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

Staphylococcus aureus Phenol-Soluble Modulins α1–α3 Act as Novel Toll-Like Receptor (TLR) 4 Antagonists to Inhibit HMGB1/TLR4/NF-κB Signaling Pathway

Phenol-soluble modulins (PSMs) have recently emerged as key virulence determinants, particularly in highly aggressive Staphylococcus aureus isolates. These peptides contribute to the pathogenesis of S. aureus infections, participating in multiple inflammatory responses. Here, we report a new role for S. aureus PSMs in high mobility group box-1 protein (HMGB1) induced inflammation by modulating toll-like receptor (TLR) 4 pathway. Direct ligation of TLR4 with S. aureus PSMα1–α3 and PSMβ1–β2 was identified by surface plasmon resonance. Remarkably, the binding affinity of TLR4 with HMGB1 was attenuated by PSMα1–α3. Further study revealed that PSMα1–α3 directly inhibited HMGB1-induced NF-κB activation and proinflammatory cytokines production in vitro using HEK-Blue hTLR4 cells and THP-1 cells. To analyze the molecular interactions between PSMs and TLR4, blast similarity search was performed and identified that PSMα1 and PSMβ2 were ideal templates for homology modeling. The three-dimensional structures of PSMα2, PSMα4, PSMβ1, and δ-toxin were successfully generated with MODELLER, and further refined using CHARMm. PSMs docking into TLR4 were done using ZDOCK, indicating that PSMα1–α3 compete with HMGB1 for interacting with the surrounding residues (336–477) of TLR4 domain. Our study reveals that S. aureus PSMα1–α3 can act as novel TLR4 antagonists, which account at least in part for the staphylococcal immune evasion. Modulation of this process will lead to new therapeutic strategies against S. aureus infections

Analyses and Research on a Model for Effective Thermal Conductivity of Laser-Clad Composite Materials

Composite materials prepared via laser cladding technology are widely used in die production and other fields. When a composite material is used for heat dissipation and heat transfer, thermal conductivity becomes an important parameter. However, obtaining effective thermal conductivity of composite materials prepared via laser cladding under different parameters requires a large number of samples and experiments. In order to improve the research efficiency of thermal conductivity of composite materials, a mathematical model of Cu/Ni composite materials was established to study the influence of cladding-layer parameters on the effective thermal conductivity of composite materials. The comparison between the model and the experiment shows that the model’s accuracy is 86.7%, and the error is due to the increase in thermal conductivity caused by the alloying of the joint, so the overall effective thermal conductivity deviation is small. This study provides a mathematical model method for studying the thermodynamic properties of laser cladding materials. It provides theoretical and practical guidance for subsequent research on the thermodynamic properties of materials during die production

Aquatic Toxic Analysis by Monitoring Fish Behavior Using Computer Vision: A Recent Progress

Video tracking based biological early warning system achieved a great progress with advanced computer vision and machine learning methods. Ability of video tracking of multiple biological organisms has been largely improved in recent years. Video based behavioral monitoring has become a common tool for acquiring quantified behavioral data for aquatic risk assessment. Investigation of behavioral responses under chemical and environmental stress has been boosted by rapidly developed machine learning and artificial intelligence. In this paper, we introduce the fundamental of video tracking and present the pioneer works in precise tracking of a group of individuals in 2D and 3D space. Technical and practical issues suffered in video tracking are explained. Subsequently, the toxic analysis based on fish behavioral data is summarized. Frequently used computational methods and machine learning are explained with their applications in aquatic toxicity detection and abnormal pattern analysis. Finally, advantages of recent developed deep learning approach in toxic prediction are presented

The Variable Hinge Region of Novel PKCs Determines Localization to Distinct Regions of the Immunological Synapse

<div><p>The immunological synapse (IS) formed between a T cell and its cognate antigen-presenting cell (APC) enables the directional secretion of cytolytic and inflammatory molecules. Synaptic architecture is established in part by a two-step cascade of novel protein kinase C (nPKC) isozymes. PKCε and PKCη arrive at the IS first, and occupy the entire synaptic membrane. Then, PKCθ accumulates in a smaller zone at the center of the contact. We investigated the molecular basis for this differential recruitment behavior using chimeric nPKC constructs and total internal reflection fluorescence microscopy. Our studies revealed that the V3 linker just N-terminal to the kinase domain plays a crucial role in specifying nPKC localization. Substitution of this linker switched the scope and the kinetics of PKCθ accumulation to that of PKCε and PKCη, and vice versa. Although the V3 was necessary for synaptic compartmentalization, it was not sufficient, as the tandem C1 domains were also required to mediate membrane association. Together, these results suggest a model whereby the V3 linker controls nPKC sub-compartmentalization after initial C1 domain-mediated accumulation at the IS.</p></div

Knowledge and practices regarding diabetic retinopathy among diabetic patients registered in a chronic disease management system in eastern China.

PurposeTo investigate the knowledge and practices regarding diabetic retinopathy (DR) among diabetic patients included in a community-based primary health system (CBPHS) in China.MethodsDiabetic patients aged 18 years and above registered in the CBPHS in Yueqing city, Zhejiang province were recruited. Information obtained by questionnaire included: demographic and socioeconomic status, knowledge about DR, and ocular and medical history. The primary outcome was whether the participant knew that DM can affect the eyes, defined according to the question: "Do you know diabetes mellitus (DM) can affect eyes? (yes or no)". A knowledge score was calculated based on the responses to seven questions, with 1 point awarded for a correct response and 0 points for an incorrect or uncertain answer.ResultsA total of 1972 diabetic patients were included in the study with an average age of 65.2±10.8 years, 45.7% were male. One thousand two hundred and nineteen patients (61.8%) knew that DM can affect the eyes. Significant differences in age, education, income status, insurance covering eye care, fasting blood glucose, duration of DM, history of hypertension existed between subjects who knew and those who did not know that DM can affect the eyes (PConclusionsThe knowledge toward DR among DM patients were still low within the chronic disease management system in eastern China. Routine ophthalmic screening, health care promotions, and educational programs should be emphasized and implemented for better DR prevention and management