro-angiogenic Role of Danqi Pill Through Activating Fatty Acids Oxidation Pathway Against Coronary Artery Disease

Coronary artery disease (CAD) is one of the leading causes of deaths worldwide. Energy metabolism disorders, including a reduction in fatty acids oxidation and upregulation of glycolysis pathway, are involved in the process of CAD. Therapeutic angiogenesis has become a promising treatment for CAD. Traditional Chinese medicines, such as Danqi Pill (DQP), have been proven to be effective in treating CAD in China for many years. However, the pro-angiogenic effects of DQP based on fatty acids oxidation are still unknown and the mechanism is worthy of investigation. In this study, left anterior descending (LAD) coronary artery was ligated to induce the CAD models in vivo, and cardiac functions were examined using echocardiography. Human umbilical vein endothelial cells (HUVEC) were subjected to H2O2-induced oxidative stress in vitro. The effects of DQP on CAD rat models and in vitro HUVEC were detected. Our results showed that DQP had cardio-protective effects in rat model. The intensity of capillaries in the marginal area of infarction of the rat heart was increased remarkably in DQP group, and the expression of PPARα and VEGF-2 were increased. The key enzymes involved in the transportation and intake of fatty acids, including CPT1A and CD36, both increased. In H2O2-induced endothelial cells injury models, DQP also showed protective roles and promoted capillary-like tube formation. DQP up-regulated key enzymes in fatty acids oxidation in H2O2-treated HUVEC. In addition, inhibition of CPT1A compromised the pro-angiogenic effects of DQP. In conclusion, fatty acids oxidation axis PPARα-CD36-CPT1A was involved in the pro-angiogenic roles of DQP against CAD. Cardiac CPT1A may serve as a target in therapeutic angiogenesis in clinics

Severe Pneumonia Caused by Coinfection With Influenza Virus Followed by Methicillin-Resistant Staphylococcus aureus Induces Higher Mortality in Mice

Background: Coinfection with influenza virus and bacteria is a major cause of high mortality during flu pandemics. Understanding the mechanisms behind such coinfections is of utmost importance both for the clinical treatment of influenza and the prevention and control of epidemics.Methods: To investigate the cause of high mortality during flu pandemics, we performed coinfection experiments with H1N1 influenza virus and Staphylococcus aureus in which mice were infected with bacteria at time points ranging from 0 to 7 days after infection with influenza virus.Results: The mortality rates of mice infected with bacteria were highest 0–3 days after infection with influenza virus; lung tissues extracted from these co-infected mice showed higher infiltrating cells and thicker lung parenchyma than lung samples from coinfected mice in which influenza virus was introduced at other times and sequences. The levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-8, and IL-6 in the 0–3 day coinfected group were significantly higher than those in the other groups (p < 0.01), as were the mRNA levels of IFN-γ, IL-6, and TNF-α. Coinfection with influenza virus and S. aureus led to high mortality rates that are directly dependent on the sequence and timing of infection by both pathogens. Moreover, coinfection following this particular schedule induced severe pneumonia, leading to increased mortality.Conclusions: Our data suggest that prevention of bacterial co-infection in the early stage of influenza virus infection is critical to reducing the risk of clinical mortality

Drugs and herbs given to prevent hepatotoxicity of tuberculosis therapy: systematic review of ingredients and evaluation studies

Background: Drugs to protect the liver are frequently prescribed in some countries as part of treatment for tuberculosis. The biological rationale is not clear, they are expensive and may do harm. We conducted a systematic review to a) describe the ingredients of "liver protection drugs"; and b) compare the evidence base for the policy against international standards. Methods: We searched international medical databases (MEDLINE, EMBASE, LILACS, CINAHL, Cochrane Central Register of Controlled Trials, and the specialised register of the Cochrane Infectious Diseases Group) and Chinese language databases (CNKI, VIP and WanFang) to April 2007. Our inclusion criteria were research papers that reported evaluating any liver protection drug or drugs for preventing liver damage in people taking anti-tuberculosis treatment. Two authors independently categorised and extracted data, and appraised the stated methods of evaluating their effectiveness. Results: Eighty five research articles met our inclusion criteria, carried out in China (77), India (2), Russia (4), Ukraine (2). These articles evaluated 30 distinct types of liver protection compounds categorised as herbal preparations, manufactured herbal products, combinations of vitamins and other non-herbal substances and manufactured pharmaceutical preparations. Critical appraisal of these articles showed that all were small, poorly conducted studies, measuring intermediate outcomes. Four trials that were described as randomised controlled trials were small, had short follow up, and did not meet international standards. Conclusion: There is no reliable evidence to support prescription of drugs or herbs to prevent liver damage in people on tuberculosis treatment

Drought Impact on Vegetation Productivity in the Lower Mekong Basin

The Lower Mekong Basin (LMB) has a typical monsoon climate, with high temperature and uneven distribution of precipitation throughout the year. As a result of climate change, the LMB has experienced extreme weather conditions during the past few decades. Few studies have focused on changes in net primary productivity (NPP) and the impacts of drought on NPP in the LMB. In th is study, we use MOD17 product to detect variations in NPP during the period 2000–2011 and assess the imapcts of climate and drought on NPP in the LMB. We found that: (1) NPP in the LMB has large variations during the period 2000-2011. Among the five countries, Cambodia experienced the largest NPP variations where is dominated by evergreen forest. Whereas NPP variation was the least in Thailand where is dominated by cropland. (2) Increased temperature caused reduced NPP, therefore negative correlation between temperature and NPP anomaly was identified in Lao PDR. In Cambodia and Southern Lao PDR, decreased precipitation caused reduced NPP, therefore positive correlation between precipitation and NPP was identified. (3) Severe droughts occurred in 2005 and 2010, which induced NPP reductions of 14.7% and 8.4%, respectively. Cambodia was the most severely affected country in 2005, with NPP reductions of 22%. Lao PDR was the most severely affected country in 2010, with NPP reduction of 12.6%. (4) Other factors, such as flooding and human activity, may also have impacts on NPP variations

Patterns of Expansion and Expression Divergence of the Polygalacturonase Gene Family in Brassica oleracea

Plant polygalacturonases (PGs) are closely related to cell-separation events during plant growth and development by degrading pectin. Identifying and investigating their diversification of evolution and expression could shed light on research on their function. We conducted sequence, molecular evolution, and gene expression analyses of PG genes in Brassica oleracea. Ninety-nine B. oleracea PGs (BoPGs) were identified and divided into seven clades through phylogenetic analysis. The exon/intron structures and motifs were conserved within, but divergent between, clades. The second conserved domain (GDDC) may be more closely related to the identification of PGs. There were at least 79 common ancestor PGs between Arabidopsis thaliana and B. oleracea. The event of whole genome triplication and tandem duplication played important roles in the rapid expansion of the BoPG gene family, and gene loss may be an important mechanism in the generation of the diversity of BoPGs. By evaluating the expression in five tissues, we found that most of the expressed BoPGs in clades A, B, and E showed ubiquitous expression characteristics, and the expressed BoPGs in clades C, D, and F were mainly responsible for reproduction development. Most of the paralogous gene pairs (76.2%) exhibited divergent expression patterns, indicating that they may have experienced neofunctionalization or subfunctionalization. The cis-elements analysis showed that up to 96 BoPGs contained the hormone response elements in their promoters. In conclusion, our comparative analysis may provide a valuable data foundation for the further functional analysis of BoPGs during the development of B. oleracea

Research on a Horizon Line Detection Method for Unmanned Surface Vehicles in Complex Environments

A critical step in the visual navigation of unmanned surface vehicles (USVs) is horizon line detection, which can be used to adjust the altitude as well as for obstacle avoidance in complex environments. In this paper, a real-time and accurate detection method for the horizon line is proposed. Our approach first differentiates the complexity of navigational scenes using the angular second moment (ASM) parameters in the grey level co-occurrence matrix (GLCM). Then, the region of interest (ROI) is initially extracted using minimal human interaction for the complex navigation scenes, while subsequent frames are dynamically acquired using automatic feature point matching. The matched ROI can be maximally removed from the complex background, and the Zernike-moment-based edges are extracted from the obtained ROI. Finally, complete sea horizon information is obtained through a linear fitting of the lower edge points to the edge information. Through various experiments carried out on a classical dataset, our own datasets, and that of another previously published paper, we illustrate the significance and accuracy of this technique for various complex environments. The results show that the performance has potential applications for the autonomous navigation and control of USVs

T4 DNA polymerase improves the efficiency of multiple site-directed mutagenesis

Site-directed mutagenesis (SDM) is a useful tool to study the functions of regulatory sequences of DNA and RNA, and the structures and functions of proteins. Numerous methods have been developed for either single or multiple SDM (MSDM). However, MSDM is sometimes difficult. Here we demonstrated that T4 DNA polymerase greatly enhanced the efficiency of MSDM. Moreover, we have also showed that it is efficient to clone multiple specific mutation-containing sequences simultaneously

A novel hermit crab optimization algorithm

Abstract High-dimensional optimization has numerous potential applications in both academia and industry. It is a major challenge for optimization algorithms to generate very accurate solutions in high-dimensional search spaces. However, traditional search tools are prone to dimensional catastrophes and local optima, thus failing to provide high-precision results. To solve these problems, a novel hermit crab optimization algorithm (the HCOA) is introduced in this paper. Inspired by the group behaviour of hermit crabs, the HCOA combines the optimal search and historical path search to balance the depth and breadth searches. In the experimental section of the paper, the HCOA competes with 5 well-known metaheuristic algorithms in the CEC2017 benchmark functions, which contain 29 functions, with 23 of these ranking first. The state of work BPSO-CM is also chosen to compare with the HCOA, and the competition shows that the HCOA has a better performance in the 100-dimensional test of the CEC2017 benchmark functions. All the experimental results demonstrate that the HCOA presents highly accurate and robust results for high-dimensional optimization problems